Supplementary References

Impact of Ultraprocessed Foods in Metabolic Health

This bibliography provides key findings from a recent literature review of the impacts of ultraprocessed foods (UPF) and metabolic health. It specifically presents evidence for the purported role of UPF in relation to three aspects of metabolic health, namely the liver, gut, and brain. Part I examines health implications of UPF, in specific relation to brain-health (/mental health). It presents epidemiological data in relation to dietary patterns and a range of health outcomes. It also reviews the role of inflammation in metabolic disease, and specifically UPF consumption and varying aspects of mental health, and neurodevelopmental conditions such as Attention-Deficit, Hyperactivity Disorder (ADHD).

The Modern Western Diet & Ultraprocessed Food (UPF)

The modern Western dietary pattern is characterized by higher intakes of ultraprocessed foods (UPF) consisting of a range of non-nutritive compounds and synthetic food additives (e.g., flavouring, colorants, preservatives, and emulsifiers) extending – but not limited to, – trans-fat, refined carbohydrates, processed meats, excess sugar, sweetened beverages and desserts, fried foods, and refined grains. UPF are industrially produced, ingredient formulations which are notoriously poor sources of whole foods, proteins, dietary fiber and micronutrients (Reales-Moreno, Tonini et al. 2022). In addition, processed foods are often packaged in synthetic materials (which are not biodegradable) containing toxins such as plastic, namely bisphenol (BPA) (Almarshad, Algonaiman et al. 2022). A recent systematic review of 20 studies (12 cohort and 8 cross-sectional) with a total of 334,114 participants and 10 health outcomes found that high UPF consumption was associated with a wide-range of negative health outcomes including an increased risk of all-cause mortality, overall cardiovascular diseases, coronary heart diseases, hypertension, metabolic syndrome, overweight and obesity, depression, irritable bowel syndrome, overall cancer, postmenopausal breast cancer, gestational obesity, and adolescent asthma (Chen, Zhang et al. 2020).

Dietary Patterns

Many epidemiological studies have examined dietary patterns in relation to public health, disease risk, and mortality (Hu 2002). Nutrients work in synergy and therefore, a single nutrient approach is wholly inadequate and does not consider complicated interactions between nutrients, for example, iron absorption is enhanced when coupled with Vitamin C (Hu 2002). A key research question is this field is whether adherence to a particular dietary pattern or dietary guideline lowers the risk of disease (Hu 2002). A common trend among epidemiologists is to contrast the Mediterranean dietary pattern with a Western dietary pattern in terms of health outcomes and disease risk. Higher Western dietary pattern scores have been associated with a wide range of negative outcomes including an increased risk for type 2 diabetes (van Dam, Rimm et al. 2002, Fung, Schulze et al. 2004), coronary heart disease (Hu, Rimm et al. 2000, Fung, Willett et al. 2001), and colon cancer (Fung, Hu et al. 2003). The Western dietary pattern is also linked to hypertension (Mendonça, Lopes et al. 2017) and metabolic syndrome in adolescents (Tavares, Fonseca et al. 2012).

Inflammation

Essentially UPF frequently contain ingredients which are considered pro-inflammatory, inflammation is an established risk factor for poor metabolic health (Giugliano, Ceriello et al. 2006) as well as neuropsychiatric conditions such as depression (Delgado, Huet et al. 2018, Bauer and Teixeira 2019). Indeed, recent data provided evidence confirming that patients with neuropsychiatric conditions exhibit key features of inflammation including several markers of immune dysfunction and inflammatory mediators e.g., cytokines, chemokines, prostaglandins, and reactive oxygen species (Bauer and Teixeira 2019). Other known risk factors associated with both the development of both depression and inflammation include poor diet, lack of exercise, altered gut permeability, obesity, smoking and poor sleep (Berk, Williams et al. 2013). Although, inflammation is a mediating pathway to neuropsychiatric conditions including depression, it is amenable to preventative and therapeutic interventions such as improving diet, smoking cessation, and exercise. Increasing consumption of oily fish and seafood containing omega-3 in addition to restricting/eliminating UPF will help decrease the production of pro-inflammatory cytokines, for example, tumor necrosis factor (TNF)α and interleukin (IL)-1,T cell cytokines (Schiepers, Wichers et al. 2005).

Depression and ADHD

Countless studies have linked depression with deficits of nutritional compounds (Khanna, Chattu et al. 2019). Furthermore, specific nutrients are thought to positively modulate biomarkers associated with depressive mood states, e.g., omega-3 essential fatty acids, extra virgin olive oil, and fruits/vegetables. Conversely, Western dietary patterns including the consumption of sweetened beverages, fried foods, processed meats, baked products have been linked with an increased risk of depression in longitudinal studies (Khanna, Chattu et al. 2019). Recent research examined the potential link between depression and UPF. The findings reported that participants in the highest quartile for UPF consumption had an increased risk of developing depression among Spanish university graduates, after adjusting for potential confounding variables. This relationship was strongest in those participants with the lowest levels of physical activity (Gómez-Donoso, Sánchez-Villegas et al. 2020). UPFs are also linked to a disruption in cognitive function (Francis and Stevenson 2013), and an increased risk of an Attention-Deficit, Hyperactivity Disorder (ADHD) diagnosis (Howard, Robinson et al. 2011).

Diet has also been found to influence ADHD symptoms (Gow, Bremner et al. 2021) and in turn impact both sleep and children’s behaviour (Blunden, Milte et al. 2011). The Raine Study is a prospective study following 2, 868 live births. At the 14 year follow-up assessment major dietary patterns were assessed using the statistical measure of factor analysis (Howard, Robinson et al. 2011). The Western style dietary pattern was associated with an ADHD diagnosis after adjusting for known confounding variables (Howard, Robinson et al. 2011). Conversely, traditional-healthy dietary patterns are associated with lower odds of an ADHD diagnosis (Woo, Kim et al. 2014). A systematic review also examined the relationship between diet and depression in children and adolescents. Overall, they found support for an association between healthy dietary patterns and better mental health and lower levels of depression (Khalid, Williams et al. 2016). A recent review examined whether diet plays a role in the prevention and management of depression in adolescents (Chopra, Mandalika et al. 2021). They reported that higher intakes of healthier foods akin to the Mediterranean diet (e.g., complex carbohydrates, omega-3 fatty acids, amino acids, and B-Vitamins) had lower rates of depression. They also reported that Western dietary patterns which included lower intakes of vegetables, sweetened beverages, and processed/junk foods were associated with an increased risk of depression (Chopra, Mandalika et al. 2021).

UltraProcessed Food Consumption and Mental Health

The field of Nutritional Psychiatry is committed to understanding the health impacts of foods in brain health (/mental health). A recent systematic review and meta-analysis examined UPF consumption and mental health. They included a total of 17 observational studies (n = 385,541); 15 cross-sectional and 2 prospective and found that greater UPF consumption was cross-sectionally associated with increased odds of depressive and anxious symptoms (Lane, Gamage et al. 2022). Another epidemiological household survey study examined ultraprocessed food consumption versus fresh food consumption and associative psychological symptoms of depression and anxiety during the COVID-19 pandemic (Coletro, Mendonça et al. 2022). The foods categories were compiled according to the NOVA classification for fresh/minimally processed food and ultra-processed food. The results reported that increased consumption of UPFs was associated with a higher incidence of anxiety and depression symptoms. This study also found that fresh/minimally processed foods were associated with a lower prevalence of depression (Coletro, Mendonça et al. 2022). The same research group also examined multiple health risk factors, including elevated consumption of UPF and subsequent implications for mental health during the COVID-19 pandemic. This was a cross-sectional study based on an epidemiological survey in two Brazilian cities. The outcome measures of depression and anxiety symptoms were evaluated employing the Generalized Anxiety Disorder 7-item (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). A qualitative food frequency questionnaire (FFQ) assessed food consumption according to the NOVA classification. Sedentary behaviour was quantified according to the amount of time per day sitting or reclining. The results reported that the non-daily consumption of fruits and vegetables and a higher consumption of UPF had a 2.6-fold increase in symptoms of poor mental health. Furthermore, participants who had all three health risk behaviours (e.g., UPF consumption, non-daily fruit/vegetable consumption and sedentary behaviour) displayed a 2.8 higher prevalence ratio for mental health disorder symptoms (Coletro, Mendonça et al. 2022).

Adolescents have one of the highest rates of consumption of UPF and beverages, with recent estimates reporting a total energy intake of between 29%-68% (Wang, Martínez Steele et al. 2021). These trends have potential implications for mental and physical health. Increasing evidence has linked the consumption of UPFs with excess calorie intake, weight gain and obesity – all of which have implications also for mental health (Wang, Martínez Steele et al. 2021). Recent statistics report that 1 in 7 adolescents experience mental health concerns, and that depression, anxiety (including emotional disorders), and behavioural problems are among the most common. The World Health Organization (WHO) has warned that failing to address poor mental health during adolescence has serious implications extending to adulthood which are both impairing and limiting (WHO 2021). UPF and drinks represent a poor quality of diet and present as a potentially modifiable risk factor for mental health problems in teenagers. A recent study recruited 560 Spanish adolescents and assessed their consumption of UPF, fruits and vegetables (servings/day) and physical activity (days per week). Measures of psychosocial function were also collected and included symptom scores pertaining to ADHD, depression, behaviour problems, anxiety, internalising and externalising problems and attention. The findings demonstrated that 26.2% of the adolescents displayed psychosocial impairment. Additionally, fruit and vegetable consumption and physical activity levels were lower than recommended. Higher UPF consumption was positively associated with elevated measures of depression, internalizing and externalizing problems. The findings of this study support previous studies suggesting that UPF consumption is linked to mental health problems (Wang, Martínez Steele et al. 2021).

References

Almarshad, M. I., et al. (2022). “Relationship between Ultra-Processed Food Consumption and Risk of Diabetes Mellitus: A Mini-Review.” Nutrients 14(12).

Studying the factors that cause diabetes and conducting clinical trials has become a priority, particularly raising awareness of the dangers of the disease and how to overcome it. Diet habits are one of the most important risks that must be understood and carefully applied to reduce the risk of diabetes. Nowadays, consuming enough home-cooked food has become a challenge, particularly with modern life performance, pushing people to use processed foods. Ultra-processed food (UPF) consumption has grown dramatically over the last few decades worldwide. This growth is accompanied by the increasing prevalence of non-communicable diseases (NCDs) such as cardiovascular diseases, hypertension, and type 2 diabetes. UPFs represent three main health concerns: (i) they are generally high in non-nutritive compounds such as sugars, sodium, and trans fat and low in nutritional compounds such as proteins and fibers, (ii) they contain different types of additives that may cause severe health issues, and (iii) they are presented in packages made of synthetic materials that may also cause undesirable health side-effects. The association between the consumption of UPF and the risk of developing diabetes was discussed in this review. The high consumption of UPF, almost more than 10% of the diet proportion, could increase the risk of developing type 2 diabetes in adult individuals. In addition, UPF may slightly increase the risk of developing gestational diabetes. Further efforts are needed to confirm this association; studies such as randomized clinical trials and prospective cohorts in different populations and settings are highly recommended. Moreover, massive improvement in foods’ dietary guidelines to increase the awareness of UPF and their health concerns is highly recommended.

Bauer, M. E. and A. L. Teixeira (2019). “Inflammation in psychiatric disorders: what comes first?” Annals of the New York Academy of Sciences 1437(1): 57-67.

Abstract Neuropsychiatric disorders (i.e., mood disorders and schizophrenia) and inflammation are closely intertwined, and possibly powering each other in a bidirectional loop. Depression facilitates inflammatory reactions and inflammation promotes depression and other neuropsychiatric disorders. Patients with neuropsychiatric disorders exhibit all cardinal features of inflammation, including increased circulating levels of inflammatory inducers, activated sensors, and inflammatory mediators targeting all tissues. Inflammation may contribute to the pathophysiology and clinical progression of these disorders. Of note, proinflammatory cytokines modulate mood behavior and cognition by reducing brain monoamine levels, activating neuroendocrine responses, promoting excitotoxicity (increased glutamate levels), and impairing brain plasticity. What are the sources of this chronic inflammation? Increasing evidence indicates that changes in neuroendocrine regulation, metabolism, diet/microbiota, and negative health behaviors are important triggers of inflammation. Finally, recent data indicate that early-life stress is associated with overt inflammation prior to the development of neuropsychiatric disorders.

Bauer, M. E. and A. L. Teixeira (2019). “Inflammation in psychiatric disorders: what comes first?” Ann N Y Acad Sci 1437(1): 57-67.

Neuropsychiatric disorders (i.e., mood disorders and schizophrenia) and inflammation are closely intertwined, and possibly powering each other in a bidirectional loop. Depression facilitates inflammatory reactions and inflammation promotes depression and other neuropsychiatric disorders. Patients with neuropsychiatric disorders exhibit all cardinal features of inflammation, including increased circulating levels of inflammatory inducers, activated sensors, and inflammatory mediators targeting all tissues. Inflammation may contribute to the pathophysiology and clinical progression of these disorders. Of note, proinflammatory cytokines modulate mood behavior and cognition by reducing brain monoamine levels, activating neuroendocrine responses, promoting excitotoxicity (increased glutamate levels), and impairing brain plasticity. What are the sources of this chronic inflammation? Increasing evidence indicates that changes in neuroendocrine regulation, metabolism, diet/microbiota, and negative health behaviors are important triggers of inflammation. Finally, recent data indicate that early-life stress is associated with overt inflammation prior to the development of neuropsychiatric disorders.

Berk, M., et al. (2013). “So depression is an inflammatory disease, but where does the inflammation come from?” BMC Medicine 11(1): 200.

We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’

Blunden, S. L., et al. (2011). “Diet and sleep in children with attention deficit hyperactivity disorder: preliminary data in Australian children.” J Child Health Care 15(1): 14-24.

Sleep disturbances are common and consequential in children with attention deficit hyperactivity disorder (ADHD). Diet also influences ADHD symptoms. Interrelationships between diet, sleep and behaviour in children diagnosed with ADHD are little studied. We investigated, via parental report, the relationships between sleep and diet in 88 Australian children aged 6-13 years old (M = 8.94, SD = 1.78). This pilot data shows that 30 per cent of the children had sleep disturbance (≥ 2 standard deviations above the mean) with significant relationships between ADHD symptoms, sleep disturbance and diet. Parents who reported more sleep disturbance also reported a higher intake of carbohydrate, fats, and, most particularly, sugar which was also a significant predictor of night time sweating. These findings suggest an interrelationship between diet and sleep in children with ADHD. Given that both sleep and dietary intake are potentially modifiable behaviours within treatment regimes of children with ADHD, further investigation is needed.

Chen, X., et al. (2020). “Consumption of ultra-processed foods and health outcomes: a systematic review of epidemiological studies.” Nutrition Journal 19(1): 86.

Consumption of ultra-processed foods (UPFs) plays a potential role in the development of obesity and other diet-related noncommunicable diseases (NCDs), but no studies have systematically focused on this. This study aimed to summarize the evidence for the association between UPFs consumption and health outcomes.

Chopra, C., et al. (2021). “Does diet play a role in the prevention and management of depression among adolescents? A narrative review.” Nutr Health 27(2): 243-263.

BACKGROUND: Depression is one of the major causes of illness and disability, while suicide is the second leading cause of death amongst adolescents. Although many factors determine the mental health of an individual, diet has been gaining popularity as a key modifiable factor in the prevention and management of depression. Nutritional Psychiatry is an emerging field where researchers suggest that the food we consume influences our mental well-being. AIM: This review aims to explore the significance of diet, nutrient deficiencies, imbalances, and unhealthy dietary patterns in the prevention and management of unipolar depression or major depressive disorder among adolescents. METHODS: Electronic databases such as PubMed, Scopus, Google Scholar, Science Direct, and MEDLINE were searched using keywords such as “mental health,” “depression,” “adolescents,” “diet,” “dietary pattern,” and pertinent articles (N = 68) were retrieved and reviewed. RESULTS: The Mediterranean and traditional diets rich in complex carbohydrates, omega-3 fatty acids, B-group vitamins and several amino acids have shown negative correlation with the incidence of depression. On the other hand, Western dietary patterns (sweetened beverages, processed/ junk food, and foods rich in saturated fatty acids), along with low consumption of fruits and vegetables have been linked to an increased risk of depression among adolescents. CONCLUSION: Dietary modification can prove to be a cost-effective strategy for the prevention and treatment of depression among adolescents. Diet and nutrition need to be recognized as key modifiable targets for the prevention of mental disorders and nutritional medicine should be considered as an integral part of psychiatric treatment.

Coletro, H. N., et al. (2022). “Ultra-processed and fresh food consumption and symptoms of anxiety and depression during the COVID – 19 pandemic: COVID Inconfidentes.” Clin Nutr ESPEN 47: 206-214.

BACKGROUND & AIM: Psychological disorders are an important health problem worldwide. A healthy diet is recommended as one of the measures to prevent and control mental disorders. Epidemiological studies have shown important associations between the consumption of diets rich in nutrients and a lower risk of developing anxiety and depression. Therefore, the aim of this study was to evaluate the association between the prevalence of anxiety and depression symptoms and food consumption, according to the degree of processing, during the COVID-19 pandemic. METHODS: An epidemiological household survey was conducted in two cities in Brazil. Anxiety and depression symptoms were assessed using validated scales (Generalized Anxiety Disorder 7-item/Patient Health Questionnaire-9), and food consumption was assessed using a qualitative food frequency questionnaire referring to consumption within the last 3 months. The foods were categorized according to the NOVA classification for fresh/minimally processed food and ultra-processed food, using the average weekly consumption as the cutoff. For data analysis, adjusted Poisson regression with robust variance was utilized to estimate the prevalence ratio and 95% confidence interval (CI). RESULTS: The consumption of fresh/minimally processed foods above the weekly average frequency was associated with a lower prevalence of symptoms of depression (PR: 0.5, 95% CI: 0.3; 0.7). Consumption above the weekly average of ultra-processed foods was associated with a higher prevalence of anxiety (PR: 1.5 and 95% CI: 1.03; 2.3) and depression symptoms (PR: 1.5, 95% CI: 1.0; 2.1, P = 0.034). CONCLUSION: Increased consumption of ultra-processed foods is associated with a higher occurrence of anxiety and depression symptoms; therefore, we recommend an increase in the consumption of fresh/minimally processed foods, as endorsed by the Dietary Guidelines for the Brazilian Population.

Delgado, I., et al. (2018). “Depressive symptoms in obesity: Relative contribution of low-grade inflammation and metabolic health.” Psychoneuroendocrinology 91: 55-61.

Background Recent reports suggest that the risk of depressive symptoms in obesity is potentiated in subjects presenting a metabolically unhealthy phenotype. Inflammation is often considered a defining criteria of metabolic health. However, this factor may drive the association of metabolic health with depressive symptoms given its well-known role in the pathophysiology of depression. This study aimed at determining the relative contribution of inflammation and metabolic abnormalities to depressive symptoms in obesity. Methods One-hundred severely obese adults (BMI ≥ 35–40 kg/m2) and 25 non-obese control individuals (BMI < 30 kg/m2) were recruited. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and Mini-International Neuropsychiatric Interview (MINI). Serum high-sensitive C-reactive protein (hs-CRP) was measured as a marker of systemic inflammation. Metabolically unhealthy obesity was defined as obesity associated with two or more metabolic alterations, including low high-density lipoprotein cholesterol, hypertriglyceridemia, high fasting glucose and hypertension. Results Total MADRS scores were significantly higher in obese subjects with significant inflammation (hs-CRP ≥ 5 mg/L) compared to those with low inflammation (hs-CRP < 5 mg/L) and non-obese controls. Interestingly, hs-CRP levels significantly predicted MADRS scores in the whole population under study and in the group of obese subjects. Overall, no association was found between MADRS scores and individual metabolic alterations or the composite measure of metabolically unhealthy obesity. Similarly, the association of hs-CRP with MADRS scores in obese patients was not modulated by metabolic health factors. Conclusions These results indicate that systemic inflammation represents a stronger contributor of obesity-related depressive symptoms than metabolic health per se. This supports the notion that inclusion of inflammation in the definition of metabolically unhealthy obesity drives the association found between poor metabolic health and depressive symptoms.

Francis, H. and R. Stevenson (2013). “The longer-term impacts of Western diet on human cognition and the brain.” Appetite 63: 119-128.

Animal work over the last three decades has generated a convincing body of evidence that a Western diet – one high in saturated fat and refined carbohydrates (HFS diet) – can damage various brain systems. In this review we examine whether there is evidence for this in humans, using converging lines of evidence from neuropsychological, epidemiological and neuroimaging data. Using the animal research as the organizing principal, we examined evidence for dietary induced impairments in frontal, limbic and hippocampal systems, and with their associated functions in learning, memory, cognition and hedonics. Evidence for the role of HFS diet in attention deficit disorder and in neurodegenerative conditions was also examined. While human research data is still at an early stage, there is evidence of an association between HFS diet and impaired cognitive function. Based upon the animal data, and a growing understanding of how HFS diets can disrupt brain function, we further suggest that there is a causal link running from HFS diet to impaired brain function in humans, and that HFS diets also contribute to the development of neurodegenerative conditions.

Fung, T., et al. (2003). “Major Dietary Patterns and the Risk of Colorectal Cancer in Women.” Archives of Internal Medicine 163(3): 309-314.

Several foods and nutrients have been implicated in the development of colon and rectal cancers. In this study, we prospectively assessed the associations between major dietary patterns and the risks of these 2 cancers in women.Using dietary information collected in 1984, 1986, 1990, and 1994 from 76 402 women aged 38 to 63 years without a history of cancer in 1984, we conducted factor analysis and identified 2 major dietary patterns: “prudent” and “Western.” We calculated factor scores for each participant and examined prospectively the associations between dietary patterns and colon and rectal cancer risks.The prudent pattern was characterized by higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains, while the Western pattern, by higher intakes of red and processed meats, sweets and desserts, french fries, and refined grains. During 12 years of follow-up, we identified 445 cases of colon cancer and 101 cases of rectal cancer. After adjusting for potential confounders, we observed a relative risk for colon cancer of 1.46 (95% confidence interval, 0.97-2.19) when comparing the highest with the lowest quintiles of the Western pattern (P value for trend across quintiles, .02). The prudent pattern had a nonsignificant inverse association with colon cancer (relative risk for fifth quintile compared with the first, 0.71; 95% confidence interval, 0.50-1.00; P for trend across quintiles, .31). We did not observe any significant association between dietary patterns and rectal cancer.We found a significant positive association between the Western dietary pattern and the risk of colon cancer.Arch Intern Med. 2003;163:309-314–>

Fung, T. T., et al. (2004). “Dietary Patterns, Meat Intake, and the Risk of Type 2 Diabetes in Women.” Archives of Internal Medicine 164(20): 2235-2240.

Although obesity is the most important risk factor for type 2 diabetes, evidence is emerging that certain foods and dietary factors may be associated with diabetes. To examine the association between major dietary patterns and risk of type 2 diabetes mellitus in a cohort of women.We prospectively assessed the associations between major dietary patterns and risk of type 2 diabetes in women. Dietary information was collected in 1984, 1986, 1990, and 1994 from 69 554 women aged 38 to 63 years without a history of diabetes, cardiovascular disease, or cancer in 1984. We conducted factor analysis and identified 2 major dietary patterns: “prudent” and “Western.” We then calculated pattern scores for each participant and examined prospectively the associations between dietary pattern scores and type 2 diabetes risks.The prudent pattern was characterized by higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains, while the Western pattern included higher intakes of red and processed meats, sweets and desserts, french fries, and refined grains. During 14 years of follow-up, we identified 2699 incident cases of type 2 diabetes. After adjusting for potential confounders, we observed a relative risk for diabetes of 1.49 (95% confidence interval [CI], 1.26-1.76, P for trend, <.001) when comparing the highest to lowest quintiles of the Western pattern. Positive associations were also observed between type 2 diabetes and red meat and other processed meats. The relative risk for diabetes for every 1-serving increase in intake is 1.26 (95% CI, 1.21-1.42) for red meat, 1.38 (95% CI, 1.23-1.56) for total processed meats, 1.73 (95% CI, 1.39-2.16) for bacon, 1.49 (95% CI, 1.04-2.11) for hot dogs, and 1.43 (95% CI, 1.22-1.69) for processed meats.The Western pattern, especially a diet higher in processed meats, may increase the risk of type 2 diabetes in women.Arch Intern Med. 2004;164:2235-2240–>

Fung, T. T., et al. (2001). “Dietary Patterns and the Risk of Coronary Heart Disease in Women.” Archives of Internal Medicine 161(15): 1857-1862.

Although substantial information on individual nutrients or foods and risk of coronary heart disease (CHD) is available, little is known about the role of overall eating pattern.Using dietary information from a food frequency questionnaire in 1984 from the Nurses’ Health Study, we conducted factor analysis and identified 2 major dietary patterns—”prudent” and “Western”—and calculated factor scores of each pattern for individuals in the cohort. We used logistic regression to examine prospectively the associations between dietary patterns and CHD risk among 69 017 women aged 38 to 63 years in 1984 without history of major chronic diseases.The prudent pattern was characterized by higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains, while the Western pattern was characterized by higher intakes of red and processed meats, sweets and desserts, french fries, and refined grains. Between 1984 and 1996, we documented 821 CHD cases. After adjusting for coronary risk factors, the prudent diet score was associated with a relative risk (RR) of 0.76 (95% confidence interval (CI), 0.60-0.98; P for trend test, .03) comparing the highest with lowest quintile. Extreme quintile comparison yielded an RR of 1.46 (95% CI, 1.07-1.99; P for trend test, .02) for the Western pattern. Those who were jointly in the highest prudent diet quintile and lowest Western diet quintile had an RR of 0.64 (95% CI, 0.44-0.92) compared with those with the opposite pattern profile.A diet high in fruits, vegetables, whole grains, legumes, poultry, and fish and low in refined grains, potatoes, and red and processed meats may lower risk of CHD.Arch Intern Med. 2001;161:1857-1862–>

Giugliano, D., et al. (2006). “The Effects of Diet on Inflammation.” Journal of the American College of Cardiology 48(4): 677-685.

Gómez-Donoso, C., et al. (2020). “Ultra-processed food consumption and the incidence of depression in a Mediterranean cohort: the SUN Project.” Eur J Nutr 59(3): 1093-1103.

PURPOSE: A growing body of evidence shows that consumption of ultra-processed foods (UPF) is associated with a higher risk of cardiometabolic diseases, which, in turn, have been linked to depression. This suggests that UPF might also be associated with depression, which is among the global leading causes of disability and disease. We prospectively evaluated the relationship between UPF consumption and the risk of depression in a Mediterranean cohort. METHODS: We included 14,907 Spanish university graduates [mean (SD) age: 36.7 year (11.7)] initially free of depression who were followed up for a median of 10.3 years. Consumption of UPF (industrial formulations made mostly or entirely from substances derived from foods and additives, with little, if any, intact food), as defined by the NOVA food classification system, was assessed at baseline through a validated semi-quantitative 136-item food-frequency questionnaire. Participants were classified as incident cases of depression if they reported a medical diagnosis of depression or the habitual use of antidepressant medication in at least one of the follow-up assessments conducted after the first 2 years of follow-up. Cox regression models were used to assess the relationship between UPF consumption and depression incidence. RESULTS: A total of 774 incident cases of depression were identified during follow-up. Participants in the highest quartile of UPF consumption had a higher risk of developing depression [HR (95% CI) 1.33 (1.07-1.64); p trend = 0.004] than those in the lowest quartile after adjusting for potential confounders. CONCLUSIONS: In a prospective cohort of Spanish university graduates, we found a positive association between UPF consumption and the risk of depression that was strongest among participants with low levels of physical activity.

Gow, R., et al. (2021). Smart Foods for ADHD and Brain Health: How Nutrition Influences Cognitive Function, Behaviour and Mood, Jessica Kingsley Publishers.

Howard, A. L., et al. (2011). “ADHD is associated with a “Western” dietary pattern in adolescents.” J Atten Disord 15(5): 403-411.

OBJECTIVE: To examine the relationship between dietary patterns and ADHD in a population-based cohort of adolescents. METHOD: The Raine Study is a prospective study following 2,868 live births. At the 14-year follow-up, the authors collected detailed adolescent dietary data, allowing for the determination of major dietary patterns using factor analysis. ADHD diagnoses were recorded according to International Classification of Deiseases, 9th Revision coding conventions. Logistic regression was used to assess the relationship between scores for major dietary pattern and ADHD diagnoses. RESULTS: Data were available for 1,799 adolescents, and a total of 115 adolescents had an ADHD diagnosis. Two major dietary patterns were identified: “Western” and “Healthy.” A higher score for the Western dietary pattern was associated with ADHD diagnosis (odds ratio=2.21, 95% confidence interval=1.18, 4.13) after adjusting for known confounding factors from pregnancy to 14 years. ADHD diagnosis was not associated with the “Healthy” dietary pattern. CONCLUSION: A Western-style diet may be associated with ADHD.

Hu, F. B. (2002). “Dietary pattern analysis: a new direction in nutritional epidemiology.” Current Opinion in Lipidology 13(1): 3-9.

Recently, dietary pattern analysis has emerged as an alternative and complementary approach to examining the relationship between diet and the risk of chronic diseases. Instead of looking at individual nutrients or foods, pattern analysis examines the effects of overall diet. Conceptually, dietary patterns represent a broader picture of food and nutrient consumption, and may thus be more predictive of disease risk than individual foods or nutrients. Several studies have suggested that dietary patterns derived from factor or cluster analysis predict disease risk or mortality. In addition, there is growing interest in using dietary quality indices to evaluate whether adherence to a certain dietary pattern (e.g. Mediterranean pattern) or current dietary guidelines lowers the risk of disease. In this review, we describe the rationale for studying dietary patterns, and discuss quantitative methods for analysing dietary patterns and their reproducibility and validity, and the available evidence regarding the relationship between major dietary patterns and the risk of cardiovascular disease.

Hu, F. B. (2002). “Dietary pattern analysis: a new direction in nutritional epidemiology.” Curr Opin Lipidol 13(1): 3-9.

Hu, F. B., et al. (2000). “Prospective study of major dietary patterns and risk of coronary heart disease in men.” Am J Clin Nutr 72(4): 912-921.

BACKGROUND: Previous studies on diet and coronary heart disease (CHD) focused primarily on individual nutrients or foods. OBJECTIVE: We examined whether overall dietary patterns derived from a food-frequency questionnaire (FFQ) predict risk of CHD in men. DESIGN: This was a prospective cohort study of 44875 men aged 40-75 y without diagnosed cardiovascular disease or cancer at baseline in 1986. RESULTS: During 8 y of follow-up, we documented 1089 cases of CHD (nonfatal myocardial infarction and fatal CHD). Using factor analysis, we identified 2 major dietary patterns using dietary data collected through a 131-item FFQ. The first factor, which we labeled the “prudent pattern,” was characterized by higher intake of vegetables, fruit, legumes, whole grains, fish, and poultry, whereas the second factor, the “Western pattern,” was characterized by higher intake of red meat, processed meat, refined grains, sweets and dessert, French fries, and high-fat dairy products. After adjustment for age and CHD risk factors, the relative risks from the lowest to highest quintiles of the prudent pattern score were 1.0, 0. 87, 0.79, 0.75, and 0.70 (95% CI: 0.56, 0.86; P: for trend = 0.0009). In contrast, the relative risks across increasing quintiles of the Western pattern score were 1.0, 1.21, 1.36, 1.40, and 1.64 (95% CI: 1.24, 2.17; P: for trend < 0.0001). These associations persisted in subgroup analyses according to cigarette smoking, body mass index, and parental history of myocardial infarction. CONCLUSIONS: These data suggest that major dietary patterns derived from the FFQ predict risk of CHD, independent of other lifestyle variables.

Khalid, S., et al. (2016). “Is there an association between diet and depression in children and adolescents? A systematic review.” Br J Nutr 116(12): 2097-2108.

This review critically evaluates previous studies investigating the association between dietary intake of children and young people and depression and related mental health problems. A systematic literature search was conducted using electronic databases such as PsycINFO, MEDLINE, PubMed and Cochrane. A total of twenty studies were identified that met inclusion criteria and were subsequently rated for quality. The studies used a range of methods to measure dietary intake and mental health. Important potential confounding variables (e.g. socio-economic status) were often not included or controlled. There were also inconsistencies in the use of key constructs, which made comparisons between studies difficult. Despite some contradictory results, overall there was support for an association between healthy dietary patterns or consumption of a high-quality diet and lower levels of depression or better mental health. Similarly, there was a relationship between unhealthy diet and consumption of low-quality diet and depression or poor mental health. However, where significant relationships were reported, effect sizes were small. Future research on the relationship between diet and mental health in young people should use more clearly defined constructs to define diet and include or control for important confounders.

Khanna, P., et al. (2019). “Nutritional Aspects of Depression in Adolescents – A Systematic Review.” Int J Prev Med 10: 42.

Depression is defined as a cluster of specific symptoms with associated impairment affecting 7.4% of the adolescents globally. As part of the systematic review, around 1000 relevant articles published between January 1978 and December 2017 were identified by systematic online search from 6 electronic databases (PubMed, PsycInfo, Science Direct, MEDLINE, Scopus, and Google Scholar) and overall, 56 relevant studies were included in the current review as per the inclusion criteria. Findings highlight the potential importance of the relationship between healthy dietary patterns or quality and positive mental health throughout life span. Various nutrition and dietary compounds have been suggested to be involved in the onset maintenance and severity of depressive symptoms and disorders. Nutritional compounds might modulate depression associated biomarkers. In this context, several healthy foods such as olive oil, fish, nuts, legumes, dairy products, fruits, and vegetables have been inversely associated with the risk of depression and might also improve symptoms. In contrast western dietary patterns including the consumption of sweetened beverages, fried foods, processed meats, baked products have been shown to be associated with an increased risk of depression in longitudinal studies. Diet and nutrition offer key modifiable targets for the prevention of mental disorders. Evidence is steadily growing for the relation between nutrition deficiencies, diet quality and mental health and for the efficacy and use of nutritional supplements to address deficiencies or as augmentation therapies. We advocate recognition of diet and nutrition as crucial factors in prevention and management of mental disorders.

Lane, M. M., et al. (2022). “Ultra-Processed Food Consumption and Mental Health: A Systematic Review and Meta-Analysis of Observational Studies.” Nutrients 14(13).

Since previous meta-analyses, which were limited only to depression and by a small number of studies available for inclusion at the time of publication, several additional studies have been published assessing the link between ultra-processed food consumption and depression as well as other mental disorders. We aimed to build on previously conducted reviews to synthesise and meta-analyse the contemporary evidence base and clarify the associations between the consumption of ultra-processed food and mental disorders. A total of 17 observational studies were included (n = 385,541); 15 cross-sectional and 2 prospective. Greater ultra-processed food consumption was cross-sectionally associated with increased odds of depressive and anxiety symptoms, both when these outcomes were assessed together (common mental disorder symptoms odds ratio: 1.53, 95%CI 1.43 to 1.63) as well as separately (depressive symptoms odds ratio: 1.44, 95%CI 1.14 to 1.82; and, anxiety symptoms odds ratio: 1.48, 95%CI 1.37 to 1.59). Furthermore, a meta-analysis of prospective studies demonstrated that greater ultra-processed food intake was associated with increased risk of subsequent depression (hazard ratio: 1.22, 95%CI 1.16 to 1.28). While we found evidence for associations between ultra-processed food consumption and adverse mental health, further rigorously designed prospective and experimental studies are needed to better understand causal pathways.

Mendonça, R. D., et al. (2017). “Ultra-Processed Food Consumption and the Incidence of Hypertension in a Mediterranean Cohort: The Seguimiento Universidad de Navarra Project.” Am J Hypertens 30(4): 358-366.

BACKGROUND: Some available evidence suggests that high consumption of ultra-processed foods (UPFs) is associated with a higher risk of obesity. Collectively, this association and the nutritional characteristics of UPFs suggest that UPFs might also be associated with hypertension. METHODS: We prospectively evaluated the relationship between UPF consumption and the risk of hypertension in a prospective Spanish cohort, the Seguimiento Universidad de Navarra project. We included 14,790 Spanish adult university graduates who were initially free of hypertension at baseline who were followed for a mean of 9.1 years (SD, 3.9 years; total person-years: 134,784). UPF (industrial formulations of chemical compounds which, beyond substances of common culinary use such as salt, sugar, oils, and fats, include substances also derived from foods but not used in culinary preparations) consumption was assessed using a validated semi-quantitative 136-item food-frequency questionnaire. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hypertension incidence. RESULTS: During follow-up, 1,702 incident cases of hypertension were identified. Participants in the highest tertile of UPF consumption had a higher risk of developing hypertension (adjusted HR, 1.21; 95% CI, 1.06, 1.37; P for trend = 0.004) than those in the lowest tertile after adjusting for potential confounders. CONCLUSIONS: In this large prospective cohort of Spanish middle-aged adult university graduates, a positive association between UPF consumption and hypertension risk was observed. Additional longitudinal studies are needed to confirm our results.

Reales-Moreno, M., et al. (2022). “Ultra-Processed Foods and Drinks Consumption Is Associated with Psychosocial Functioning in Adolescents.” Nutrients 14(22).

Adolescents show one of the highest rates of ultra-processed foods and drinks (UPF) consumption, and studies indicate an association between their consumption and internalizing problems. We aim to investigate whether UPF consumption associates with dysfunctions in other psychosocial domains, as well as sex effects. In 560 Spanish adolescents (14-17 years old), we assessed the UPF products consumed in the previous day, fruits and vegetables consumption (servings/day), and physical activity (days/week). Psychosocial functioning (total and subscales) was assessed through the Pediatric Symptom Checklist-Youth self-report. Associations between UPF and psychosocial functioning were assessed using linear regression models, adjusting for sex, age, fruits and vegetables consumption, and physical activity. Sex-specific associations were also explored. Participants reported a daily consumption of 7.72 UPF servings per day, with male adolescents showing higher consumption than female adolescents. Consumption of fruits and vegetables and physical activity levels were lower than recommended. Psychosocial impairment was present in 26.2% of the participants. Higher UPF consumption was associated with higher presence of depressive symptoms and internalizing and externalizing problems in the whole sample and in male adolescents. The present study supports previous studies suggesting that UPF consumption may interact with mental health problems and indicates that these effects may go beyond internalizing problems.

Schiepers, O. J., et al. (2005). “Cytokines and major depression.” Prog Neuropsychopharmacol Biol Psychiatry 29(2): 201-217.

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The ‘cytokine hypothesis of depression’ implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces ‘sickness behaviour’, which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Tavares, L. F., et al. (2012). “Relationship between ultra-processed foods and metabolic syndrome in adolescents from a Brazilian Family Doctor Program.” Public Health Nutrition 15(1): 82-87.

ObjectiveTo estimate the association between food intake and metabolic syndrome (MetS).DesignCross-sectional design conducted from July 2006 to December 2007.SettingAdolescents assisted by the Family Doctor Program (FDP) in Niterói, a metropolitan area in Rio de Janeiro State, Brazil.SubjectsSurvey of 210 adolescents. Individuals with three or more of the following components of MetS were classified as having this syndrome: TAG ≥ 110 mg/dl; HDL cholesterol < 50 mg/dl for girls aged 12–19 years and boys aged 12–14 years or <45 mg/dl for boys aged 15–19 years; waist circumference ≥75th percentile; serum glucose >100 mg/dl; and blood pressure ≥90th percentile. A semi-quantitative FFQ was used, and foods were grouped as: unprocessed or minimally processed foods (Group 1), processed culinary and food industry ingredients (Group 2) and ultra-processed foods (Group 3). The associations between food consumption and MetS were adjusted for sociodemographic, behavioural and family history covariates and were estimated using generalized estimation equations with the Poisson regression model.ResultsMetS was diagnosed in 6·7 % of the adolescents; the most frequent diagnostic criteria included the reduction of HDL cholesterol (46·7 %), elevated serum glucose (17·1 %) and the elevation of waist circumference (16·7 %). Crude analysis showed higher average daily intakes of energy, carbohydrates and ultra-processed foods among adolescents with MetS. After statistical adjustment, the intake of ultra-processed foods (≥3rd quartile) remained associated with MetS (prevalence ratio = 2·5; P = 0·012).ConclusionsHigh consumption of ultra-processed foods was associated with the prevalence of MetS in this adolescents group.

van Dam, R. M., et al. (2002). “Dietary patterns and risk for type 2 diabetes mellitus in U.S. men.” Ann Intern Med 136(3): 201-209.

BACKGROUND: The role of diet in the development of type 2 diabetes mellitus remains unsettled. OBJECTIVE: To examine the association between major dietary patterns and risk for type 2 diabetes mellitus. DESIGN: Prospective cohort study. SETTING: United States. PARTICIPANTS: 42 504 male health professionals, 40 to 75 years of age, without diagnosed diabetes, cardiovascular disease, or cancer at baseline. MEASUREMENTS: Using factor analysis based on data from food-frequency questionnaires, we identified and validated two major dietary patterns that we labeled “prudent” (characterized by higher consumption of vegetables, fruit, fish, poultry and whole grains) and “western” (characterized by higher consumption of red meat, processed meat, French fries, high-fat dairy products, refined grains, and sweets and desserts). Relative risks and 95% CIs were adjusted for potential confounders, including body mass index (BMI), physical activity, and cigarette smoking. RESULTS: During 12 years of follow-up (466 508 person-years), we documented 1321 cases of type 2 diabetes. The prudent dietary pattern score was associated with a modestly lower risk for type 2 diabetes (relative risk for extreme quintiles, 0.84 [CI, 0.70 to 1.00]). In contrast, the western dietary pattern score was associated with an increased risk for type 2 diabetes (relative risk, 1.59 [CI, 1.32 to 1.93]; P < 0.001 for trend). A high score for the western dietary pattern combined with low physical activity (relative risk comparing extreme quintiles of dietary pattern score and physical activity, 1.96 [CI, 1.35 to 2.84]) or obesity (relative risk for BMI > or = 30 kg/m2 vs. <25 kg/m2, 11.2 [CI, 8.07 to 15.6]) was associated with a particularly high risk for type 2 diabetes. CONCLUSION: Our findings suggest that a western dietary pattern is associated with a substantially increased risk for type 2 diabetes in men.

Wang, L., et al. (2021). “Trends in Consumption of Ultraprocessed Foods Among US Youths Aged 2-19 Years, 1999-2018.” Jama 326(6): 519-530.

IMPORTANCE: The childhood obesity rate has been steadily rising among US youths during the past 2 decades. Increasing evidence links consumption of ultraprocessed foods to excessive calorie consumption and weight gain, but trends in the consumption of ultraprocessed foods among US youths have not been well characterized. OBJECTIVE: To characterize trends in the consumption of ultraprocessed foods among US youths. DESIGN, SETTING, AND PARTICIPANTS: Serial cross-sectional analysis using 24-hour dietary recall data from a nationally representative sample of US youths aged 2-19 years (n = 33 795) from 10 cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999-2000 to 2017-2018. EXPOSURES: Secular time. MAIN OUTCOMES AND MEASURES: Percentage of total energy consumed from ultraprocessed foods as defined by NOVA, an established food classification system that categorizes food according to the degree of food processing. RESULTS: Dietary intake from youths were analyzed (weighted mean age, 10.7 years; 49.1% were girls). From 1999 to 2018, the estimated percentage of total energy from consumption of ultraprocessed foods increased from 61.4% to 67.0% (difference, 5.6% [95% CI, 3.5% to 7.7%]; P < .001 for trend), whereas the percentage of total energy from consumption of unprocessed or minimally processed foods decreased from 28.8% to 23.5% (difference, -5.3% [95% CI, -7.5% to -3.2%]; P < .001 for trend). Among the subgroups of ultraprocessed foods, the estimated percentage of energy from consumption of ready-to-heat and -eat mixed dishes increased from 2.2% to 11.2% (difference, 8.9% [95% CI, 7.7% to 10.2%]) and from consumption of sweet snacks and sweets increased from 10.7% to 12.9% (difference, 2.3% [95% CI, 1.0% to 3.6%]), but the estimated percentage of energy decreased for sugar-sweetened beverages from 10.8% to 5.3% (difference, -5.5% [95% CI, -6.5% to -4.5%]) and for processed fats and oils, condiments, and sauces from 7.1% to 4.0% (difference, -3.1% [95% CI, -3.7% to -2.6%]) (all P < .05 for trend). There was a significantly larger increase in the estimated percentage of energy from consumption of ultraprocessed foods among non-Hispanic Black youths (from 62.2% to 72.5%; difference, 10.3% [95% CI, 6.8% to 13.8%]) and Mexican American youths (from 55.8% to 63.5%; difference, 7.6% [95% CI, 4.4% to 10.9%]) than the increase among non-Hispanic White youths (from 63.4% to 68.6%; difference, 5.2% [95% CI, 2.1% to 8.3%]) (P = .04 for trends). CONCLUSIONS AND RELEVANCE: Based on the NHANES cycles from 1999 to 2018, the estimated proportion of energy intake from consumption of ultraprocessed foods has increased among youths in the US and has consistently comprised the majority of their total energy intake.

WHO (2021) Adolescent Mental Health

Globally, one in seven 10-19-year-olds experiences a mental disorder, accounting for 13% of the global burden of disease in this age group.

Depression, anxiety and behavioural disorders are among the leading causes of illness and disability among adolescents.

Suicide is the fourth leading cause of death among 15-29 year-olds.

The consequences of failing to address adolescent mental health conditions extend to adulthood, impairing both physical and mental health and limiting opportunities to lead fulfilling lives as adults

Woo, H. D., et al. (2014). “Dietary patterns in children with attention deficit/hyperactivity disorder (ADHD).” Nutrients 6(4): 1539-1553.

The role of diet in the behavior of children has been controversial, but the association of several nutritional factors with childhood behavioral disorders has been continually suggested. We conducted a case-control study to identify dietary patterns associated with attention deficit hyperactivity disorder (ADHD). The study included 192 elementary school students aged seven to 12 years. Three non-consecutive 24-h recall (HR) interviews were employed to assess dietary intake, and 32 predefined food groups were considered in a principal components analysis (PCA). PCA identified four major dietary patterns: the “traditional” pattern, the “seaweed-egg” pattern, the “traditional-healthy” pattern, and the “snack” pattern. The traditional-healthy pattern is characterized by a diet low in fat and high in carbohydrates as well as high intakes of fatty acids and minerals. The multivariate-adjusted odds ratio (OR) of ADHD for the highest tertile of the traditional-healthy pattern in comparison with the lowest tertile was 0.31 (95% CI: 0.12-0.79). The score of the snack pattern was positively associated with the risk of ADHD, but a significant association was observed only in the second tertile. A significant association between ADHD and the dietary pattern score was not found for the other two dietary patterns. In conclusion, the traditional-healthy dietary pattern was associated with lower odds having ADHD.

Health Benefits of the Mediterranean Diet

It has long been known that the Mediterranean diet, a combination of vegetables, fruits, whole grains, oily fish and seafood, extra virgin olive oil, herbs, spices, nuts, and seeds has health promoting benefits. Furthermore, a healthy diet which is rich in antioxidant and anti-inflammatory components is influential in terms of promoting healthy aging and longevity Furthermore, improving diet is arguably one of the easiest modifiable ways to maintain human health, reduce inflammation and safeguard against the premature development of diseases linked to poor metabolic health (Gouveri et al., 2020) and neurodegeneration (Gantenbein & Kanaka-Gantenbein, 2021). The last few decades have witnessed a marked increase in the burden of non-communicable diseases including the group of conditions collectively known as metabolic syndrome (e.g., coronary heart disease, Type 2 diabetes, obesity, stroke, non-alcoholic fatty liver disease) or insulin resistance syndrome in modern, western societies and those countries under development. The World Health Organization (WHO) state that non-communicable diseases account for 70% of all deaths worldwide. The key factors related to the emergence of these diseases are poor diet (e.g., ultraprocessed (junk) foods and sweetened beverages characterized by excess sugar, refined carbohydrates, synthetic food additives, and cheap, industrially produced vegetable oils (e.g., soybean, safflower, canola, corn oil etc. which contain proinflammatory, linoleic acid (LA) omega-6 fats), lack of physical exercise and smoking which can lead to hypertension, hyperlipidemia, insulin resistance, obesity (Sandoval-Insausti et al., 2020), cardiovascular disease and mortality (Costa de Miranda et al., 2021).

References for the Health Benefits of a Mediterranean Diet

Costa de Miranda, R., Rauber, F., & Levy, R. B. (2021). Impact of ultra-processed food consumption on metabolic health. Curr Opin Lipidol, 32(1), 24-37. https://doi.org/10.1097/mol.0000000000000728

Gantenbein, K. V., & Kanaka-Gantenbein, C. (2021). Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing. Nutrients, 13(6), 1951. https://www.mdpi.com/2072-6643/13/6/1951

Gouveri, E., Marakomichelakis, G., & Diamantopoulos, E. J. (2020). Chapter 34 – The Mediterranean diet and metabolic syndrome. In V. R. Preedy & R. R. Watson (Eds.), The Mediterranean Diet (Second Edition) (pp. 371-379). Academic Press. https://doi.org/https://doi.org/10.1016/B978-0-12-818649-7.00034-5

Sandoval-Insausti, H., Jiménez-Onsurbe, M., Donat-Vargas, C., Rey-García, J., Banegas, J. R., Rodríguez-Artalejo, F., & Guallar-Castillón, P. (2020). Ultra-Processed Food Consumption Is Associated with Abdominal Obesity: A Prospective Cohort Study in Older Adults. Nutrients, 12(8). https://doi.org/10.3390/nu12082368

Feed the Gut: Psychobiome

The field of Nutritional Science (and Psychiatry) has established the link between the gut and the brain, and why this bidirectional relationship is critical for mood and well-being. An entirely new field capturing the psychobiome has now emerged. A parallel component of this field is psychobiotics, the scientific exploration to discover which microbiomes are beneficial to our psychological and physical health (Economist, 2022). Psychobiotics can be regarded as beneficial bacteria such as probiotics which influence the gut-brain axis and exert antidepressant effects by supporting cognition and emotional function.

The bacteria in the gut produce, among other things, tryptophan, the amino acid thought to have come entirely from the diet. The sorts of microorganisms found in yogurt specifically, and fermented foods generally, have also been shown by trials to reduce anxiety. Most astonishing to Dr Dinan is the finding that a person’s capacity to deal with stress can be altered by a single strain of bacterium. Studies show that two species of Bifidobacterium and one of Lactobacillus each reduce stress. In a trial on germfree mice, an abnormal stress response was reversed when they were given oral doses of Bifidobacterium infantis. These findings have given rise to the notion of “psychobiotics”—bacteria that, when ingested, may have similar effects to antidepressants or anti-anxiety medication.

References

Economist, T. (2022). https://www.economist.com/christmas-specials/2022/12/20/how-food-affects-the-mind-as-well-as-the-body

Table A. Food Additives. Synthetic and natural colorants which may have potentially harmful side-effects

Center for Science in the Public Interest https://www.cspinet.org/sites/default/files/attachment/food-dyes-rainbow-of-risks.pdf
Office of Environmental Health Hazard Assessment (Potera 2010)https://oehha.ca.gov/media/downloads/risk-assessment/report/fooddyesassessmentdraft082820.pdf
(Kobylewski and Jacobson 2012)
(Arnold, Lofthouse et al. 2012)
(Boris and Mandel 1994)
(McCann, Barrett et al. 2007)
(Rowe and Rowe 1994)
(Schab and Trinh 2004)
(Potera 2010)
(Peiperl, Prival et al. 1995)
(Dipalma 1990)
(Stenius and Lemola 1976)
(Settipane, Chafee et al. 1976)
(Neuman, Elian et al. 1978)
(Settipane, Chafee et al. 1976)
Food Standards Australia New Zealand https://www.foodstandards.gov.au/consumer/additives/pages/tableoffoodadditivep5753.aspx
(Fernando and Clarke 2009)
https://www.webmd.com/vitamins/ai/ingredientmono-846/canthaxanthin
(Chen, Yan et al. 2014, Suzuki, Miura et al. 2020)
(Krewski, Yokel et al. 2007)
(Jovanović, Jovanović et al. 2018)

Arnold, L. E., et al. (2012). “Artificial food colors and attention-deficit/hyperactivity symptoms: conclusions to dye for.” Neurotherapeutics 9(3): 599-609.

The effect of artificial food colors (AFCs) on child behavior has been studied for more than 35 years, with accumulating evidence from imperfect studies. This article summarizes the history of this controversial topic and testimony to the 2011 Food and Drug Administration Food Advisory Committee convened to evaluate the current status of evidence regarding attention-deficit/hyperactivity disorder (ADHD). Features of ADHD relevant to understanding the AFC literature are explained: ADHD is a quantitative diagnosis, like hypertension, and some individuals near the threshold may be pushed over it by a small symptom increment. The chronicity and pervasiveness make caregiver ratings the most valid measure, albeit subjective. Flaws in many studies include nonstandardized diagnosis, questionable sample selection, imperfect blinding, and nonstandardized outcome measures. Recent data suggest a small but significant deleterious effect of AFCs on children’s behavior that is not confined to those with diagnosable ADHD. AFCs appear to be more of a public health problem than an ADHD problem. AFCs are not a major cause of ADHD per se, but seem to affect children regardless of whether or not they have ADHD, and they may have an aggregated effect on classroom climate if most children in the class suffer a small behavioral decrement with additive or synergistic effects. Possible biological mechanisms with published evidence include the effects on nutrient levels, genetic vulnerability, and changes in electroencephalographic beta-band power. A table clarifying the Food and Drug Administration and international naming systems for AFCs, with cross-referencing, is provided.

Boris, M. and F. S. Mandel (1994). “Foods and additives are common causes of the attention deficit hyperactive disorder in children.” Ann Allergy 72(5): 462-468.

The attention deficit hyperactive disorder (ADHD) is a neurophysiologic problem that is detrimental to children and their parents. Despite previous studies on the role of foods, preservatives and artificial colorings in ADHD this issue remains controversial. This investigation evaluated 26 children who meet the criteria for ADHD. Treatment with a multiple item elimination diet showed 19 children (73%) responded favorably, P < .001. On open challenge, all 19 children reacted to many foods, dyes, and/or preservatives. A double-blind placebo controlled food challenge (DBPCFC) was completed in 16 children. There was a significant improvement on placebo days compared with challenge days (P = .003). Atopic children with ADHD had a significantly higher response rate than the nonatopic group. This study demonstrates a beneficial effect of eliminating reactive foods and artificial colors in children with ADHD. Dietary factors may play a significant role in the etiology of the majority of children with ADHD.

Chen, T., et al. (2014). “Genotoxicity of titanium dioxide nanoparticles.” J Food Drug Anal 22(1): 95-104.

Titanium dioxide nanoparticles (TiO(2)-NPs, <100 nm) are increasingly being used in pharmaceuticals and cosmetics due to the unique properties derived from their small sizes. However, their large surface-area to mass ratio and high redox potential may negatively impact human health and the environment. TiO(2)-NPs can cause inflammation, pulmonary damage, fibrosis, and lung tumors and they are possibly carcinogenic to humans. Because cancer is a disease involving mutation, there are a large number of studies on the genotoxicity of TiO(2)-NPs. In this article, we review the results that have been reported in the literature, with a focus on data generated from the standard genotoxicity assays. The data include genotoxicity results from the Ames test, in vitro and in vivo Comet assay, in vitro and in vivo micronucleus assay, sister chromatid exchange assay, mammalian cell hypoxanthine-guanine phosphoribosyl transferase gene assay, the wing somatic mutation and recombination assay, and the mouse phosphatidylinositol glycan, class A gene assay. Inconsistent results have been found in these assays, with both positive and negative responses being reported. The in vitro systems for assessing the genotoxicity of TiO(2)-NPs have generated a greater number of positive results than the in vivo systems, and tests for DNA and chromosome damage have produced more positive results than the assays measuring gene mutation. Nearly all tests for measuring the mutagenicity of TiO(2)-NPs were negative. The current data indicate that the genotoxicity of TiO(2)-NPs is mediated mainly through the generation of oxidative stress in cells.

Dipalma, J. R. (1990). “Tartrazine sensitivity.” Am Fam Physician 42(5): 1347-1350.

Tartrazine (FD & C Yellow No. 5) is an approved azo dye present in many drugs and food products. During the 1970s, many cases of tartrazine sensitivity were reported. This led to new regulations that required the listing of azo dyes on package inserts of drugs and on packages of food products. Tartrazine sensitivity is most frequently manifested by urticaria and asthma. Although azo dyes have been implicated in accentuating hyperkinetic syndromes, tartrazine is not considered an offender. Vasculitis, purpura and contact dermatitis infrequently occur as manifestations of tartrazine sensitivity. Cross-sensitivity in aspirin-sensitive and NSAID-sensitive patients may also occur. The mechanism of sensitivity is obscure and has been called pseudoallergic. Management consists mainly of avoidance of drugs and food products that contain tartrazine.

Fernando, S. L. and L. R. Clarke (2009). “Salicylate intolerance: a masquerader of multiple adverse drug reactions.” BMJ Case Rep 2009.

A female in her early 50s presented with a long-standing history of episodic urticaria and angioedema. She also reported urticarial reactions after ingestion of aspirin, prednisone and multiple antibiotics. These medications were all taken during upper respiratory tract infections. An elimination diet followed by a series of open challenges to food chemicals demonstrated an urticarial eruption following the ingestion of mints, which contain high levels of salicylates. A double-blinded placebo-controlled challenge to salicylate confirmed her sensitivity and explained her reaction to aspirin. The patient informed her treating physician of her copious ingestion of mints during upper respiratory tract infections. Drug hypersensitivity to antibiotics and prednisone was excluded on the basis of negative radioallergosorbent tests (RASTs) and/or absent skin-test responses and/or tolerance to oral challenges. This patient had a salicylate intolerance that caused her episodic urticaria and angioedema, and also masqueraded as a drug allergy due to the concurrent ingestion of mints.

Jovanović, B., et al. (2018). “The effects of a human food additive, titanium dioxide nanoparticles E171, on Drosophila melanogaster – a 20 generation dietary exposure experiment.” Scientific Reports 8(1): 17922.

In this study, fruit flies (Drosophila melanogaster) were exposed to an estimated daily human E171 consumption concentration for 20 generations. Exposure to E171 resulted in: a change in normal developmental and reproductive dynamics, reduced fecundity after repetitive breeding, increased genotoxicity, the appearance of aberrant phenotypes and morphologic changes to the adult fat body. Marks of adaptive evolution and directional selection were also exhibited. The larval stages were at a higher risk of sustaining damage from E171 as they had a slower elimination rate of TiO2 compared to the adults. This is particularly worrisome, since among the human population, children tend to consume higher daily concentrations of E171 than do adults. The genotoxic effect of E171 was statistically higher in each subsequent generation compared to the previous one. Aberrant phenotypes were likely caused by developmental defects induced by E171, and were not mutations, since the phenotypic features were not transferred to any progeny even after 5 generations of consecutive crossbreeding. Therefore, exposure to E171 during the early developmental period carries a higher risk of toxicity. The fact that the daily human consumption concentration of E171 interferes with and influences fruit fly physiological, ontogenetic, genotoxic, and adaptive processes certainly raises safety concerns.

Kobylewski, S. and M. F. Jacobson (2012). “Toxicology of food dyes.” Int J Occup Environ Health 18(3): 220-246.

BACKGROUND: Food dyes, synthesized originally from coal tar and now petroleum, have long been controversial because of safety concerns. Many dyes have been banned because of their adverse effects on laboratory animals or inadequate testing. CONCLUSIONS: This review finds that all of the nine currently US-approved dyes raise health concerns of varying degrees. Red 3 causes cancer in animals, and there is evidence that several other dyes also are carcinogenic. Three dyes (Red 40, Yellow 5, and Yellow 6) have been found to be contaminated with benzidine or other carcinogens. At least four dyes (Blue 1, Red 40, Yellow 5, and Yellow 6) cause hypersensitivity reactions. Numerous microbiological and rodent studies of Yellow 5 were positive for genotoxicity. Toxicity tests on two dyes (Citrus Red 2 and Orange B) also suggest safety concerns, but Citrus Red 2 is used at low levels and only on some Florida oranges and Orange B has not been used for several years. The inadequacy of much of the testing and the evidence for carcinogenicity, genotoxicity, and hypersensitivity, coupled with the fact that dyes do not improve the safety or nutritional quality of foods, indicates that all of the currently used dyes should be removed from the food supply and replaced, if at all, by safer colorings. It is recommended that regulatory authorities require better and independent toxicity testing, exercise greater caution regarding continued approval of these dyes, and in the future approve only well-tested, safe dyes.

Krewski, D., et al. (2007). “Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide.” J Toxicol Environ Health B Crit Rev 10 Suppl 1(Suppl 1): 1-269.

McCann, D., et al. (2007). “Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial.” Lancet 370(9598): 1560-1567.

BACKGROUND: We undertook a randomised, double-blinded, placebo-controlled, crossover trial to test whether intake of artificial food colour and additives (AFCA) affected childhood behaviour. METHODS: 153 3-year-old and 144 8/9-year-old children were included in the study. The challenge drink contained sodium benzoate and one of two AFCA mixes (A or B) or a placebo mix. The main outcome measure was a global hyperactivity aggregate (GHA), based on aggregated z-scores of observed behaviours and ratings by teachers and parents, plus, for 8/9-year-old children, a computerised test of attention. This clinical trial is registered with Current Controlled Trials (registration number ISRCTN74481308). Analysis was per protocol. FINDINGS: 16 3-year-old children and 14 8/9-year-old children did not complete the study, for reasons unrelated to childhood behaviour. Mix A had a significantly adverse effect compared with placebo in GHA for all 3-year-old children (effect size 0.20 [95% CI 0.01-0.39], p=0.044) but not mix B versus placebo. This result persisted when analysis was restricted to 3-year-old children who consumed more than 85% of juice and had no missing data (0.32 [0.05-0.60], p=0.02). 8/9-year-old children showed a significantly adverse effect when given mix A (0.12 [0.02-0.23], p=0.023) or mix B (0.17 [0.07-0.28], p=0.001) when analysis was restricted to those children consuming at least 85% of drinks with no missing data. INTERPRETATION: Artificial colours or a sodium benzoate preservative (or both) in the diet result in increased hyperactivity in 3-year-old and 8/9-year-old children in the general population.

Neuman, I., et al. (1978). “The danger of “yellow dyes” (tartrazine) to allergic subjects.” Clin Allergy 8(1): 65-68.

Oral administration of 50 mg tartrazine to 122 patients with a variety of allergic disorders caused the following reactions: general weakness, heatwaves, palpitations, blurred vision, rhinorrhoea, feeling of suffocation, pruritus and urticaria. There was activation of the fibrinolytic pathway as shown by reduction of plasminogen with high pre-kallikrein and low kallikrein values. Reduction in complement activity (CH50) was seen in three out of sixteen reactions.

Peiperl, M. D., et al. (1995). “Determination of combined benzidine in FD&C Yellow No. 6 (Sunset Yellow FCF).” Food Chem Toxicol 33(10): 829-839.

Samples from 67 manufactured lots of FD&C Yellow No. 6 (Sunset Yellow FCF; Colour Index No. 15985) were analysed for combined benzidine. These samples were selected from those submitted to the US Food and Drug Administration for certification between October 1991 and December 1992 by 13 dye distributors. Dithionite was used to reduce any combined benzidine present in the form of azo or disazo dyes to free benzidine. This reduction was followed by extraction, diazotization and coupling with 2-naphthol-3,6-disulfonic acid disodium salt (R salt). The total benzidine was quantified as benzidine-R salt disazo dye by HPLC with detection at 540 nm and a quantification limit of 10 ng benzidine/g FD&C Yellow No. 6. Of the 67 samples analysed, 34 were found to contain more than 10 ng combined benzidine/g. Of these, 30 samples were from one manufacturing company, including three of its subsidaries. The level of combined benzidine found ranged from 11 to 104 ng/g, except for one sample containing 941 ng/g.

Potera, C. (2010). “The artificial food dye blues.” Environ Health Perspect 118(10): A428.

Rowe, K. S. and K. J. Rowe (1994). “Synthetic food coloring and behavior: a dose response effect in a double-blind, placebo-controlled, repeated-measures study.” J Pediatr 125(5 Pt 1): 691-698.

OBJECTIVE: To establish whether there is an association between the ingestion of synthetic food colorings and behavioral change in children referred for assessment of “hyperactivity.” PARTICIPANTS: From approximately 800 children referred to the Royal Children’s Hospital (Melbourne) for assessment of suspected hyperactivity, 200 were included in a 6-week open trial of a diet free of synthetic food coloring. The parents of 150 children reported behavioral improvement with the diet, and deterioration on the introduction of foods noted to contain synthetic coloring. A 30-item behavioral rating inventory was devised from an examination of the clinical histories of 50 suspected reactors. Thirty-four other children (23 suspected reactors, 11 uncertain reactors) and 20 control subjects, aged 2 to 14 years, were studied. DESIGN: A 21-day, double-blind, placebo-controlled, repeated-measures study used each child as his or her own control. Placebo, or one of six dose levels of tartrazine (1, 2, 5, 10, 20, 50 mg), was administered randomly each morning, and behavioral ratings were recorded by parents at the end of each 24 hours. RESULTS: The study identified 24 children as clear reactors (19 of 23 “suspected reactors,” 3 of 11 “uncertain reactors,” and 2 of 20 “control subjects”). They were irritable and restless and had sleep disturbance. Significant reactions were observed at all six dose levels. A dose response effect was obtained. With a dose increase greater than 10 mg, the duration of effect was prolonged. CONCLUSION: Behavioral changes in irritability, restlessness, and sleep disturbance are associated with the ingestion of tartrazine in some children. A dose response effect was observed.

Schab, D. W. and N. H. Trinh (2004). “Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials.” J Dev Behav Pediatr 25(6): 423-434.

Burgeoning estimates of the prevalence of childhood attention-deficit/hyperactivity disorder (ADHD) raise the possibility of a widespread risk factor. We seek to assess whether artificial food colorings (AFCs) contribute to the behavioral symptomatology of hyperactive syndromes. We searched ten electronic databases for double-blind placebo-controlled trials evaluating the effects of AFCs. Fifteen trials met the primary inclusion criteria. Meta-analytic modeling determined the overall effect size of AFCs on hyperactivity to be 0.283 (95% CI, 0.079 to 0.488), falling to 0.210 (95% CI, 0.007 to 0.414) when the smallest and lowest quality trials were excluded. Trials screening for responsiveness before enrollment demonstrated the greatest effects. Despite indications of publication bias and other limitations, this study is consistent with accumulating evidence that neurobehavioral toxicity may characterize a variety of widely distributed chemicals. Improvement in the identification of responders is required before strong clinical recommendations can be made.

Settipane, G. A., et al. (1976). “Significance of tartrazine sensitivity in chronic urticaria of unknown etiology.” J Allergy Clin Immunol 57(6): 541-546.

Of 38 patients with chronic urticaria of unknown etiology who were evaluated for food and drug additive sensitivity, 53% (20/38) had urticaria for 1 yr or more. Total eosinophil counts were not elevated in most patients, and the frequency of atopy was found to be similar to that in a general population. Of these 38 patients, 10 (26%) had a personal history of aspirin intolerance, but elimination of aspirin did not relieve the urticaria. In a double-blind crossover challenge with 0.22 mg of tartrazine and a control, tartrazine sensitivity was found in 8% (3/38) of patients with chronic urticaria and 20% (2/10) of patients with aspirin intolerance.

Stenius, B. S. and M. Lemola (1976). “Hypersensitivity to acetylsalicylic acid (ASA) and tartrazine in patients with asthma.” Clin Allergy 6(2): 119-129.

One-hundred and forty asthmatics were tested perorally with acetylsalicylic acid (ASA), and/or with the azo-colour tartrazine; a fall in PEF of more than 20% was accepted as a positive result. About one quarter of the patients displayed a positive reaction to one of the two tested agents. No significant correlation was found between the reactions of these, and the presence of atopy, nasal polyposis, sinusitis, rhinitis, sensitivity to cold air, the age at onset, duration of asthma, or history of sensitivity to alcoholic drinks. The history suggested sensitivity to ingested, possibly coloured, food and drink, in only about one third of the tartrazine-positive cases. The ASA provocation tests were mainly applied to patients with doubtful or negative histories of sensitivity to ASA-containing drugs. The frequency of cross-reactivity between the two tested agents was statistically significant; patients reacting to tartrazine were for the most part, also sensitive to ASA. Tests for sensitivity to analgesics and food additives should be conducted as a routine measure in asthmatics, and sensitive patients should be given information on suitable medication and dietary control.

Suzuki, T., et al. (2020). “Genotoxicity assessment of titanium dioxide nanoparticle accumulation of 90 days in the liver of gpt delta transgenic mice.” Genes Environ 42: 7.

BACKGOUND: A variety of in vivo and in vitro studies to assess the genotoxicity of titanium dioxide nanoparticles (TiO(2) NPs) have been reported, but the results are inconsistent. Recently, we reported that TiO(2) NPs exhibit no genotoxic effects in the liver and erythrocytes during a relatively brief period following intravenous injection into mice. However, there is no information about long-term genotoxicity due to TiO(2) NP accumulation in tissues. In this study, we investigated the long-term mutagenic effects of TiO(2) NPs and the localization of residual TiO(2) NPs in mouse liver after multiple intravenous injections. RESULTS: Male gpt delta C57BL/6 J mice were administered with various doses of TiO(2) NPs weekly for 4 consecutive weeks. The long-term mutagenic effects on the liver were analyzed using gpt and Spi(-) mutation assays 90 days after the final injection. We also quantified the amount of titanium in the liver using inductively coupled plasma mass spectrometry and observed the localization of TiO(2) NPs in the liver using transmission electron microscopy. Although TiO(2) NPs were found in the liver cells, the gpt and Spi(-) mutation frequencies in the liver were not significantly increased by the TiO(2) NP administration. CONCLUSIONS: These results clearly show that TiO(2) NPs have no mutagenic effects on the liver, even though the particles remain in the liver long-term.

Table B. Food Additives. Synthetic and natural preservatives linked to potential harms

(Mamur, Yüzbaşıoğlu et al. 2012)
(Schlatter, Würgler et al. 1992)
(Mamur, Yüzbaşıoğlu et al. 2010)
Research paper by Patel and Ramani (2017): https://www.researchgate.net/publication/339974034_In_vitro_determination_of_genotoxic_effects_of_sodium_benzoate_preservative_on_human_peripheral_blood_lymphocytes
(McCann, Barrett et al. 2007)
Article: http://www.foodcomm.org.uk/press/childrens_medicine
(Mancini, Paul et al. 2015)
Article: https://pubchem.ncbi.nlm.nih.gov/compound/7175
(Vally and Misso 2012)
Government health sheet: https://www.epa.gov/sites/default/files/2016-09/documents/biphenyl.pdf
(Li, Hogan et al. 2016)
Article: https://pubchem.ncbi.nlm.nih.gov/compound/2-Phenylphenol#section=Toxicity or National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 7017, 2-Phenylphenol. Retrieved February 24, 2023 from https://pubchem.ncbi.nlm.nih.gov/compound/2-Phenylphenol
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/2-hydroxybiphenyl
(John, Arnold et al. 2001)
(Agency 2012)https://www.foodstandards.gov.au/consumer/additives/pages/tableoffoodadditivep5753.aspx
Government website: https://webwiser.nlm.nih.gov/substance?substanceId=486&identifier=Formic%20Acid&identifierType=name&menuItemId=62&catId=83
(Garai, Banerjee et al. 2022)
(Paula Neto, Ausina et al. 2017)
(Sambu, Hemaram et al. 2022)
Government article: https://www.cfs.gov.hk/english/programme/programme_rafs/programme_rafs_fa_02_09.html#:~:text=Ingestion%20of%20a%20small%20amount,is%20its%20cancer%20causing%20potential.
(Safety 2017)
(İnci, Zararsız et al. 2013)
(Songur, Ozen et al. 2010)
(Mortensen, Aguilar et al. 2017)
(Neth, Love et al. 2021)
(Kurokawa, Maekawa et al. 1990)
https://pubchem.ncbi.nlm.nih.gov/compound/Sodium-Tetraborate
(Bolt, Başaran et al. 2012)

References

Agency, F. S. (2012). Table of food additive permissions in the US and Europe.

Bolt, H. M., et al. (2012). “Human Environmental and Occupational Exposures to Boric Acid: Reconciliation with Experimental Reproductive Toxicity Data.” Journal of Toxicology and Environmental Health, Part A 75(8-10): 508-514.

Garai, P., et al. (2022). “Mechanistic insights to lactic and formic acid toxicity on benthic oligochaete worm Tubifex tubifex.” Environ Sci Pollut Res Int 29(58): 87319-87333.

Lactic and formic acid are two commonly found monocarboxylic organic acids. Lactic acid is discharged into the water bodies as acidic industrial effluent from the food, cosmetic, chemical, and pharmaceutical industries, whereas formic acid is discharged from various paper, leather tanning, and textile processing industries. The present study investigated the toxicity of both organic acids upon the benthic oligochaete worm Tubifex tubifex. The 96-h median lethal concentration (LC(50)) values for lactic and formic acid are determined as 143.81 mg/l and 57.99 mg/l respectively. The effects of two sublethal concentrations (10% and 30% of 96 h LC(50)) of these acids on differential expression of oxidative stress enzymes are investigated. The comparative analysis of acute toxicity demonstrates that formic acid exposure is more detrimental to T. tubifex than lactic acid. The in silico structural analysis predicts that formic acid can interact with cytochrome c oxidase of the electron transport system and thereby inhibits its functionality and induces reactive oxygen species production. Integrated biomarker response (IBR) analysis illustrates that overall oxidative stress of formic acid to T. tubifex is significantly higher than that of lactic acid, which supports the structural analysis. It is concluded from this study that toxicokinetic-toxicodynamic and species sensitivity distributions studies are helpful for ecological risk management of environmental toxicants.

İnci, M., et al. (2013). “Toxic effects of formaldehyde on the urinary system.” Turk J Urol 39(1): 48-52.

Formaldehyde is a chemical substance with a pungent odor that is highly soluble in water and occurs naturally in organisms. Formaldehyde, when taken into organisms, is metabolized into formic acid in the liver and erythrocytes and is then excreted, either with the urine and feces or via the respiratory system. Form-aldehyde is widely used in the industrial and medical fields, and employees in these sectors are frequently exposed to it. Anatomists and medical students are affected by formaldehyde gas during dissection lessons. Because full protection from formaldehyde is impossible for employees in industrial plants using this chemical and for workers in laboratory conditions, several measures can be implemented to prevent and/or reduce the toxic effects of formaldehyde. In this review, we aimed to identify the toxic effects of formaldehyde on the urinary system.

John, M. K. S., et al. (2001). “Dietary Effects of ortho-Phenylphenol and Sodium ortho-Phenylphenate on Rat Urothelium.” Toxicological Sciences 59(2): 346-351.

Ortho-phenylphenol (OPP) and sodium ortho-phenylphenate (NaOPP) are pesticides used commercially in the food industry that have been shown to be carcinogenic to rat urothelium. Dietary administration of 1.25% OPP or 2.0% NaOPP caused increased incidences of urothelial hyperplasia and eventually caused tumors in male F344 rats, with NaOPP apparently having a more potent effect. In other studies, various sodium salts such as saccharin and ascorbate enhanced bladder carcinogenesis, although the acid forms of these salts did not. In studies with high dietary doses of these sodium salts, an amorphous precipitate was produced in the urine; precipitate formation was pH dependent. In previous experiments in which high doses of OPP were fed for up to 17 weeks, severe hyperplasia of the urothelium was produced, but without the formation of an urinary amorphous precipitate, calculi, or abnormal microcrystalluria. In addition, we found no evidence of OPP-DNA adduct formation in the urothelium. The present study was conducted to determine if feeding NaOPP • 4 H20 to male F344 rats as 2.0% of the diet resulted in the formation of an amorphous precipitate in the urine, and if NaOPP caused an increased mineral concentration in the urine and/or kidneys. NaOPP administration produced a higher urinary pH than did OPP fed as 1.25% of the diet. Neither amorphous precipitate nor other solids were observed in the urine of the OPP or NaOPP-treated rats, and urinary calcium concentrations in the treated groups were similar to control. OPP and NaOPP had similar proliferative effects on rat urothelium after 10 weeks of treatment by light microscopy, scanning electron microscopy (SEM), and bromodeoxyuridine (BrdU) labeling indices. The results of this study indicate that formation of abnormal urinary solids is not part of the mechanism by which OPP or NaOPP exert their effects on the rat bladder epithelium.

Kurokawa, Y., et al. (1990). “Toxicity and carcinogenicity of potassium bromate–a new renal carcinogen.” Environ Health Perspect 87: 309-335.

Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

Li, Z., et al. (2016). “Human Health Effects of Biphenyl: Key Findings and Scientific Issues.” Environ Health Perspect 124(6): 703-712.

BACKGROUND: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) has evaluated the human health hazards of biphenyl exposure. OBJECTIVES: We review key findings and scientific issues regarding expected human health effects of biphenyl. METHODS: Scientific literature from 1926 through September 2012 was critically evaluated to identify potential human health hazards associated with biphenyl exposure. Key issues related to the carcinogenicity and noncancer health hazards of biphenyl were examined based on evidence from experimental animal bioassays and mechanistic studies. DISCUSSION: Systematic consideration of experimental animal studies of oral biphenyl exposure took into account the variety of study designs (e.g., study sizes, exposure levels, and exposure durations) to reconcile differing reported results. The available mechanistic and toxicokinetic evidence supports the hypothesis that male rat urinary bladder tumors arise through urinary bladder calculi formation but is insufficient to hypothesize a mode of action for liver tumors in female mice. Biphenyl and its metabolites may induce genetic damage, but a role for genotoxicity in biphenyl-induced carcinogenicity has not been established. CONCLUSIONS: The available health effects data for biphenyl provides suggestive evidence for carcinogenicity in humans, based on increased incidences of male rat urinary bladder tumors at high exposure levels and on female mouse liver tumors. Kidney toxicity is also a potential human health hazard of biphenyl exposure. CITATION: Li Z, Hogan KA, Cai C, Rieth S. 2016. Human health effects of biphenyl: key findings and scientific issues. Environ Health Perspect 124:703-712; http://dx.doi.org/10.1289/ehp.1509730.

Mamur, S., et al. (2012). “Genotoxicity of food preservative sodium sorbate in human lymphocytes in vitro.” Cytotechnology 64(5): 553-562.

The genotoxic effects of antimicrobial food additive sodium sorbate (SS) was assessed by using chromosome aberrations (CAs), sister-chromatid exchanges (SCEs), and micronucleus (MN) in cultured human lymphocytes and comet assay in isolated human lymphocytes. Lymphocytes were treated with four concentrations (100, 200, 400 and 800 μg/ml) of SS as well as a negative (sterile distilled water) and a positive control (Mitomycin-C: MMC for cultured lymphocytes and H(2)O(2) for isolated lymphocytes). The result of this study indicated that SS increased the frequency of CAs at both 24 and 48 h period compared to control. When gaps were included, this increase was significant at 200, 400 and 800 μg/ml concentrations at 24 h and, at all concentrations at 48 h treatment time. When gaps were excluded, this increase was significant at only 800 μg/ml concentration at both 24 and 48 h treatments. In addition, SS increased SCEs/cell and MN frequency at 400 and 800 μg/ml concentrations at both 24 and 48 h compared to negative control. Furthermore, this additive caused DNA damage at all concentrations in isolated human lymphocytes after 1 h in vitro exposure. The present results show that SS is genotoxic to the human peripheral blood lymphocytes in vitro at the highest concentrations.

Mamur, S., et al. (2010). “Does potassium sorbate induce genotoxic or mutagenic effects in lymphocytes?” Toxicology in Vitro 24(3): 790-794.

The present study evaluates the genotoxic potential of potassium sorbate (PS) in cultured and isolated human lymphocytes. To assess the damage caused by PS in humans, we designed in vitro experiments by measuring chromosomal aberrations (CAs), sister-chromatid exchanges (SCEs), micronucleus (MN) and comet assays. Lymphocytes were treated with negative control (sterile distilled water), positive control (MMC for cultured lymphocytes, and H2O2 for isolated lymphocytes) and four concentrations (125, 250, 500, and 1000μg/ml) of PS. According to the results, PS treatment significantly increases the CAs (with or without gaps at 500 and 1000μg/ml concentrations) and SCEs (at 250, 500, 1000μg/ml for 24h and 125, 250, 500, 1000μg/ml for 48h) compared with vehicle control. Following treatment of the isolated lymphocytes for 1h, significant PS-induced DNA strand breaks were observed, at all concentrations. However, PS failed to significantly affect the MN assay. On the contrary, PS does not cause cell cycle delay as noted by the non-significant decrease in the cytokinesis-block proliferation index (CBPI) and replicative index (RI). Only a slight decrease was observed in the mitotic index (MI) at the highest concentration for both treatment times. From the results, PS is clearly seen to be genotoxic to the human peripheral blood lymphocytes in vitro.

Mancini, F. R., et al. (2015). “Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249-E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France.” Food Addit Contam Part A Chem Anal Control Expo Risk Assess 32(3): 293-306.

This study aimed to estimate the exposure to seven additives (benzoates, parabens, nitrites, nitrates, BHA, BHT and aspartame) in children aged less than 3 years old in France. A conservative approach, combining individual consumption data with maximum permitted levels, was carried out for all the additives. More refined estimates using occurrence data obtained from products’ labels (collected by the French Observatory of Food Quality) were conducted for those additives that exceeded the acceptable daily intake (ADI). Information on additives’ occurrence was obtained from the food labels. When the ADI was still exceeded, the exposure estimate was further refined using measured concentration data, if available. When using the maximum permitted level (MPL), the ADI was exceeded for benzoates (1.94 mg kg(-1) bw day(-1)), nitrites (0.09 mg kg(-1) bw day(-1)) and BHA (0.39 mg kg(-1) bw day(-1)) in 25%, 54% and 20% of the entire study population respectively. The main food contributors identified with this approach were current foods as these additives are not authorised in specific infant food: vegetable soups and broths for both benzoates and BHA, delicatessen and meat for nitrites. The exposure estimate was significantly reduced when using occurrence data, but in the upper-bound scenario the ADI was still exceeded significantly by the age group 13-36 months for benzoates (2%) and BHA (1%), and by the age group 7-12 months (16%) and 13-36 months (58%) for nitrites. Measured concentration data were available exclusively for nitrites and the results obtained using these data showed that the nitrites’ intake was below the ADI for all the population considered in this study. These results suggest that refinement of exposure, based on the assessment of food levels, is needed to estimate the exposure of children to BHA and benzoates for which the risk of exceeding the ADI cannot be excluded when using occurrence data.

Mortensen, A., et al. (2017). “Re-evaluation of potassium nitrite (E 249) and sodium nitrite (E 250) as food additives.” Efsa j 15(6): e04786.

The Panel on Food Additives and Nutrient Sources added to Food (ANS) provided a scientific opinion re-evaluating the safety of potassium nitrite (E 249) and sodium nitrite (E 250) when used as food additives. The ADIs established by the SCF (1997) and by JECFA (2002) for nitrite were 0-0.06 and 0-0.07 mg/kg bw per day, respectively. The available information did not indicate in vivo genotoxic potential for sodium and potassium nitrite. Overall, an ADI for nitrite per se could be derived from the available repeated dose toxicity studies in animals, also considering the negative carcinogenicity results. The Panel concluded that an increased methaemoglobin level, observed in human and animals, was a relevant effect for the derivation of the ADI. The Panel, using a BMD approach, derived an ADI of 0.07 mg nitrite ion/kg bw per day. The exposure to nitrite resulting from its use as food additive did not exceed this ADI for the general population, except for a slight exceedance in children at the highest percentile. The Panel assessed the endogenous formation of nitrosamines from nitrites based on the theoretical calculation of the NDMA produced upon ingestion of nitrites at the ADI and estimated a MoE > 10,000. The Panel estimated the MoE to exogenous nitrosamines in meat products to be < 10,000 in all age groups at high level exposure. Based on the results of a systematic review, it was not possible to clearly discern nitrosamines produced from the nitrite added at the authorised levels, from those found in the food matrix without addition of external nitrite. In epidemiological studies there was some evidence to link (i) dietary nitrite and gastric cancers and (ii) the combination of nitrite plus nitrate from processed meat and colorectal cancers. There was evidence to link preformed NDMA and colorectal cancers.

Neth, M. R., et al. (2021). “Fatal Sodium Nitrite Poisoning: Key Considerations for Prehospital Providers.” Prehosp Emerg Care 25(6): 844-850.

Sodium nitrite is a powerful oxidizing agent that causes hypotension and limits oxygen transport and delivery in the body through the formation of methemoglobin. Clinical manifestations can include cyanosis, hypoxia, altered consciousness, dysrhythmias, and death. The majority of reports on sodium nitrite poisonings have been the result of unintentional exposures. We report a case of an intentional fatal overdose of sodium nitrite. A 17-year-old female reportedly drank approximately one tablespoon of sodium nitrite in a self-harm attempt. The patient was hypotensive and cyanotic upon EMS arrival. The patient decompensated rapidly into a bradycardic arrest during transport despite intubation, push-dose epinephrine, and intravenous fluid resuscitation. In the Emergency Department (ED), she received methylene blue and packed red cells but could not be resuscitated despite a prolonged effort. EMS professionals should consider sodium nitrite toxicity in patients with a suspected overdose who present with a cyanotic appearance, pulse oximetry that remains around 85% despite oxygen, and dark brown blood seen on venipuncture. Early prehospital contact with the Poison Control Center and ED prenotification in poisoned patients is encouraged.

Paula Neto, H. A., et al. (2017). “Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation.” Front Immunol 8: 1478.

Food additives are compounds used in order to improve food palatability, texture, and shelf life. Despite a significant effort to assure safety of use, toxicological analysis of these substances, generally, rely on their direct toxicity to target organs (liver and kidney) or their genotoxic effects. Much less attention is paid to the effects of these compounds on cells of the immune system. This is of relevance given that metabolic dysregulation and obesity have a strong immune-mediated component. Obese individuals present a state of chronic low-grade inflammation that contributes to the establishment of insulin resistance and other metabolic abnormalities known as the metabolic syndrome. Obesity and metabolic syndrome are currently recognized as worldwide epidemics that pose a profound socioeconomic impact and represent a concern to public health. Cells of the immune system contribute to both the maintenance of “lean homeostasis” and the metabolic dysregulation observed in obese individuals. Although much attention has been drawn in the past decades to obesity and metabolic syndrome as a result of ingesting highly processed food containing large amounts of fat and simple sugars, mounting evidence suggest that food additives may also be important contributors to metabolic derangement. Herein, we review pieces of evidence from the literature showing that food additives have relevant effects on cells of the immune system that could contribute to immune-mediated metabolic dysregulation. Considering their potential to predispose individuals to develop obesity and metabolic syndrome, their use should be taken with caution or maybe revisited.

Safety, C. f. F. (2017). Formaldehyde in Food, The Government of Hong Kong Special Administrative Region

Sambu, S., et al. (2022). “Toxicological and Teratogenic Effect of Various Food Additives: An Updated Review.” Biomed Res Int 2022: 6829409.

Scientific evidence is mounting that synthetic chemicals used as food additives may have harmful impacts on health. Food additives are chemicals that are added to food to keep it from spoiling, as well as to improve its colour and taste. Some are linked to negative health impacts, while others are healthy and can be ingested with little danger. According to several studies, health issues such as asthma, attention deficit hyperactivity disorder (ADHD), heart difficulties, cancer, obesity, and others are caused by harmful additives and preservatives. Some food additives may interfere with hormones and influences growth and development. It is one of the reasons why so many children are overweight. Children are more likely than adults to be exposed to these types of dietary intakes. Several food additives are used by women during pregnancy and breast feeding that are not fully safe. We must take specific precaution to avoid consuming dangerous compounds before they begin to wreak havoc on our health. This study is intended to understand how the preservatives induce different health problem in the body once it is consumed. This review focuses on some specific food additives such as sodium benzoate, aspartame, tartrazine, carrageenan, and potassium benzoate, as well as vitamin A. Long-term use of food treated with the above-mentioned food preservatives resulted in teratogenicity and other allergens, according to the study. Other health issues can be avoided in the future by using natural food additives derived from plants and other natural sources.

Schlatter, J., et al. (1992). “The potential genotoxicity of sorbates: effects on cell cycle in vitro in V79 cells and somatic mutations in Drosophila.” Food Chem Toxicol 30(10): 843-851.

Sodium sorbate, potassium sorbate and an oxidation product of sodium sorbate, 4,5-epoxy-2-hexenoic acid, were tested for their genotoxic potential in cultured V79 Chinese hamster cells and in somatic cells of Drosophila melanogaster (wing spot test, SMART). In Drosophila only the epoxide showed a weak genotoxic effect. In V79 cells, freshly prepared sodium sorbate solutions at the highest concentrations only (2.5 mg/ml, 24 hr exposure) arrested mitosis at the G2/M cell cycle phase and potassium sorbate (2.5 mg/ml) had no effect. This arrest was reversible after a 24-hr recovery interval. Sodium sorbate solutions stored for up to 208 days were cytotoxic at 2.5 mg/ml, induced cell cycle arrest in the G2/M phase and increased cellular protein content, indicating an action similar to spindle poisoning and a chemical stress reaction (adaptation processes, modification of transcription). Potassium sorbate solutions stored for 28 days were also cytotoxic. With 4,5-epoxy-2-hexenoic acid at concentrations up to 0.01 mg/ml no effects were seen. At higher concentrations (at least 0.1 mg/ml) cell killing was observed, which probably resulted from unphysiologically lowered pH in the culture medium. Overall, the results are interpreted as an indication of a weak genotoxic potential of stored sodium sorbate solutions. Thus, sorbic acid and its potassium salt at the concentrations used for food preservation can still be considered as safe for human consumption.

Songur, A., et al. (2010). “The toxic effects of formaldehyde on the nervous system.” Rev Environ Contam Toxicol 203: 105-118.

Formaldehyde (FA) is found in the polluted atmosphere of cities, domestic air (e.g., paint, insulating materials, chipboard and plywood, fabrics, furniture, paper), and cigarette smoke, etc.; therefore, everyone and particularly susceptible children may be exposed to FA. FA is also widely used in industrial and medical settings and as a sterilizing agent, disinfectant, and preservative. Therefore, employees may be highly exposed to it in there settings. Of particular concern to the authors are anatomists and medical students, who can be highly exposed to formaldehyde vapor during dissection sessions. Formaldehyde is toxic over a range of doses; chances of exposure and subsequent harmful effects are increased as (room) temperature increases, because of FA’s volatility. Many studies have been conducted to evaluate the effects of FA during systemic and respiratory exposures in rats. This review compiles that literature and emphasizes the neurotoxic effects of FA on neuronal morphology, behavior, and biochemical parameters. The review includes the results of some of the authors’ work related to FA neurotoxicity, and such neurotoxic effects from FA exposure were experimentally demonstrated. Moreover, the effectiveness of some antioxidants such as melatonin, fish omega-3, and CAPE was observed in the treatment of the harmful effects of FA. Despite the harmful effects from FA exposure, it is commonly used in Turkey and elsewhere in dissection laboratories. Consequently, all anatomists must know and understand the effects of this toxic agent on organisms and the environment, and take precautions to avoid unnecessary exposure. The reviewed studies have indicated that FA has neurotoxic characteristics and systemic toxic effects. It is hypothesized that inhalation of FA, during the early postnatal period, is linked to some neurological diseases that occur in adults. Although complete prevention is impossible for laboratory workers and members of industries utilizing FA, certain precautions can be taken to decrease and/or prevent the toxic effects of FA.

Vally, H. and N. L. Misso (2012). “Adverse reactions to the sulphite additives.” Gastroenterol Hepatol Bed Bench 5(1): 16-23.

Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however exposure may also occur through the use of pharmaceutical products, as well as in occupational settings. Most studies report a prevalence of sulphite sensitivity of 3 to 10% among asthmatic subjects who ingest these additives. However, the severity of these reactions varies, and steroid-dependent asthmatics, those with marked airway hyperresponsiveness, and children with chronic asthma, appear to be at greater risk. Although a number of potential mechanisms have been proposed, the precise mechanisms underlying sulphite sensitivity remain unclear.

Table C. Food Additives. Synthetic and natural antioxidants linked to potential harms

(Baran, Köktürk et al. 2018)
(Nakagawa, Moldéus et al. 1996)
(van der Heijden, Janssen et al. 1986)
(Verhagen, Schilderman et al. 1991)
(Jayalakshmi and Sharma 1986)
(Xu, Liu et al. 2021)
Government Report: https://food.ec.europa.eu/system/files/2020-12/sci-com_scf_reports_25.pdf
(Ritz, Hahn et al. 2012)
(Huang, Ma et al. 2019)
(Wu, Geng et al. 2021)
Thermo Fisher safety data scientific report: https://www.fishersci.com/store/msds?partNumber=AC138750025&countryCode=US&language=en
National library of Medicine: https://pubchem.ncbi.nlm.nih.gov/compound/3_3_-Thiodipropionic-acid
https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2017.4721
(Taylor, Remington et al. 2015)

Baran, A., et al. (2018). “Determination of developmental toxicity of zebrafish exposed to propyl gallate dosed lower than ADI (Acceptable Daily Intake).” Regul Toxicol Pharmacol 94: 16-21.

Propyl gallate (PG) is an antioxidant substance widely used in cosmetics, pharmaceutical and food industries. The aim of this study was to evaluate the potential toxic effect of PG injected to zebrafish embryos. To this end, zebrafish embryos were exposed to PG with 0, 1, 10 and 50 ppm concentrations which are lower than ADI and were monitored at 24, 48, 72 and 96 hpf. Survival rate, hatching rate and malformations were evaluated during this period. Moreover, it has been detected the accumulation of fluorescence signal of ROS and apoptotic cell in whole body at the end of 96 hpf. According to results, survival rate slightly decreased in highest concentration, and PG accelerated hatching in 1 and 10 ppm concentrations whereas delayed in 50 ppm concentration. In addition, it has been detected accumulation of fluorescence signal of ROS and apoptotic cells in a dose dependent-manner. Consequently, it has been considered that increased embryonic or larval malformation in this study may have been caused by ROS-induced apoptosis. The obtained data suggested that the developmental toxicity caused by PG and/or multiple hydroxyl groups arose when PG hydrolyze to gallic acid is probably triggered by the induction of ROS formation and consequent apoptosis.

Huang, C., et al. (2019). “Iron overload resulting from the chronic oral administration of ferric citrate induces parkinsonism phenotypes in middle-aged mice.” Aging (Albany NY) 11(21): 9846-9861.

Iron homeostasis is critical for maintaining normal brain physiological functions, and its mis-regulation can cause neurotoxicity and play a part in the development of many neurodegenerative disorders. The high incidence of iron deficiency makes iron supplementation a trend, and ferric citrate is a commonly used iron supplement. In this study, we found that the chronic oral administration of ferric citrate (2.5 mg/day and 10 mg/day) for 16 weeks selectively induced iron accumulation in the corpus striatum (CPu), substantia nigra (SN) and hippocampus, which typically caused parkinsonism phenotypes in middle-aged mice. Histopathological analysis showed that apoptosis- and oxidative stress-mediated neurodegeneration and dopaminergic neuronal loss occurred in the brain, and behavioral tests showed that defects in the locomotor and cognitive functions of these mice developed. Our research provides a new perspective for ferric citrate as a food additive or in clinical applications and suggests a new potential approach to develop animal models for Parkinson’s disease (PD).

Jayalakshmi, C. P. and J. D. Sharma (1986). “Effect of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on rat erythrocytes.” Environ Res 41(1): 235-238.

The widespread use of antioxidants in the food processing industries, especially oil and oil based ones, has great economic advantages. Yet since the ban on the further usage of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) by the FAO in 1980, there have been several reports indicating that BHA and BHT might have both beneficial and detrimental effects. Studies were performed in healthy mature rats both males and females in a 1:1 ratio. In vitro estimations of the percentage hemolysis (50% hemolysis indicating a 50% toxicity level) showed that BHT is more toxic than BHA and the hemolytic activities (kinetics) showed a peak at 60-65% after 12 min with BHT and at 50% after 20 min with BHA. This clearly indicates that at the concentrations of 0.75%, BHA and BHT are harmful to the blood. Further work of dietary effects on blood is in progress. Thus while BHA and BHT are known to be metabolized in the liver and eliminated through the urine, they might be very detrimental to the circulatory system.

Nakagawa, Y., et al. (1996). “Relationship between mitochondrial dysfunction and toxicity of propyl gallate in isolated rat hepatocytes.” Toxicology 114(2): 135-145.

The relationship between cytotoxicity and mitochondrial dysfunction caused by propyl gallate (PG) has been studied in hepatocytes freshly prepared from fasted rats. Hepatocytes isolated from fasted (18 h) rats were significantly more susceptible to the toxicity of PG than hepatocytes from fed rats. The addition of fructose (15 mM), an alternative carbohydrate source, to hepatocyte suspensions resulted in the prevention of PG (1 mM)-induced cell killing accompanied by decrease in intracellular ATP loss during a 3 h-incubation period. Despite this, fructose did not completely prevent an abrupt loss of intracellular glutathione caused by PG, but effectively inhibited the loss of protein thiol levels. Fructose elicited a concentration (0.5-20mM)-dependent protection against the cytotoxicity of 1.5 mM PG. The incubation of hepatocytes with sodium azide (4 mM), an inhibitor of oxidative phosphorylation, enhanced the toxicity induced by PG (1 mM), but coincubation with fructose delayed the onset of toxicity. Neither azide alone nor fructose plus azide did affect the cell viability during the incubation period. Furthermore, the addition of 2 mM salicylamide, nontoxic to hepatocytes during the incubation period, enhanced PG (1 mM)-induced cytotoxicity and decreased the loss of free PG. These results indicate that the onset of cytotoxicity caused by PG may depend on the intracellular energy status and that mitochondria are critical target for the compound. In addition, the toxicity caused by the inhibition of mitochondrial ATP synthesis is related to the concentration of PG remaining in cell suspensions.

Ritz, E., et al. (2012). “Phosphate additives in food–a health risk.” Dtsch Arztebl Int 109(4): 49-55.

BACKGROUND: Hyperphosphatemia has been identified in the past decade as a strong predictor of mortality in advanced chronic kidney disease (CKD). For example, a study of patients in stage CKD 5 (with an annual mortality of about 20%) revealed that 12% of all deaths in this group were attributable to an elevated serum phosphate concentration. Recently, a high-normal serum phosphate concentration has also been found to be an independent predictor of cardiovascular events and mortality in the general population. Therefore, phosphate additives in food are a matter of concern, and their potential impact on health may well have been underappreciated. METHODS: We reviewed pertinent literature retrieved by a selective search of the PubMed and EU databases (www.zusatzstoffe-online.de, www.codexalimentarius.de), with the search terms “phosphate additives” and “hyperphosphatemia.” RESULTS: There is no need to lower the content of natural phosphate, i.e. organic esters, in food, because this type of phosphate is incompletely absorbed; restricting its intake might even lead to protein malnutrition. On the other hand, inorganic phosphate in food additives is effectively absorbed and can measurably elevate the serum phosphate concentration in patients with advanced CKD. Foods with added phosphate tend to be eaten by persons at the lower end of the socioeconomic scale, who consume more processed and “fast” food. The main pathophysiological effect of phosphate is vascular damage, e.g. endothelial dysfunction and vascular calcification. Aside from the quality of phosphate in the diet (which also requires attention), the quantity of phosphate consumed by patients with advanced renal failure should not exceed 1000 mg per day, according to the guidelines. CONCLUSION: Prospective controlled trials are currently unavailable. In view of the high prevalence of CKD and the potential harm caused by phosphate additives to food, the public should be informed that added phosphate is damaging to health. Furthermore, calls for labeling the content of added phosphate in food are appropriate.

Taylor, S. L., et al. (2015). 18 – Detection and control of soybeans as a food allergen. Handbook of Food Allergen Detection and Control. S. Flanagan, Woodhead Publishing: 341-366.

Soybeans and ingredients derived from soybeans are widely used in foods for a variety of technological and nutritional purposes. Soybeans are also considered as a commonly allergenic food on a worldwide basis. However, recent evidence suggests that the prevalence of soybean allergy in the overall population may actually be rather low and suggests that soybeans might be removed from lists of priority allergenic foods. The potency and severity of soybean allergy also appears to be less than some other allergenic foods such as peanut and milk. The identification of the major soy allergens has proven difficult although the best evidence suggests that the main seed storage proteins, glycinin and conglycinin, are probably the most important soy allergens. Soy-specific immunoassay methods exist to detect soy protein residues in foods and these methods can be used to validate preventive allergen controls in food processing facilities where shared equipment is used for both soybean-based and other foods.

van der Heijden, C. A., et al. (1986). “Toxicology of gallates: a review and evaluation.” Food Chem Toxicol 24(10-11): 1067-1070.

The propyl, octyl and dodecyl esters of gallic acid have been studied extensively in a large number of animal experiments involving oral dosing. Experimental data on general toxicity and studies on reproduction, teratogenicity and mutagenicity are also available. Most of the key toxicity studies, however, date back to the 1950s, do not meet current standards of toxicity testing and do not provide evidence for carcinogenic or mutagenic action of the gallates. Mutagenicity studies with octyl gallate and dodecyl gallate are lacking. The biokinetics of propyl gallate apparently differ from those of octyl and dodecyl gallate, the octyl and dodecyl esters being absorbed and hydrolysed to a lesser degree than the propyl ester. In toxicity studies with propyl gallate, growth retardation, anaemia, kidney and liver changes and hyperplasia of the forestomach were the most prominent effects at dose levels above 10,000 mg/kg feed. At 5000 mg/kg feed, liver enzyme induction was seen. In the available studies with octyl gallate or dodecyl gallate as the test compound, effects were found at 3000 mg/kg feed or higher levels. In studies performed with the various gallates, no effects were observed at a dose level of 1000 mg/kg feed, a level that was adopted as the no-effect level by the FAO/WHO Joint Expert Committee on Food Additives (JECFA) in 1976. This committee established an acceptable daily intake (ADI) for man of 0.2 mg/kg body weight (as a sum of propyl, octyl and dodecyl gallates). A re-evaluation of the toxicity of gallates indicates that a ‘classic’ long-term toxicity study of propyl gallate meeting current standards is required. As yet, the available toxicological evidence indicates that gallates may be used safely as antioxidants.

Verhagen, H., et al. (1991). “Butylated hydroxyanisole in perspective.” Chem Biol Interact 80(2): 109-134.

Butylated hydroxyanisole (BHA) is a synthetic food antioxidant used to prevent oils, fats and shortenings from oxidative deterioration and rancidity. This review depicts the current knowledge on BHA. The physical and chemical characteristics of BHA are summarized and its function as a food antioxidant is made clear. The toxicological characteristics of BHA and its metabolic fate in man and animal are briefly reviewed. Special emphasis is laid on the carcinogenicity of BHA in the forestomach of rodents and to related events in the forestomach and other tissues in experimental animals. At present there is sufficient evidence for carcinogenicity of BHA, but there is hardly any indication that BHA is genotoxic. Therefore risk assessment for this epigenetic carcinogen is based on non-stochastic principles. However, the mechanism underlying the tumorigenicity of BHA is not known. In the last part of this review an attempt is made to unravel the unknown mechanism of carcinogenicity. It is hypothesized that BHA gives rise to tumor formation in rodent forestomach by inducing heritable changes in DNA. Evidence is being provided that reactive oxygen species, in particular hydroxylradicals, may play a crucial role. The key question with respect to risk assessment for BHA is whether or not the underlying mechanism is thresholded, which is important for the choice of the appropriate model to assess the risk, if any, for man and to manage any potential risk.

Wu, W., et al. (2021). “Ammonium Ferric Citrate induced Ferroptosis in Non-Small-Cell Lung Carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity.” Int J Med Sci 18(8): 1899-1909.

The morbidity and mortality rates associated with non-small-cell lung carcinoma (NSCLC) are increasing every year, placing new demands on existing therapies and drugs. Ammonium ferric citrate (AFC) is often used as a food additive for iron supplementation; however, to our knowledge, no studies have investigated whether AFC can induce ferroptosis in NSCLC. In this study, we demonstrated that specific concentrations of AFC effectively inhibit the proliferation and invasion of lung cancer cell lines in vitro using a cell proliferation inhibition test, a transwell assay, and flow cytometry analysis of cell cycle and apoptosis. In addition, AFC significantly induced oxidative stress injury in lung cancer cell lines. A quantitative polymerase chain reaction assay showed that AFC markedly reduced the expression levels of cell growth factors, negative regulators of ferroptosis, and autophagy regulators. Lastly, a protein-protein interaction analysis revealed that glutathione peroxidase 4 (GPX4) exerted its biological role through the regulation of the GSS/GSR complex and downstream GGT family proteins. When the expression of GPX4 changes, its biological activities, such as the glutathione metabolic process, cellular biosynthetic process, cellular response to chemical stimulus, and antioxidant activity, change accordingly, thereby affecting the survival quality and physiological and biochemical activities of cells. Overall, this study verifies that AFC has the biological activity of activating oxidative stress injury in NSCLC cell lines, leading to a decrease in their autophagy and inducing ferroptosis. We also confirmed that the GPX4-GSS/GSR-GGT axis is a crucial target of AFC-induced ferroptosis.

Xu, X., et al. (2021). “Synthetic phenolic antioxidants: Metabolism, hazards and mechanism of action.” Food Chem 353: 129488.

Synthetic phenolic antioxidants can interact with peroxides produced by food. This paper reviews correlation between BHA, BHT and TBHQ metabolism and harms they cause and provides a theoretical basis for rational use of BHA, BHT and TBHQ in food, and also put some attention on the transformation and metabolic products of PG. We introduce BHA, BHT, TBHQ, PG and their possible metabolic pathways, and discuss possible harms and their specific mechanisms responsible. Excessive addition or incorrect use of synthetic phenolic antioxidants results in carcinogenicity, cytotoxicity, oxidative stress induction and endocrine disrupting effects, which warrant attention. BHA carcinogenicity is related to production of metabolites TBHQ and TQ, and cytotoxic effect of BHA is the main cause of apoptosis induction. BHT carcinogenicity depends on DNA damage degree, and tumour promotion is mainly related to production of quinone methylation metabolites. TBHQ carcinogenicity is related to induction of metabolite TQ and enzyme CYP1A1.

Table D. Food Additives. Synthetic and natural thickening agents and emulsifiers linked to potential harms

(Zar, Graeber et al. 2007)
(Pillai, Hothi et al. 2014)
Science direct link: https://www.sciencedirect.com/topics/medicine-and-dentistry/propylene-glycol
European Medicines Agency online article: https://www.ema.europa.eu/en/documents/report/propylene-glycol-used-excipient-report-published-support-questions-answers-propylene-glycol-used_en.pdf
(Fowles, Banton et al. 2013)
(Cawley 2001)
(Harris, Sherman et al. 1951)
(Gould and Scott 2005)
(Juśkiewicz and Zduńczyk 2004)
(Miclotte, De Paepe et al. 2020)
(Naimi, Viennois et al. 2021)
(Partridge, Lloyd et al. 2019)
(Holder, Peters et al. 2019)
(Harris, Sherman et al. 1951)
(Bampidis, Azimonti et al. 2019)https://www.efsa.europa.eu/en/efsajournal/pub/5651
(Bampidis, Azimonti et al. 2019)
https://www.ewg.org/skindeep/ingredients/705225-potassium_sorbate
https://www.webmd.com/vitamins/ai/ingredientmono-1495/malic-acid
(Liu, Zhan et al. 2022)
(Hadrup, Frederiksen et al. 2022)
(Witkowski, Grajeta et al. 2022)

Bampidis, V., et al. (2019). “Safety and efficacy of sorbitan monolaurate as a feed additive for all animal species.” Efsa j 17(3): e05651.

The additive sorbitan monolaurate consists of sorbitol (and its anhydrides) esterified with fatty acids derived from coconut oil. It is intended to be used as a technological additive, functional group: emulsifier, in feedingstuffs for all animal species, at a maximum concentration of 85 mg/kg complete feed. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that sorbitan monolaurate is safe for all animal species at the proposed maximum content of 85 mg/kg complete feed and that the use of sorbitan monolaurate in animal nutrition is not expected to pose a risk for the consumer under the proposed conditions of use. Users are unlikely to be exposed to sorbitan monolaurate via inhalation. Sorbitan monolaurate is irritant to skin and eyes and it is not considered a skin sensitiser. Owing the lack of data, the FEEDAP Panel cannot conclude on the safety of the additive for the environment. Sorbitan monolaurate is authorised for use as a food additive with the function of emulsifier. The technological effect underlying its use as a food additive could reasonably be expected to be seen when used in feed.

Cawley, M. J. (2001). “Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review.” Pharmacotherapy 21(9): 1140-1144.

A 34-year-old woman with a history of renal insufficiency induced by long-term cocaine use was admitted with acute shortness of breath remarkable for submandibular and anterior throat swelling. She required intubation, mechanical ventilation, and sedation. Sedation was administered with daily infusions of intravenous lorazepam 65, 313, and 305 mg for 3 days, respectively. Forty-eight hours into the infusion the patient experienced anion gap metabolic acidosis with hyperlactatemia, hyperosmolality, and increased osmolal gap. Propylene glycol (PG), a component of lorazepam intravenous formulation, was considered the potential source of the metabolic abnormality. The patient received greater than 40 times the acceptable recommended amount of PG over 72 hours. Cessation of lorazepam produced major improvements in lactic acid, serum osmolality, and anion and osmolal gaps. The large PG exposure associated with long-term cocaine-induced renal insufficiency produced a toxic metabolic state. Agents containing PG should be avoided in patients with compromised renal function (creatinine clearance < or = 30 ml/min) induced by cocaine use.

Fowles, J. R., et al. (2013). “A toxicological review of the propylene glycols.” Crit Rev Toxicol 43(4): 363-390.

The toxicological profiles of monopropylene glycol (MPG), dipropylene glycol (DPG), tripropylene glycol (TPG) and polypropylene glycols (PPG; including tetra-rich oligomers) are collectively reviewed, and assessed considering regulatory toxicology endpoints. The review confirms a rich data set for these compounds, covering all of the major toxicological endpoints of interest. The metabolism of these compounds share common pathways, and a consistent profile of toxicity is observed. The common metabolism provides scientific justification for adopting a read-across approach to describing expected hazard potential from data gaps that may exist for specific oligomers. None of the glycols reviewed presented evidence of carcinogenic, mutagenic or reproductive/developmental toxicity potential to humans. The pathologies reported in some animal studies either occurred at doses that exceeded experimental guidelines, or involved mechanisms that are likely irrelevant to human physiology and therefore are not pertinent to the exposures experienced by consumers or workers. At very high chronic doses, MPG causes a transient, slight decrease in hemoglobin in dogs and at somewhat lower doses causes Heinz bodies to form in cats in the absence of any clinical signs of anemia. Some evidence for rare, idiosyncratic skin reactions exists for MPG. However, the larger data set indicates that these compounds have low sensitization potential in animal studies, and therefore are unlikely to represent human allergens. The existing safety evaluations of the FDA, USEPA, NTP and ATSDR for these compounds are consistent and point to the conclusion that the propylene glycols present a very low risk to human health.

Gould, S. and R. C. Scott (2005). “2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD): a toxicology review.” Food Chem Toxicol 43(10): 1451-1459.

2-Hydroxylpropyl-beta-cyclodextrin (HP-beta-CD) is an alternative to alpha-, beta- and gamma-cyclodextrin, with improved water solubility and may be more toxicologically benign. This paper reviews the toxicity of HP-beta-CD, using both literature information and novel data, and presents new information. In addition, it includes a brief review from studies of the metabolism and pharmacokinetics of HP-beta-CD in both humans and animals. This review concludes that HP-beta-CD is well tolerated in the animal species tested (rats, mice and dogs), particularly when dosed orally, and shows only limited toxicity. In short duration studies, there were slight biochemical changes whereas studies of a longer duration, up to three months, produced additional minor haematological changes but no histopathological changes. When dosed intravenously, histopathological changes were seen in the lungs, liver and kidney but all findings were reversible and no effect levels were achieved. The carcinogenicity studies showed an increase in tumours in rats in the pancreas and intestines which are both considered to be rat-specific. There were also non-carcinogenic changes noted in the urinary tract, but these changes were also reversible and did not impair renal function. There were no effects on embryo-foetal development in either rats or rabbits. HP-beta-CD has been shown to be well tolerated in humans, with the main adverse event being diarrhoea and there have been no adverse events on kidney function, documented to date.

Hadrup, N., et al. (2022). “Asthma-inducing potential of 28 substances in spray cleaning products-Assessed by quantitative structure activity relationship (QSAR) testing and literature review.” J Appl Toxicol 42(1): 130-153.

Exposure to spray cleaning products constitutes a potential risk for asthma induction. We set out to review whether substances in such products are potential inducers of asthma. We identified 101 spray cleaning products for professional use. Twenty-eight of their chemical substances were selected. We based the selection on (a) positive prediction for respiratory sensitisation in humans based on quantitative structure activity relationship (QSAR) in the Danish (Q)SAR Database, (b) positive QSAR prediction for severe skin irritation in rabbits and (c) knowledge on the substances’ physico-chemical characteristics and toxicity. Combining the findings in the literature and QSAR predictions, we could group substances into four classes: (1) some indication in humans for asthma induction: chloramine, benzalkonium chloride; (2) some indication in animals for asthma induction: ethylenediaminetetraacetic acid (EDTA), citric acid; (3) equivocal data: hypochlorite; (4) few or lacking data: nitriloacetic acid, monoethanolamine, 2-(2-aminoethoxy)ethanol, 2-diethylaminoethanol, alkyldimethylamin oxide, 1-aminopropan-2-ol, methylisothiazolinone, benzisothiazolinone and chlormethylisothiazolinone; three specific sulphonates and sulfamic acid, salicylic acid and its analogue sodium benzoate, propane-1,2-diol, glycerol, propylidynetrimethanol, lactic acid, disodium malate, morpholine, bronopol and benzyl alcohol. In conclusion, we identified an asthma induction potential for some of the substances. In addition, we identified major knowledge gaps for most substances. Thus, more data are needed to feed into a strategy of safe-by-design, where substances with potential for induction of asthma are avoided in future (spray) cleaning products. Moreover, we suggest that QSAR predictions can serve to prioritise substances that need further testing in various areas of toxicology.

Harris, R. S., et al. (1951). “Nutritional and pathological effects of sorbitan monolaurate, polyoxyethylene sorbitan monolaurate, polyoxyethylene monolaurate, and polyoxyethylene monostearate when fed to rats.” Archives of Biochemistry and Biophysics 34(2): 249-258.

Holder, M. K., et al. (2019). “Dietary emulsifiers consumption alters anxiety-like and social-related behaviors in mice in a sex-dependent manner.” Scientific Reports 9(1): 172.

Dietary emulsifiers carboxylmethylcellulose (CMC) and polysorbate 80 (P80) alter the composition of the intestinal microbiota and induce chronic low-grade inflammation, ultimately leading to metabolic dysregulations in mice. As both gut microbiota and intestinal health can influence social and anxiety-like behaviors, we investigated whether emulsifier consumption would detrimentally influence behavior. We confirmed that emulsifier exposure induced chronic intestinal inflammation, increased adiposity, and altered gut microbiota composition in both male and female mice, although the specific microboal taxa altered following emulsifier consumption occurred in a sex-dependent manner. Importantly, emulsifier treatment altered anxiety-like behaviors in males and reduced social behavior in females. It also changed expression of neuropeptides implicated in the modulation of feeding as well as social and anxiety-related behaviors. Multivariate analyses revealed that CMC and P80 produced distinct clustering of physiological, neural, and behavioral effects in male and female mice, suggesting that emulsifier treatment leads to a syndrome of sex-dependent changes in microbiota, physiology, and behavior. This study reveals that these commonly used food additives may potentially negatively impact anxiety-related and social behaviors and may do so via different mechanisms in males and females.

Juśkiewicz, J. and Z. Zduńczyk (2004). “Effects of cellulose, carboxymethylcellulose and inulin fed to rats as single supplements or in combinations on their caecal parameters.” Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 139(4): 513-519.

We compared the effect of diets containing different nondigestible carbohydrates: cellulose (C), inulin (IN) and carboxymethylcellulose (CMC) as single supplements or in dietary combination on caecal physiology of rats. Sixty male Wistar rats (Rattus norvegicus) were divided into five groups and for 4 weeks were fed a casein diet with the compared carbohydrates (4% of diet) or a combination of IN+C or IN+CMC (both 4+4%). Diet intake and FCR index remained unaffected by the treatments, whereas IN improved the body weight gain of rats compared to CMC. Compared to C group, all diets containing IN and CMC decreased the caecal pH as well as enlarged the caecum, thus increasing the weights of contents and tissue, especially upon CMC treatment. Rats given carboxymethylcellulose (CMC and IN+CMC groups) had watery caecal digesta, and some of them suffered from diarrhoea. In the case of CMC, the caecal enlargement was due to tissue hypertrophy and digesta accumulation mostly in response to an increased bulk of contents. Unlike C+IN, the dietary combination of CMC- and inulin-enhanced fermentation in the caecum of rats, however the proportion of acetate, propionate and butyrate was less beneficial. Compared to CMC, inulin gave a higher concentration of SCFA, especially of butyrate and propionate. The action of inulin in the caecum of rats could be pronounced by dietary treatment combined with CMC.

Liu, C., et al. (2022). “Food Additives Associated with Gut Microbiota Alterations in Inflammatory Bowel Disease: Friends or Enemies?” Nutrients 14(15).

During the 21st century, the incidence and prevalence of inflammatory bowel disease (IBD) is rising globally. Despite the pathogenesis of IBD remaining largely unclear, the interactions between environmental exposure, host genetics and immune response contribute to the occurrence and development of this disease. Growing evidence implicates that food additives might be closely related to IBD, but the involved molecular mechanisms are still poorly understood. Food additives may be categorized as distinct types in accordance with their function and property, including artificial sweeteners, preservatives, food colorant, emulsifiers, stabilizers, thickeners and so on. Various kinds of food additives play a role in modifying the interaction between gut microbiota and intestinal inflammation. Therefore, this review comprehensively synthesizes the current evidence on the interplay between different food additives and gut microbiome alterations, and further elucidates the potential mechanisms of food additives-associated microbiota changes involved in IBD.

Miclotte, L., et al. (2020). “Dietary Emulsifiers Alter Composition and Activity of the Human Gut Microbiota in vitro, Irrespective of Chemical or Natural Emulsifier Origin.” Frontiers in Microbiology 11.

The use of additives in food products has become an important public health concern. In recent reports, dietary emulsifiers have been shown to affect the gut microbiota, contributing to a pro-inflammatory phenotype and metabolic syndrome. So far, it is not yet known whether similar microbiome shifts are observable for a more diverse set of emulsifier types and to what extent these effects vary with the unique features of an individual’s microbiome. To bridge this gap, we investigated the effect of five dietary emulsifiers on the fecal microbiota from 10 human individuals upon a 48 h exposure. Community structure was assessed with quantitative microbial profiling, functionality was evaluated by measuring fermentation metabolites, and pro-inflammatory properties were assessed with the phylogenetic prediction algorithm PICRUSt, together with a TLR5 reporter cell assay for flagellin. A comparison was made between two mainstream chemical emulsifiers (carboxymethylcellulose and P80), a natural extract (soy lecithin), and biotechnological emulsifiers (sophorolipids and rhamnolipids). While fecal microbiota responded in a donor-dependent manner to the different emulsifiers, profound differences between emulsifiers were observed. Rhamnolipids, sophorolipids, and soy lecithin eliminated 91 ± 0, 89 ± 1, and 87 ± 1% of the viable bacterial population after 48 h, yet they all selectively increased the proportional abundance of putative pathogens. Moreover, profound shifts in butyrate (−96 ± 6, −73 ± 24, and −34 ± 25%) and propionate (+13 ± 24, +88 ± 50, and +29 ± 16%) production were observed for these emulsifiers. Phylogenetic prediction indicated higher motility, which was, however, not confirmed by increased flagellin levels using the TLR5 reporter cell assay. We conclude that dietary emulsifiers can severely impact the gut microbiota, and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin. As biotechnological emulsifiers were especially more impactful than chemical emulsifiers, caution is warranted when considering them as more natural alternatives for clean label strategies.

Naimi, S., et al. (2021). “Direct impact of commonly used dietary emulsifiers on human gut microbiota.” Microbiome 9(1): 66.

Epidemiologic evidence and animal studies implicate dietary emulsifiers in contributing to the increased prevalence of diseases associated with intestinal inflammation, including inflammatory bowel diseases and metabolic syndrome. Two synthetic emulsifiers in particular, carboxymethylcellulose and polysorbate 80, profoundly impact intestinal microbiota in a manner that promotes gut inflammation and associated disease states. In contrast, the extent to which other food additives with emulsifying properties might impact intestinal microbiota composition and function is not yet known.

Partridge, D., et al. (2019). “Food additives: Assessing the impact of exposure to permitted emulsifiers on bowel and metabolic health – introducing the FADiets study.” Nutr Bull 44(4): 329-349.

Emulsifiers are common components of processed foods consumed as part of a Western diet. Emerging in vitro cell-line culture, mouse model and human intestinal tissue explant studies have all suggested that very low concentrations of the food emulsifier polysorbate 80 may cause bacterial translocation across the intestinal epithelium, intestinal inflammation and metabolic syndrome. This raises the possibility that dietary emulsifiers might be factors in conditions such as coronary artery disease, type 2 diabetes and Crohn’s disease. The potential mechanism behind the observed effects of this emulsifier is uncertain but may be mediated via changes in the gut microbiota or by increased bacterial translocation, or both. It is also unknown whether these effects are generalisable across all emulsifiers and detergents, including perhaps the natural emulsifier lecithin or even conjugated bile acids, particularly if the latter escape reabsorption and pass through to the distal ileum or colon. A major objective of the Medical Research Council (MRC)-funded Mechanistic Nutrition in Health (MECNUT) Emulsifier project is therefore to investigate the underlying mechanisms and effects of a range of synthetic and natural emulsifiers and detergents in vitro and in vivo, and to determine the effects of a commonly consumed emulsifier (soya lecithin) on gut and metabolic health through a controlled dietary intervention study in healthy human volunteers – the FADiets study. This report provides an overview of the relevant literature, discussing the impact of emulsifiers and other additives on intestinal and metabolic health, and gives an overview of the studies being undertaken as part of the MECNUT Emulsifier project.

Pillai, U., et al. (2014). “Severe propylene glycol toxicity secondary to use of anti-epileptics.” Am J Ther 21(4): e106-109.

Propylene glycol toxicity presenting as high anion gap metabolic acidosis and osmolar gap has been extensively reported in literature, and most of them are secondary to intravenous lorazepam infusion. However, propylene glycol is used as a solvent in a number of medications that are frequently utilized in critical care setting, and hence one should be aware that the toxicity is possible from a variety of medication. Phenobarbital and phenytoin are one of those, and we hereby report a novel case of propylene glycol toxicity secondary to phenobarbital and phenytoin infusion in a patient with refractory status epilepticus. Furthermore, our patient had end-stage renal disease, which we think could have been an important precipitating factor for the toxicity. Because most of the symptoms from propylene glycol toxicity can mimic sepsis-which is very common in critical care unit patients-this life threatening scenario could be easily missed. Regular monitoring of osmolar gap is an easily available intervention in the at risk patients.

Witkowski, M., et al. (2022). “Hypersensitivity Reactions to Food Additives-Preservatives, Antioxidants, Flavor Enhancers.” Int J Environ Res Public Health 19(18).

There have been reports of food hypersensitivity reactions to food additives (HFA) for many years. The mechanisms of HFA and their frequency are difficult to precisely define, as most of the data come from outdated studies with poor methodology. In 2020, the European Food Safety Authority completed a review of additives, examining their influence on the occurrence of HFA, but did not include all of them. The aim of this review is to systematise knowledge about selected groups of food additives (FAs) and the HFA induced by them. We also briefly discuss the issues of diagnosis and therapy in this disease. FAs are commonly used in prosscessed foods, but HFA appears to be a rare phenomenon. Identification of the FA responsible for hypersensitivity and its treatment is difficult. Diagnosis is a challenge for the clinician and for the patient. A food diary is a helpful diagnostic tool. It allows diet therapy to be monitored based on the partial or complete elimination of products containing a harmful additive. An elimination diet must not be deficient, and symptomatic pharmacotherapy may be necessary if its application is ineffective. Taking all this into account, we conclude that it is necessary to conduct randomised multicentre studies based on the double-blind placebo control protocol in this field.

Zar, T., et al. (2007). “Recognition, treatment, and prevention of propylene glycol toxicity.” Semin Dial 20(3): 217-219.

Propylene glycol is a commonly used solvent for oral, intravenous, and topical pharmaceutical preparations. Although it is considered safe, large intravenous doses given over a short period of time can be toxic. Underlying renal insufficiency and hepatic dysfunction raise risk for toxicity. Toxic effects include hyperosmolality, increased anion gap metabolic acidosis (due to lactic acidosis), acute kidney injury, and sepsis-like syndrome. Treatment of toxicity includes hemodialysis to effectively remove propylene glycol. Prevention is best achieved by limiting the dose of propylene glycol infused.

Table E. Food Additives. Synthetic sweeteners and natural flavor enhancers linked to potential harms

(Kallscheuer 2018)
(Baines and Brown 2016) – Science Direct: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/guanosine-monophosphate
(Kurihara 2015)
(Gregson and Simmonds 1971)
(Maiuolo, Oppedisano et al. 2016)
(Mahbub, Yamaguchi et al. 2017)
(1999)(1999). “Cyclamates.” IARC Monogr Eval Carcinog Risks Hum 73: 195-222.

Baines, D. and M. Brown (2016). Flavor Enhancers: Characteristics and Uses. Encyclopedia of Food and Health. B. Caballero, P. M. Finglas and F. Toldrá. Oxford, Academic Press: 716-723.

Flavor enhancers amplify and intensify the flavor impact of other flavor compounds in the mouth. The most commonly used flavor enhancers are the sodium salt of glutamic acid, monosodium glutamate (MSG), and the nucleotides disodium-5′-inosinate and disodium-5′-guanylate. Due to their higher flavor potency and synergistic behavior, nucleotides have increasingly been replacing MSG in foods. Flavor enhancers are present naturally in a wide range of foods, especially meat, fish, mushrooms, and cheese. Nucleotides in the diet have been associated with a number of health benefits, especially in infants.

Gregson, R. A. and M. B. Simmonds (1971). “Qualitative gustatory characteristics of disodium-5′-guanylate.” Br J Psychol 62(1): 81-88.

Kallscheuer, N. (2018). “Engineered Microorganisms for the Production of Food Additives Approved by the European Union-A Systematic Analysis.” Front Microbiol 9: 1746.

In the 1950s, the idea of a single harmonized list of food additives for the European Union arose. Already in 1962, the E-classification system, a robust food safety system intended to protect consumers from possible food-related risks, was introduced. Initially, it was restricted to colorants, but at later stages also preservatives, antioxidants, emulsifiers, stabilizers, thickeners, gelling agents, sweeteners, and flavorings were included. Currently, the list of substances authorized by the European Food Safety Authority (EFSA) (referred to as “E numbers”) comprises 316 natural or artificial substances including small organic molecules, metals, salts, but also more complex compounds such as plant extracts and polymers. Low overall concentrations of such compounds in natural producers due to inherent regulation mechanisms or production processes based on non-regenerative carbon sources led to an increasing interest in establishing more reliable and sustainable production platforms. In this context, microorganisms have received significant attention as alternative sources providing access to these compounds. Scientific advancements in the fields of molecular biology and genetic engineering opened the door toward using engineered microorganisms for overproduction of metabolites of their carbon metabolism such as carboxylic acids and amino acids. In addition, entire pathways, e.g., of plant origin, were functionally introduced into microorganisms, which holds the promise to get access to an even broader range of accessible products. The aim of this review article is to give a systematic overview on current efforts during construction and application of microbial cell factories for the production of food additives listed in the EU “E numbers” catalog. The review is focused on metabolic engineering strategies of industrially relevant production hosts also discussing current bottlenecks in the underlying metabolic pathways and how they can be addressed in the future.

Kurihara, K. (2015). “Umami the Fifth Basic Taste: History of Studies on Receptor Mechanisms and Role as a Food Flavor.” Biomed Res Int 2015: 189402.

Three umami substances (glutamate, 5′-inosinate, and 5′-guanylate) were found by Japanese scientists, but umami has not been recognized in Europe and America for a long time. In the late 1900s, umami was internationally recognized as the fifth basic taste based on psychophysical, electrophysiological, and biochemical studies. Three umami receptors (T1R1 + T1R3, mGluR4, and mGluR1) were identified. There is a synergism between glutamate and the 5′-nucleotides. Among the above receptors, only T1R1 + T1R3 receptor exhibits the synergism. In rats, the response to a mixture of glutamate and 5′-inosinate is about 1.7 times larger than that to glutamate alone. In human, the response to the mixture is about 8 times larger than that to glutamate alone. Since glutamate and 5′-inosinate are contained in various foods, we taste umami induced by the synergism in daily eating. Hence umami taste induced by the synergism is a main umami taste in human.

Mahbub, M. H., et al. (2017). “Alteration in plasma free amino acid levels and its association with gout.” Environ Health Prev Med 22(1): 7.

BACKGROUND: Studies on the association of plasma-free amino acids with gout are very limited and produced conflicting results. Therefore, we sought to explore and characterize the plasma-free amino acid (PFAA) profile in patients with gout and evaluate its association with the latter. METHODS: Data from a total of 819 subjects (including 34 patients with gout) undergoing an annual health examination program in Shimane, Japan were considered for this study. Venous blood samples were collected from the subjects and concentrations of 19 plasma amino acids were determined by high-performance liquid chromatography-electrospray ionization-mass spectrometry. Student’s t-test was applied for comparison of variables between patient and control groups. The relationships between the presence or absence of gout and individual amino acids were investigated by logistic regression analysis controlling for the effects of potential demographic confounders. RESULTS: Among 19 amino acids, the levels of 10 amino acids (alanine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, tryptophan, valine) differed significantly (P < .001 to .05) between the patient and control groups. Univariate logistic regression analysis revealed that plasma levels of alanine, isoleucine, leucine, phenylalanine, tryptophan and valine had significant positive associations (P < .005 to .05) whereas glycine and serine had significant inverse association (P < .05) with gout. CONCLUSIONS: The observed significant changes in PFAA profiles may have important implications for improving our understanding of pathophysiology, diagnosis and prevention of gout. The findings of this study need further confirmation in future large-scale studies involving a larger number of patients with gout.

Maiuolo, J., et al. (2016). “Regulation of uric acid metabolism and excretion.” Int J Cardiol 213: 8-14.

Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which also contribute to modulate energy metabolism and signal transduction, are structural components of some coenzymes and have been shown to play important roles in the physiology of platelets, muscles and neurotransmission. All cells require a balanced quantity of purines for growth, proliferation and survival. Under physiological conditions the enzymes involved in the purine metabolism maintain in the cell a balanced ratio between their synthesis and degradation. In humans the final compound of purines catabolism is uric acid. All other mammals possess the enzyme uricase that converts uric acid to allantoin that is easily eliminated through urine. Overproduction of uric acid, generated from the metabolism of purines, has been proven to play emerging roles in human disease. In fact the increase of serum uric acid is inversely associated with disease severity and especially with cardiovascular disease states. This review describes the enzymatic pathways involved in the degradation of purines, getting into their structure and biochemistry until the uric acid formation.

Table F. Food Additives. Criteria to escape Tier III – Criterion: Trans fats

(Pipoyan, Stepanyan et al. 2021)
(Wallis, Bengtsson et al. 2022)
(Micha and Mozaffarian 2008)
(Micha and Mozaffarian 2008)
(Amico, Wootan et al. 2021)
(Hyseni, Bromley et al. 2017)
(Vinikoor, Millikan et al. 2010)
(de Souza, Mente et al. 2015)
(Oteng, Loregger et al. 2019)
(Oteng and Kersten 2020)

Amico, A., et al. (2021). “The Demise of Artificial Trans Fat: A History of a Public Health Achievement.” Milbank Q 99(3): 746-770.

Policy Points This article describes a strategic combination of research, advocacy, corporate campaigns, communications, grassroots mobilization, legislation, regulatory actions, and litigation against companies and government to secure a national policy to remove artificial trans fat from the US food system. Sharing lessons we learned can help inform policymakers, academics, policy practitioners, and students across disciplines. Some of our lessons are that system change means that all consumers benefit without the need for individual behavior change; research can both identify opportunities to improve health and support policy adoption; policy efforts can serve as public education campaigns; policy campaigns can drive marketplace changes; and engaging forward-thinking companies can diffuse opposition to passing a policy. CONTEXT: For many decades, partially hydrogenated vegetable oil (PHO), the primary source of artificial trans fat in the American diet, was used widely in processed and restaurant foods. In the early 1990s, studies linked the consumption of artificial trans fat with heart disease. This article details how research and advocacy led to eliminating artificial trans fat from the US food supply. METHODS: We synthesized published studies of the health impact of trans fat, the legislative history of state and local trans fat bills, the Food and Drug Administration’s (FDA) regulatory docket on trans fat labeling and its declaration that PHOs are no longer Generally Recognized as Safe (GRAS), and our own files, which included strategy documents, notes from meetings with the FDA staff, correspondence between advocates and the FDA, fact sheets, press releases, news clips, and other materials. FINDINGS: This history of trans fat provides insights into policy strategy and advocacy best practices that resulted in the removal of trans fat from food in the United States, preventing an estimated 50,000 premature deaths a year. The lessons we learned are that system change benefits all consumers without the need for individual behavior change; research can both identify opportunities to improve health through policy and support policy adoption; policy campaigns can serve as public education campaigns; policy can drive changes to products and the marketplace; and engaging forward-thinking companies can help diffuse opposition to passing a policy. Securing this policy required the persistence of scientists and health advocates in first discovering the risks and then using the science to secure policies to mitigate the identified harm. CONCLUSIONS: An understanding of the tactics used to help attain the targeted policies and how challenges were addressed (such as through communications, leveraging an expanding research base and expert reports, showing that a national policy was feasible through voluntary corporate changes and state and local policy, and litigation against companies and government agencies) may provide a model for scientists, students, advocates, and policymakers. We hope this account will inform efforts to address other public health challenges, such as the current threats of excessive exposure to sodium and added sugars, which persist in the US food system.

de Souza, R. J., et al. (2015). “Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies.” Bmj 351: h3978.

OBJECTIVE: To systematically review associations between intake of saturated fat and trans unsaturated fat and all cause mortality, cardiovascular disease (CVD) and associated mortality, coronary heart disease (CHD) and associated mortality, ischemic stroke, and type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Central Registry of Controlled Trials, Evidence-Based Medicine Reviews, and CINAHL from inception to 1 May 2015, supplemented by bibliographies of retrieved articles and previous reviews. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Observational studies reporting associations of saturated fat and/or trans unsaturated fat (total, industrially manufactured, or from ruminant animals) with all cause mortality, CHD/CVD mortality, total CHD, ischemic stroke, or type 2 diabetes. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed study risks of bias. Multivariable relative risks were pooled. Heterogeneity was assessed and quantified. Potential publication bias was assessed and subgroup analyses were undertaken. The GRADE approach was used to evaluate quality of evidence and certainty of conclusions. RESULTS: For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90,501-339,090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12,942-230,135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was “very low.” The certainty of associations of trans fat with CHD outcomes was “moderate” and “very low” to “low” for other associations. CONCLUSIONS: Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.

Hyseni, L., et al. (2017). “Systematic review of dietary trans-fat reduction interventions.” Bull World Health Organ 95(12): 821-830g.

OBJECTIVE: To systematically review published studies of interventions to reduce people’s intake of dietary trans-fatty acids (TFAs). METHODS: We searched online databases (CINAHL, the CRD Wider Public Health database, Cochrane Database of Systematic Reviews, Ovid®, MEDLINE®, Science Citation Index and Scopus) for studies evaluating TFA interventions between 1986 and 2017. Absolute decrease in TFA consumption (g/day) was the main outcome measure. We excluded studies reporting only on the TFA content in food products without a link to intake. We included trials, observational studies, meta-analyses and modelling studies. We conducted a narrative synthesis to interpret the data, grouping studies on a continuum ranging from interventions targeting individuals to population-wide, structural changes. RESULTS: After screening 1084 candidate papers, we included 23 papers: 12 empirical and 11 modelling studies. Multiple interventions in Denmark achieved a reduction in TFA consumption from 4.5 g/day in 1976 to 1.5 g/day in 1995 and then virtual elimination after legislation banning TFAs in manufactured food in 2004. Elsewhere, regulations mandating reformulation of food reduced TFA content by about 2.4 g/day. Worksite interventions achieved reductions averaging 1.2 g/day. Food labelling and individual dietary counselling both showed reductions of around 0.8 g/day. CONCLUSION: Multicomponent interventions including legislation to eliminate TFAs from food products were the most effective strategy. Reformulation of food products and other multicomponent interventions also achieved useful reductions in TFA intake. By contrast, interventions targeted at individuals consistently achieved smaller reductions. Future prevention strategies should consider this effectiveness hierarchy to achieve the largest reductions in TFA consumption.

Micha, R. and D. Mozaffarian (2008). “Trans fatty acids: effects on cardiometabolic health and implications for policy.” Prostaglandins Leukot Essent Fatty Acids 79(3-5): 147-152.

In both developed and developing countries, trans fatty acids (TFA) are largely consumed from partially hydrogenated vegetable oils. This article focuses on TFA as a modifiable dietary risk factor for cardiovascular disease, reviewing the evidence for lipid and non-lipid effects; the relations of trans fat intake with clinical endpoints; and current policy and legislative issues. In both observational cohort studies and randomized clinical trials, TFA adversely affect lipid profiles (including raising LDL and triglyceride levels, and reducing HDL levels), systemic inflammation, and endothelial function. More limited but growing evidence suggests that TFA also exacerbate visceral adiposity and insulin resistance. These potent effects of TFA on a multitude of cardiovascular risk factors are consistent with the strong associations seen in prospective cohort studies between TFA consumption and risk of myocardial infarction and coronary heart disease (CHD) death. The documented harmful effects of TFA along with the feasibility of substituting partially hydrogenated vegetable oils with healthy alternatives indicate little reason for continued presence of industrially produced TFA in food preparation and manufacturing or in home cooking fats/oils. A comprehensive strategy to eliminate the use of industrial TFA in both developed and developing countries, including education, food labeling, and policy and legislative initiatives, would likely prevent tens of thousands of CHD events worldwide each year.

Oteng, A. B. and S. Kersten (2020). “Mechanisms of Action of trans Fatty Acids.” Adv Nutr 11(3): 697-708.

Human studies have established a positive association between the intake of industrial trans fatty acids and the development of cardiovascular diseases, leading several countries to enact laws that restrict the presence of industrial trans fatty acids in food products. However, trans fatty acids cannot be completely eliminated from the human diet since they are also naturally present in meat and dairy products of ruminant animals. Moreover, bans on industrial trans fatty acids have not yet been instituted in all countries. The epidemiological evidence against trans fatty acids by far overshadows mechanistic insights that may explain how trans fatty acids achieve their damaging effects. This review focuses on the mechanisms that underlie the deleterious effects of trans fatty acids by juxtaposing effects of trans fatty acids against those of cis-unsaturated fatty acids and saturated fatty acids (SFAs). This review also carefully explores the argument that ruminant trans fatty acids have differential effects from industrial trans fatty acids. Overall, in vivo and in vitro studies demonstrate that industrial trans fatty acids promote inflammation and endoplasmic reticulum (ER) stress, although to a lesser degree than SFAs, whereas cis-unsaturated fatty acids are protective against ER stress and inflammation. Additionally, industrial trans fatty acids promote fat storage in the liver at the expense of adipose tissue compared with cis-unsaturated fatty acids and SFAs. In cultured hepatocytes and adipocytes, industrial trans fatty acids, but not cis-unsaturated fatty acids or SFAs, stimulate the cholesterol synthesis pathway by activating sterol regulatory element binding protein (SREBP) 2-mediated gene regulation. Interestingly, although industrial and ruminant trans fatty acids show similar effects on human plasma lipoproteins, in preclinical models, only industrial trans fatty acids promote inflammation, ER stress, and cholesterol synthesis. Overall, clearer insight into the molecular mechanisms of action of trans fatty acids may create new therapeutic windows for the treatment of diseases characterized by disrupted lipid metabolism.

Oteng, A. B., et al. (2019). “Industrial Trans Fatty Acids Stimulate SREBP2-Mediated Cholesterogenesis and Promote Non-Alcoholic Fatty Liver Disease.” Mol Nutr Food Res 63(19): e1900385.

SCOPE: The mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non-alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids. METHODS AND RESULTS: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated, or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element-binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage-activating protein (SCAP), yet independent of liver-X receptor and ubiquitin regulatory X domain-containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. CONCLUSION: Elaidate induces cholesterogenesis in vitro by activating the SCAP-SREBP2 axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

Pipoyan, D., et al. (2021). “The Effect of Trans Fatty Acids on Human Health: Regulation and Consumption Patterns.” Foods 10(10).

Health effects of trans fatty acids (TFAs) on human organisms can vary according to their type, structure, composition, and origin. Even though the adverse health effects of industrial TFAs (iTFAs) have been widely discussed, the health effects of natural TFAs (nTFAs) are still questionable. Hence, it is important to review the literature and provide an overall picture on the health effects of different TFAs coming from industrial and ruminant sources, underlining those types that have adverse health effects as well as suggesting methods for reducing their harmful effects. Multiple databases (PubMed, Medline, Cochrane Library, etc.) were searched with the key words “trans fatty acid sources”, “ruminant”, “industrial”, “conjugated trans linoleic acid”, “human”, “coronary heart disease”, “cancer”, etc. Reference lists of the studies were scanned discussing the health effects of iTFAs and nTFAs. The review of the literature showed that iTFAs are found to be more harmful than ruminant-produced nTFAs. Although several beneficial effects (such as reduced risk of diabetes) for nTFAs have been observed, they should be used with caution. Since during labeling it is usually not mentioned whether the TFAs contained in food are of industrial or natural origin, the general suggestion is to reduce their consumption.

Vinikoor, L. C., et al. (2010). “trans-Fatty acid consumption and its association with distal colorectal cancer in the North Carolina Colon Cancer Study II.” Cancer Causes Control 21(1): 171-180.

Recently, the potential health effects of trans-fatty acid consumption have raised concerns. A few studies have examined the risk of colorectal cancer with increasing consumption of trans-fatty acids, but none investigated the risk of rectal cancer, which may have different risk factors than colon cancer. Our objective was to explore the relationship between trans-fatty acid consumption and distal colorectal (sigmoid, rectosigmoid, and rectal) cancer using a case-control study of Whites (n = 1,516) and African Americans (n = 392) in North Carolina from 2001 to 2006. Matched cases and controls were interviewed about demographic information, lifestyle factors, and diet. White cases reported higher mean consumption of trans-fatty acid than White controls, but mean consumption was similar for African American cases and controls. Relative to the lowest quartile, the highest quartiles of energy-adjusted trans-fatty acid consumption were positively associated with distal colorectal cancer for Whites [adjusted ORs for the third and fourth quartiles are 1.54 (95%CI: 1.12, 2.13) and 1.45 (95%CI: 1.04, 2.03), respectively]. Consumption was not associated with distal colorectal cancer in African Americans [adjusted ORs for the third and fourth quartiles are 0.98 (95%CI: 0.47, 2.05) and 0.87 (95%CI 0.42, 1.81), respectively]. In conclusion, high consumption of trans-fatty acids was positively associated with distal colorectal cancer among Whites.

Wallis, J. G., et al. (2022). “Molecular Approaches Reduce Saturates and Eliminate trans Fats in Food Oils.” Front Plant Sci 13: 908608.

Vegetable oils composed of triacylglycerols (TAG) are a major source of calories in human diets. However, the fatty acid compositions of these oils are not ideal for human nutrition and the needs of the food industry. Saturated fatty acids contribute to health problems, while polyunsaturated fatty acids (PUFA) can become rancid upon storage or processing. In this review, we first summarize the pathways of fatty acid metabolism and TAG synthesis and detail the problems with the oil compositions of major crops. Then we describe how transgenic expression of desaturases and downregulation of the plastid FatB thioesterase have provided the means to lower oil saturates. The traditional solution to PUFA rancidity uses industrial chemistry to reduce PUFA content by partial hydrogenation, but this results in the production of trans fats that are even more unhealthy than saturated fats. We detail the discoveries in the biochemistry and molecular genetics of oil synthesis that provided the knowledge and tools to lower oil PUFA content by blocking their synthesis during seed development. Finally, we describe the successes in breeding and biotechnology that are giving us new, high-oleic, low PUFA varieties of soybean, canola and other oilseed crops.

Table F – Food Additives. Criteria to escape Tier III – No synthetic emulsifiers in fermented milk products

No additives with health risks – please see Word documents titled Supplementary Tables 1-5

(Chassaing, Compher et al. 2022)
(Partridge, Lloyd et al. 2019)
(Rousta, Oka et al. 2021)
(Chassaing, Koren et al. 2015)
(Chassaing, Van de Wiele et al. 2017)
(Bancil, Sandall et al. 2021)
(Laster, Bonnes et al. 2019)
(Cox, Sandall et al. 2021)
(Halmos, Mack et al. 2019)
(Roberts, Rushworth et al. 2013)

References

Bancil, A. S., et al. (2021). “Food Additive Emulsifiers and Their Impact on Gut Microbiome, Permeability, and Inflammation: Mechanistic Insights in Inflammatory Bowel Disease.” J Crohns Colitis 15(6): 1068-1079.

The global burden of inflammatory bowel disease [IBD] has increased over the 21st century. Despite multiple studies investigating the pathogenesis of IBD, the causative mechanisms pertaining to its increased prevalence remain unclear. There is growing evidence that aspects of a ‘Western diet’ increase the risk of developing IBD. More recently, evidence implicating dietary emulsifiers has accumulated, with ecological studies showing a positive correlation between inflammatory bowel disease and emulsifier consumption. Further to these, cell and animal studies have demonstrated plausible mechanisms by which dietary emulsifiers may contribute to IBD pathogenesis through mechanisms including: promotion of pro-inflammatory intestinal microbiota; disruption of mucus architecture; increased intestinal permeability; activation of inflammatory pathways; and disruption of the cell cycle. This review critically analyses the current evidence for these mechanisms that may be of pathological relevance to IBD, evaluates recent dietary trials, acknowledges the challenges of dietary intervention studies, and gives an overview of ongoing and future clinical trials in this important area.

Chassaing, B., et al. (2022). “Randomized Controlled-Feeding Study of Dietary Emulsifier Carboxymethylcellulose Reveals Detrimental Impacts on the Gut Microbiota and Metabolome.” Gastroenterology 162(3): 743-756.

BACKGROUND & AIMS: Epidemiologic and murine studies suggest that dietary emulsifiers promote development of diseases associated with microbiota dysbiosis. Although the detrimental impact of these compounds on the intestinal microbiota and intestinal health have been demonstrated in animal and in vitro models, impact of these food additives in healthy humans remains poorly characterized. METHODS: To examine this notion in humans, we performed a double-blind controlled-feeding study of the ubiquitous synthetic emulsifier carboxymethylcellulose (CMC) in which healthy adults consumed only emulsifier-free diets (n = 9) or an identical diet enriched with 15 g per day of CMC (n = 7) for 11 days. RESULTS: Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity. Moreover, CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids. Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition. CONCLUSIONS: These results support the notion that the broad use of CMC in processed foods may be contributing to increased prevalence of an array of chronic inflammatory diseases by altering the gut microbiome and metabolome (ClinicalTrials.gov, number NCT03440229).

Chassaing, B., et al. (2015). “Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.” Nature 519(7541): 92-96.

The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

Chassaing, B., et al. (2017). “Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation.” Gut 66(8): 1414-1427.

OBJECTIVE: The intestinal microbiota plays a central role in the development of many chronic inflammatory diseases including IBD and metabolic syndrome. Administration of substances that alter microbiota composition, including the synthetic dietary emulsifiers polysorbate 80 (P80) and carboxymethylcellulose (CMC), can promote such inflammatory disorders. However, that inflammation itself impacts microbiota composition has obfuscated defining the extent to which these compounds or other substances act directly upon the microbiota versus acting on host parameters that promote inflammation, which subsequently reshapes the microbiota. DESIGN: We examined the direct impact of CMC and P80 on the microbiota using the mucosal simulator of the human intestinal microbial ecosystem (M-SHIME) model that maintains a complex stable human microbiota in the absence of a live host. RESULTS: This approach revealed that both P80 and CMC acted directly upon human microbiota to increase its proinflammatory potential, as revealed by increased levels of bioactive flagellin. The CMC-induced increase in flagellin was rapid (1 day) and driven by altered microbiota gene expression. In contrast, the P80-induced flagellin increase occurred more slowly and was closely associated with altered species composition. Transfer of both emulsifier-treated M-SHIME microbiotas to germ-free recipient mice recapitulated many of the host and microbial alterations observed in mice directly treated with emulsifiers. CONCLUSIONS: These results demonstrate a novel paradigm of deconstructing host-microbiota interactions and indicate that the microbiota can be directly impacted by these commonly used food additives, in a manner that subsequently drives intestinal inflammation.

Cox, S., et al. (2021). “Food additive emulsifiers: a review of their role in foods, legislation and classifications, presence in food supply, dietary exposure, and safety assessment.” Nutr Rev 79(6): 726-741.

Food additive intakes have increased with the increase in “ultra-processed” food consumption. Food additive emulsifiers have received particular research attention in recent years due to preliminary evidence of adverse gastrointestinal and metabolic health effects. In this review, the use of emulsifiers as food additives is discussed, and the current estimations of exposure to, and safety of, emulsifiers are critically assessed. Food additive emulsifier research is complicated by heterogeneity in additives considered to be emulsifiers and labelling of them on foods globally. Major limitations exist in estimating food additive emulsifier exposure, relating predominantly to a lack of available food occurrence and concentration data. Development of brand-specific food additive emulsifier databases are crucial to accurately estimating emulsifier exposure. Current research on the health effects of food additive emulsifiers are limited to in vitro and murine studies and small, acute studies in humans, and future research should focus on controlled human trials of longer duration.

Halmos, E. P., et al. (2019). “Review article: emulsifiers in the food supply and implications for gastrointestinal disease.” Aliment Pharmacol Ther 49(1): 41-50.

BACKGROUND: Dietary emulsifiers are the latest food additives to be associated with intestinal, cardiovascular and metabolic health. Most recently, there are postulations around certain emulsifiers playing a role in the development of Crohn’s disease. AIM: To review the use of food-based emulsifiers, their content in the food supply and mechanisms by which they might exert potentially detrimental biological effects. METHODS: Information on emulsifiers and thickeners relevant to human health was critically examined. RESULTS: The term, “emulsifier,” has been used loosely and has included thickeners as well as agents that truly promote emulsions. These comprise proteins, phospholipids and carbohydrates, alone or in combination, and play roles in optimising food appearance, texture and mouthfeel, delivering or disguising flavours and achieving palatable low-fat foods. Their presence in the food supply is common, but not “ubiquitous” as frequently stated. Strict regulations limit the amount added to foods, but the lack of established methodologies to measure the actual food content of these diverse compounds limits our knowledge of consumption. Emulsifiers and thickeners have effects on the gut microbiota, mucosal barrier and inflammatory pathways, and can induce disease in experimental models. However, differentiating pharmacological from physiological effects and translating findings in experimental animals to humans raise uncertainties about the relevance of such effects. CONCLUSIONS: There is limited evidence to directly link emulsifiers and thickeners to human disease, but multiple potential pathogenic mechanisms. Knowledge of actual dietary intake and high-quality interventional studies is needed to enable the risks associated with their intake to be understood.

Laster, J., et al. (2019). “Increased Use of Emulsifiers in Processed Foods and the Links to Obesity.” Curr Gastroenterol Rep 21(11): 61.

PURPOSE OF REVIEW: The purpose of this review is to discuss the implications of the increased prevalence of emulsifiers in processed foods in daily consumption, the links to obesity both in mice and in vitro studies, and how those findings correlate with humans. RECENT FINDINGS: There is rising interest in understanding the contributors to the obesity epidemic. One potential component recently studied has been the consumption of processed foods causing inflammatory changes leading to metabolic syndrome. This phenomenon has been shown in several mice and in vitro studies with changes in microbiome composition, elevated fasting blood glucose, hyperphagia, increased weight gain and adiposity, hepatic steatosis increased inflammatory markers, and a correlation with increased incidence of colorectal cancer. Emulsifiers are found in most foods consumed in the US population, which has increased over the years. This review focuses on understanding the initial approved safe levels of emulsifier consumption, the preceding increased use in foods with higher daily consumption than was previously tested, measuring these levels in animal models, and the positive association with obesity and metabolic syndrome. Future research will require prospectively studying emulsifier consumption more accurately along with the associated respective changes in the microbiome to determine the relationship to obesity.

Roberts, C. L., et al. (2013). “Hypothesis: Increased consumption of emulsifiers as an explanation for the rising incidence of Crohn’s disease.” J Crohns Colitis 7(4): 338-341.

Crohn’s disease (CD) incidence has increased over the past fifty years but the explanation is unclear. CD can be brought into remission by liquid enteral feeding, but the mechanism for this response is unknown. We suggest that consumption of emulsifiers in processed foods may promote CD by increasing bacterial translocation. This is supported by evidence that (i) geographical variation in CD correlates with emulsifier consumption as does the increasing incidence of CD in Japan; (ii) although CD incidence also correlates with fat consumption, the response to enteral feeding is not affected by the fat content of the feed and (iii) very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. The hypothesis should be testable by trials of enteral feeding with/without emulsifiers.

Rousta, E., et al. (2021). “The Emulsifier Carboxymethylcellulose Induces More Aggressive Colitis in Humanized Mice with Inflammatory Bowel Disease Microbiota Than Polysorbate-80.” Nutrients 13(10).

Commonly used synthetic dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate-80 (P80), promote intestinal inflammation. We compared abilities of CMC vs. P80 to potentiate colitis and impact human microbiota in an inflammatory environment using a novel colitis model of ex-germ-free (GF) IL10(-/-) mice colonized by pooled fecal transplant from three patients with active inflammatory bowel diseases. After three days, mice received 1% CMC or P80 in drinking water or water alone for four weeks. Inflammation was quantified by serial fecal lipocalin 2 (Lcn-2) and after four weeks by blinded colonic histologic scores and colonic inflammatory cytokine gene expression. Microbiota profiles in cecal contents were determined by shotgun metagenomic sequencing. CMC treatment significantly increased fecal Lcn-2 levels compared to P80 and water treatment by one week and throughout the experiment. Likewise, CMC treatment increased histologic inflammatory scores and colonic inflammatory cytokine gene expression compared with P80 and water controls. The two emulsifiers differentially affected specific intestinal microbiota. CMC did not impact bacterial composition but significantly decreased Caudoviricetes (bacteriophages), while P80 exposure non-significantly increased the abundance of both Actinobacteria and Proteobacteria. Commonly used dietary emulsifiers have different abilities to induce colitis in humanized mice. CMC promotes more aggressive inflammation without changing bacterial composition.

Table F – Food Additives. Criteria to escape Tier III – Criterion: Added Fructose

Added Fructose: No more than 2 g of added fructose per serving, whole fruit excluded

(Herman and Birnbaum 2021)
(Shi, Liu et al. 2021)
(Smith, Dyson et al. 2022)
(Merino, Fernández-Díaz et al. 2019, Muriel, López-Sánchez et al. 2021)
(Hannou, Haslam et al. 2018)
(Febbraio and Karin 2021)
(Spagnuolo, Iossa et al. 2020)
(Jung, Bae et al. 2022)
(Jang, Hui et al. 2018)
(Turck, Bohn et al. 2022)

References and Abstract

Febbraio, M. A. and M. Karin (2021). “”Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis.” Cell Metab 33(12): 2316-2328.

Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.

Hannou, S. A., et al. (2018). “Fructose metabolism and metabolic disease.” J Clin Invest 128(2): 545-555.

Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.

Herman, M. A. and M. J. Birnbaum (2021). “Molecular aspects of fructose metabolism and metabolic disease.” Cell Metab 33(12): 2329-2354.

Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.

Jang, C., et al. (2018). “The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids.” Cell Metab 27(2): 351-361.e353.

Excessive consumption of sweets is a risk factor for metabolic syndrome. A major chemical feature of sweets is fructose. Despite strong ties between fructose and disease, the metabolic fate of fructose in mammals remains incompletely understood. Here we use isotope tracing and mass spectrometry to track the fate of glucose and fructose carbons in vivo, finding that dietary fructose is cleared by the small intestine. Clearance requires the fructose-phosphorylating enzyme ketohexokinase. Low doses of fructose are ∼90% cleared by the intestine, with only trace fructose but extensive fructose-derived glucose, lactate, and glycerate found in the portal blood. High doses of fructose (≥1 g/kg) overwhelm intestinal fructose absorption and clearance, resulting in fructose reaching both the liver and colonic microbiota. Intestinal fructose clearance is augmented both by prior exposure to fructose and by feeding. We propose that the small intestine shields the liver from otherwise toxic fructose exposure.

Jung, S., et al. (2022). “Dietary Fructose and Fructose-Induced Pathologies.” Annu Rev Nutr 42: 45-66.

The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases.

Merino, B., et al. (2019). “Intestinal Fructose and Glucose Metabolism in Health and Disease.” Nutrients 12(1).

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.

Muriel, P., et al. (2021). “Fructose and the Liver.” Int J Mol Sci 22(13).

Chronic diseases represent a major challenge in world health. Metabolic syndrome is a constellation of disturbances affecting several organs, and it has been proposed to be a liver-centered condition. Fructose overconsumption may result in insulin resistance, oxidative stress, inflammation, elevated uric acid levels, increased blood pressure, and increased triglyceride concentrations in both the blood and liver. Non-alcoholic fatty liver disease (NAFLD) is a term widely used to describe excessive fatty infiltration in the liver in the absence of alcohol, autoimmune disorders, or viral hepatitis; it is attributed to obesity, high sugar and fat consumption, and sedentarism. If untreated, NAFLD can progress to nonalcoholic steatohepatitis (NASH), characterized by inflammation and mild fibrosis in addition to fat infiltration and, eventually, advanced scar tissue deposition, cirrhosis, and finally liver cancer, which constitutes the culmination of the disease. Notably, fructose is recognized as a major mediator of NAFLD, as a significant correlation between fructose intake and the degree of inflammation and fibrosis has been found in preclinical and clinical studies. Moreover, fructose is a risk factor for liver cancer development. Interestingly, fructose induces a number of proinflammatory, fibrogenic, and oncogenic signaling pathways that explain its deleterious effects in the body, especially in the liver.

Shi, Y. N., et al. (2021). “Fructose and metabolic diseases: too much to be good.” Chin Med J (Engl) 134(11): 1276-1285.

Excessive consumption of fructose, the sweetest of all naturally occurring carbohydrates, has been linked to worldwide epidemics of metabolic diseases in humans, and it is considered an independent risk factor for cardiovascular diseases. We provide an overview about the features of fructose metabolism, as well as potential mechanisms by which excessive fructose intake is associated with the pathogenesis of metabolic diseases both in humans and rodents. To accomplish this aim, we focus on illuminating the cellular and molecular mechanisms of fructose metabolism as well as its signaling effects on metabolic and cardiovascular homeostasis in health and disease, highlighting the role of carbohydrate-responsive element-binding protein in regulating fructose metabolism.

Smith, E. V. L., et al. (2022). “Maternal Fructose Intake, Programmed Mitochondrial Function and Predisposition to Adult Disease.” Int J Mol Sci 23(20).

Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring.

Spagnuolo, M. S., et al. (2020). “Sweet but Bitter: Focus on Fructose Impact on Brain Function in Rodent Models.” Nutrients 13(1).

Fructose consumption has drastically increased during the last decades due to the extensive commercial use of high-fructose corn syrup as a sweetener for beverages, snacks and baked goods. Fructose overconsumption is known to induce obesity, dyslipidemia, insulin resistance and inflammation, and its metabolism is considered partially responsible for its role in several metabolic diseases. Indeed, the primary metabolites and by-products of gut and hepatic fructolysis may impair the functions of extrahepatic tissues and organs. However, fructose itself causes an adenosine triphosphate (ATP) depletion that triggers inflammation and oxidative stress. Many studies have dealt with the effects of this sugar on various organs, while the impact of fructose on brain function is, to date, less explored, despite the relevance of this issue. Notably, fructose transporters and fructose metabolizing enzymes are present in brain cells. In addition, it has emerged that fructose consumption, even in the short term, can adversely influence brain health by promoting neuroinflammation, brain mitochondrial dysfunction and oxidative stress, as well as insulin resistance. Fructose influence on synaptic plasticity and cognition, with a major impact on critical regions for learning and memory, was also reported. In this review, we discuss emerging data about fructose effects on brain health in rodent models, with special reference to the regulation of food intake, inflammation, mitochondrial function and oxidative stress, insulin signaling and cognitive function.

Turck, D., et al. (2022). “Tolerable upper intake level for dietary sugars.” Efsa j 20(2): e07074.

Following a request from five European Nordic countries, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was tasked to provide scientific advice on a tolerable upper intake level (UL) or a safe level of intake for dietary (total/added/free) sugars based on available data on chronic metabolic diseases, pregnancy-related endpoints and dental caries. Specific sugar types (fructose) and sources of sugars were also addressed. The intake of dietary sugars is a well-established hazard in relation to dental caries in humans. Based on a systematic review of the literature, prospective cohort studies do not support a positive relationship between the intake of dietary sugars, in isocaloric exchange with other macronutrients, and any of the chronic metabolic diseases or pregnancy-related endpoints assessed. Based on randomised control trials on surrogate disease endpoints, there is evidence for a positive and causal relationship between the intake of added/free sugars and risk of some chronic metabolic diseases: The level of certainty is moderate for obesity and dyslipidaemia (> 50-75% probability), low for non-alcoholic fatty liver disease and type 2 diabetes (> 15-50% probability) and very low for hypertension (0-15% probability). Health effects of added vs. free sugars could not be compared. A level of sugars intake at which the risk of dental caries/chronic metabolic diseases is not increased could not be identified over the range of observed intakes, and thus, a UL or a safe level of intake could not be set. Based on available data and related uncertainties, the intake of added and free sugars should be as low as possible in the context of a nutritionally adequate diet. Decreasing the intake of added and free sugars would decrease the intake of total sugars to a similar extent. This opinion can assist EU Member States in setting national goals/recommendations.

Table F – Food Additives. Criteria to escape Tier III: (Target of) no more than 4 g of added glucose per serving

References

(Johnson, Appel et al. 2009)
(Vos, Kaar et al. 2017)
(Pan and Hu 2011)
(Malik and Hu 2022)
(Hu 2013)
(Malik and Hu 2019)
(Calcaterra, Cena et al. 2023)
(Mozaffarian 2016)
(Stanhope 2016)
(Rupérez, Mesana et al. 2019)

References

Calcaterra, V., et al. (2023). “Sugar-Sweetened Beverages and Metabolic Risk in Children and Adolescents with Obesity: A Narrative Review.” Nutrients 15(3).

Sugar-sweetened beverages (SSBs) are major contributors of free sugars to the diet. A strong relationship between SSB intake and weight gain is described. METHODS: we performed a narrative review to present an overview of the role of SSBs as a pivotal contributor in the development of obesity and metabolism-related complications. RESULTS: different factors influence SSB consumption in children, including economic variables, individual attributes and behaviors to environmental factors, parent features and parents’ behaviors. Data suggest that SSB intake has a negative effect on weight and obesity-related diseases. The leading mechanism linking SSB intake to the risk of gaining weight is decreased satiety and incomplete compensatory reduction in energy intake at meals following ingestion of liquid calories. Additionally, the effects of SSBs on gut microbiota and on eating behaviors were also reported. An association between SSB intake, weight gain and cardiometabolic risks is evident. Consumption of SSBs had a significant impact on the prevalence of obesity and related metabolic risks, including insulin resistance, type 2 diabetes, hypertension and metabolic syndrome. CONCLUSIONS: Limiting consumption of SSBs and increasing knowledge of the effect of SSBs on early metabolic and cardiovascular disorders will be useful in developing strategies to counteract the problem and to prevent obesity and related complications.Key future research areas for which further studies are needed include investigating the long-term effects of SSBs on health outcomes as well as analyzing the health effects of sugar consumed in solid compared to liquid forms and further elucidating the biological mechanisms of sugar addiction and energy compensation.

Hu, F. B. (2013). “Resolved: there is sufficient scientific evidence that decreasing sugar-sweetened beverage consumption will reduce the prevalence of obesity and obesity-related diseases.” Obes Rev 14(8): 606-619.

Sugar-sweetened beverages (SSBs) are the single largest source of added sugar and the top source of energy intake in the U.S. diet. In this review, we evaluate whether there is sufficient scientific evidence that decreasing SSB consumption will reduce the prevalence of obesity and its related diseases. Because prospective cohort studies address dietary determinants of long-term weight gain and chronic diseases, whereas randomized clinical trials (RCTs) typically evaluate short-term effects of specific interventions on weight change, both types of evidence are critical in evaluating causality. Findings from well-powered prospective cohorts have consistently shown a significant association, established temporality and demonstrated a direct dose-response relationship between SSB consumption and long-term weight gain and risk of type 2 diabetes (T2D). A recently published meta-analysis of RCTs commissioned by the World Health Organization found that decreased intake of added sugars significantly reduced body weight (0.80 kg, 95% confidence interval [CI] 0.39-1.21; P < 0.001), whereas increased sugar intake led to a comparable weight increase (0.75 kg, 0.30-1.19; P = 0.001). A parallel meta-analysis of cohort studies also found that higher intake of SSBs among children was associated with 55% (95% CI 32-82%) higher risk of being overweight or obese compared with those with lower intake. Another meta-analysis of eight prospective cohort studies found that one to two servings per day of SSB intake was associated with a 26% (95% CI 12-41%) greater risk of developing T2D compared with occasional intake (less than one serving per month). Recently, two large RCTs with a high degree of compliance provided convincing data that reducing consumption of SSBs significantly decreases weight gain and adiposity in children and adolescents. Taken together, the evidence that decreasing SSBs will decrease the risk of obesity and related diseases such as T2D is compelling. Several additional issues warrant further discussion. First, prevention of long-term weight gain through dietary changes such as limiting consumption of SSBs is more important than short-term weight loss in reducing the prevalence of obesity in the population. This is due to the fact that once an individual becomes obese, it is difficult to lose weight and keep it off. Second, we should consider the totality of evidence rather than selective pieces of evidence (e.g. from short-term RCTs only). Finally, while recognizing that the evidence of harm on health against SSBs is strong, we should avoid the trap of waiting for absolute proof before allowing public health action to be taken.

Johnson, R. K., et al. (2009). “Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.” Circulation 120(11): 1011-1020.

High intakes of dietary sugars in the setting of a worldwide pandemic of obesity and cardiovascular disease have heightened concerns about the adverse effects of excessive consumption of sugars. In 2001 to 2004, the usual intake of added sugars for Americans was 22.2 teaspoons per day (355 calories per day). Between 1970 and 2005, average annual availability of sugars/added sugars increased by 19%, which added 76 calories to Americans’ average daily energy intake. Soft drinks and other sugar-sweetened beverages are the primary source of added sugars in Americans’ diets. Excessive consumption of sugars has been linked with several metabolic abnormalities and adverse health conditions, as well as shortfalls of essential nutrients. Although trial data are limited, evidence from observational studies indicates that a higher intake of soft drinks is associated with greater energy intake, higher body weight, and lower intake of essential nutrients. National survey data also indicate that excessive consumption of added sugars is contributing to overconsumption of discretionary calories by Americans. On the basis of the 2005 US Dietary Guidelines, intake of added sugars greatly exceeds discretionary calorie allowances, regardless of energy needs. In view of these considerations, the American Heart Association recommends reductions in the intake of added sugars. A prudent upper limit of intake is half of the discretionary calorie allowance, which for most American women is no more than 100 calories per day and for most American men is no more than 150 calories per day from added sugars.

Malik, V. S. and F. B. Hu (2019). “Sugar-Sweetened Beverages and Cardiometabolic Health: An Update of the Evidence.” Nutrients 11(8).

Sugar-sweetened beverages (SSBs) have little nutritional value and a robust body of evidence has linked the intake of SSBs to weight gain and risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and some cancers. Metabolic Syndrome (MetSyn) is a clustering of risk factors that precedes the development of T2D and CVD; however, evidence linking SSBs to MetSyn is not clear. To make informed recommendations about SSBs, new evidence needs to be considered against existing literature. This review provides an update on the evidence linking SSBs and cardiometabolic outcomes including MetSyn. Findings from prospective cohort studies support a strong positive association between SSBs and weight gain and risk of T2D and coronary heart disease (CHD), independent of adiposity. Associations with MetSyn are less consistent, and there appears to be a sex difference with stroke with greater risk in women. Findings from short-term trials on metabolic risk factors provide mechanistic support for associations with T2D and CHD. Conclusive evidence from cohort studies and trials on risk factors support an etiologic role of SSB in relation to weight gain and risk of T2D and CHD. Continued efforts to reduce intake of SSB should be encouraged to improve the cardiometabolic health of individuals and populations.

Malik, V. S. and F. B. Hu (2022). “The role of sugar-sweetened beverages in the global epidemics of obesity and chronic diseases.” Nat Rev Endocrinol 18(4): 205-218.

Sugar-sweetened beverages (SSBs) are a major source of added sugars in the diet. A robust body of evidence has linked habitual intake of SSBs with weight gain and a higher risk (compared with infrequent SSB consumption) of type 2 diabetes mellitus, cardiovascular diseases and some cancers, which makes these beverages a clear target for policy and regulatory actions. This Review provides an update on the evidence linking SSBs to obesity, cardiometabolic outcomes and related cancers, as well as methods to grade the strength of nutritional research. We discuss potential biological mechanisms by which constituent sugars can contribute to these outcomes. We also consider global trends in intake, alternative beverages (including artificially-sweetened beverages) and policy strategies targeting SSBs that have been implemented in different settings. Strong evidence from cohort studies on clinical outcomes and clinical trials assessing cardiometabolic risk factors supports an aetiological role of SSBs in relation to weight gain and cardiometabolic diseases. Many populations show high levels of SSB consumption and in low-income and middle-income countries, increased consumption patterns are associated with urbanization and economic growth. As such, more intensified policy efforts are needed to reduce intake of SSBs and the global burden of obesity and chronic diseases.

Mozaffarian, D. (2016). “Dietary and Policy Priorities for Cardiovascular Disease, Diabetes, and Obesity: A Comprehensive Review.” Circulation 133(2): 187-225.

Suboptimal nutrition is a leading cause of poor health. Nutrition and policy science have advanced rapidly, creating confusion yet also providing powerful opportunities to reduce the adverse health and economic impacts of poor diets. This review considers the history, new evidence, controversies, and corresponding lessons for modern dietary and policy priorities for cardiovascular diseases, obesity, and diabetes mellitus. Major identified themes include the importance of evaluating the full diversity of diet-related risk pathways, not only blood lipids or obesity; focusing on foods and overall diet patterns, rather than single isolated nutrients; recognizing the complex influences of different foods on long-term weight regulation, rather than simply counting calories; and characterizing and implementing evidence-based strategies, including policy approaches, for lifestyle change. Evidence-informed dietary priorities include increased fruits, nonstarchy vegetables, nuts, legumes, fish, vegetable oils, yogurt, and minimally processed whole grains; and fewer red meats, processed (eg, sodium-preserved) meats, and foods rich in refined grains, starch, added sugars, salt, and trans fat. More investigation is needed on the cardiometabolic effects of phenolics, dairy fat, probiotics, fermentation, coffee, tea, cocoa, eggs, specific vegetable and tropical oils, vitamin D, individual fatty acids, and diet-microbiome interactions. Little evidence to date supports the cardiometabolic relevance of other popular priorities: eg, local, organic, grass-fed, farmed/wild, or non-genetically modified. Evidence-based personalized nutrition appears to depend more on nongenetic characteristics (eg, physical activity, abdominal adiposity, gender, socioeconomic status, culture) than genetic factors. Food choices must be strongly supported by clinical behavior change efforts, health systems reforms, novel technologies, and robust policy strategies targeting economic incentives, schools and workplaces, neighborhood environments, and the food system. Scientific advances provide crucial new insights on optimal targets and best practices to reduce the burdens of diet-related cardiometabolic diseases.

Pan, A. and F. B. Hu (2011). “Effects of carbohydrates on satiety: differences between liquid and solid food.” Current Opinion in Clinical Nutrition & Metabolic Care 14(4): 385-390.

Purpose of review To examine the satiety effect of carbohydrates with a focus on the comparison of liquid and solid food and their implications for energy balance and weight management. Recent findings A number of studies have examined the role of dietary fiber, whole grains, and glycemic index or glycemic load on satiety and subsequent energy intake, but results remain inconclusive. Intake of liquid carbohydrates, particularly sugar-sweetened beverages, has increased considerably across the globe in recent decades in both adolescents and adults. In general, liquid carbohydrates produce less satiety compared with solid carbohydrates. Some energy from liquids may be compensated for at subsequent meals but because the compensation is incomplete, it leads to an increase in total long-term energy intake. Recent studies also suggest some potential differential responses of satiety by characteristics of the patients (e.g., race, sex, and body weight status). These differences warrant further research. Summary Satiety is a complex process influenced by a number of properties in food. The physical form (solid vs. liquid) of carbohydrates is an important component that may affect the satiety process and energy intake. Accumulating evidence suggests that liquid carbohydrates generally produce less satiety than solid forms.

Rupérez, A. I., et al. (2019). “Dietary sugars, metabolic effects and child health.” Curr Opin Clin Nutr Metab Care 22(3): 206-216.

PURPOSE OF REVIEW: To describe current findings on sugar intake in children worldwide, including sugar sources and their impact on child health focusing on cardiometabolic alterations usually associated to obesity. RECENT FINDINGS: In children less than 4 years, intakes of added sugars across countries ranged from 9.8 to 11.2% of total energy; in children 4-10 years, it ranged from less than 3-18%; and in adolescents, it ranged from 13.6 to 16.6%. For most countries, intakes of added sugars were greater than the recommended upper limit of 10% of total energy for children and adolescents and less or around 10% in infants. In most studies, soft drinks and fruit-based drinks accounted for the greatest proportion of the added sugars intake, followed by milk products and sweet bakery products. High added sugar intake has been associated with increased obesity risk and fat deposition in the liver, contributing to dyslipidemia, high blood pressure, insulin resistance and cardio-metabolic risk. SUMMARY: As a high added sugar intake is associated with cardio-metabolic conditions in children and adolescents, the current scenario supports the need for stronger targeted long-term policies that prevent the excessive sugar intake in young populations.

Stanhope, K. L. (2016). “Sugar consumption, metabolic disease and obesity: The state of the controversy.” Crit Rev Clin Lab Sci 53(1): 52-67.

The impact of sugar consumption on health continues to be a controversial topic. The objective of this review is to discuss the evidence and lack of evidence that allows the controversy to continue, and why resolution of the controversy is important. There are plausible mechanisms and research evidence that supports the suggestion that consumption of excess sugar promotes the development of cardiovascular disease (CVD) and type 2 diabetes (T2DM) both directly and indirectly. The direct pathway involves the unregulated hepatic uptake and metabolism of fructose, leading to liver lipid accumulation, dyslipidemia, decreased insulin sensitivity and increased uric acid levels. The epidemiological data suggest that these direct effects of fructose are pertinent to the consumption of the fructose-containing sugars, sucrose and high fructose corn syrup (HFCS), which are the predominant added sugars. Consumption of added sugar is associated with development and/or prevalence of fatty liver, dyslipidemia, insulin resistance, hyperuricemia, CVD and T2DM, often independent of body weight gain or total energy intake. There are diet intervention studies in which human subjects exhibited increased circulating lipids and decreased insulin sensitivity when consuming high sugar compared with control diets. Most recently, our group has reported that supplementing the ad libitum diets of young adults with beverages containing 0%, 10%, 17.5% or 25% of daily energy requirement (Ereq) as HFCS increased lipid/lipoprotein risk factors for CVD and uric acid in a dose-response manner. However, un-confounded studies conducted in healthy humans under a controlled, energy-balanced diet protocol that enables determination of the effects of sugar with diets that do not allow for body weight gain are lacking. Furthermore, recent reports conclude that there are no adverse effects of consuming beverages containing up to 30% Ereq sucrose or HFCS, and the conclusions from several meta-analyses suggest that fructose has no specific adverse effects relative to any other carbohydrate. Consumption of excess sugar may also promote the development of CVD and T2DM indirectly by causing increased body weight and fat gain, but this is also a topic of controversy. Mechanistically, it is plausible that fructose consumption causes increased energy intake and reduced energy expenditure due to its failure to stimulate leptin production. Functional magnetic resonance imaging (fMRI) of the brain demonstrates that the brain responds differently to fructose or fructose-containing sugars compared with glucose or aspartame. Some epidemiological studies show that sugar consumption is associated with body weight gain, and there are intervention studies in which consumption of ad libitum high-sugar diets promoted increased body weight gain compared with consumption of ad libitum low- sugar diets. However, there are no studies in which energy intake and weight gain were compared in subjects consuming high or low sugar, blinded, ad libitum diets formulated to ensure both groups consumed a comparable macronutrient distribution and the same amounts of fiber. There is also little data to determine whether the form in which added sugar is consumed, as beverage or as solid food, affects its potential to promote weight gain. It will be very challenging to obtain the funding to conduct the clinical diet studies needed to address these evidence gaps, especially at the levels of added sugar that are commonly consumed. Yet, filling these evidence gaps may be necessary for supporting the policy changes that will help to turn the food environment into one that does not promote the development of obesity and metabolic disease.

Vos, M. B., et al. (2017). “Added Sugars and Cardiovascular Disease Risk in Children: A Scientific Statement From the American Heart Association.” Circulation 135(19): e1017-e1034.

BACKGROUND: Poor lifestyle behaviors are leading causes of preventable diseases globally. Added sugars contribute to a diet that is energy dense but nutrient poor and increase risk of developing obesity, cardiovascular disease, hypertension, obesity-related cancers, and dental caries. METHODS AND RESULTS: For this American Heart Association scientific statement, the writing group reviewed and graded the current scientific evidence for studies examining the cardiovascular health effects of added sugars on children. The available literature was subdivided into 5 broad subareas: effects on blood pressure, lipids, insulin resistance and diabetes mellitus, nonalcoholic fatty liver disease, and obesity. CONCLUSIONS: Associations between added sugars and increased cardiovascular disease risk factors among US children are present at levels far below current consumption levels. Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia. The committee found that it is reasonable to recommend that children consume ≤25 g (100 cal or ≈6 teaspoons) of added sugars per day and to avoid added sugars for children <2 years of age. Although added sugars most likely can be safely consumed in low amounts as part of a healthy diet, few children achieve such levels, making this an important public health target.

Table F – Food Additives. Criteria to escape Tier III: Heavy metals: No more than 0.02 ppm of lead; No more than 0.03 ppm of cadmium; No more than 0.01 ppm of arsenic; No more than 0.05 ppm of mercury and: No more than 0.04 ppm of glyphosate

Lead References: 1-10

FDA government online article: https://www.fda.gov/food/environmental-contaminants-food/lead-food-foodwares-and-dietary-supplements
FDA government online article: https://www.fda.gov/food/environmental-contaminants-food/what-you-can-do-limit-exposure-arsenic-and-lead-juices
(Vasconcelos Neto, Silva et al. 2019)
(Cabrera, Gallego et al. 2020)
(Kumar, Kumar et al. 2020)
European Commission online article: https://food.ec.europa.eu/safety/chemical-safety/contaminants/catalogue/lead_en#:~:text=Cereal%20products%20and%20grains%2C%20vegetables,of%20the%20general%20adult%20population.
(Union 2006)
Environmental Defense Fund online article: https://www.edf.org/health/lead-food-hidden-health-threat
(Ciobanu, Slencu et al. 2012)
(Yao, Shao et al. 2022)

Cadmium: Refs 11-20

(Kim et al., 2019)
(Awata, Linder et al. 2017)
(Abt, Fong Sam et al. 2018)
(Alves Peixoto, Oliveira et al. 2018)
(Abt and Robin 2020)
(Genchi, Sinicropi et al. 2020)
(Kumar and Sharma 2019)
(Huang, He et al. 2017)
FDA Government online article: https://www.fda.gov/science-research/peer-review-scientific-information-and-assessments/external-peer-review-fdas-draft-toxicological-reference-value-cadmium
FDA online article: https://www.fda.gov/food/conversations-experts-food-topics/what-fda-doing-protect-consumers-toxic-metals-foods

Arsenic: Refs 20-30

FDA government online article: https://www.fda.gov/food/environmental-contaminants-food/arsenic-food-and-dietary-supplements
FDA guide to reducing inorganic arsenic in apple juice: https://www.fda.gov/media/86110/download
(Jomova, Jenisova et al. 2011)
(Hughes 2002)
(Medina-Pizzali, Robles et al. 2018)
(Brandon, Janssen et al. 2014)
(Mania, Rebeniak et al. 2015)
(Rahman, Granberg et al. 2017)
(Rehman, Khan et al. 2021)
European Commission Food Safety Government online article: https://food.ec.europa.eu/safety/chemical-safety/contaminants/catalogue/arsenic_en

Mercury: refs 30-40

European Commission for Food Safety online article: (EFSA Dietetic Products and Allergies 2014)
European Commission setting maximum levels for certain contaminants in foodstuffs: http://data.europa.eu/eli/reg/2006/1881/oj
(Padmakumar, Premkala Raveendran et al. 2019)
(Collado-López, Betanzos-Robledo et al. 2022)
(Bernhoft 2012)
(Oken and Bellinger 2008)
(Deroma, Parpinel et al. 2013)
(Castoldi, Johansson et al. 2008)
(Mendola, Selevan et al. 2002)
(Bjørklund, Chirumbolo et al. 2019)

Glyphosate: refs 40-45

(Myers, Antoniou et al. 2016)
(Milesi, Lorenz et al. 2021)
(Soares, Silva et al. 2021)
(Peillex and Pelletier 2020)
FDA government online article: https://www.fda.gov/food/pesticides/questions-and-answers-glyphosate

References

Abt, E., et al. (2018). “Cadmium and lead in cocoa powder and chocolate products in the US Market.” Food Addit Contam Part B Surveill 11(2): 92-102.

Cocoa powder and chocolate products are known to sometimes contain cadmium (Cd) and lead (Pb) from environmental origins. A convenience sample of cocoa powder, dark chocolate, milk chocolate, and cocoa nib products was purchased at retail in the US and analysed using inductively coupled plasma mass spectrometry to assess Cd and Pb concentrations. Cd and Pb were evaluated in relation to the percent cocoa solids and to the reported origin of the cocoa powder and chocolate products. Cd ranged from 0.004 to 3.15 mg/kg and Pb ranged from <LOD to 0.38 mg/kg. Cd and Pb were significantly correlated with percent cocoa, with correlations varying by product type and geographic origin. Geographic variation was observed for Cd, with higher Cd concentrations found in products reported as originating from Latin America than from Africa. The influence of percent cocoa solids and cocoa origin on Cd levels are relevant to international standards for Cd in chocolate products.

Abt, E. and L. P. Robin (2020). “Perspective on Cadmium and Lead in Cocoa and Chocolate.” J Agric Food Chem 68(46): 13008-13015.

Cocoa and chocolate can contain cadmium (Cd) and lead (Pb) from natural and anthropogenic sources. This perspective provides background on the origin, occurrence, and factors affecting Cd and Pb levels in chocolate products as well as ongoing international efforts to mitigate Cd and Pb in these popular foods, particularly the higher Cd levels observed in some cocoa and chocolate originating from parts of Latin America. Information on factors contributing to higher Cd levels in Latin America, including elevated soil Cd, is increasing, but more work is needed to identify successful mitigation methods.

Alves Peixoto, R. R., et al. (2018). “Risk assessment of cadmium and chromium from chocolate powder.” Food Addit Contam Part B Surveill 11(4): 256-263.

An evaluation of the exposition of cadmium and chromium via chocolate drink powder consumption was conducted. The element levels were determined in 34 samples of chocolate drink powder samples of several types (traditional, light, diet, and organic) available in the Brazilian market. The samples were previously treated using acid mineralisation assisted by microwave radiation and analysed by graphite furnace atomic absorption spectrometry. Concentrations of Cd were in the range 14-124 and 81-4790 µg kg(-1) for Cr. The contributions of daily consumption of chocolate drink powder for children would represent 4-35% of the provisional tolerable weekly intake of Cd and 0.03-0.14% of the tolerable daily intake of Cr. Target hazard quotients lower than 0.04 and 0.001 were obtained for Cd and Cr, respectively, indicating that the exposure to these elements through chocolate drink powder do not present any potential risk to human health.

Awata, H., et al. (2017). “Association of Dietary Intake and Biomarker Levels of Arsenic, Cadmium, Lead, and Mercury among Asian Populations in the United States: NHANES 2011-2012.” Environ Health Perspect 125(3): 314-323.

BACKGROUND: We have recently shown that biomarker levels of selected metals are higher in Asians than in other U.S. ethnic groups, with important differences within selected Asian subgroups. Much of this difference may be dietary in origin; however, this is not well established. OBJECTIVE: We evaluated dietary intake of toxic metals as a source of increased biomarker levels of metals among U.S. Asians. METHODS: We estimated daily food consumption and dietary intake of arsenic, cadmium, lead, and mercury by combining 24-hr dietary intake recall data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) with data from the USDA Food Composition Intake Database and FDA Total Dietary Study. We analyzed associations between dietary metal intake and biomarker levels of the metals using linear regression. Further, estimated food consumption and metal intake levels were compared between Asians and other racial/ethnic groups (white, black, Mexican American, and other Hispanic) and within three Asian subgroups (Chinese, Indian Asian, and other Asians). RESULTS: Significant associations (p < 0.05) were found between biomarker levels and estimated dietary metal intake for total and inorganic arsenic and mercury among Asians. Asians had the highest daily fish and rice consumption across the racial/ethnic groups. Fish was the major contributor to dietary mercury and total arsenic intake, whereas rice was the major contributor to inorganic arsenic dietary intake. Fish consumption across the Asian subgroups varied, with Asian Indians having lower fish consumption than the other Asian subgroups. Rice consumption was similar across the Asian subgroups. CONCLUSIONS: We confirmed that estimated dietary intake of arsenic (total and inorganic) and mercury is significantly associated with their corresponding biomarkers in U.S. Asians, using nationally representative data. In contrast, estimated dietary intake of cadmium and lead were not significantly associated with their corresponding biomarker levels in U.S. Asians. Citation: Awata H, Linder S, Mitchell LE, Delclos GL. 2017. Association of dietary intake and biomarker levels of arsenic, cadmium, lead, and mercury among Asian populations in the United States: NHANES 2011-2012. Environ Health Perspect 125:314-323; http://dx.doi.org/10.1289/EHP28.

Bernhoft, R. A. (2012). “Mercury toxicity and treatment: a review of the literature.” J Environ Public Health 2012: 460508.

Mercury is a toxic heavy metal which is widely dispersed in nature. Most human exposure results from fish consumption or dental amalgam. Mercury occurs in several chemical forms, with complex pharmacokinetics. Mercury is capable of inducing a wide range of clinical presentations. Diagnosis of mercury toxicity can be challenging but can be obtained with reasonable reliability. Effective therapies for clinical toxicity have been described.

Bjørklund, G., et al. (2019). “Mercury exposure and its effects on fertility and pregnancy outcome.” Basic Clin Pharmacol Toxicol 125(4): 317-327.

Mercury (Hg), a highly toxic environmental pollutant, shows harmfulness which still represents a big concern for human health, including hazards to fertility and pregnancy outcome. Research has shown that Hg could induce impairments in the reproductive function, cellular deformation of the Leydig cells and the seminiferous tubules, and testicular degeneration as well as abnormal menstrual cycles. Some studies investigated spontaneous abortion and complicated fertility outcome due to occupational Hg exposure. Moreover, there is a relation between inhaled Hg vapour and reproductive outcome. This MiniReview evaluates the hypothesis that exposure to Hg may increase the risk of reduced fertility, spontaneous abortion and congenital deficits or abnormalities.

Brandon, E. F., et al. (2014). “Arsenic: bioaccessibility from seaweed and rice, dietary exposure calculations and risk assessment.” Food Addit Contam Part A Chem Anal Control Expo Risk Assess 31(12): 1993-2003.

Arsenic is a metalloid that occurs in food and the environment in different chemical forms. Inorganic arsenic is classified as a class I carcinogen. The inorganic arsenic intake from food and drinking water varies depending on the geographic arsenic background. Non-dietary exposure to arsenic is likely to be of minor importance for the general population within the European Union. In Europe, arsenic in drinking water is on average low, but food products (e.g. rice and seaweed) are imported from all over the world including from regions with naturally high arsenic levels. Therefore, specific populations living in Europe could also have a high exposure to inorganic arsenic due to their consumption pattern. Current risk assessment is based on exposure via drinking water. For a good estimation of the risks of arsenic in food, it is important to investigate if the bioavailability of inorganic arsenic from food is different from drinking water. The present study further explores the issue of European dietary exposure to inorganic arsenic via rice and seaweed and its associated health risks. The bioavailability of inorganic arsenic was measured in in vitro digestion experiments. The data indicate that the bioavailability of inorganic arsenic is similar for rice and seaweed compared with drinking water. The calculated dietary intake for specific European Union populations varied between 0.44 and 4.51 µg kg⁻¹ bw day⁻¹. The margins of exposure between the inorganic intake levels and the BMDL0.5 values as derived by JECFA are low. Decreasing the intake of inorganic arsenic via Hijiki seaweed could be achieved by setting legal limits similar to those set for rice by the Codex Alimentarius Commission in July 2014.

Cabrera, C., et al. (2020). “Determination of Levels of Lead Contamination in Food and Feed Crops.” Journal of AOAC INTERNATIONAL 77(5): 1249-1252.

A rapid, precise procedure is described for the determination of lead in food and feed products with electrothermal atomic absorption spectrophotometry. Samples were mineralized in a microwave acid digestion bomb in the presence of nitric acid and vanadium pentoxide. Lead concentrations were determined directly from digested samples. The detection limit was 0.04 ng/mL. Accuracy and precision were checked against National Institute of Standards and Technology standard reference material. The analytical method was tested with 51 food and feed crops from Mediterranean zones in Spain and found to be suitable for these products. Lead concentrations in samples ranged from not detectable to 2.695 μg/g (fresh weight).

Castoldi, A. F., et al. (2008). “Human developmental neurotoxicity of methylmercury: impact of variables and risk modifiers.” Regul Toxicol Pharmacol 51(2): 201-214.

Methylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainly based on human data coming from the massive episodes of poisoning in Japan and Iraq, as well as from large scale epidemiological studies concerning childhood development and neurotoxicity in relation to in utero exposure in various fish eating communities around the world. Despite the extensive literature and research, the threshold dose for MeHg neurotoxic effects is still unclear, in particular when it comes to subtle effects on neurobehaviour. In this article clinical and epidemiological findings concerning the neurodevelopmental toxicity of MeHg are reviewed. Much attention is focussed on the potential impact of factors, such as diet and nutrition, gender, pattern of exposure and co-exposure to other neurotoxic pollutants, which may modulate MeHg toxic effects. These factors, together with the notion that some symptoms may ensue or exacerbate with aging, contribute to the difficulties in the definition of safe levels for developmental exposure.

Ciobanu, C., et al. (2012). “Estimation of dietary intake of cadmium and lead through food consumption.” Rev Med Chir Soc Med Nat Iasi 116(2): 617-623.

Cadmium and lead are toxic metals occurring in the environment naturally and from anthropogenic activities and can lead to chemical contamination of products entering in the human food chain. The consumption of polluted food is the main source of lead and cadmium intake in the non-smoking population. Lead is a heavy metal that can affect different organs and systems in humans including the peripheral and central nervous system, the gastrointestinal tract, muscles, kidneys, and the hemopoetic system. Neurological symptoms can range from fatigue, headache, and lethargy to peripheral neuropathy, severe convulsions, encephalopathy, and even coma. The direct neurotoxic actions of lead include apoptosis, excitotoxicity. Lead has been associated with impaired neurobehavioral functioning in children, decrements in intelligence quotient (IQ) while the critical effect of long-term exposure to cadmium is renal tubular dysfunction, which is irreversible; chronic renal failure is the final and severe endpoint. Cadmium is able to induce bone damage (Itai-ltai). The body burden of cadmium and lead depends mostly on the dietary intake of these elements. This paper aims to present a brief overview of cadmium and lead contents present in foodstuffs from different countries and the estimated dietary intake of cadmium and lead through food consumption. It has been shown that in some countries the concentrations of cadmium and lead contained in foodstuffs are higher than normal therefore the health of the people consuming them is in danger.

Collado-López, S., et al. (2022). “Heavy Metals in Unprocessed or Minimally Processed Foods Consumed by Humans Worldwide: A Scoping Review.” Int J Environ Res Public Health 19(14).

Heavy metals (HM) can be accumulated along the food chain; their presence in food is a global concern for human health because some of them are toxic even at low concentrations. Unprocessed or minimally processed foods are good sources of different nutrients, so their safety and quality composition should be guaranteed in the most natural form that is obtained for human consumption. The objective of this scoping review (ScR) is to summarize the existing evidence about the presence of HM content (arsenic (As), lead (Pb), cadmium (Cd), mercury (Hg), methylmercury (MeHg), and aluminum (Al)) in unprocessed or minimally processed foods for human consumption worldwide during the period of 2011-2020. As a second objective, we identified reported HM values in food with respect to Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) International Food Standards for Maximum Limits (MLs) for contaminants in food. This ScR was conducted in accordance with the Joanna Briggs Institute (JBI) methodology and PRISMA Extension for Scoping Reviews (PRISMA-ScR); advance searches were performed in PubMed, ScienceDirect and FAO AGRIS (Agricultural Science and Technology Information) databases by two reviewers who independently performed literature searches with specific eligibility criteria. We classified individual foods in food groups and subgroups according to the Global Individual Information Food Consumption Data Tool (FAO/WHO GIFT). We homologated all the reported HM units to parts per million (ppm) to determine the weighted mean HM concentration per country and food group/subgroup of the articles included. Then, we compared HM concentration findings with FAO/WHO MLs. Finally, we used a Geographic Information System (GIS) to present our findings. Using our search strategy, we included 152 articles. Asia was the continent with the highest number of publications (n = 79, 51.3%), with China being the country with the largest number of studies (n = 34). Fish and shellfish (n = 58), followed by vegetables (n = 39) and cereals (n = 38), were the food groups studied the most. Fish (n = 42), rice (n = 33), and leafy (n = 28) and fruiting vegetables (n = 29) were the most studied food subgroups. With respect to the HM of interest, Cd was the most analyzed, followed by Pb, As, Hg and Al. Finally, we found that many of the HM concentrations reported exceeded the FAO/OMS MLs established for Cd, Pb and As globally in all food groups, mainly in vegetables, followed by the roots and tubers, and cereals food groups. Our study highlights the presence of HM in the most natural forms of food around the world, in concentrations that, in fact, exceed the MLs, which affects food safety and could represent a human health risk. In countries with regulations on these topics, a monitoring system is recommended to evaluate and monitor compliance with national standards. For countries without a regulation system, it is recommended to adopt international guidelines, such as those of FAO, and implement a monitoring system that supervises national compliance. In both cases, the information must be disseminated to the population to create social awareness. This is especially important to protect the population from the consumption of internal production and for the international markets of the globalized world.

Deroma, L., et al. (2013). “Neuropsychological assessment at school-age and prenatal low-level exposure to mercury through fish consumption in an Italian birth cohort living near a contaminated site.” Int J Hyg Environ Health 216(4): 486-493.

The relative effects of prenatal and postnatal low-level mercury exposure and fish intake on child neurodevelopment are still controversial. Limited evidence is available from Mediterranean populations. In this prospective study, we measured the Verbal and Performance IQ in Italian children at school-age who were resident in an area declared as a National contaminated site because of mercury pollution, taking into account the possible beneficial effect of fish consumption and potential confounders. A mother-child cohort made up of 242 children was established at birth in Northeastern Italy in 2001. Their mothers were interviewed approximately 2 months after delivery to determine type, quantity, and origin of fish consumed during pregnancy and about a number of mother, child and family characteristics. Total mercury (THg) and methyl mercury (MeHg) were assessed in maternal hair and breast milk and in the child’s hair. When children reached 7-9 years of age, 154 (63.6%) parents gave consent to participate in a follow-up evaluation. On that occasion, a child’s hair sample was collected to determine the current concentration of THg, mothers were asked to complete a self-administered questionnaire, and children underwent neuropsychological testing. Verbal IQ, performance IQ and full scale IQ were measured by the Wechsler Intelligence Scale for Children (WISC III) administered by psychologists at school or local health centers. Demographic, socioeconomic and lifestyle information, medical information of the child’s family and the child’s dietary habits were collected using a questionnaire filled in by mothers. Multivariable linear regression models were used to evaluate the association between prenatal THg exposure through fish consumption of mothers in pregnancy and children’s IQ after adjustment for possible confounders such as fish consumption of mothers in pregnancy, child’s fish consumption at follow-up, child’s birthweight, maternal cigarette smoking during pregnancy, house size and property place of residence during pregnancy and gender. THg in the child’s hair at 7 years of age was fairly correlated with THg in maternal hair at delivery (rs=0.35; p<0.0001) and was strongly correlated with child’s seafood consumption (rs=0.50, p<0.0001). No differences in maternal THg levels were found when comparing children with low or extremely low or high or extremely high scores vs others, considering separately full scale, verbal, and performance IQs. Children born from mothers with hair THg levels greater than or equal to 2000ng/g had full scale, verbal and performance IQs which were 4-5 points lower than children born from women with lower THg levels, but these differences were not statistically significant. Fresh fish intake of mothers in pregnancy was slightly positively associated with full scale and performance but not so with verbal IQs. Canned fish showed to be negatively associated with all the outcome variables. Unexpectedly, children born to mothers from one town showed IQ scores significantly lower than the other children; however, none of the many variables considered in these analyses could explain this result. The relatively low Hg levels found in the biological samples did not provide evidence of high and extensive Hg exposure in this population. Although THg levels in maternal and child’s biological samples are correlated with fish consumption, the effects of THg and fish on neurological outcomes go in opposite directions. These results do not allow to develop recommendations regarding fish consumption in pregnancy but suggest that keeping THg hair levels<2000ng/g might be desirable.

EFSA Dietetic Products, N. and Allergies (2014). “Scientific Opinion on health benefits of seafood (fish and shellfish) consumption in relation to health risks associated with exposure to methylmercury.” EFSA Journal 12(7): 3761.

Abstract Following a request from the European Commission to address the risks and benefits as regards fish/seafood consumption related to relevant beneficial substances (e.g. nutrients such as n-3 long-chain polyunsaturated fatty acids) and the contaminant methylmercury, the Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on health benefits of seafood consumption in relation to health risks associated with exposure to methylmercury. In the present Opinion, the NDA Panel has reviewed the role of seafood in European diets and evaluated the beneficial effects of seafood consumption in relation to health outcomes and population subgroups that have been identified by the FAO/WHO Joint Expert Consultation on the Risks and Benefits of Fish Consumption and/or the EFSA Panel on Contaminants in the context of a risk assessment related to the presence of mercury and methylmercury in food as relevant for the assessment. These included the effects of seafood consumption during pregnancy on functional outcomes of children’s neurodevelopment and the effects of seafood consumption on cardiovascular disease risk in adults. The Panel concluded that consumption of about 1-2 servings of seafood per week and up to 3-4 servings per week during pregnancy has been associated with better functional outcomes of neurodevelopment in children compared to no consumption of seafood. Such amounts have also been associated with a lower risk of coronary heart disease mortality in adults and are compatible with current intakes and recommendations in most of the European countries considered. These associations refer to seafood per se andinclude beneficial and adverse effects of nutrients and non-nutrients (i.e. including contaminants such as methylmercury) contained in seafood. No additional benefits on neurodevelopmental outcomes and no benefit on coronary heart disease mortality risk might be expected at higher intakes.

Genchi, G., et al. (2020). “The Effects of Cadmium Toxicity.” Int J Environ Res Public Health 17(11).

Cadmium (Cd) is a toxic non-essential transition metal that poses a health risk for both humans and animals. It is naturally occurring in the environment as a pollutant that is derived from agricultural and industrial sources. Exposure to cadmium primarily occurs through the ingestion of contaminated food and water and, to a significant extent, through inhalation and cigarette smoking. Cadmium accumulates in plants and animals with a long half-life of about 25-30 years. Epidemiological data suggest that occupational and environmental cadmium exposure may be related to various types of cancer, including breast, lung, prostate, nasopharynx, pancreas, and kidney cancers. It has been also demonstrated that environmental cadmium may be a risk factor for osteoporosis. The liver and kidneys are extremely sensitive to cadmium’s toxic effects. This may be due to the ability of these tissues to synthesize metallothioneins (MT), which are Cd-inducible proteins that protect the cell by tightly binding the toxic cadmium ions. The oxidative stress induced by this xenobiotic may be one of the mechanisms responsible for several liver and kidney diseases. Mitochondria damage is highly plausible given that these organelles play a crucial role in the formation of ROS (reactive oxygen species) and are known to be among the key intracellular targets for cadmium. When mitochondria become dysfunctional after exposure to Cd, they produce less energy (ATP) and more ROS. Recent studies show that cadmium induces various epigenetic changes in mammalian cells, both in vivo and in vitro, causing pathogenic risks and the development of various types of cancers. The epigenetics present themselves as chemical modifications of DNA and histones that alter the chromatin without changing the sequence of the DNA nucleotide. DNA methyltransferase, histone acetyltransferase, histone deacetylase and histone methyltransferase, and micro RNA are involved in the epigenetic changes. Recently, investigations of the capability of sunflower (Helianthus annuus L.), Indian mustard (Brassica juncea), and river red gum (Eucalyptus camaldulensis) to remove cadmium from polluted soil and water have been carried out. Moreover, nanoparticles of TiO(2) and Al(2)O(3) have been used to efficiently remove cadmium from wastewater and soil. Finally, microbial fermentation has been studied as a promising method for removing cadmium from food. This review provides an update on the effects of Cd exposure on human health, focusing on the cellular and molecular alterations involved.

Huang, Y., et al. (2017). “Toxicity of cadmium and its health risks from leafy vegetable consumption.” Food Funct 8(4): 1373-1401.

Cadmium (Cd) is a highly toxic heavy metal and has spread widely in the environment in recent decades. This review summarizes current knowledge about Cd contamination of leafy vegetables, its toxicity, exposure, health risks, and approaches to reducing its toxicity in humans. Leafy vegetable consumption has been identified as a dominant exposure pathway of Cd in the human body. An overview of Cd pollution in leafy vegetables as well as the main sources of Cd is given. Notable estimated daily intakes and health risks of Cd exposure through vegetable consumption for humans are revealed in occupational exposure areas and even in some reference areas. Vegetable consumption is one of the most significant sources of exposure to Cd, particularly in occupational exposure regions. Therefore, numerous approaches have been developed to minimize the accumulation of Cd in leafy vegetables, among which the breeding of Cd pollution-safe cultivars is one of the most effective tools. Furthermore, dietary supplements from leafy vegetables perform positive roles in alleviating Cd toxicity in humans with regard to the effects of essential mineral elements, vitamins and phytochemicals taken into the human body via leafy vegetable consumption.

Hughes, M. F. (2002). “Arsenic toxicity and potential mechanisms of action.” Toxicol Lett 133(1): 1-16.

Exposure to the metalloid arsenic is a daily occurrence because of its environmental pervasiveness. Arsenic, which is found in several different chemical forms and oxidation states, causes acute and chronic adverse health effects, including cancer. The metabolism of arsenic has an important role in its toxicity. The metabolism involves reduction to a trivalent state and oxidative methylation to a pentavalent state. The trivalent arsenicals, including those methylated, have more potent toxic properties than the pentavalent arsenicals. The exact mechanism of the action of arsenic is not known, but several hypotheses have been proposed. At a biochemical level, inorganic arsenic in the pentavalent state may replace phosphate in several reactions. In the trivalent state, inorganic and organic (methylated) arsenic may react with critical thiols in proteins and inhibit their activity. Regarding cancer, potential mechanisms include genotoxicity, altered DNA methylation, oxidative stress, altered cell proliferation, co-carcinogenesis, and tumor promotion. A better understanding of the mechanism(s) of action of arsenic will make a more confident determination of the risks associated with exposure to this chemical.

Jomova, K., et al. (2011). “Arsenic: toxicity, oxidative stress and human disease.” J Appl Toxicol 31(2): 95-107.

Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress.

Kumar, A., et al. (2020). “Lead Toxicity: Health Hazards, Influence on Food Chain, and Sustainable Remediation Approaches.” Int J Environ Res Public Health 17(7).

Lead (Pb) toxicity has been a subject of interest for environmental scientists due to its toxic effect on plants, animals, and humans. An increase in several Pb related industrial activities and use of Pb containing products such as agrochemicals, oil and paint, mining, etc. can lead to Pb contamination in the environment and thereby, can enter the food chain. Being one of the most toxic heavy metals, Pb ingestion via the food chain has proven to be a potential health hazard for plants and humans. The current review aims to summarize the research updates on Pb toxicity and its effects on plants, soil, and human health. Relevant literature from the past 20 years encompassing comprehensive details on Pb toxicity has been considered with key issues such as i) Pb bioavailability in soil, ii) Pb biomagnification, and iii) Pb- remediation, which has been addressed in detail through physical, chemical, and biological lenses. In the review, among different Pb-remediation approaches, we have highlighted certain advanced approaches such as microbial assisted phytoremediation which could possibly minimize the Pb load from the resources in a sustainable manner and would be a viable option to ensure a safe food production system.

Kumar, S. and A. Sharma (2019). “Cadmium toxicity: effects on human reproduction and fertility.” Rev Environ Health 34(4): 327-338.

Background Cadmium (Cd) is a non-essential toxic heavy metal, an environmental toxicant, and toxic at a low concentration, and it has no known beneficial role in the human body. Its exposure induces various health impairments including hostile reproductive health. Objective The present review discusses the information on exposure to Cd and human reproductive health impairments including pregnancy or its outcome with respect to environmental and occupational exposure. Methods The present review provides current information on the reproductive toxic potential of Cd in humans. The data were collected using various websites and consulting books, reports, etc. We have included recent data which were published from 2000 onward in this review. Results Cd exposure affects human male reproductive organs/system and deteriorates spermatogenesis, semen quality especially sperm motility and hormonal synthesis/release. Based on experimental and human studies, it also impairs female reproduction and reproductive hormonal balance and affects menstrual cycles. Based on the literature, it might be concluded that exposure to Cd at low doses has adverse effects on both human male and female reproduction and affects pregnancy or its outcome. Further, maternal prenatal Cd exposure might have a differential effect on male and female offspring especially affecting more female offspring. Hence, efforts must be made to prevent exposure to Cd. Conclusion Cd affects both male and female reproduction, impairs hormone synthesis/regulation and deteriorates pregnancy rate or its outcome even at lower doses.

Mania, M., et al. (2015). “Total and inorganic arsenic in fish, seafood and seaweeds–exposure assessment.” Rocz Panstw Zakl Hig 66(3): 203-210.

BACKGROUND: According to the European Food Safety Authority (EFSA), fish, seafood and seaweeds are foodstuffs that significantly contribute to dietary arsenic intake. With the exception of some algal species, the dominant compounds of arsenic in such food products are the less toxic organic forms. Both the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and EFSA recommend that speciation studies be performed to determine the different chemical forms in which arsenic is present in food due to the differences in their toxicity. Knowing such compositions can thus enable a complete exposure assessment to be made. OBJECTIVES: Determination of total and inorganic arsenic contents in fish, their products, seafood and seaweeds present on the Polish market. This was then followed by an exposure assessment of consumers to inorganic arsenic in these foodstuffs. MATERIAL AND METHODS: Total and inorganic arsenic was determined in 55 samples of fish, their products, seafood as well as seaweeds available on the market. The analytical method was hydride generation atomic absorption spectrometry (HGAAS), after dry ashing of samples and reduction of arsenic to arsenic hydride using sodium borohydride. In order to isolate only the inorganic forms of arsenic prior to mineralisation, samples were subjected to concentrated HCl hydrolysis, followed by reduction with hydrobromic acid and hydrazine sulphate after which triple chloroform extractions and triple 1M HCl re-extractions were performed. Exposure of adults was estimated in relation to the Benchmark Dose Lower Confidence Limit (BMDL0.5) as set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) that resulted in a 0.5% increase in lung cancer (3.0 μg/kg body weight (b.w.) per day). RESULTS: Mean total arsenic content from all investigated fish samples was 0.46 mg/kg (90th percentile 0.94 mg/kg), whilst the inorganic arsenic content never exceeded the detection limit of the analytical method used (0.025 mg/kg). In fish products, mean total arsenic concentration was 1.48 mg/kg (90th percentile: 2.42 mg/kg), whilst in seafood they were 0.87 mg/ kg (90th percentile: 2.23 mg/kg), for inorganic arsenic contamination at the 90th percentile was 0.043 mg/kg with most results however being less than 0.025 mg/kg. The highest inorganic arsenic levels were determined in the Hijiki algal species samples (102.7 mg/kg), whereas the other algal samples gave a mean inorganic concentration of 0.41 mg/kg (90th percentile 0.86 mg/kg). The estimated average adults exposure to inorganic arsenic in fish, seafood and seaweeds was less than 0.5% of the lowest BMDL0.5 dose. Only for the Hijiki seaweed it was at 4.9% BMDL0.5. CONCLUSIONS: Results demonstrate that dietary arsenic intake from fish, seafood and seaweed along with all their products do not constitute a significant health threat to consumers apart from the seaweed species Hizikia fusiformis in which over 40% of all the inorganic arsenic compounds were found.

Medina-Pizzali, M., et al. (2018). “[Arsenic Intake: Impact in Human Nutrition and Health].” Rev Peru Med Exp Salud Publica 35(1): 93-102.

Arsenic is an element that is widely distributed throughout the environment. Its compounds are mainly in the state of pentavalent and trivalent oxidation; and in inorganic and organic forms. Arsenical species vary in their degree of toxicity, with inorganic compounds being more toxic than organic and trivalent compounds more toxic than pentavalent compounds. There would be interconversion between the less toxic species and other more toxic species and the cooking and processing methods could affect it. Arsenic is a carcinogenic agent and causes multiple negative effects on human health in the short and long term. Non-occupational human exposure to arsenic occurs mainly through water and food. The regulation is variable for each country and is based on WHO standards, the Codex Alimentarius, and the European Union. Many studies focus on determining the total arsenic content but do not identify arsenical species in foods. Globally, fish and seafood, chicken, meat, rice, and seaweed have high levels of arsenic. In Peru, there are few studies on total arsenic content and arsenical species in food despite the fact that we have areas with high levels of environmental contamination. The objective of this review is to discuss exposure to arsenic through food and water intake, related regulations, toxicity, consequences on human health and main foods that contribute to its intake.

Mendola, P., et al. (2002). “Environmental factors associated with a spectrum of neurodevelopmental deficits.” Ment Retard Dev Disabil Res Rev 8(3): 188-197.

A number of environmental agents have been shown to demonstrate neurotoxic effects either in human or laboratory animal studies. Critical windows of vulnerability to the effects of these agents occur both pre- and postnatally. The nervous system is relatively unique in that different parts are responsible for different functional domains, and these develop at different times (e.g., motor control, sensory, intelligence and attention). In addition, the many cell types in the brain have different windows of vulnerability with varying sensitivities to environmental agents. This review focuses on two environmental agents, lead and methylmercury, to illustrate the neurobehavioral and cognitive effects that can result from early life exposures. Special attention is paid to distinguishing between the effects detected following episodes of poisoning and those detected following lower dose exposures. Perinatal and childhood exposure to high doses of lead results in encephalopathy and convulsions. Lower-dose lead exposures have been associated with impairment in intellectual function and attention. At high levels of prenatal exposure, methylmercury produces mental retardation, cerebral palsy and visual and auditory deficits in children of exposed mothers. At lower levels of methylmercury exposure, the effects in children have been more subtle. Other environmental neurotoxicants that have been shown to produce developmental neurotoxicity include polychlorinated biphenyls (PCBs), dioxins, pesticides, ionizing radiation, environmental tobacco smoke, and maternal use of alcohol, tobacco, marijuana and cocaine. Exposure to environmental agents with neurotoxic effects can result in a spectrum of adverse outcomes from severe mental retardation and disability to more subtle changes in function depending on the timing and dose of the chemical agent.

Milesi, M. M., et al. (2021). “Glyphosate Herbicide: Reproductive Outcomes and Multigenerational Effects.” Front Endocrinol (Lausanne) 12: 672532.

Glyphosate base herbicides (GBHs) are the most widely applied pesticides in the world and are mainly used in association with GBH-tolerant crop varieties. Indiscriminate and negligent use of GBHs has promoted the emergence of glyphosate resistant weeds, and consequently the rise in the use of these herbicides. Glyphosate, the active ingredient of all GBHs, is combined with other chemicals known as co-formulants that enhance the herbicide action. Nowadays, the safety of glyphosate and its formulations remain to be a controversial issue, as evidence is not conclusive whether the adverse effects are caused by GBH or glyphosate, and little is known about the contribution of co-formulants to the toxicity of herbicides. Currently, alarmingly increased levels of glyphosate have been detected in different environmental matrixes and in foodstuff, becoming an issue of social concern. Some in vitro and in vivo studies have shown that glyphosate and its formulations exhibit estrogen-like properties, and growing evidence has indicated they may disrupt normal endocrine function, with adverse consequences for reproductive health. Moreover, multigenerational effects have been reported and epigenetic mechanisms have been proved to be involved in the alterations induced by the herbicide. In this review, we provide an overview of: i) the routes and levels of human exposure to GBHs, ii) the potential estrogenic effects of glyphosate and GBHs in cell culture and animal models, iii) their long-term effects on female fertility and mechanisms of action, and iv) the consequences on health of successive generations.

Myers, J. P., et al. (2016). “Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement.” Environ Health 15: 19.

The broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Since the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold. Further increases in the volume applied are likely due to more and higher rates of application in response to the widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed (soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health Organization’s International Agency for Research on Cancer recently concluded that glyphosate is “probably carcinogenic to humans.” In response to changing GBH use patterns and advances in scientific understanding of their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4) Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We offer a series of recommendations related to the need for new investments in epidemiological studies, biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and Prevention.

Oken, E. and D. C. Bellinger (2008). “Fish consumption, methylmercury and child neurodevelopment.” Curr Opin Pediatr 20(2): 178-183.

PURPOSE OF REVIEW: To summarize recent evidence regarding associations of early life exposure to mercury from maternal fish consumption during pregnancy, thimerosal in vaccines and dental amalgam with child neurodevelopment. RECENT FINDINGS: Recent publications have built upon previous evidence demonstrating mild detrimental neurocognitive effects from prenatal methylmercury exposure from maternal fish consumption during pregnancy. New studies examining the effects of prenatal fish consumption as well as methylmercury suggest there are benefits from prenatal fish consumption, but also that consumption of fish high in mercury should be avoided. Future studies incorporating information on both the methylmercury and the docosahexaenoic acid contained within fish will help to refine recommendations to optimize outcomes for mothers and children. Additional recent studies have supported the safety of vaccines containing thimerosal and of dental amalgam for repair of dental caries in children. SUMMARY: Exposure to mercury may harm child development. Interventions intended to reduce exposure to low levels of mercury in early life must, however, be carefully evaluated in consideration of the potential attendant harm from resultant behavior changes, such as reduced docosahexaenoic acid exposure from lower seafood intake, reduced uptake of childhood vaccinations and suboptimal dental care.

Padmakumar, V., et al. (2019). “Levels of Mercury in Fish-Eating Children, With and Without Amalgam Restoration.” J Pharm Bioallied Sci 11(Suppl 2): S397-s401.

BACKGROUND: Mercury is a naturally occurring metal that exists in three forms: elemental (metallic), inorganic, and organic mercury. Amalgam, which is an alloy of inorganic mercury, is used as a restorative material in dentistry. Organic mercury gets ingested in the body mainly by the consumption of seafood. Mercury is also stated to cause various adverse health effects such as gastrointestinal disturbances, dermatitis, muscle weakness, and neurological disorders. In recent years, the use of amalgam has become a controversy stating the various adverse effects of mercury. Hence, the study was conducted to determine and compare the variation in levels of organic and inorganic mercury in fish-eating children before and after placement of amalgam restoration. MATERIALS AND METHODS: Seventy-five subjects, 42 males (56%) and 35 females (44%) of age group ranging 7-13 years, living in South Canara district of Karnataka, India, were selected as a part of the study. Hair and urine samples were collected for estimation of organic and inorganic levels of mercury, respectively. Informed consent was collected from all the participating subjects. RESULTS: On comparison between organic and inorganic mercury levels during the study period, the concentration of organic mercury in hair samples was greater irrespective of amalgam restorations present (1.172 and 0.085, respectively; P < 0.001). CONCLUSION: Thus inorganic levels of mercury do not seem to pose a threat as much as the organic levels observed in hair, which remain fairly constant for a longer period of time. Hence in a coastal region where this study was undertaken and fish being a staple food, the risk could probably be attributed to more of an organic toxicity than an inorganic one. Thus amalgam is relatively safe to be practiced and the controversy against it should be reevaluated.

Peillex, C. and M. Pelletier (2020). “The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity.” J Immunotoxicol 17(1): 163-174.

Glyphosate, or N-phosphomethyl(glycine), is an organophosphorus compound and a competitive inhibitor of the shikimate pathway that allows aromatic amino acid biosynthesis in plants and microorganisms. Its utilization in broad-spectrum herbicides, such as RoundUp(®), has continued to increase since 1974; glyphosate, as well as its primary metabolite aminomethylphosphonic acid, is measured in soils, water, plants, animals and food. In humans, glyphosate is detected in blood and urine, especially in exposed workers, and is excreted within a few days. It has long been regarded as harmless in animals, but growing literature has reported health risks associated with glyphosate and glyphosate-based herbicides. In 2017, the International Agency for Research on Cancer (IARC) classified glyphosate as “probably carcinogenic” in humans. However, other national agencies did not tighten their glyphosate restrictions and even prolonged authorizations of its use. There are also discrepancies between countries’ authorized levels, demonstrating an absence of a clear consensus on glyphosate to date. This review details the effects of glyphosate and glyphosate-based herbicides on fish and mammal health, focusing on the immune system. Increasing evidence shows that glyphosate and glyphosate-based herbicides exhibit cytotoxic and genotoxic effects, increase oxidative stress, disrupt the estrogen pathway, impair some cerebral functions, and allegedly correlate with some cancers. Glyphosate effects on the immune system appear to alter the complement cascade, phagocytic function, and lymphocyte responses, and increase the production of pro-inflammatory cytokines in fish. In mammals, including humans, glyphosate mainly has cytotoxic and genotoxic effects, causes inflammation, and affects lymphocyte functions and the interactions between microorganisms and the immune system. Importantly, even as many outcomes are still being debated, evidence points to a need for more studies to better decipher the risks from glyphosate and better regulation of its global utilization.

Rahman, A., et al. (2017). “Early life arsenic exposure, infant and child growth, and morbidity: a systematic review.” Arch Toxicol 91(11): 3459-3467.

Epidemiological studies have suggested a negative association between early life arsenic exposure and fetal size at birth, and subsequently with child morbidity and growth. However, our understanding of the relationship between arsenic exposure and morbidity and growth is limited. This paper aims to systematically review original human studies with an analytical epidemiological study design that have assessed arsenic exposure in fetal life or early childhood and evaluated the association with one or several of the following outcomes: fetal growth, birth weight or other birth anthropometry, infant and child growth, infectious disease morbidity in infancy and early childhood. A literature search was conducted in PubMed, TOXLINE, Web of Science, SciFinder and Scopus databases filtered for human studies. Based on the predefined eligibility criteria, two authors independently evaluated the studies. A total of 707 studies with morbidity outcomes were identified, of which six studies were eligible and included in this review. For the growth outcomes, a total of 2959 studies were found and nine fulfilled the criteria and were included in the review. A majority of the papers (10/15) emanated from Bangladesh, three from the USA, one from Romania and one from Canada. All included studies on arsenic exposure and morbidity showed an increased risk of respiratory tract infections and diarrhea. The findings in the studies of arsenic exposure and fetal, infant, and child growth were heterogeneous. Arsenic exposure was not associated with fetal growth. There was limited evidence of negative associations between arsenic exposures and birth weight and growth during early childhood. More studies from arsenic-affected low- and middle-income countries are needed to support the generalizability of study findings.

Rehman, M. U., et al. (2021). “Fate of arsenic in living systems: Implications for sustainable and safe food chains.” J Hazard Mater 417: 126050.

Arsenic, a group 1 carcinogen for humans, is abundant as compared to other trace elements in the environment and is present mainly in the Earth’s crust and soil. The arsenic distributions in different geographical regions are dependent on their geological histories. Anthropogenic activities also contribute significantly to arsenic release into the environment. Arsenic presents several complications to humans, animals, and plants. The physiology of plants and their growth and development are affected by arsenic. Arsenic is known to cause cancer and several types of organ toxicity, such as cardiotoxicity, nephrotoxicity, and hepatotoxicity. In the environment, arsenic exists in variable forms both as inorganic and organic species. From arsenic containing compartments, plants can absorb and accumulate arsenic. Crops grown on these contaminated soils pose several-fold higher toxicity to humans compared with drinking water if arsenic enters the food chain. Information regarding arsenic transfer at different trophic levels in food chains has not been summarized until now. The present review focuses on the food chain perspective of arsenic, which affects all components of the food chain during its course. The circumstances that facilitate arsenic accumulation in flora and fauna, as components of the food chain, are outlined in this review.

Soares, D., et al. (2021). “Glyphosate Use, Toxicity and Occurrence in Food.” Foods 10(11).

Glyphosate is a systemic, broad-spectrum and post-emergent herbicide. The use of glyphosate has grown in the last decades, and it is currently the most used herbicide worldwide. The rise of glyphosate consumption over the years also brought an increased concern about its possible toxicity and consequences for human health. However, a scientific community consensus does not exist at the present time, and glyphosate’s safety and health consequences are controversial. Since glyphosate is mainly applied in fields and can persist several months in the soil, concerns have been raised about the impact that its presence in food can cause in humans. Therefore, this work aims to review the glyphosate use, toxicity and occurrence in diverse food samples, which, in certain cases, occurs at violative levels. The incidence of glyphosate at levels above those legally allowed and the suspected toxic effects of this compound raise awareness regarding public health.

Union, E. (2006). Consolidated text: Commission Regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs.

Vasconcelos Neto, M. C. d., et al. (2019). “Lead contamination in food consumed and produced in Brazil: Systematic review and meta-analysis.” Food Research International 126: 108671.

This systematic review (SR) evaluated evidence of lead (Pb) levels in foods consumed or produced in Brazil. Seventy-seven publications were included in this review, corresponding to a total of 8466 food samples that were grouped into 12 food categories with similar characteristics (infant food; sugar; beverages; meat and meat products; nuts, cocoa and products; fruits and fruit products; grains, cereals and products; milk and milk products; eggs; oil and fat spreads; vegetables and vegetable products and other foods). The random model was used to establish levels of Pb in food categories. We used the software R® to perform the meta-analysis. The overall occurrence of Pb was estimated at 0.0541 mg/kg, and ranged from 0.0004 mg/kg to 0.4842 mg/kg. The SR and meta-analysis presented relevant results about Pb contamination on foods, despite the high heterogeneity. They were understood as a viable strategy to answer questions regarding prevalence of Pb which is necessary for the risk assessment of Pb intake in foods.

Yao, M., et al. (2022). “Dietary fiber ameliorates lead-induced gut microbiota disturbance and alleviates neuroinflammation.” J Sci Food Agric 102(15): 6795-6803.

Dietary fiber (DF) is a carbohydrate from the edible part of plants and has the functions of promoting gastrointestinal motility, regulating gut microbiota (GM) and improving health. Lead is a non-essential toxic heavy metal that can accumulate in the environment over time and enter the body through the respiratory tract, skin and gastrointestinal tract. Lead not only causes disturbances in GM but also leads to loss of homeostasis of immune functions, causes neuronal damage and results in neuroinflammation. The scientific literature has reported that DF had anti-inflammatory activity as a natural product. This review highlights the role of DF and its metabolic products in alleviating lead-induced neuroinflammation by inducing changes in the species and quantity of GM and regulating the immune system, providing a potential dietary protective strategy for lead-induced disease. © 2022 Society of Chemical Industry.

Table F – Food Additives. Criteria to escape Tier III – Criterion: Less than 3:1 ratio of omega-6 to omega-3 fatty acids per serving (refs 1-10) and No more than 5g of omega-6 fatty acids per serving (11-20)

(Simopoulos 2002)
(Simopoulos 2008)
(Simopoulos 2006)
(Simopoulos 2010)
(Elbandy 2022)
(Elbandy 2022)
(Gómez Candela, Bermejo López et al. 2011)
(Simopoulos 2016)
(Van Name, Savoye et al. 2020)
(Jang and Park 2020)
(Blasbalg, Hibbeln et al. 2011)
(Ramsden, Zamora et al. 2013)
(Román, Jackson et al. 2019)
(Selmin, Papoutsis et al. 2021)
(Rousseau 2021)
(Gow and Hibbeln 2014)
(Hallahan, Ryan et al. 2016)
(Gow and Hibbeln 2014)
(Hibbeln and Gow 2014)
(Lewis, Hibbeln et al. 2011)

References:

Blasbalg, T. L., et al. (2011). “Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century.” Am J Clin Nutr 93(5): 950-962.

BACKGROUND: The consumption of omega-3 (n-3) and omega-6 (n-6) essential fatty acids in Western diets is thought to have changed markedly during the 20th century. OBJECTIVE: We sought to quantify changes in the apparent consumption of essential fatty acids in the United States from 1909 to 1999. DESIGN: We calculated the estimated per capita consumption of food commodities and availability of essential fatty acids from 373 food commodities by using economic disappearance data for each year from 1909 to 1999. Nutrient compositions for 1909 were modeled by using current foods (1909-C) and foods produced by traditional early 20th century practices (1909-T). RESULTS: The estimated per capita consumption of soybean oil increased >1000-fold from 1909 to 1999. The availability of linoleic acid (LA) increased from 2.79% to 7.21% of energy (P < 0.000001), whereas the availability of α-linolenic acid (ALA) increased from 0.39% to 0.72% of energy by using 1909-C modeling. By using 1909-T modeling, LA was 2.23% of energy, and ALA was 0.35% of energy. The ratio of LA to ALA increased from 6.4 in 1909 to 10.0 in 1999. The 1909-T but not the 1909-C data showed substantial declines in dietary availability (percentage of energy) of n-6 arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Predicted net effects of these dietary changes included declines in tissue n–3 highly unsaturated fatty acid status (36.81%, 1909-T; 31.28%, 1909-C; 22.95%, 1999) and declines in the estimated omega-3 index (8.28, 1909-T; 6.51, 1909-C; 3.84, 1999). CONCLUSION: The apparent increased consumption of LA, which was primarily from soybean oil, has likely decreased tissue concentrations of EPA and DHA during the 20th century.

Elbandy, M. (2022). “Anti-Inflammatory Effects of Marine Bioactive Compounds and Their Potential as Functional Food Ingredients in the Prevention and Treatment of Neuroinflammatory Disorders.” Molecules 28(1).

Functional foods include enhanced, enriched, fortified, or whole foods that impart health benefits beyond their nutritional value, particularly when consumed as part of a varied diet on a regular basis at effective levels. Marine sources can serve as the sources of various healthy foods and numerous functional food ingredients with biological effects can be derived from these sources. Microalgae, macroalgae, crustaceans, fungi, bacteria fish, and fish by-products are the most common marine sources that can provide many potential functional food ingredients including phenolic compounds, proteins and peptides, and polysaccharides. Neuroinflammation is closely linked with the initiation and progression of various neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. Activation of astrocytes and microglia is a defense mechanism of the brain to counter damaged tissues and detrimental pathogens, wherein their chronic activation triggers neuroinflammation that can further exacerbate or induce neurodegeneration. Currently, available therapeutic agents only provide symptomatic relief from these disorders and no therapies are available to stop or slow down the advancement of neurodegeneration. Thereffore, natural compounds that can exert a protective effect against these disorders have therapeutic potential. Numerous chemical compounds, including bioactive peptides, fatty acids, pigments, alkaloids, and polysaccharides, have already been isolated from marine sources that show anti-inflammatory properties, which can be effective in the treatment and prevention of neuroinflammatory disorders. The anti-inflammatory potential of marine-derived compounds as functional food ingredients in the prevention and treatment of neurological disorders is covered in this review.

Gómez Candela, C., et al. (2011). “Importance of a balanced omega 6/omega 3 ratio for the maintenance of health: nutritional recommendations.” Nutr Hosp 26(2): 323-329.

The modification of dietary patterns has led to a change in fatty acid consumption, with an increase in the consumption of ω-6 fatty acids and a marked reduction in the consumption of ω-3 fatty acids. This in turn has given rise to an imbalance in the ω-6/ω-3 ratio, which is now very different from the original 1:1 ratio of humans in the past. Given the involvement of ω-6 and ω-3 essential fatty acids in disease processes, the present article examines changes in dietary patterns that have led to the present reduction in the consumption of ω-3 essential fatty acids, and to study the importance of the ω-6/ω-3 balance in maintaining good health. In addition, an assessment is made of the established recommendations for preventing a poor intake of ω-3 essential fatty acids, and the possible options for compensating the lack of these fatty acids in the diet.

Gow, R. V. and J. R. Hibbeln (2014). “Omega-3 fatty acid and nutrient deficits in adverse neurodevelopment and childhood behaviors.” Child Adolesc Psychiatr Clin N Am 23(3): 555-590.

Nutritional insufficiencies of omega-3 highly unsaturated fatty acids (HUFAs) may have adverse effects on brain development and neurodevelopmental outcomes. A recent meta-analysis reported a small to modest effect size for the efficacy of omega-3 in youth. Several controlled trials of omega-3 HUFAs combined with micronutrients show sizable reductions in aggressive, antisocial, and violent behavior in youth and young adult prisoners. Studies of HUFAs in youth, however, remain lacking. As the evidence base for omega-3 HUFAs as potential psychiatric treatment develops, dietary adjustments to increase omega-3 and reduce omega-6 HUFA consumption are sensible recommendations based on general health considerations.

Hallahan, B., et al. (2016). “Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression.” Br J Psychiatry 209(3): 192-201.

BACKGROUND: Trials evaluating efficacy of omega-3 highly unsaturated fatty acids (HUFAs) in major depressive disorder report discrepant findings. AIMS: To establish the reasons underlying inconsistent findings among randomised controlled trials (RCTs) of omega-3 HUFAs for depression and to assess implications for further trials. METHOD: A systematic bibliographic search of double-blind RCTs was conducted between January 1980 and July 2014 and an exploratory hypothesis-testing meta-analysis performed in 35 RCTs including 6665 participants receiving omega-3 HUFAs and 4373 participants receiving placebo. RESULTS: Among participants with diagnosed depression, eicosapentaenoic acid (EPA)-predominant formulations (>50% EPA) demonstrated clinical benefits compared with placebo (Hedge’s G = 0.61, P<0.001) whereas docosahexaenoic acid (DHA)-predominant formulations (>50% DHA) did not. EPA failed to prevent depressive symptoms among populations not diagnosed for depression. CONCLUSIONS: Further RCTs should be conducted on study populations with diagnosed or clinically significant depression of adequate duration using EPA-predominant omega-3 HUFA formulations.

Hibbeln, J. R. and R. V. Gow (2014). “The potential for military diets to reduce depression, suicide, and impulsive aggression: a review of current evidence for omega-3 and omega-6 fatty acids.” Mil Med 179(11 Suppl): 117-128.

The current burden of psychological distress and illness poses as a significant barrier to optimal force efficacy. Here we assess nutrients in military diets, specifically highly unsaturated essential fatty acids, in the reduction of risk or treatment of psychiatric distress. Moderate to strong evidence from several meta-analyses of prospective cohort trials indicate that Mediterranean diet patterns reduce risk of clinical depressions. Specific nutrients and foods of biological interest in relation to mental health outcomes are then discussed and evaluated. Moderate evidence indicates that when fish consumption decreases and simultaneously omega-6 increases, the risk of clinical depressive symptoms are elevated. One meta-analysis examining tissue compositions provides moderate to strong evidence that higher levels of omega-3 highly unsaturated fatty acids (HUFAs) (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) are associated with decreased risk of clinical depressions. Other meta-analytic reviews of randomized placebo-controlled trials provide moderate to strong evidence of significantly improving clinically depressive symptoms when the formulation given was >50% in eicosapentaenoic acid. Finally, a meta-analysis of omega-3 HUFAs provides modest evidence of clinical efficacy for attention-deficit hyperactivity disorder. This article recommends that a rebalancing of the essential fatty acid composition of U.S. military diets, achieve tissue compositions of HUFAs consistent with traditional Mediterranean diets, may help reduce military psychiatric distress and simultaneously increase force efficacy substantially.

Jang, H. and K. Park (2020). “Omega-3 and omega-6 polyunsaturated fatty acids and metabolic syndrome: A systematic review and meta-analysis.” Clin Nutr 39(3): 765-773.

BACKGROUND & AIMS: Previous studies suggest that polyunsaturated fatty acids (PUFAs) may reduce the risk of metabolic diseases, but some have shown ambiguous results. The aim of this study was to systematically evaluate and summarize available evidence on the association between omega-3 and omega-6 PUFA levels and risk of metabolic syndrome (MetS). METHODS: A systematic literature search of articles published until December 2017 was conducted in PubMed, Web of Science, and Cochrane Library databases. Meta-analyses of the highest vs. lowest categories of omega-3 and omega-6 PUFAs were conducted using the random effects models. RESULTS: Thirteen studies (2 case-control, 9 cross-sectional, 1 nested case-control, and 1 prospective cohort) with 36,542 individuals were included. Higher omega-3 PUFA levels in diets or blood were associated with a 26% reduction in the risk of MetS (odds ratio (OR)/relative risk (RR) 0.74, 95% confidence interval (CI) 0.62-0.89). This inverse association was evident among studies with Asian populations (OR/RR 0.69, 95% CI 0.54-0.87), but not among those with American/European populations (OR/RR 0.84, 95% CI 0.55-1.28). Null results were found regarding the association between circulating/dietary omega-6 PUFAs and MetS. CONCLUSION: The present meta-analysis indicates that higher intakes of omega-3 PUFAs, but not omega-6 PUFAs, was associated with lower MetS risk; adding to the current body of evidence on the metabolic health effects of circulating/dietary omega-3 PUFAs.

Lewis, M. D., et al. (2011). “Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison.” J Clin Psychiatry 72(12): 1585-1590.

BACKGROUND: The recent escalation of US military suicide deaths to record numbers has been a sentinel for impaired force efficacy and has accelerated the search for reversible risk factors. OBJECTIVE: To determine whether deficiencies of neuroactive, highly unsaturated omega-3 essential fatty acids (n-3 HUFAs), in particular docosahexaenoic acid (DHA), are associated with increased risk of suicide death among a large random sample of active-duty US military. METHOD: In this retrospective case-control study, serum fatty acids were quantified as a percentage of total fatty acids among US military suicide deaths (n = 800) and controls (n = 800) matched for age, date of collection of sera, sex, rank, and year of incident. Participants were active-duty US military personnel (2002-2008). For cases, age at death ranged from 17-59 years (mean = 27.3 years, SD = 7.3 years). Outcome measures included death by suicide, postdeployment health assessment questionnaire (Department of Defense Form 2796), and ICD-9 mental health diagnosis data. RESULTS: Risk of suicide death was 14% higher per SD of lower DHA percentage (OR = 1.14; 95% CI, 1.02-1.27; P < .03) in adjusted logistic regressions. Among men, risk of suicide death was 62% greater with low serum DHA status (adjusted OR = 1.62; 95% CI, 1.12-2.34; P < .01, comparing DHA below 1.75% [n = 1,389] to DHA of 1.75% and above [n = 141]). Risk of suicide death was 52% greater in those who reported having seen wounded, dead, or killed coalition personnel (OR = 1.52; 95% CI, 1.11-2.09; P < .01). CONCLUSION: This US military population had a very low and narrow range of n-3 HUFA status. Although these data suggest that low serum DHA may be a risk factor for suicide, well-designed intervention trials are needed to evaluate causality.

Ramsden, C. E., et al. (2013). “Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis.” Bmj 346: e8707.

OBJECTIVE: To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death. DESIGN: Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data. SETTING: Ambulatory, coronary care clinic in Sydney, Australia. PARTICIPANTS: 458 men aged 30-59 years with a recent coronary event. INTERVENTIONS: Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups. OUTCOME MEASURES: All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group. RESULTS: The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07). CONCLUSIONS: Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats. TRIAL REGISTRATION: Clinical trials NCT01621087.

Román, G. C., et al. (2019). “Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease.” Rev Neurol (Paris) 175(10): 724-741.

The mechanisms of action of the dietary components of the Mediterranean diet are reviewed in prevention of cardiovascular disease, stroke, age-associated cognitive decline and Alzheimer disease. A companion article provides a comprehensive review of extra-virgin olive oil. The benefits of consumption of long-chain ω-3 fatty acids are described. Fresh fish provides eicosapentaenoic acid while α-linolenic acid is found in canola and soybean oils, purslane and nuts. These ω-3 fatty acids interact metabolically with ω-6 fatty acids mainly linoleic acid from corn oil, sunflower oil and peanut oil. Diets rich in ω-6 fatty acids inhibit the formation of healthier ω-3 fatty acids. The deleterious effects on lipid metabolism of excessive intake of carbohydrates, in particular high-fructose corn syrup and artificial sweeteners, are explained. The critical role of the ω-3 fatty acid docosahexaenoic acid in the developing and aging brain and in Alzheimer disease is addressed. Nutritional epidemiology studies, prospective population-based surveys, and clinical trials confirm the salutary effects of fish consumption on prevention of coronary artery disease, stroke and dementia. Recent recommendations on fish consumption by pregnant women and potential mercury toxicity are reviewed. The polyphenols and flavonoids of plant origin play a critical role in the Mediterranean diet, because of their antioxidant and anti-inflammatory properties of benefit in type-2 diabetes mellitus, cardiovascular disease, stroke and cancer prevention. Polyphenols from fruits and vegetables modulate tau hyperphosphorylation and beta amyloid aggregation in animal models of Alzheimer disease. From the public health viewpoint worldwide the daily consumption of fruits and vegetables has become the main tool for prevention of cardiovascular disease and stroke. We review the important dietary role of cereal grains in prevention of coronary disease and stroke. Polyphenols from grapes, wine and alcoholic beverages are discussed, in particular their effects on coagulation. The mechanisms of action of probiotics and vitamins are also included.

Rousseau, G. (2021). “Microbiota, a New Playground for the Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Diseases.” Mar Drugs 19(2).

Several cardioprotective mechanisms attributed to Omega-3 polyunsaturated fatty acids (PUFAs) have been studied and widely documented. However, in recent years, studies have supported the concept that the intestinal microbiota can play a much larger role than we had anticipated. Microbiota could contribute to several pathologies, including cardiovascular diseases. Indeed, an imbalance in the microbiota has often been reported in patients with cardiovascular disease and produces low-level inflammation. This inflammation contributes to, more or less, long-term development of cardiovascular diseases. It can also worsen the symptoms and the consequences of these pathologies. According to some studies, omega-3 PUFAs in the diet could restore this imbalance and mitigate its harmful effects on cardiovascular diseases. Many mechanisms are involved and included: (1) a reduction of bacteria producing trimethylamine (TMA); (2) an increase in bacteria producing butyrate, which has anti-inflammatory properties; and (3) a decrease in the production of pro-inflammatory cytokines. Additionally, omega-3 PUFAs would help maintain better integrity in the intestinal barrier, thereby preventing the translocation of intestinal contents into circulation. This review will summarize the effects of omega-3 PUFAs on gut micro-biota and the potential impact on cardiac health.

Selmin, O. I., et al. (2021). “n-6 High Fat Diet Induces Gut Microbiome Dysbiosis and Colonic Inflammation.” Int J Mol Sci 22(13).

Background: Concerns are emerging that a high-fat diet rich in n-6 PUFA (n-6HFD) may alter gut microbiome and increase the risk of intestinal disorders. Research is needed to model the relationships between consumption of an n-6HFD starting at weaning and development of gut dysbiosis and colonic inflammation in adulthood. We used a C57BL/6J mouse model to compare the effects of exposure to a typical American Western diet (WD) providing 58.4%, 27.8%, and 13.7% energy (%E) from carbohydrates, fat, and protein, respectively, with those of an isocaloric and isoproteic soybean oil-rich n-6HFD providing 50%E and 35.9%E from total fat and carbohydrates, respectively on gut inflammation and microbiome profile. Methods: At weaning, male offspring were assigned to either the WD or n-6HFD through 10-16 weeks of age. The WD included fat exclusively from palm oil whereas the n-6HFD contained fat exclusively from soybean oil. We recorded changes in body weight, cyclooxygenase-2 (COX-2) expression, colon histopathology, and gut microbiome profile. Results: Compared to the WD, the n-6HFD increased plasma levels of n-6 fatty acids; colonic expression of COX-2; and the number of colonic inflammatory and hyperplastic lesions. At 16 weeks of age, the n-6HFD caused a marked reduction in the gut presence of Firmicutes, Clostridia, and Lachnospiraceae, and induced growth of Bacteroidetes and Deferribacteraceae. At the species level, the n-6HFD sustains the gut growth of proinflammatory Mucispirillum schaedleri and Lactobacillus murinus. Conclusions: An n-6HFD consumed from weaning to adulthood induces a shift in gut bacterial profile associated with colonic inflammation.

Simopoulos, A. P. (2002). “The importance of the ratio of omega-6/omega-3 essential fatty acids.” Biomed Pharmacother 56(8): 365-379.

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today’s Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world.

Simopoulos, A. P. (2006). “Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases.” Biomed Pharmacother 60(9): 502-507.

Anthropological and epidemiological studies and studies at the molecular level indicate that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1 to 16.7/1. A high omega-6/omega-3 ratio, as is found in today’s Western diets, promotes the pathogenesis of many diseases, including cardiovascular disease, cancer, osteoporosis, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 polyunsaturated fatty acids (PUFA) (a lower omega-6/omega-3 ratio), exert suppressive effects. Increased dietary intake of linoleic acid (LA) leads to oxidation of low-density lipoprotein (LDL), platelet aggregation, and interferes with the incorporation of EFA in cell membrane phospholipids. Both omega-6 and omega-3 fatty acids influence gene expression. Omega-3 fatty acids have anti-inflammatory effects, suppress interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6), whereas omega-6 fatty acids do not. Because inflammation is at the base of many chronic diseases, dietary intake of omega-3 fatty acids plays an important role in the manifestation of disease, particularly in persons with genetic variation, as for example in individuals with genetic variants at the 5-lipoxygenase (5-LO). Carotid intima media thickness (IMT) taken as a marker of the atherosclerotic burden is significantly increased, by 80%, in the variant group compared to carriers with the common allele, suggesting increased 5-LO promoter activity associated with the (variant) allele. Dietary arachidonic acid (AA) and LA increase the risk for cardiovascular disease in those with the variants, whereas dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease the risk. A lower ratio of omega-6/omega-3 fatty acids is needed for the prevention and management of chronic diseases. Because of genetic variation, the optimal omega-6/omega-3 fatty acid ratio would vary with the disease under consideration.

Simopoulos, A. P. (2008). “The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases.” Exp Biol Med (Maywood) 233(6): 674-688.

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today’s Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a lower omega-6/omega-3 ratio), exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries.

Simopoulos, A. P. (2010). “Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk.” Exp Biol Med (Maywood) 235(7): 785-795.

The tissue composition of polyunsaturated fatty acids is important to health and depends on both dietary intake and metabolism controlled by genetic polymorphisms that should be taken into consideration in the determination of nutritional requirements. Therefore at the same dietary intake of linoleic acid (LA) and alpha-linolenic acid (ALA), their respective health effects may differ due to genetic differences in metabolism. Delta-5 and delta-6 desaturases, FADS1 and FADS2, respectively, influence the serum, plasma and membrane phospholipid levels of LA, ALA and long-chain polyunsaturated fatty acids during pregnancy, lactation, and may influence an infant’s IQ, atopy and coronary heart disease (CHD) risk. At low intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), polymorphisms at the 5-lipoxygenase (5-LO) level increase the risk for CHD whereas polymorphisms at cyclooxgenase-2 increase the risk for prostate cancer. At high intakes of LA the risk for breast cancer increases. EPA and DHA influence gene expression. In future, intervention studies on the biological effects of LA, ALA and LC-PUFAs, and the effects of genetic variants in FADS1 and FADS2, 5-LO and cyclooxygenase-2 should be taken into consideration both in the determination of nutritional requirements and chronic disease risk. Furthermore, genome-wide association studies need to include environmental exposures and include diet in the interaction between genetic variation and disease association.

Simopoulos, A. P. (2016). “An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity.” Nutrients 8(3): 128.

In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity. Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity.

Van Name, M. A., et al. (2020). “A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.” J Nutr 150(9): 2314-2321.

BACKGROUND: Recent literature suggests that the Western diet’s imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon’s signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.

Table F – Food Additives. Criteria to escape Tier III – Criterion: Less than 2:1 ratio of kilocalories to milligrams of sodium

(Rust and Ekmekcioglu 2017)
(Fodor, Whitmore et al. 1999)
(Aliasgharzadeh, Tabrizi et al. 2022)
(Jafarnejad, Mirzaei et al. 2020)
(He, Li et al. 2013)
(He and MacGregor 2004)
(Neal, Wu et al. 2021)
(Fulgoni, Agarwal et al. 2014)
Action on salt consumer group report: https://www.actiononsalt.org.uk/media/action-on-salt/awareness/shake-the-salt-habit2022/Roundtable-Report_Accelerating-Salt-Reduction-in-the-UK.pdf
World Health Organization (WHO) online article\: https://www.who.int/europe/news/item/20-12-2018-european-salt-action-network-restates-its-support-for-who-goal-of-reducing-salt-intake-to-5-g-per-day-or-less
Johns Hopkins Bloomberg School of Public Health: https://globalhypertensionathopkins.org/courses/sodium

References

Aliasgharzadeh, S., et al. (2022). “Effect of salt reduction interventions in lowering blood pressure: A comprehensive systematic review and meta-analysis of controlled clinical trials.” PLOS ONE 17(12): e0277929.

BACKGROUND: Excessive salt intake results in hypertension (HTN), which is a major risk factor for cardiovascular disease (CVD). This review and meta-analysis aimed to evaluate the effect of salt reduction interventions on systolic blood pressure (SBP) and diastolic blood pressure (DBP). METHODS: Studies were identified via systematic searches of the databases, including PubMed, Embase, Scopus, and Web of Science. All the studies examining the effectiveness of salt reduction interventions on blood pressure (BP), regardless of age, sex, and HTN status, were included in the systematic review, and eligible studies were used in the meta-analysis. A random-effect model was applied for quantitative data synthesis. RESULTS: A total of 50 trials extracted from 40 articles (21 trials on nutrition education,10 on self-help materials,17 on salt substitutes, and 2 on food reformulation) were included in the systematic review. The pooled results of 44 eligible trials showed that salt substitution and nutrition education interventions had significant effects on both SBP (WMD: -7.44 mmHg, P<0.001 and WMD: -2.75 mmHg, P<0.001, respectively), and DBP (WMD: -3.77 mmHg, P<0.001 and WMD: -2.11 mmHg, P<0.001, respectively). Furthermore, using self-help materials led to a significant reduction in SBP among subjects aged 25-60 years (WMD: -2.60 mmHg, P = 0.008); it also decreased both SBP and DBP among those who were hypertensive (WMD: -3.87 mmHg, P = 0.003 and WMD: -2.91 mmHg, P<0.001, respectively). CONCLUSION: Our results supported that salt substitution and nutrition education are effective nutrition strategies to lower BP. It seems that multi-component approaches could be more effective in improving BP status. However, further trials are required.

Fodor, J. G., et al. (1999). “Lifestyle modifications to prevent and control hypertension. 5. Recommendations on dietary salt. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada.” Cmaj 160(9 Suppl): S29-34.

OBJECTIVE: To provide updated, evidence-based recommendations concerning the effects of dietary salt intake on the prevention and control of hypertension in adults (except pregnant women). The guidelines are intended for use in clinical practice and public education campaigns. OPTIONS: Restriction of dietary salt intake may be an alternative to antihypertensive medications or may supplement such medications. Other options include other nonpharmacologic treatments for hypertension and no treatment. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996 using the terms hypertension, blood pressure, vascular resistance, sodium chloride, sodium, diet, sodium or sodium chloride dietary, sodium restricted/reducing diet, clinical trials, controlled clinical trial, randomized controlled trial and random allocation. Both trials and review articles were obtained, and other relevant evidence was obtained from the reference lists of the articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design and graded according to level of evidence. In addition, a systematic review of all published randomized controlled trials relating to dietary salt intake and hypertension was conducted. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: For normotensive people, a marked change in sodium intake is required to achieve a modest reduction in blood pressure (there is a decrease of 1 mm Hg in systolic blood pressure for every 100 mmol decrease in daily sodium intake). For hypertensive patients, the effects of dietary salt restriction are most pronounced if age is greater than 44 years. A decrease of 6.3 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood pressure per 100 mmol decrease in daily sodium intake was observed in people of this age group. For hypertensive patients 44 years of age and younger, the decreases were 2.4 mm Hg for systolic blood pressure and negligible for diastolic blood pressure. A diet in which salt is moderately restricted appears not to be associated with health risks. RECOMMENDATIONS: (1) Restriction of salt intake for the normotensive population is not recommended at present, because of insufficient evidence demonstrating that this would lead to a reduced incidence of hypertension. (2) To avoid excessive intake of salt, people should be counselled to choose foods low in salt (e.g., fresh fruits and vegetables), to avoid foods high in salt (e.g., pre-prepared foods), to refrain from adding salt at the table and minimize the amount of salt used in cooking, and to increase awareness of the salt content of food choices in restaurants. (3) For hypertensive patients, particularly those over the age of 44 years, it is recommended that the intake of dietary sodium be moderately restricted, to a target range of 90-130 mmol per day (which corresponds to 3-7 g of salt per day). (4) The salt consumption of hypertensive patients should be determined by interview. VALIDATION: These recommendations were reviewed by all of the sponsoring organizations and by participants in a satellite symposium of the fourth International Conference on Preventive Cardiology. They have not been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada.

Fulgoni, V. L., 3rd, et al. (2014). “Sodium intake in US ethnic subgroups and potential impact of a new sodium reduction technology: NHANES Dietary Modeling.” Nutr J 13(1): 120.

BACKGROUND: Because excessive dietary sodium intake is a major contributor to hypertension, a reduction in dietary sodium has been recommended for the US population. Using the National Health and Nutrition Examination Survey (NHANES) 2007-2010 data, we estimated current sodium intake in US population ethnic subgroups and modeled the potential impact of a new sodium reduction technology on sodium intake. METHODS: NHANES 2007-2010 data were analyzed using The National Cancer Institute method to estimate usual intake in population subgroups. Potential impact of SODA-LO® Salt Microspheres sodium reduction technology on sodium intake was modeled using suggested sodium reductions of 20-30% in 953 foods and assuming various market penetrations. SAS 9.2, SUDAAN 11, and NHANES survey weights were used in all calculations with assessment across age, gender and ethnic groups. RESULTS: Current sodium intake across all population subgroups exceeds the Dietary Guidelines 2010 recommendations and has not changed during the last decade. However, sodium intake measured as a function of food intake has decreased significantly during the last decade for all ethnicities. “Grain Products” and “Meat, Poultry, Fish, & Mixtures” contribute about 2/3rd of total sodium intake. Sodium reduction, using SODA-LO® Salt Microspheres sodium reduction technology (with 100% market penetration) was estimated to be 185-323 mg/day or 6.3-8.4% of intake depending upon age, gender and ethnic group. CONCLUSIONS: Current sodium intake in US ethnic subgroups exceeds the recommendations and sodium reduction technologies could potentially help reduce dietary sodium intake among those groups.

He, F. J., et al. (2013). “Effect of longer-term modest salt reduction on blood pressure.” Cochrane Database Syst Rev(4): Cd004937.

BACKGROUND: A reduction in salt intake lowers blood pressure (BP) and, thereby, reduces cardiovascular risk. A recent meta-analysis by Graudal implied that salt reduction had adverse effects on hormones and lipids which might mitigate any benefit that occurs with BP reduction. However, Graudal’s meta-analysis included a large number of very short-term trials with a large change in salt intake, and such studies are irrelevant to the public health recommendations for a longer-term modest reduction in salt intake. We have updated our Cochrane meta-analysis. OBJECTIVES: To assess (1) the effect of a longer-term modest reduction in salt intake (i.e. of public health relevance) on BP and whether there was a dose-response relationship; (2) the effect on BP by sex and ethnic group; (3) the effect on plasma renin activity, aldosterone, noradrenaline, adrenaline, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides. SEARCH METHODS: We searched MEDLINE, EMBASE, Cochrane Hypertension Group Specialised Register, Cochrane Central Register of Controlled Trials, and reference list of relevant articles. SELECTION CRITERIA: We included randomised trials with a modest reduction in salt intake and duration of at least 4 weeks. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Random effects meta-analyses, subgroup analyses and meta-regression were performed. MAIN RESULTS: Thirty-four trials (3230 participants) were included. Meta-analysis showed that the mean change in urinary sodium (reduced salt vs usual salt) was -75 mmol/24-h (equivalent to a reduction of 4.4 g/d salt), the mean change in BP was -4.18 mmHg (95% CI: -5.18 to -3.18, I (2)=75%) for systolic and -2.06 mmHg (95% CI: -2.67 to -1.45, I (2)=68%) for diastolic BP. Meta-regression showed that age, ethnic group, BP status (hypertensive or normotensive) and the change in 24-h urinary sodium were all significantly associated with the fall in systolic BP, explaining 68% of the variance between studies. A 100 mmol reduction in 24 hour urinary sodium (6 g/day salt) was associated with a fall in systolic BP of 5.8 mmHg (95%CI: 2.5 to 9.2, P=0.001) after adjusting for age, ethnic group and BP status. For diastolic BP, age, ethnic group, BP status and the change in 24-h urinary sodium explained 41% of the variance between studies. Meta-analysis by subgroup showed that, in hypertensives, the mean effect was -5.39 mmHg (95% CI: -6.62 to -4.15, I (2)=61%) for systolic and -2.82 mmHg (95% CI: -3.54 to -2.11, I (2)=52%) for diastolic BP. In normotensives, the mean effect was -2.42 mmHg (95% CI: -3.56 to -1.29, I (2)=66%) for systolic and -1.00 mmHg (95% CI: -1.85 to -0.15, I (2)=66%) for diastolic BP. Further subgroup analysis showed that the decrease in systolic BP was significant in both whites and blacks, men and women. Meta-analysis of hormone and lipid data showed that the mean effect was 0.26 ng/ml/hr (95% CI: 0.17 to 0.36, I (2)=70%) for plasma renin activity, 73.20 pmol/l (95% CI: 44.92 to 101.48, I (2)=62%) for aldosterone, 31.67 pg/ml (95% CI: 6.57 to 56.77, I (2)=5%) for noradrenaline, 6.70 pg/ml (95% CI: -0.25 to 13.64, I (2)=12%) for adrenaline, 0.05 mmol/l (95% CI: -0.02 to 0.11, I (2)=0%) for cholesterol, 0.05 mmol/l (95% CI: -0.01 to 0.12, I (2)=0%) for LDL, -0.02 mmol/l (95% CI: -0.06 to 0.01, I (2)=16%) for HDL, and 0.04 mmol/l (95% CI: -0.02 to 0.09, I (2)=0%) for triglycerides. AUTHORS’ CONCLUSIONS: A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. With salt reduction, there is a small physiological increase in plasma renin activity, aldosterone and noradrenaline. There is no significant change in lipid levels. These results provide further strong support for a reduction in population salt intake. This will likely lower population BP and, thereby, reduce cardiovascular disease. Additionally, our analysis demonstrates a significant association between the reduction in 24-h urinary sodium and the fall in systolic BP, indicating the greater the reduction in salt intake, the greater the fall in systolic BP. The current recommendations to reduce salt intake from 9-12 to 5-6 g/d will have a major effect on BP, but are not ideal. A further reduction to 3 g/d will have a greater effect and should become the long term target for population salt intake.

He, F. J. and G. A. MacGregor (2004). “Effect of longer-term modest salt reduction on blood pressure.” Cochrane Database Syst Rev(3): Cd004937.

BACKGROUND: Many randomised trials assessing the effect of salt reduction on blood pressure show reduction in blood pressure in individuals with high blood pressure. However, there is controversy about the magnitude and the clinical significance of the fall in blood pressure in individuals with normal blood pressure. Several meta-analyses of randomised salt reduction trials have been published in the last few years. However, most of these included trials of very short duration (e.g. 5 days) and included trials with salt loading followed by salt deprivation (e.g. from 20 to 1 g/day) over only a few days. These short-term experiments are not appropriate to inform public health policy which is for a modest reduction in salt intake over a prolonged period of time. A meta-analysis by Hooper et al is an important attempt to look at whether advice to achieve a long-term salt reduction (i.e. more than 6 months) in randomised trials causes a fall in blood pressure. However, most trials included in this meta-analysis achieved a small reduction in salt intake; on average, salt intake was reduced by 2 g/day. It is, therefore, not surprising that this analysis showed a small fall in blood pressure, and that a dose-response to salt reduction was not demonstrable. OBJECTIVES: To assess the effect of the currently recommended modest reduction in salt intake (WHO 2003; SACN 2003; Whelton 2002), on blood pressure in individuals with normal and elevated blood pressure. To assess whether the magnitude of the reduction in blood pressure is dependent on the magnitude of the reduction in salt intake. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Cochrane library, CINAHL, and reference list of original and review articles. SELECTION CRITERIA: We included randomised trials with a modest reduction in salt intake and a duration of 4 or more weeks. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two persons. Mean effect sizes were calculated using both fixed and random effect models using Review Manager 4.2.1 software. Weighted linear regression was used to examine the relationship between the change in urinary sodium and the change in blood pressure. We used funnel plots to detect publication and other biases in the meta-analysis. MAIN RESULTS: Seventeen trials in individuals with elevated blood pressure (n=734) and 11 trials in individuals with normal blood pressure (n=2220) were included. In individuals with elevated blood pressure the median reduction in 24-h urinary sodium excretion was 78 mmol (4.6 g/day of salt), the mean reduction in systolic blood pressure was -4.97 mmHg (95%CI:-5.76 to -4.18), and the mean reduction in diastolic blood pressure was -2.74 mmHg (95% CI:-3.22 to -2.26). In individuals with normal blood pressure the median reduction in 24-h urinary sodium excretion was 74 mmol (4.4 g/day of salt), the mean reduction in systolic blood pressure was -2.03 mmHg (95% CI: -2.56 to -1.50) mmHg, and the mean reduction in diastolic blood pressure was -0.99 mmHg (-1.40 to -0.57). Weighted linear regression analyses showed a correlation between the reduction in urinary sodium and the reduction in blood pressure. REVIEWERS’ CONCLUSIONS: Our meta-analysis demonstrates that a modest reduction in salt intake for a duration of 4 or more weeks has a significant and, from a population viewpoint, important effect on blood pressure in both individuals with normal and elevated blood pressure. These results support other evidence suggesting that a modest and long-term reduction in population salt intake could reduce strokes, heart attacks, and heart failure. Furthermore, our meta-analysis demonstrates a correlation between the magnitude of salt reduction and the magnitude of blood pressure reduction. Within the daily intake range of 3 to 12 g/day, the lower the salt intake achieved, the lower the blood pressure.

Jafarnejad, S., et al. (2020). “The hypotensive effect of salt substitutes in stage 2 hypertension: a systematic review and meta-analysis.” BMC Cardiovasc Disord 20(1): 98.

BACKGROUND: Hypertension (HTN) is a ubiquitous risk factor for numerous non-communicable diseases, including cardiovascular disease and stroke. There are currently no wholly effective pharmacological therapies for subjects with HTN. However, salt substitutes have emerged as a potential therapy for the treatment of HTN. The aim of the present study was to assess the effect of salt substitutes on reducing systolic blood pressure (SBP) and diastolic BP (DBP), following a meta-analysis of randomized controlled trials. METHODS: Studies were found via systematic searches of the Pubmed/Medline, Scopus, Ovid, Google Scholar and Cochrane library. Ten studies, comprised of 11 trials and 1119 participants, were included in the meta-analysis. RESULTS: Pooled weighted mean differences showed significant reductions of SBP (WMD - 8.87 mmHg; 95% CI - 11.19, - 6.55, p < 0.001) and DBP (WMD - 4.04 mmHg; 95% CI - 5.70, - 2.39) with no statistically significant heterogeneity between the 11 included comparisons of SBPs and DBPs. The stratified analysis of trials based on the mean age of participants showed a significant reduction in the mean difference of SBP in both adults (< 65 years old) and elderly (≥65 years old). However, the DBP-lowering effect of salt substitutes was only observed in adult patients (WMD - 4.22 mmHg; 95% CI - 7.85, - 0.58), but not in the elderly subjects. CONCLUSIONS: These findings suggest that salt-substitution strategies could be used for lowering SBP and DBP in patients with stage 2 HTN; providing a nutritional platform for the treatment, amelioration, and prevention of HTN.

Neal, B., et al. (2021). “Effect of Salt Substitution on Cardiovascular Events and Death.” New England Journal of Medicine 385(12): 1067-1077.

Rust, P. and C. Ekmekcioglu (2017). “Impact of Salt Intake on the Pathogenesis and Treatment of Hypertension.” Adv Exp Med Biol 956: 61-84.

Excessive dietary salt (sodium chloride) intake is associated with an increased risk for hypertension, which in turn is especially a major risk factor for stroke and other cardiovascular pathologies, but also kidney diseases. Besides, high salt intake or preference for salty food is discussed to be positive associated with stomach cancer, and according to recent studies probably also obesity risk. On the other hand a reduction of dietary salt intake leads to a considerable reduction in blood pressure, especially in hypertensive patients but to a lesser extent also in normotensives as several meta-analyses of interventional studies have shown. Various mechanisms for salt-dependent hypertension have been put forward including volume expansion, modified renal functions and disorders in sodium balance, impaired reaction of the renin-angiotensin-aldosterone-system and the associated receptors, central stimulation of the activity of the sympathetic nervous system, and possibly also inflammatory processes.Not every person reacts to changes in dietary salt intake with alterations in blood pressure, dividing people in salt sensitive and insensitive groups. It is estimated that about 50-60 % of hypertensives are salt sensitive. In addition to genetic polymorphisms, salt sensitivity is increased in aging, in black people, and in persons with metabolic syndrome or obesity. However, although mechanisms of salt-dependent hypertensive effects are increasingly known, more research on measurement, storage and kinetics of sodium, on physiological properties, and genetic determinants of salt sensitivity are necessary to harden the basis for salt reduction recommendations.Currently estimated dietary intake of salt is about 9-12 g per day in most countries of the world. These amounts are significantly above the WHO recommended level of less than 5 g salt per day. According to recent research results a moderate reduction of daily salt intake from current intakes to 5-6 g can reduce morbidity rates. Potential risks of salt reduction, like suboptimal iodine supply, are limited and manageable. Concomitant to salt reduction, potassium intake by higher intake of fruits and vegetables should be optimised, since several studies have provided evidence that potassium rich diets or interventions with potassium can lower blood pressure, especially in hypertensives.In addition to dietary assessment the gold standard for measuring salt intake is the analysis of sodium excretion in the 24 h urine. Spot urine samples are appropriate alternatives for monitoring sodium intake. A weakness of dietary evaluations is that the salt content of many foods is not precisely known and information in nutrient databases are limited. A certain limitation of the urine assessment is that dietary sources contributing to salt intake cannot be identified.Salt reduction strategies include nutritional education, improving environmental conditions (by product reformulation and optimization of communal catering) up to mandatory nutrition labeling and regulated nutrition/health claims, as well as legislated changes in the form of taxation.Regarding dietary interventions for the reduction of blood pressure the Dietary Approaches to Stop Hypertension (DASH) diet can be recommended. In addition, body weight should be normalized in overweight and obese people (BMI less than 25 kg/m(2)), salt intake should not exceed 5 g/day according to WHO recommendations (<2 g sodium/day), no more than 1.5 g sodium/d in blacks, middle- and older-aged persons, and individuals with hypertension, diabetes, or chronic kidney disease, intake of potassium (~4.7 g/day) should be increased and alcohol consumption limited. In addition, regular physical activity (endurance, dynamic resistance, and isometric resistance training) is very important.

Supplementary Table G. Criteria to achieve Tier II – Criterion: No oil that has more than 40% omega-6 fatty acids

(sunflower, cottonseed, soybean, canola/rapeseed, or corn oil)

1.(Simopoulos 2016)
(Hibbeln, Nieminen et al. 2006)
(Patterson, Wall et al. 2012)
(Ascherio and Willett 1997)
(Tarrago-Trani, Phillips et al. 2006)
(Misra, Singhal et al. 2010)
(Wendell, Baffi et al. 2014)
(Fernandes 1994)
(Berger, Smesny et al. 2017)
(Loef and Walach 2013)
(Lauretti and Praticò 2017)
(Golomb and Bui 2015)
(Golomb, Evans et al. 2012)
(Alvheim, Malde et al. 2012)
(Deol, Evans et al. 2015)
(Deol, Evans et al. 2015)
(Rudolph, Young et al. 2017)
(Simopoulos 2016)
(DiNicolantonio and O’Keefe 2018)
(Patterson, Wall et al. 2012)

References:

Alvheim, A. R., et al. (2012). “Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity.” Obesity (Silver Spring) 20(10): 1984-1994.

Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The backbone of both endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) is the ω-6 fatty acid arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA + 1 en% eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in medium-fat diets (35 en% fat) and high-fat diets (60 en%) for 14 weeks from weaning. Increasing LA from 1 en% to 8 en% elevated AA-phospholipids (PL) in liver and erythrocytes, tripled 2-AG + 1-AG and AEA associated with increased food intake, feed efficiency, and adiposity in mice. Reducing AA-PL by adding 1 en% long-chain ω-3 fats to 8 en% LA diets resulted in metabolic patterns resembling 1 en% LA diets. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. These animal diets modeled 20th century increases of human LA consumption, changes that closely correlate with increasing prevalence rates of obesity. In summary, dietary LA increased tissue AA, and subsequently elevated 2-AG + 1-AG and AEA resulting in the development of diet-induced obesity. The adipogenic effect of LA can be prevented by consuming sufficient EPA and DHA to reduce the AA-PL pool and normalize endocannabinoid tone.

Ascherio, A. and W. C. Willett (1997). “Health effects of trans fatty acids.” Am J Clin Nutr 66(4 Suppl): 1006s-1010s.

Trans Fatty acids are formed during the process of partial hydrogenation in which liquid vegetable oils are converted to margarine and vegetable shortening. Concern has existed that this process may have adverse consequences because natural essential fatty acids are destroyed and the new artificial isomers are structurally similar to saturated fats, lack the essential metabolic activity of the parent compounds, and inhibit the enzymatic desaturation of linoleic and linolenic acid. In the past 5 y a series of metabolic studies has provided unequivocal evidence that trans fatty acids increase plasma concentrations of low-density-lipoprotein cholesterol and reduce concentrations of high-density-lipoprotein (HDL) cholesterol relative to the parent natural fat. In these same studies, trans fatty acids increased the plasma ratio of total to HDL cholesterol nearly twofold compared with saturated fats. On the basis of these metabolic effects and the known relation of blood lipid concentrations to risk of coronary artery disease, we estimate conservatively that 30,000 premature deaths/y in the United States are attributable to consumption of trans fatty acids. Epidemiologic studies, although not conclusive on their own, are consistent with adverse effects of this magnitude or even larger. Because there are no known nutritional benefits of trans fatty acids and clear adverse metabolic consequences exist, prudent public policy would dictate that their consumption be minimized and that information on the trans fatty acid content of foods be available to consumers.

Berger, M. E., et al. (2017). “Omega-6 to omega-3 polyunsaturated fatty acid ratio and subsequent mood disorders in young people with at-risk mental states: a 7-year longitudinal study.” Translational Psychiatry 7(8): e1220-e1220.

While cross-sectional studies suggest that patients with mood disorders have a higher ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) and lower levels of omega-3 PUFAs, it is unknown if a high n-6/3 ratio indicates vulnerability for depression. We tested this hypothesis in a 7-year follow-up study of young individuals with an ultra-high risk (UHR) phenotype. We conducted a secondary analysis of the Vienna omega-3 study, a longitudinal study of omega-3 PUFAs in individuals at UHR for psychosis (n=69). Levels of n-6 and n-3 PUFAs were measured in the phosphatidylethanolamine fraction of erythrocyte membranes at intake into the study. Mood disorder diagnosis was ascertained with the Structured Clinical Interview for DSM-IV-TR and confirmed by review of medical records and interviews of caregivers. A higher n-6/3 PUFA ratio at baseline predicted mood disorders in UHR individuals over a 7-year (median) follow-up (odds ratio=1.89, 95% CI=1.075–3.338, P=0.03). This association remained significant after adjustment for age, gender, smoking, severity of depressive symptoms at baseline and n-3 supplementation. Consistent results were obtained for individual PUFAs, including lower levels of eicosapentaenoic acid and docosahexaenoic acid. The predictive capacity of these findings was specific to mood disorders as no associations were found for any other psychiatric disorder. To our knowledge, our data provide the first prospective evidence that the n-6/3 PUFA ratio is associated with an increased risk for mood disorders in young people exhibiting an UHR phenotype. These findings may have important implications for treatment and risk stratification beyond clinical characteristics.

Deol, P., et al. (2015). “Soybean Oil Is More Obesogenic and Diabetogenic than Coconut Oil and Fructose in Mouse: Potential Role for the Liver.” PLOS ONE 10(7): e0132672.

The obesity epidemic in the U.S. has led to extensive research into potential contributing dietary factors, especially fat and fructose. Recently, increased consumption of soybean oil, which is rich in polyunsaturated fatty acids (PUFAs), has been proposed to play a causal role in the epidemic. Here, we designed a series of four isocaloric diets (HFD, SO-HFD, F-HFD, F-SO-HFD) to investigate the effects of saturated versus unsaturated fat, as well as fructose, on obesity and diabetes. C57/BL6 male mice fed a diet moderately high in fat from coconut oil and soybean oil (SO-HFD, 40% kcal total fat) showed statistically significant increases in weight gain, adiposity, diabetes, glucose intolerance and insulin resistance compared to mice on a diet consisting primarily of coconut oil (HFD). They also had fatty livers with hepatocyte ballooning and very large lipid droplets as well as shorter colonic crypt length. While the high fructose diet (F-HFD) did not cause as much obesity or diabetes as SO-HFD, it did cause rectal prolapse and a very fatty liver, but no balloon injury. The coconut oil diet (with or without fructose) increased spleen weight while fructose in the presence of soybean oil increased kidney weight. Metabolomics analysis of the liver showed an increased accumulation of PUFAs and their metabolites as well as γ-tocopherol, but a decrease in cholesterol in SO-HFD. Liver transcriptomics analysis revealed a global dysregulation of cytochrome P450 (Cyp) genes in SO-HFD versus HFD livers, most notably in the Cyp3a and Cyp2c families. Other genes involved in obesity (e.g., Cidec, Cd36), diabetes (Igfbp1), inflammation (Cd63), mitochondrial function (Pdk4) and cancer (H19) were also upregulated by the soybean oil diet. Taken together, our results indicate that in mice a diet high in soybean oil is more detrimental to metabolic health than a diet high in fructose or coconut oil.

DiNicolantonio, J. J. and J. H. O’Keefe (2018). “Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis.” Open Heart 5(2): e000898.

Fernandes, G. (1994). “Dietary lipids and risk of autoimmune disease.” Clin Immunol Immunopathol 72(2): 193-197.

In summary, it is well established that moderate calorie restriction or reduction in overall high calorie food intake prevents or forestalls the development of age-associated disease incidence such as breast cancer and renal disease in rodents. A similar approach could also readily be applied in humans for preventing the risk and rise of life-shortening diseases. Many age-associated diseases, particularly autoimmune diseases with viral etiology, appear to be exacerbated in the presence of adverse lipid intake such as an increased level of vegetable oils or trans-fatty acids from the usage of hydrogenated dietary oils. At present, nearly 35-40% of the total calories are from dietary fats and/or of lipid origin. Although usage of saturated fat, which increases cardiovascular disease, has been reduced to a large extent in the United States, consumption of both monounsaturated and polyunsaturated fats of omega-6 origin has either increased or simply been substituted in place of saturated fats. Further, for the past 50 years, a significant reduction in highly polyunsaturated fat consumption such as marine oil has also occurred specifically in the United States. The reduction in omega-3 lipids of marine or vegetable source occurs primarily because of short shelf life due to rancidity. However, the increased consumption of omega-6 or a vegetable source of oils and decreased omega-3 intake may increase in vivo the production of free radicals and higher proinflammatory cytokines. Our ongoing studies reveal that proinflammatory vegetable oil could increase autoimmune disease by increasing the free radical formation by decreasing the antioxidant enzyme mRNA levels, thereby further decreasing immune function, particularly the production of anti-inflammatory cytokines such as IL-2 and TGF beta mRNA levels. In contrast, omega-3 lipid intake in the presence of an antioxidant supplement appears to exert protection against autoimmunity by enhancing antioxidant enzymes and TGF beta mRNA levels and by preventing the rise in oncogene expression. However, detailed studies are required to establish the protective and deleterious role of different commonly consumed lipids or dietary oils by the general population, particularly during middle and aging years. Further, we also propose that combining nonsteroidal drug therapy along with moderate calorie reduction in the presence of more protective omega-3 dietary lipids of either marine or vegetable source and decreasing the levels of mono- and polyunsaturated lipids may provide additional protection against the age-associated rise in malignancy and autoimmune disorders.

Golomb, B. A. and A. K. Bui (2015). “A Fat to Forget: Trans Fat Consumption and Memory.” PLOS ONE 10(6): e0128129.

Purpose We sought to assess the relation of dietary trans fatty acid (dTFA) consumption to word-memory. Methods We analyzed cross-sectional data from the 1999-2005 UCSD Statin Study. Participants were 1018 adult men and non-procreative women age ≥20 without diagnosed diabetes, CVD, or extreme LDL-cholesterol. Primary analyses focused on men, as only men (N = 694) were effectively represented in younger adult ages. “Recurrent words” assessed word memory. dTFA (grams/day) estimates were calculated from the Fred Hutchinson Food Frequency Questionnaire. Regression, stratified at age 45, assessed the relation between memory and dTFA in various adjustment models. Major findings were replicated in the full sample (including women). Potential mediators were examined. Results An age-by-dTFA interaction was significant. dTFA adversely predicted memory in younger adults (only), robust to adjustment model. Each gram/day dTFA was associated with an estimated 0.76 fewer words recalled (full model) (SE = 0.27, 95%CI = 0.22,1.3, P = 0.006). Adjustment for systolic blood pressure, waist circumference and BMI (but not lipid or glycemic variables) attenuated the relationship, consistent with mediation by factors involving, relating to, or concurrently influencing, these factors. Conclusion Greater dTFA was significantly associated with worse word recall in younger adults. Prooxidant and energetic detriments of dTFA and triangulation with other evidence offer prospects for causality.

Golomb, B. A., et al. (2012). “Trans Fat Consumption and Aggression.” PLOS ONE 7(3): e32175.

Background Dietary trans fatty acids (dTFA) are primarily synthetic compounds that have been introduced only recently; little is known about their behavioral effects. dTFA inhibit production of omega-3 fatty acids, which experimentally have been shown to reduce aggression. Potential behavioral effects of dTFA merit investigation. We sought to determine whether dTFA are associated with aggression/irritability. Methodolgy/Prinicpal Findings We capitalized on baseline dietary and behavioral assessments in an existing clinical trial to analyze the relationship of dTFA to aggression. Of 1,018 broadly sampled baseline subjects, the 945 adult men and women who brought a completed dietary survey to their baseline visit are the target of this analysis. Subjects (seen 1999–2004) were not on lipid medications, and were without LDL-cholesterol extremes, diabetes, HIV, cancer or heart disease. Outcomes assessed adverse behaviors with impact on others: Overt Aggression Scale Modified-aggression subscale (primary behavioral endpoint); Life History of Aggression; Conflict Tactics Scale; and self-rated impatience and irritability. The association of dTFA to aggression was analyzed via regression and ordinal logit, unadjusted and adjusted for potential confounders (sex, age, education, alcohol, and smoking). Additional analyses stratified on sex, age, and ethnicity, and examined the prospective association. Greater dTFA were strongly significantly associated with greater aggression, with dTFA more consistently predictive than other assessed aggression predictors. The relationship was upheld with adjustment for confounders, was preserved across sex, age, and ethnicity strata, and held cross-sectionally and prospectively. Conclusions/Significance This study provides the first evidence linking dTFA with behavioral irritability and aggression. While confounding is always a concern in observational studies, factors including strength and consistency of association, biological gradient, temporality, and biological plausibility add weight to the prospect of a causal connection. Our results may have relevance to public policy determinations regarding dietary trans fats. Clinicaltrials.gov # NCT00330980

Hibbeln, J. R., et al. (2006). “Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity.” Am J Clin Nutr 83(6 Suppl): 1483s-1493s.

BACKGROUND: The worldwide diversity of dietary intakes of n-6 and n-3 fatty acids influences tissue compositions of n-3 long-chain fatty acids (LCFAs: eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) and risks of cardiovascular and mental illnesses. OBJECTIVE: We aimed to estimate healthy dietary allowances for n-3 LCFAs that would meet the nutrient requirements of 97-98% of the population. DESIGN: Deficiency in n-3 LCFAs was defined as attributable risk from 13 morbidity and mortality outcomes, including all causes, coronary heart disease, stroke, cardiovascular disease, homicide, bipolar disorder, and major and postpartum depressions. Dietary availability of n-3 LCFAs from commodities for 38 countries and tissue composition data were correlated by best fit to each illness in deficiency risk models. RESULTS: The potential attributable burden of disease ranged from 20.8% (all-cause mortality in men) to 99.9% (bipolar disorder). n-3 LCFA intake for Japan (0.37% of energy, or 750 mg/d) met criteria for uniformly protecting >98% of the populations worldwide. n-3 LCFA intakes needed to meet a tissue target representative of Japan (60% n-3 in LCFA) ranged from 278 mg/d (Philippines, with intakes of 0.8% of energy as linoleate, 0.08% of energy as alpha-linolenate, and 0.06% of energy as arachidonic acid) to 3667 mg/d (United States, with 8.91% of energy as linoleate, 1.06% of energy as alpha-linolenate, and 0.08% of energy as arachidonic acid). CONCLUSIONS: With caveats inherent for ecologic, nutrient disappearance analyses, a healthy dietary allowance for n-3 LCFAs for current US diets was estimated at 3.5 g/d for a 2000-kcal diet. This allowance for n-3 LCFAs can likely be reduced to one-tenth of that amount by consuming fewer n-6 fats.

Lauretti, E. and D. Praticò (2017). “Effect of canola oil consumption on memory, synapse and neuropathology in the triple transgenic mouse model of Alzheimer’s disease.” Scientific Reports 7(1): 17134.

In recent years consumption of canola oil has increased due to lower cost compared with olive oil and the perception that it shares its health benefits. However, no data are available on the effect of canola oil intake on Alzheimer’s disease (AD) pathogenesis. Herein, we investigated the effect of chronic daily consumption of canola oil on the phenotype of a mouse model of AD that develops both plaques and tangles (3xTg). To this end mice received either regular chow or a chow diet supplemented with canola oil for 6 months. At this time point we found that chronic exposure to the canola-rich diet resulted in a significant increase in body weight and impairments in their working memory together with decrease levels of post-synaptic density protein-95, a marker of synaptic integrity, and an increase in the ratio of insoluble Aβ 42/40. No significant changes were observed in tau phosphorylation and neuroinflammation. Taken together, our findings do not support a beneficial effect of chronic canola oil consumption on two important aspects of AD pathophysiology which includes memory impairments as well as synaptic integrity. While more studies are needed, our data do not justify the current trend aimed at replacing olive oil with canola oil.

Loef, M. and H. Walach (2013). “The Omega-6/Omega-3 Ratio and Dementia or Cognitive Decline: A Systematic Review on Human Studies and Biological Evidence.” Journal of Nutrition in Gerontology and Geriatrics 32(1): 1-23.

Misra, A., et al. (2010). “Obesity, the metabolic syndrome, and type 2 diabetes in developing countries: role of dietary fats and oils.” J Am Coll Nutr 29(3 Suppl): 289s-301s.

Developing countries are undergoing rapid nutrition transition concurrent with increases in obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM). From a healthy traditional high-fiber, low-fat, low-calorie diet, a shift is occurring toward increasing consumption of calorie-dense foods containing refined carbohydrates, fats, red meats, and low fiber. Data show an increase in the supply of animal fats and increased intake of saturated fatty acid (SFAs) (obtained from coconut oil, palm oil, and ghee [clarified butter]) in many developing countries, particularly in South Asia and South-East Asia. In some South Asian populations, particularly among vegetarians, intake of n-3 polyunsaturated fatty acids (PUFAs) (obtained from flaxseed, mustard, and canola oils) and long-chain (LC) n-3 PUFAs (obtained from fish and fish oils) is low. Further, the effect of supplementation of n-3 PUFAs on metabolic risk factors and insulin resistance, except for demonstrated benefit in terms of decreased triglycerides, needs further investigation among South Asians. Data also show that intake of monounsaturated fatty acids (MUFAs) ranged from 4.7% to 16.4%en in developing countries, and supplementing it from olive, canola, mustard, groundnut, and rice bran oils may reduce metabolic risk. In addition, in some developing countries, intake of n-6 PUFAs (obtained from sunflower, safflower, corn, soybean, and sesame oils) and trans-fatty acids (TFAs) is increasing. These data show imbalanced consumption of fats and oils in developing countries, which may have potentially deleterious metabolic and glycemic consequences, although more research is needed. In view of the rapid rise of T2DM in developing countries, more aggressive public health awareness programs coupled with governmental action and clear country-specific guidelines are required, so as to promote widespread use of healthy oils, thus curbing intake of SFAs and TFAs, and increasing intake of n-3 PUFAs and MUFAs. Such actions would contribute to decelerating further escalation of “epidemics” of obesity, the metabolic syndrome, and T2DM in developing countries.

Patterson, E., et al. (2012). “Health implications of high dietary omega-6 polyunsaturated Fatty acids.” J Nutr Metab 2012: 539426.

Omega-6 (n-6) polyunsaturated fatty acids (PUFA) (e.g., arachidonic acid (AA)) and omega-3 (n-3) PUFA (e.g., eicosapentaenoic acid (EPA)) are precursors to potent lipid mediator signalling molecules, termed “eicosanoids,” which have important roles in the regulation of inflammation. In general, eicosanoids derived from n-6 PUFA are proinflammatory while eicosanoids derived from n-3 PUFA are anti-inflammatory. Dietary changes over the past few decades in the intake of n-6 and n-3 PUFA show striking increases in the (n-6) to (n-3) ratio (~15 : 1), which are associated with greater metabolism of the n-6 PUFA compared with n-3 PUFA. Coinciding with this increase in the ratio of (n-6) : (n-3) PUFA are increases in chronic inflammatory diseases such as nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, obesity, inflammatory bowel disease (IBD), rheumatoid arthritis, and Alzheimer’s disease (AD). By increasing the ratio of (n-3) : (n-6) PUFA in the Western diet, reductions may be achieved in the incidence of these chronic inflammatory diseases.

Rudolph, M. C., et al. (2017). “Early infant adipose deposition is positively associated with the n-6 to n-3 fatty acid ratio in human milk independent of maternal BMI.” Int J Obes (Lond) 41(4): 510-517.

BACKGROUND/OBJECTIVES: Excessive infant weight gain in the first 6-month of life is a powerful predictor of childhood obesity and related health risks. In mice, omega-6 fatty acids (FAs) serve as potent ligands driving adipogenesis during early development. The ratio of omega-6 relative to omega-3 (n-6/n-3) FA in human milk (HM) has increased threefold over the last 30 years, but the impact of this shift on infant adipose development remains undetermined. This study investigated how maternal obesity and maternal dietary FA (as reflected in maternal red blood cells (RBCs) composition) influenced HM n-6 and n-3 FAs, and whether the HM n-6/n-3 ratio was associated with changes in infant adipose deposition between 2 weeks and 4 months postpartum. SUBJECTS/METHODS: Forty-eight infants from normal weight (NW), overweight (OW) and obese (OB) mothers were exclusively or predominantly breastfed over the first 4 months of lactation. Mid-feed HM and maternal RBC were collected at either transitional (2 weeks) or established (4 months) lactation, along with infant body composition assessed using air-displacement plethysmography. The FA composition of HM and maternal RBC was measured quantitatively by lipid mass spectrometry. RESULTS: In transitional and established HM, docosahexaenoic acid (DHA) was lower (P=0.008; 0.005) and the arachidonic acid (AA)/DHA+eicosapentaenoic acid (EPA) ratio was higher (P=0.05; 0.02) in the OB relative to the NW group. Maternal prepregnancy body mass index (BMI) and AA/DHA+EPA ratios in transitional and established HM were moderately correlated (P=0.018; 0.001). Total infant fat mass was increased in the upper AA/DHA+EPA tertile of established HM relative to the lower tertile (P=0.019). The amount of changes in infant fat mass and percentage of body fat were predicted by AA/EPA+DHA ratios in established HM (P=0.038; 0.010). CONCLUSIONS: Perinatal infant exposures to a high AA/EPA+DHA ratio during the first 4 months of life, which is primarily reflective of maternal dietary FA, may significantly contribute to the way infants accumulate adipose.

Simopoulos, A. P. (2016). “An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity.” Nutrients 8(3): 128.

Tarrago-Trani, M. T., et al. (2006). “New and existing oils and fats used in products with reduced trans-fatty acid content.” J Am Diet Assoc 106(6): 867-880.

The US Food and Drug Administration’s final ruling on trans-fatty acid labeling issued in 2003 has caused a rapid transformation in the fat and oil industries. Novel ingredients and improved technologies are emerging to replace partially hydrogenated fats in foods. We present an overview of the structure and formation of trans fatty acids in foods, and a comprehensive review of the newly formulated products and current procedures practiced by the edible oil industry to reduce or eliminate trans fatty acids in response to the Food and Drug Administration’s regulations mandating trans fat labeling of foods.

Wendell, S. G., et al. (2014). “Fatty acids, inflammation, and asthma.” J Allergy Clin Immunol 133(5): 1255-1264.

Fatty acids and consequently diet play an essential role in the formation of inflammatory mediators involved in the pathogenesis of asthma. Because intake variations of omega-6 (n-6) and omega-3 (n-3) fatty acids ultimately determine cell membrane incorporation, changes in diet have the potential to modify downstream production of inflammatory mediators derived from these compounds. It has long been hypothesized that decreasing the n-6/n-3 ratio could reduce the production of more proinflammatory mediators while increasing the formation of downstream metabolites that can serve to limit or resolve inflammation. In turn, these changes would result in improved asthma outcomes or would lower the risk for asthma incidence. This review will focus on the role of fatty acid inflammatory and resolving mediators and will summarize the clinical and epidemiologic data on how diet and obesity alter fatty acid profiles that can contribute to asthma.

Table G – Criteria to achieve Tier II – Criterion: The Importance of Vitamins and Minerals (Vitamin A, C, D, E, Calcium, Folate, Iron, Magnesium and Zinc); at least 250 mg of combined EPA/DHA per serving; at least 1 g of ALA per serving; dietary fiber ratio (to carbohydrate) >1:10

Refs 1-5: Vitamin D

(Föcker, Antel et al. 2017)
(Libuda, Timmesfeld et al. 2020)
(Xie, Huang et al. 2022)
(Anglin, Samaan et al. 2013)
(Spedding 2014)

Refs: 6-11: Iron

(Benson, Shah et al. 2021)
(Mirza, Abdul-Kadir et al. 2018)
(Means 2020)
(Lynch, Pfeiffer et al. 2018)
Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/Iron-HealthProfessional
(Al Zenki, Alomirah et al. 2015)

Refs 12-16: Vitamin A

Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional
(Wiseman, Bar-El Dadon et al. 2017)
(DeMaeyer 1986)
(Bar-El Dadon and Reifen 2017)
(Bar-El Dadon and Reifen 2017)

Refs 17-21: Vitamin C

(Carr and Rowe 2020)
(Padayatty and Levine 2016)
(Granger and Eck 2018)
(Pecoraro, Martini et al. 2019)
Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional

Refs 22-26: Vitamin E

Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional
(Brigelius-Flohé 2021)
(Azzi 2021)
(Lewis, Meydani et al. 2019)
(Ulatowski and Manor 2015)

Refs 27-32 Calcium

Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional
(Cormick, Betran et al. 2021)
(Alyahya 2017)
(Alyahya, Lee et al. 2014)
(Takaya 2021)
(Shlisky, Mandlik et al. 2022)

Refs 33-38: Folate

(Pope, Artuch et al. 2019)
(Czeizel, Dudás et al. 2013)
(Scaglione and Panzavolta 2014)
(Ebara 2017)
(Reynolds 2014)
Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional

Refs 39-46: Magnesium

Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional
(Ismail, Ismail et al. 2018)
(Razzaque 2018)
(Gant, Soedamah-Muthu et al. 2018)
(Reddy and Edwards 2019)
(Effatpanah, Rezaei et al. 2019)
(Hemamy, Pahlavani et al. 2021)
(Gröber, Schmidt et al. 2015)

Refs 47-54: Zinc

Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional
(Maret and Sandstead 2006)
(Choi, Liu et al. 2018)
(Ackland and Michalczyk 2016)
(Shankar and Prasad 1998)
(Fernández-Cao, Warthon-Medina et al. 2019)
(Granero, Pardo-Garrido et al. 2021)
(Talebi, Miraghajani et al. 2022)

Refs 55-75: At least 250 mg of combined EPA/DHA per serving

(Zhang, Fulgoni et al. 2018)
(Checa-Ros, Haro-García et al. 2019)
(Wu, Zhou et al. 2015)
(Parletta, Niyonsenga et al. 2016)
(Martinat, Rossitto et al. 2021)
(Liao, Xie et al. 2019)
(Hu, Hu et al. 2019)
(Karaszewska, Ingenhoven et al. 2021)
(Bloch and Qawasmi 2011)
(Wozniak, Farrell et al. 2022)
(Hawkey and Nigg 2014)
(Gow, Hibbeln et al. 2015)
(Hallahan, Ryan et al. 2016)
(Guu, Mischoulon et al. 2019)
(Freeman, Hibbeln et al. 2006)
(Hibbeln, Davis et al. 2007)
Government Fact Sheet online article: https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional
The Global Exchange for EPA and DHA omega-3 dose recommendations: https://goedomega3.com/intake-recommendations
(1995)
(Best, Gibson et al. 2022)
The International Society for the Study of Fatty Acids and Lipids (ISSFAL) dietary recommendations: https://www.issfal.org/pufa-recommendations

Refs 76-85: At least 1 g of ALA per serving

(Yuan, Xie et al. 2022)
(Burns-Whitmore, Froyen et al. 2019)
(Stark, Crawford et al. 2008)
(Crawford, Galli et al. 2000)
(Brenna, Salem et al. 2009)
(Burdge 2004)
(Burdge and Calder 2005)
(Fu, Wang et al. 2021)
(Parikh, Maddaford et al. 2019)
(Blondeau, Lipsky et al. 2015)

Refs 86-90: Dietary fiber ratio (to carbohydrate) >1:10

(Blondeau, Lipsky et al. 2015)
(Dong, Wang et al. 2022)
(Hashimoto, Tanaka et al. 2018)
(Holscher 2017)
(Guan, Yu et al. 2021)

References:

(1995). “ISSFAL Board Statement: recommendations for the essential fatty acid requirement for infant formulas. International Society for the Study of Fatty Acids and Lipids.” J Am Coll Nutr 14(2): 213-214.

Ackland, M. L. and A. A. Michalczyk (2016). “Zinc and infant nutrition.” Arch Biochem Biophys 611: 51-57.

Zinc is essential for a wide variety of cellular processes in all cells. It is a critical dietary nutrient, particularly in the early stages of life. In the early neonatal period, adequate sources of zinc can be obtained from breast milk. In rare circumstances, the mammary gland produces zinc deficient milk that is potentially lethal for exclusively breast-fed infants. This can be overcome by zinc supplementation to the infant. Alterations to key zinc transporters provide insights into the mechanisms of cellular zinc homeostasis. The bioavailability of zinc in food depends on the presence of constituents that may complex zinc. In many countries, zinc deficiency is a major health issue due to poor nourishment. Young children are particularly affected. Zinc deficiency can impair immune function and contributes to the global burden of infectious diseases including diarrhoea, pneumonia and malaria. Furthermore, zinc deficiency may extend its influence across generations by inducing epigenetic effects that alter the expression of genes. This review discusses the significance of adequate zinc nutrition in infants, factors that influence zinc nutrition, the consequences of zinc deficiency, including its contribution to the global burden of disease, and addresses some of the knowledge gaps in zinc biology.

Al Zenki, S., et al. (2015). “Prevalence and Determinants of Anemia and Iron Deficiency in Kuwait.” Int J Environ Res Public Health 12(8): 9036-9045.

The objective of this study was to assess the prevalence of anemia and iron deficiency (ID) of a nationally representative sample of the Kuwait population. We also determined if anemia differed by socioeconomic status or by RBC folate and vitamins A and B12 levels. The subjects who were made up of 1830 males and females between the ages of 2 months to 86 years, were divided into the following age groups (0-5, 5-11, 12-14, 15-19, 20-49, ≥50 years). Results showed that the prevalence of anemia was 3% in adult males and 17% in females. The prevalence of ID varied according to age between 4% (≥50 years) and 21% (5-11 years) and 9% (12-14 years) and 23% (15-19 years), respectively, in males and females. The prevalence of anemia and ID was higher in females compared to males. Adults with normal ferritin level, but with low RBC folate and vitamins A and B12 levels had higher prevalence of anemia than those with normal RBC folate and vitamins A and B12 levels. This first nationally representative nutrition and health survey in Kuwait indicated that anemia and ID are prevalent and ID contributes significantly to anemia prevalence.

Alyahya, K., et al. (2014). “Risk factors of low vitamin D status in adolescent females in Kuwait: implications for high peak bone mass attainment.” Arch Osteoporos 9: 178.

Risks of low vitamin D status in Kuwaiti adolescent girls are high parathyroid hormone (PTH), high waist/hip ratio, veiling and not having a private room. Low vitamin D status is likely to have a negative impact on their bone mass and accrual. INTRODUCTION: Low serum 25-hydroxyvitamin D (25OHD) levels are repeatedly found in females in the Middle East, which is a cause for concern particularly for adolescent females. This is because vitamin D has been shown to promote bone mineral accrual in adolescence. PURPOSE: The aim of this study was to assess the risk factors of low vitamin D status in adolescent females and to assess its impact on their bone mass. METHODS: Serum 25OHD and PTH were measured in 232 females. Anthropometric measurements and skin colour were obtained. Bone measurements at the lumbar spine were performed using dual-energy x-ray absorptiometry (DXA). Data on food intake, physical activity (PA) and sun exposure were taken. Binary logistic regression was used to assess the risk factors of serum 25OHD levels <25 nmol/L and multiple linear regression was used to assess the predictors of bone mineral variables. RESULTS: Median 25OHD was 19.4 nmol/L (IQR 16.4-23.68), among which 98.7 % obtained <50 nmol/L. PTH >7 pmol/L (odds ratio (OR) 4.3; 95 % CI 1.8, 10.2), not having a private room (OR 3.7; 95 % CI 1.4, 9.8), veiling (OR 2.4; 95 % CI 1.1, 5.5) and waist/hip ratio >0.75 (OR 2.1; 95 % CI 1.0, 4.3) were risk factors of low vitamin D status, whereas, height, weight, month since menarche, PTH, animal protein intake and PA were independent predictors of bone mineral content (p < 0.05). CONCLUSION: Low vitamin D status is prevalent in Kuwaiti adolescent females, which may have a negative impact on their bone mineralization and accrual. Further investigation is needed to reveal the underlying causes.

Alyahya, K. O. (2017). “Vitamin D levels in schoolchildren: a cross-sectional study in Kuwait.” BMC Pediatr 17(1): 213.

BACKGROUND: Ongoing studies in the Middle East, particularly in the Arabian Gulf countries, have reported extremely low levels of serum vitamin D across age and gender. In Kuwait, vitamin D deficiency is prevalent in adolescent girls and in adult women. A number of risk factors have been reported, among which gender, age, and obesity are a few. Because adequate vitamin D status is necessary to promote bone mineral accrual in childhood, and because low vitamin D levels have been associated with a wide range of health problems, there is concern that growing children with low vitamin D may be at higher risk for developing diseases. The aim of this study was to assess vitamin D levels in elementary schoolchildren. METHODS: Kuwaiti schoolchildren were recruited and assessed for their serum vitamin D, 25(OH)D, parathyroid hormone (PTH) and adjusted serum calcium (adj-Ca). Anthropometric measurements and data on lifestyle and health status were recorded during an interview. RESULTS: In a total of 199 schoolchildren, median (IQR) age was 8.5 (7.0-9.5 years), 25(OH)D was 30 (22-39 nmol/L), PTH was 4.7 (3.8-5.9 pmol/L), and adj-Ca was 2.39 (2.33-2.44 mmol/L). Boys had higher levels of 25(OH)D (18.3% vs 6.6% had levels ≥50 nmol/L) and lower levels of PTH (94.6% vs 80.2% had levels <7 pmol/L) than girls. Significant risk factors for 25(OH)D levels <25 nmol/L included being ≤8.5 years old (OR 4.95, 95% CI: 1.92-12.74), having PTH ≥7 pmol/L (OR 2.28, 95% CI: 1.17-4.46), being female (OR 2.44, 95% CI: 1.22-4.88), and being overweight or obese (OR 2.18, 95% CI: 1.11-4.26). CONCLUSIONS: The results show relatively low levels of 25(OH)D in young schoolchildren in Kuwait, with lower levels in girls. Given the association of 25(OH)D with a wide range of ailments, it is necessary to further examine the causes and risk factors of low vitamin D in this age group to prevent associated health problems.

Anglin, R. E., et al. (2013). “Vitamin D deficiency and depression in adults: systematic review and meta-analysis.” Br J Psychiatry 202: 100-107.

BACKGROUND: There is conflicting evidence about the relationship between vitamin D deficiency and depression, and a systematic assessment of the literature has not been available. AIMS: To determine the relationship, if any, between vitamin D deficiency and depression. METHOD: A systematic review and meta-analysis of observational studies and randomised controlled trials was conducted. RESULTS: One case-control study, ten cross-sectional studies and three cohort studies with a total of 31 424 participants were analysed. Lower vitamin D levels were found in people with depression compared with controls (SMD = 0.60, 95% CI 0.23-0.97) and there was an increased odds ratio of depression for the lowest v. highest vitamin D categories in the cross-sectional studies (OR = 1.31, 95% CI 1.0-1.71). The cohort studies showed a significantly increased hazard ratio of depression for the lowest v. highest vitamin D categories (HR = 2.21, 95% CI 1.40-3.49). CONCLUSIONS: Our analyses are consistent with the hypothesis that low vitamin D concentration is associated with depression, and highlight the need for randomised controlled trials of vitamin D for the prevention and treatment of depression to determine whether this association is causal.

Azzi, A. (2021). “Reflections on a century of vitamin E research: Looking at the past with an eye on the future.” Free Radic Biol Med 175: 155-160.

The name vitamin E, was given by Barnett and Sure who suggested that the factor proposed by Evans and Bishop as substance “X,” be termed vitamin “E” as the next vitamin after the A, B, C and D vitamins had been already described. The identification of vitamin E with a-tocopherol was made in 1936 by Evans’ group. One year later β-tocopherol and 11 years later δ-tocopherol were isolated. Tocotrienol (named zetatocopherol) was first described in 1957 and later isolated in 1961. The antioxidant property of tocopherols was reported by Olcott and Emerson in 1937. Inherited vitamin E deficiency, AVED, characterized by a form of neuromyopathy was first described in 1981. The disease, was localized to chromosome 8q and found to be caused by a mutation of the a-TTP gene. The subsequent paragraphs are not a comprehensive review but only critical reflections on some important aspects of vitamin E research.

Bar-El Dadon, S. and R. Reifen (2017). “Vitamin A and the epigenome.” Crit Rev Food Sci Nutr 57(11): 2404-2411.

The epigenetic phenomena refer to heritable changes in gene expression other than those in the DNA sequence, such as DNA methylation and histone modifications. Major research progress in the last few years has provided further proof that environmental factors, including diet and nutrition, can influence physiologic and pathologic processes through epigenetic alterations, which in turn influence gene expression. This influence is termed nutritional epigenetics, and one prominent example is the regulation of gene transcription by vitamin A through interaction to its nuclear receptor. Vitamin A is critical throughout life. Together with its derivatives, it regulates diverse processes including reproduction, embryogenesis, vision, growth, cellular differentiation and proliferation, maintenance of epithelial cellular integrity and immune function. Here we review the epigenetic role of vitamin A in cancer, stem cells differentiation, proliferation, and immunity. The data presented here show that retinoic acid is a potent agent capable of inducing alterations in epigenetic modifications that produce various effects on the phenotype. Medical benefits of vitamin A as an epigenetic modulator, especially with respect to its chronic use as nutritional supplement, should rely on our further understanding of its epigenetic effects during health and disease, as well as through different generations.

Benson, C. S., et al. (2021). “The effect of iron deficiency and anaemia on women’s health.” Anaesthesia 76 Suppl 4: 84-95.

Iron deficiency and anaemia are global health problems and major causes of morbidity in women. Current definitions of anaemia in women are historic and have been challenged by recent data from observational studies. Menstrual loss, abnormal uterine bleeding and pregnancy put women at risk of developing iron deficiency which can result in severe fatigue, reduced exercise capacity and poor work performance. Iron deficiency and anaemia during pregnancy are associated with adverse maternal and fetal outcomes, including neurocognitive deficits in children born to iron-deficient mothers. Both iron deficiency and anaemia are common in women undergoing surgery but their association with poor outcomes remains uncertain. The enduring burden of iron deficiency and anaemia in women suggests that current strategies for recognition, prevention and treatment are limited in their utility. Improvements in our understanding of iron homeostasis and the development of new iron preparations, which are better absorbed with fewer side-effects, may improve therapeutic effectiveness of oral iron. Intravenous iron is efficacious for correcting anaemia rapidly but high-quality data on patient-centred outcomes and cost-effectiveness are currently lacking. Many recommendations for the treatment of iron deficiency and anaemia in national guidelines are not supported by high-quality evidence. There is a need for robust epidemiological data and well-designed clinical trials. The latter will require collaborative working between researchers and patients to design studies in ways that incorporate patients’ perspectives on the research process and target outcomes that matter to them.

Best, K. P., et al. (2022). “ISSFAL statement number 7 – Omega-3 fatty acids during pregnancy to reduce preterm birth.” Prostaglandins Leukot Essent Fatty Acids 186: 102495.

Globally, preterm birth is the leading cause of death in children under the age of 5 years and survivors may suffer life-long consequences. Following many years of investigation, there is strong evidence that a proportion of preterm births can be prevented by increasing maternal dietary omega-3 long chain polyunsaturated fatty acid (LCPUFA) intake during pregnancy. This Statement provides a synthesis of contemporary evidence on the role of omega-3 LCPUFA on prevention of preterm birth and is designed to provide fatty acid-specific knowledge and guidance for medical practitioners, midwives, health services, professional bodies and policy makers to consider for their contextual situations. The evidence synthesis, which underpins this statement, is based on the 2018 Cochrane systematic review with supplemental evidence from RCTs completed since that time as well as other systematic reviews. Heterogeneity between studies was explored to understand how the effect of omega-3 supplementation may vary in different population groups and by dose and type of omega-3 supplementation. Most trials were conducted in upper-middle or high-income countries and the evidence are most applicable in those settings. The evidence synthesis confirmed that omega-3 LCPUFA, particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have an important role to play in determining gestational length in singleton pregnancies. Adequate intake of omega-3 LCPUFA in early pregnancy, consistent with existing nutritional guidelines, is associated with a lower risk of preterm and early preterm births for women with singleton pregnancies. Therefore, women with adequate omega-3 intakes in early pregnancy should maintain these intakes. Women who are low in omega-3 fatty acids will benefit most from omega-3 LCPUFA supplementation to reduce their risk of early birth. In such cases supplementation with a total of about 1000 mg of DHA plus EPA is effective at reducing risk of early birth, preferably with supplementation commencing before 20 weeks’ gestation.

Bloch, M. H. and A. Qawasmi (2011). “Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology: systematic review and meta-analysis.” J Am Acad Child Adolesc Psychiatry 50(10): 991-1000.

OBJECTIVE: Several studies have demonstrated differences in omega-3 fatty acid composition in plasma and in erythrocyte membranes in patients with attention-deficit/hyperactivity disorder (ADHD) compared with unaffected controls. Omega-3 fatty acids have anti-inflammatory properties and can alter central nervous system cell membrane fluidity and phospholipid composition. Cell membrane fluidity can alter serotonin and dopamine neurotransmission. The goal of this meta-analysis was to examine the efficacy of omega-3 fatty acid supplementation in children with ADHD. METHOD: PubMed was searched for randomized placebo-controlled trials examining omega-3 fatty acid supplementation in children with ADHD symptomatology. The primary outcome measurement was standardized mean difference in rating scales of ADHD severity. Secondary analyses were conducted to determine the effects of dosing of different omega-3 fatty acids in supplements. RESULTS: Ten trials involving 699 children were included in this meta-analysis. Omega-3 fatty acid supplementation demonstrated a small but significant effect in improving ADHD symptoms. Eicosapentaenoic acid dose within supplements was significantly correlated with supplement efficacy. No evidence of publication bias or heterogeneity between trials was found. CONCLUSION: Omega-3 fatty acid supplementation, particularly with higher doses of eicosapentaenoic acid, was modestly effective in the treatment of ADHD. The relative efficacy of omega-3 fatty acid supplementation was modest compared with currently available pharmacotherapies for ADHD such as psychostimulants, atomoxetine, or α(2) agonists. However, given its relatively benign side-effect profile and evidence of modest efficacy, it may be reasonable to use omega-3 fatty supplementation to augment traditional pharmacologic interventions or for families who decline other psychopharmacologic options.

Blondeau, N., et al. (2015). “Alpha-linolenic acid: an omega-3 fatty acid with neuroprotective properties-ready for use in the stroke clinic?” Biomed Res Int 2015: 519830.

Alpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brain’s vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain-derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders.

Brenna, J. T., et al. (2009). “alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans.” Prostaglandins Leukot Essent Fatty Acids 80(2-3): 85-91.

Blood levels of polyunsaturated fatty acids (PUFA) are considered biomarkers of status. Alpha-linolenic acid, ALA, the plant omega-3, is the dietary precursor for the long-chain omega-3 PUFA eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Studies in normal healthy adults consuming western diets, which are rich in linoleic acid (LA), show that supplemental ALA raises EPA and DPA status in the blood and in breast milk. However, ALA or EPA dietary supplements have little effect on blood or breast milk DHA levels, whereas consumption of preformed DHA is effective in raising blood DHA levels. Addition of ALA to the diets of formula-fed infants does raise DHA, but no level of ALA tested raises DHA to levels achievable with preformed DHA at intakes similar to typical human milk DHA supply. The DHA status of infants and adults consuming preformed DHA in their diets is, on average, greater than that of people who do not consume DHA. With no other changes in diet, improvement of blood DHA status can be achieved with dietary supplements of preformed DHA, but not with supplementation of ALA, EPA, or other precursors.

Brigelius-Flohé, R. (2021). “Vitamin E research: Past, now and future.” Free Radic Biol Med 177: 381-390.

The early history of vitamin E from its discovery by Herbert M. Evans and Katharine J. S. Bishop in 1922 up to its chemical synthesis by Paul Karrer and coworkers in 1938 and the development of the concept that vitamin E acts as an antioxidant in vivo are recalled. Some more recent results shedding doubt on this hypothesis are reviewed. They comprise influence of vitamin E on enzyme activities, signaling cascades, gene expression and bio-membrane structure. The overall conclusion is that our knowledge of the vitamin’s mechanism of action still remains fragmentary. The metabolism of tocopherols and tocotrienols is presented and discussed in respect to bioactivity of the metabolites, interference with drug metabolism and the future design of clinical trials. Some strategies are recommended how to reach the final goal: the identification of the primary vitamin E target(s) and the analysis of the downstream events up to the physiological phenomena.

Burdge, G. (2004). “Alpha-linolenic acid metabolism in men and women: nutritional and biological implications.” Curr Opin Clin Nutr Metab Care 7(2): 137-144.

PURPOSE OF REVIEW: This review critically evaluates current knowledge of alpha-linolenic acid metabolism in adult humans based on the findings of studies using stable isotope tracers and on increased dietary alpha-linolenic acid intake. The relative roles of alpha-linolenic acid and of longer-chain polyunsaturated fatty acids in cell structure and function are discussed together with an overview of the major metabolic fates of alpha-linolenic acid. The extent of partitioning towards beta-oxidation and carbon recycling in humans is described. The use and limitations of stable isotope tracers to estimate alpha-linolenic acid desaturation and elongation are discussed. A consensus view of the extent of alpha-linolenic acid conversion to longer-chain fatty acids in humans is presented. The extent to which increasing dietary alpha-linolenic acid intake alters the concentrations of longer-chain n-3 fatty acids is described. The biological and nutritional implications of these findings are discussed. RECENT FINDINGS: Conversion of alpha-linolenic acid to eicosapentaenoic acid is limited in men and further transformation to docosahexaenoic acid is very low. A lower proportion of alpha-linolenic acid is used as a substrate for beta-oxidation in women compared with men, while the fractional conversion to longer-chain fatty acids is greater, possibly due to the regulatory effects of oestrogen. SUMMARY: Overall, alpha-linolenic acid appears to be a limited source of longer-chain n-3 fatty acids in man and so adequate intakes of preformed n-3 polyunsaturated fatty acids, in particular docosahexaenoic acid, may be important for maintaining optimal tissue function. Capacity to upregulate alpha-linolenic acid transformation in women may be important for meeting the demands of the fetus and neonate for docosahexaenoic acid.

Burdge, G. C. and P. C. Calder (2005). “Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults.” Reprod Nutr Dev 45(5): 581-597.

The principal biological role of alpha-linolenic acid (alphaLNA; 18:3n-3) appears to be as a precursor for the synthesis of longer chain n-3 polyunsaturated fatty acids (PUFA). Increasing alphaLNA intake for a period of weeks to months results in an increase in the proportion of eicosapentaenoic acid (EPA; 20:5n-3) in plasma lipids, in erythrocytes, leukocytes, platelets and in breast milk but there is no increase in docosahexaenoic acid (DHA; 22:6n-3), which may even decline in some pools at high alphaLNA intakes. Stable isotope tracer studies indicate that conversion of alphaLNA to EPA occurs but is limited in men and that further transformation to DHA is very low. The fractional conversion of alphaLNA to the longer chain n-3 PUFA is greater in women which may be due to a regulatory effect of oestrogen. A lower proportion of alphaLNA is used for beta-oxidation in women compared with men. Overall, alphaLNA appears to be a limited source of longer chain n-3 PUFA in humans. Thus, adequate intakes of preformed long chain n-3 PUFA, in particular DHA, may be important for maintaining optimal tissue function. Capacity to up-regulate alphaLNA conversion in women may be important for meeting the demands of the fetus and neonate for DHA.

Burns-Whitmore, B., et al. (2019). “Alpha-Linolenic and Linoleic Fatty Acids in the Vegan Diet: Do They Require Dietary Reference Intake/Adequate Intake Special Consideration?” Nutrients 11(10).

Good sources of the long-chain n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) include cold-water fish and seafood; however, vegan diets (VGNs) do not include animal-origin foods. Typically, US omnivores obtain enough dietary EPA and DHA, but unless VGNs consume algal n-3 supplements, they rely on endogenous production of long-chain fatty acids. VGN diets have several possible concerns: (1) VGNs have high intakes of linoleic acid (LA) as compared to omnivore/non-vegetarian diets. (2) High intakes of LA competitively interfere with the endogenous conversion of alpha-linolenic acid (ALA) to EPA and DHA. (3) High somatic levels of LA/low ALA indicate a decreased ALA conversion to EPA and DHA. (4) Some, not all VGNs meet the Dietary Reference Intake Adequate Intake (DRI-AI) for dietary ALA and (5) VGN diets are high in fiber, which possibly interferes with fat absorption. Consequently, health professionals and Registered Dietitians/Registered Dietitian Nutritionists working with VGNs need specific essential fatty acid diet guidelines. The purpose of this review was: (1) to suggest that VGNs have a DRI-AI Special Consideration requirement for ALA and LA based on VGN dietary and biochemical indicators of status and (2) to provide suggestions to ensure that VGNs receive adequate intakes of LA and ALA.

Carr, A. C. and S. Rowe (2020). “Factors Affecting Vitamin C Status and Prevalence of Deficiency: A Global Health Perspective.” Nutrients 12(7).

A recent review of global vitamin C status has indicated a high prevalence of deficiency, particularly in low- and middle-income countries, as well as in specific subgroups within high-income countries. Here, we provide a narrative review of potential factors influencing vitamin C status globally. The in vivo status of vitamin C is primarily affected by dietary intake and supplement use, with those who supplement having a higher mean status and a lower prevalence of deficiency. Dietary intake can be influenced by cultural aspects such as traditional cooking practices and staple foods, with many staple foods, such as grains, contributing negligible vitamin C to the diet. Environmental factors can also affect vitamin C intake and status; these include geographic region, season, and climate, as well as pollution, the latter partly due to enhanced oxidative stress. Demographic factors such as sex, age, and race are known to affect vitamin C status, as do socioeconomic factors such as deprivation, education and social class, and institutionalization. Various health aspects can affect vitamin C status; these include body weight, pregnancy and lactation, genetic variants, smoking, and disease states, including severe infections as well as various noncommunicable diseases such as cardiovascular disease and cancer. Some of these factors have changed over time; therefore, we also explore if vitamin C status has shown temporal changes. Overall, there are numerous factors that can affect vitamin C status to different extents in various regions of the world. Many of these factors are not taken into consideration during the setting of global dietary intake recommendations for vitamin C.

Checa-Ros, A., et al. (2019). “Early monitoring of fatty acid profile in children with attention deficit and/or hyperactivity disorder under treatment with omega-3 polyunsaturated fatty acids.” Minerva Pediatr 71(4): 313-325.

BACKGROUND: Cognitive effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) might make them helpful in attention deficit/hyperactivity disorder (ADHD). However, the results derived from supplementation studies in children depend on the respective combinations and the study period. We aimed to investigate the serum fatty acid profile, attention scores and the tolerability in a group of ADHD children after receiving methylphenidate (MPH) and ω-3 PUFAs for 1 month. METHODS: A combination of MPH (1 mg/kg/day) and eicosapentaenoic (EPA, 70 mg/day) + docosahexaenoic acids (DHA, 250 mg/day) was administered to 40 ADHD children (7-15 years). An analysis of serum fatty acids by gas chromatography and an assessment of attention by using the Magallanes Scale of Visual Attention (MSVA) were carried out before and after 1 month of treatment. RESULTS: Our data revealed significant decreases of several ω-6 PUFAs, like arachidonic acid (P<0.0259). EPA and DHA concentrations increased by 27% and 3% respectively, and the ω-6/ω-3 index slightly decreased. The quality of attention significantly increased (P<0.026) and an improvement of ADHD core symptoms was reported both by parents and by teachers. No severe side effects occurred. CONCLUSIONS: Results demonstrate that the combination of MPH and EPA+DHA at the tested doses has positive clinical effects and an adequate safety profile. Therefore, our study suggests that ω-3 PUFAs may represent a feasible and a safe adjuvant therapy in children with ADHD and might enhance the effects of MPH. Further long-term follow-up studies are required to confirm these initial findings.

Choi, S., et al. (2018). “Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases.” Acta Pharmacol Sin 39(7): 1120-1132.

Zinc is an essential nutrient for human health and has anti-oxidative stress and anti-inflammatory functions. The association between zinc deficiency and the development of cardiovascular diseases (CVDs) has been supported by numerous studies. Supplementing zinc can reduce the risk of atherosclerosis and protect against myocardial infarction and ischemia/reperfusion injury. In this review we summarize the evidence in the literature, to consolidate the current knowledge on the dysregulation of zinc homeostasis in CVDs, and to explore the significant roles of the zinc homeostasis-regulatory proteins in cardiac physiology and pathophysiology. Moreover, this review also deliberates on the potential diagnostic and prognostic implications of zinc/zinc homeostasis-associated molecules (ZIP, ZnT, and MTs) in CVDs.

Cormick, G., et al. (2021). “Effect of Calcium Fortified Foods on Health Outcomes: A Systematic Review and Meta-Analysis.” Nutrients 13(2).

Calcium supplementation and fortification are strategies widely used to prevent adverse outcome in population with low-calcium intake which is highly frequent in low-income settings. We aimed to determine the effectiveness and cost-effectiveness of calcium fortified foods on calcium intake and related health, or economic outcomes. We performed a systematic review and meta-analysis involving participants of any age or gender, drawn from the general population. We searched PubMed, Agricola, EMBASE, CINAHL, Global Health, EconLit, the FAO website and Google until June 2019, without language restrictions. Pair of reviewers independently selected, extracted data and assessed the risk of bias of included studies using Covidence software. Disagreements were resolved by consensus. We performed meta-analyses using RevMan 5.4 and subgroup analyses by study design, age group, and fortification levels. We included 20 studies of which 15 were randomized controlled trials (RCTs), three were non-randomised studies and two were economic evaluations. Most RCTs had high risk of bias on randomization or blinding. Most represented groups were women and children from 1 to 72 months, most common intervention vehicles were milk and bakery products with a fortification levels between 96 and 1200 mg per 100 g of food. Calcium intake increased in the intervention groups between 460 mg (children) and 1200 mg (postmenopausal women). Most marked effects were seen in children. Compared to controls, height increased 0.83 cm (95% CI 0.00; 1.65), plasma parathyroid hormone decreased -1.51 pmol/L, (-2.37; -0.65), urine:calcium creatinine ratio decreased -0.05, (-0.07; -0.03), femoral neck and hip bone mineral density increased 0.02 g/cm(2) (0.01; 0.04) and 0.03 g/cm(2) (0.00; 0.06), respectively. The largest cost savings (43%) reported from calcium fortification programs came from prevented hip fractures in older women from Germany. Our study highlights that calcium fortification leads to a higher calcium intake, small benefits in children’s height and bone health and also important evidence gaps for other outcomes and populations that could be solved with high quality experimental or quasi-experimental studies in relevant groups, especially as some evidence of calcium supplementation show controversial results on the bone health benefit on older adults.

Crawford, M., et al. (2000). “Role of plant-derived omega-3 fatty acids in human nutrition.” Ann Nutr Metab 44(5-6): 263-265.

An international workshop on the role of plant-derived omega-3 fatty acids in human nutrition took place in Milan on February 9, 2000. The meeting was sponsored by the Nutrition Foundation of Italy and was organized by its Scientific Director, Dr. Andrea Poli. It was attended by experts in polyunsaturated fatty acids and human lipid nutrition. This is the first meeting devoted to the health aspects of alpha-linolenic acid, the omega-3 fatty acid contained in plant-derived edible products, as distinct from the more widely studied long-chain omega-3 products typically present in fish and fish-derived products. This report, which is based on updated scientific evidence presented and discussed at the workshop, was prepared by the international expert panel.

Czeizel, A. E., et al. (2013). “Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects.” Nutrients 5(11): 4760-4775.

Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin’s statement: “An ounce of prevention is better than a pound of care”.

DeMaeyer, E. M. (1986). “The WHO programme of prevention and control of vitamin A deficiency, xerophthalmia and nutritional blindness.” Nutr Health 4(2): 105-112.

The vast extent and the world wide distribution of vitamin A deficiency is discussed. Its epidemiology is reviewed and sources of vitamin A in diets recorded, along with the high requirements of children. Strategy for prevention is described under three headings–short, medium and long term steps. Strategies in many countries received notice.

Conservative estimates project over 500,000 cases/year of new active corneal lesions and 6-7 million cases of noncorneal xerophthalmia attributable to vitamin A deficiency on a worldwide basis. Vitamin A deficiency affects growth, the differentiation of epithelial tissues, and immune competence. The most dramatic impact, however, is on the eye and includes night blindness, xerosis of the conjunctiva and cornea, and ultimately corneal ulceration and necrosis of the cornea. Vitamin A deficiency occurs when body stores are exhausted and supply fails to meet the body’s requirements, either because there is a dietary insufficiency, requirements are increased, or intestinal absorption, transport and metabolism are impaired as a result of conditions such as diarrhea. Vitamin A deficiency is the single most frequent cause of blindness among preschool children in developing countries. The younger the child, the more severe is the disease and the higher the risk that corneal destruction will be followed by death. The most important step in preventing vitamin A deficiency is ensuring that children’s diets include adequate amounts of carotene containing cereals, tubers, vegetables, and fruits. An overall strategy designed to prevent and control vitamin A deficiency, xerophthalmia, and nutritional blindness may be defined in terms of action taken in the short, medium, and long term. A short-term, emergency measure includes the administration to vulnerable groups of single, large doses of vitamin A on a periodic basis. In the medium-term, the fortification of a dietary vehicle (e.g., sugar or monosodium glutamate) with vitamin A can be initiated. Increased dietary intake of vitamin A through home gardening and nutrition education programs comprises the longterm solution to this problem. The World Health Organization plans to launch a 10-year program of support to countries where vitamin A deficiency is a significant public health problem.

Dong, Q., et al. (2022). “Greater Protection of Lower Dietary Carbohydrate to Fiber Ratio (CFR) against Poor Blood Pressure Control in Patients with Essential Hypertension: A Cross-Sectional Study.” Nutrients 14(21).

(1) Background: Carbohydrate combined with dietary fiber (DF) applied as a surrogate marker of overall carbohydrate quality is a more essential determinant of cardiometabolic health. However, to date, no studies have applied this metric to analyze its associations with poor blood pressure control in hypertensive patients. (2) Methods: A cross-sectional design was implemented in one tertiary hospital and one community hospital in China. Using Feihua Nutrition Software to analyze participants’ two-day dietary log, the quantity of carbohydrate and fiber was obtained and the carbohydrate to fiber ratio (CFR) was calculated. The participants were divided into Q1, Q2, Q3, and Q4 groups by quartile method, from low to high according to CFR. The poor systolic and diastolic blood pressure (SBP and DBP) controls were defined as ≥140 mmHg and ≥90 mmHg, respectively. (3) Results: A convenience sample of 459 participants was included and the mean CFR was 29.6. Taking Q1 as reference, after adjusting for covariates, the CFR in Q4 was associated with higher poor SBP-controlled rate (OR, 4.374; 95% CI, 2.236-8.559). Taking Q2 as reference, after adjusting for covariates, the CFRs in Q3 and Q4 were associated with higher poor DBP-controlled rates [(OR = 1.964, 95% CI: 1.016-3.795) and (OR = 4.219, 95% CI: 2.132-8.637), respectively]. The CFR was the stronger protective determinant of SBP and DBP than DF or carbohydrate alone. (4) Conclusions: A higher CFR is a stronger risk factor for blood pressure (BP) control, and low CFR foods or a combination of corresponding food components, should be recommended in the dietary management of hypertensive patients.

Ebara, S. (2017). “Nutritional role of folate.” Congenit Anom (Kyoto) 57(5): 138-141.

Folate functions as a coenzyme to transfer one-carbon units that are necessary for deoxythymidylate synthesis, purine synthesis, and various methylation reactions. Ingested folate becomes a functional molecule through intestinal absorption, circulation, transport to cells, and various modifications to its structure. Associations between nutritional folate status and chronic diseases such as cardiovascular disease, cancer, and cognitive dysfunction have been reported. It has also been reported that maternal folate nutritional status is related to the risk of neural tube defects (NTDs) in the offspring. It has also been recommended that folate be consumed in the diet to promote the maintenance of good health. To reduce the risk of NTDs, supplementation with folic acid (a synthetic form of folate) during the periconceptional period has also been recommended. This paper describes the basic features and nutritional role of folate.

Effatpanah, M., et al. (2019). “Magnesium status and attention deficit hyperactivity disorder (ADHD): A meta-analysis.” Psychiatry Res 274: 228-234.

Current research suggests conflicting evidence surrounding the association between serum magnesium levels and the diagnosis of attention deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aims to explore, summarize and quantify the published literature addressing this topic. We conducted an exhaustive literature search on Scopus and PubMed for all the relevant observational studies published up to August 2018. A meta-analysis using a random-effects model was used to summarize the overall association between serum magnesium level and ADHD from the available data. We identified seven studies which reported the mean and standard deviation (SD) of magnesium concentration in both ADHD and control groups. The random-effects meta-analysis showed that subjects with ADHD had 0.105 mmol/l (95% CI: -0.188, -0.022; P < 0.013) lower serum magnesium levels compared with to their healthy controls. Moreover, we observed striking and statistically significant heterogeneity among the included studies (I(2) = 96.2%, P = 0.0103). The evidence from this meta-analysis supports the theory that an inverse relationship between serum magnesium deficiency and ADHD exists. High heterogeneity amongst the included studies suggests that there is a residual need for observational and community-based studies to further investigate this issue.

Fernández-Cao, J. C., et al. (2019). “Zinc Intake and Status and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.” Nutrients 11(5).

Zinc could have a protective role against type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aimed to evaluate the association between dietary, supplementary, and total zinc intake, as well as serum/plasma and whole blood zinc concentration, and risk of T2DM. Observational studies, conducted on cases of incident diabetes or T2DM patients and healthy subjects that reported a measure of association between zinc exposure and T2DM, were selected. Random effects meta-analyses were applied to obtain combined results. Stratified meta-analyses and meta-regressions were executed to assess sources of heterogeneity, as well as the impact of covariates on the findings. From 12,136 publications, 16 studies were selected. The odds ratio (OR) for T2DM comparing the highest versus lowest zinc intake from diet was 0.87 (95% CI: 0.78-0.98). Nevertheless, no association between supplementary or total zinc intake from both diet and supplementation, and T2DM was observed. A direct relationship was found between serum/plasma zinc levels and T2DM (OR = 1.64, 95% CI: 1.25-2.14). A moderately high dietary zinc intake, in relation to the Dietary Reference Intake, could reduce by 13% the risk of T2DM, and up to 41% in rural areas. Conversely, elevated serum/plasma zinc concentration was associated with an increased risk of T2DM by 64%, suggesting disturbances in zinc homeostasis.

Föcker, M., et al. (2017). “Vitamin D and mental health in children and adolescents.” Eur Child Adolesc Psychiatry 26(9): 1043-1066.

While vitamin D is known to be relevant for bone health, evidence has recently accumulated for an impact on mental health. To identify the potential benefits and limitations of vitamin D for mental health, an understanding of the physiology of vitamin D, the cut-off values for vitamin D deficiency and the current status of therapeutic trials is paramount. Results of a systematic PUBMED search highlight the association of vitamin D levels and mental health conditions. Here, we focus on children and adolescents studies as well as randomized controlled trials on depression in adults. 41 child and adolescent studies were identified including only 1 randomized controlled and 7 non-controlled supplementation trials. Overall, results from 25 cross-sectional studies as well as from 8 longitudinal studies suggest a role of vitamin D in the pathogenesis of mental disorders in childhood and adolescence. Findings from supplementation trials seem to support this hypothesis. However, randomized controlled trials in adults revealed conflicting results. Randomized controlled trials in childhood and adolescents are urgently needed to support the potential of vitamin D as a complementary therapeutic option in mental disorders. Study designs should consider methodological challenges, e.g., hypovitaminosis D at baseline, appropriate supplementation doses, sufficient intervention periods, an adequate power, clinically validated diagnostic instruments, and homogenous, well-defined risk groups.

Freeman, M. P., et al. (2006). “Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry.” J Clin Psychiatry 67(12): 1954-1967.

OBJECTIVE: To determine if the available data support the use of omega-3 essential fatty acids (EFA) for clinical use in the prevention and/or treatment of psychiatric disorders. PARTICIPANTS: The authors of this article were invited participants in the Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association (APA). EVIDENCE: Published literature and data presented at scientific meetings were reviewed. Specific disorders reviewed included major depressive disorder, bipolar disorder, schizophrenia, dementia, borderline personality disorder and impulsivity, and attention-deficit/hyperactivity disorder. Meta-analyses were conducted in major depressive and bipolar disorders and schizophrenia, as sufficient data were available to conduct such analyses in these areas of interest. CONSENSUS PROCESS: The subcommittee prepared the manuscript, which was reviewed and approved by the following APA committees: the Committee on Research on Psychiatric Treatments, the Council on Research, and the Joint Reference Committee. CONCLUSIONS: The preponderance of epidemiologic and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mood disorders. Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p = .02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry. Treatment recommendations and directions for future research are described. Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications.

Fu, Y., et al. (2021). “Associations among Dietary Omega-3 Polyunsaturated Fatty Acids, the Gut Microbiota, and Intestinal Immunity.” Mediators Inflamm 2021: 8879227.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), which are essential fatty acids that humans should obtain from diet, have potential benefits for human health. In addition to altering the structure and function of cell membranes, omega-3 PUFAs (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA), and docosapentaenoic acid (DPA)) exert different effects on intestinal immune tolerance and gut microbiota maintenance. Firstly, we review the effect of omega-3 PUFAs on gut microbiota. And the effects of omega-3 PUFAs on intestinal immunity and inflammation were described. Furthermore, the important roles of omega-3 PUFAs in maintaining the balance between gut immunity and the gut microbiota were discussed. Additional factors, such as obesity and diseases (NAFLD, gastrointestinal malignancies or cancer, bacterial and viral infections), which are associated with variability in omega-3 PUFA metabolism, can influence omega-3 PUFAs-microbiome-immune system interactions in the intestinal tract and also play roles in regulating gut immunity. This review identifies several pathways by which the microbiota modulates the gut immune system through omega-3 PUFAs. Omega-3 supplementation can be targeted to specific pathways to prevent and alleviate intestinal diseases, which may help researchers identify innovative diagnostic methods.

Gant, C. M., et al. (2018). “Higher Dietary Magnesium Intake and Higher Magnesium Status Are Associated with Lower Prevalence of Coronary Heart Disease in Patients with Type 2 Diabetes.” Nutrients 10(3).

In type 2 diabetes mellitus (T2D), the handling of magnesium is disturbed. Magnesium deficiency may be associated with a higher risk of coronary heart disease (CHD). We investigated the associations between (1) dietary magnesium intake; (2) 24 h urinary magnesium excretion; and (3) plasma magnesium concentration with prevalent CHD in T2D patients. This cross-sectional analysis was performed on baseline data from the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 ± 9 years, 57% men, and diabetes duration of 11 (7-18) years). Prevalence ratios (95% CI) of CHD by sex-specific quartiles of magnesium indicators, as well as by magnesium intake per dietary source, were determined using multivariable Cox proportional hazard models. CHD was present in 100 (22%) subjects. Adjusted CHD prevalence ratios for the highest compared to the lowest quartiles were 0.40 (0.20, 0.79) for magnesium intake, 0.63 (0.32, 1.26) for 24 h urinary magnesium excretion, and 0.62 (0.32, 1.20) for plasma magnesium concentration. For every 10 mg increase of magnesium intake from vegetables, the prevalence of CHD was, statistically non-significantly, lower (0.75 (0.52, 1.08)). In this T2D cohort, higher magnesium intake, higher 24 h urinary magnesium excretion, and higher plasma magnesium concentration are associated with a lower prevalence of CHD.

Gow, R. V., et al. (2015). “Current evidence and future directions for research with omega-3 fatty acids and attention deficit hyperactivity disorder.” Curr Opin Clin Nutr Metab Care 18(2): 133-138.

PURPOSE OF REVIEW: Nutritional insufficiencies of nutrients such as omega-3 highly unsaturated fatty acids (HUFAs), vitamins and minerals have been linked to suboptimal developmental outcomes including attention deficit hyperactivity disorder (ADHD). Although the predominant treatment is currently psychostimulant medications, randomized clinical trials with omega-3 HUFAs have reported small-to-modest effects in reducing symptoms of ADHD in children despite arguable individual methodological and design misgivings. RECENT FINDINGS: This review presents, discusses and critically evaluates data and findings from meta-analytic and systematic reviews and clinical trials published within the last 12 months. Recent trajectories of this research are discussed, such as comparing eicosapentaenoic acid and docosahexaenoic acid and testing the efficacy of omega-3 HUFAs as an adjunct to methylphenidate. Discussion includes highlighting limitations and potential future directions such as addressing variable findings by accounting for other nutritional deficiencies and behavioural food intolerances. SUMMARY: The authors conclude that given the current economic burden of ADHD, estimated in the region of $77 billion in the USA alone, in addition to the fact that a proportion of patients with ADHD are either treatment resistant, nonresponders or withdraw from medication because of adverse side-effects, the investigation of nonpharmacological interventions including omega-3 HUFAs in clinical practice warrants extrapolating.

Granero, R., et al. (2021). “The Role of Iron and Zinc in the Treatment of ADHD among Children and Adolescents: A Systematic Review of Randomized Clinical Trials.” Nutrients 13(11).

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder common from childhood to adulthood, affecting 5% to 12% among the general population in developed countries. Potential etiological factors have been identified, including genetic causes, environmental elements and epigenetic components. Nutrition is currently considered an influencing factor, and several studies have explored the contribution of restriction and dietary supplements in ADHD treatments. Iron is an essential cofactor required for a number of functions, such as transport of oxygen, immune function, cellular respiration, neurotransmitter metabolism (dopamine production), and DNA synthesis. Zinc is also an essential trace element, required for cellular functions related to the metabolism of neurotransmitters, melatonin, and prostaglandins. Epidemiological studies have found that iron and zinc deficiencies are common nutritional deficits worldwide, with important roles on neurologic functions (poor memory, inattentiveness, and impulsiveness), finicky appetite, and mood changes (sadness and irritability). Altered levels of iron and zinc have been related with the aggravation and progression of ADHD. OBJECTIVE: This is a systematic review focused on the contribution of iron and zinc in the progression of ADHD among children and adolescents, and how therapies including these elements are tolerated along with its effectiveness (according to PRISMA guidelines). METHOD: The scientific literature was screened for randomized controlled trials published between January 2000 to July 2021. The databases consulted were Medline, PsycINFO, Web of Science, and Google Scholar. Two independent reviewers screened studies, extracted data, and assessed quality and risk of bias (CONSORT, NICE, and Cochrane checklists used). CONCLUSION: Nine studies met the eligibility criteria and were selected. Evidence was obtained regarding the contribution of iron-zinc supplementation in the treatment of ADHD among young individuals. The discussion was focused on how the deficits of these elements contribute to affectation on multiple ADHD correlates, and potential mechanisms explaining the mediational pathways. Evidence also suggested that treating ADHD with diet interventions might be particularly useful for specific subgroups of children and adolescents, but further investigations of the effects of these diet interventions are needed.

Granger, M. and P. Eck (2018). “Dietary Vitamin C in Human Health.” Adv Food Nutr Res 83: 281-310.

Vitamin C is essential to prevent scurvy in humans and is implicated in the primary prevention of common and complex diseases such as coronary heart disease, stroke, and cancer. This chapter reviews the latest knowledge about dietary vitamin C in human health with an emphasis on studies of the molecular mechanisms of vitamin C maintenance as well as gene-nutrient interactions modifying these relationships. Epidemiological evidence indicates 5% prevalence for vitamin C deficiency and 13% prevalence for suboptimal status even in industrialized countries. The daily intake (dose) and the corresponding systemic concentrations (response) are related in a saturable relationship, and low systemic vitamin C concentrations in observational studies are associated with negative health outcomes. However, there is no evidence that vitamin C supplementation impacts the risks for all-cause mortality, impaired cognitive performance, reduced quality of life, the development of eye diseases, infections, cardiovascular disease, and cancers. This might be related to the fact that prevention would not be realized by supplementation in populations already adequately supplied through dietary sources. Recent genetic association studies indicate that the dietary intake might not be the sole determinant of systemic concentrations, since variations in genes participating in redox homeostasis and vitamin C transport had been associated with lowered plasma concentrations. However, impact sizes are generally low and these phenomena might only affect individual of suboptimal dietary supply.

Gröber, U., et al. (2015). “Magnesium in Prevention and Therapy.” Nutrients 7(9): 8199-8226.

Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status-primarily hypomagnesemia as it is seen more common than hypermagnesemia-might result in unwanted neuromuscular, cardiac or nervous disorders. Based on magnesium’s many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer’s disease, insulin resistance and type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD).

Guan, Z. W., et al. (2021). “Soluble Dietary Fiber, One of the Most Important Nutrients for the Gut Microbiota.” Molecules 26(22).

Dietary fiber is a widely recognized nutrient for human health. Previous studies proved that dietary fiber has significant implications for gastrointestinal health by regulating the gut microbiota. Moreover, mechanistic research showed that the physiological functions of different dietary fibers depend to a great extent on their physicochemical characteristics, one of which is solubility. Compared with insoluble dietary fiber, soluble dietary fiber can be easily accessed and metabolized by fiber-degrading microorganisms in the intestine and produce a series of beneficial and functional metabolites. In this review, we outlined the structures, characteristics, and physiological functions of soluble dietary fibers as important nutrients. We particularly focused on the effects of soluble dietary fiber on human health via regulating the gut microbiota and reviewed their effects on dietary and clinical interventions.

Guu, T. W., et al. (2019). “International Society for Nutritional Psychiatry Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder.” Psychother Psychosom 88(5): 263-273.

Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.

Hallahan, B., et al. (2016). “Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression.” Br J Psychiatry 209(3): 192-201.

Hashimoto, Y., et al. (2018). “Intake of Carbohydrate to Fiber Ratio Is a Useful Marker for Metabolic Syndrome in Patients with Type 2 Diabetes: A Cross-Sectional Study.” Ann Nutr Metab 72(4): 329-335.

BACKGROUND/AIMS: The effect of low carbohydrate diet on human health is still controversial. Whole grain, which is carbohydrate rich in fiber, has protective effects on human health. Thus, we assumed that intake of carbohydrate to fiber ratio has an important role in human health. METHODS: This is a post-hoc analysis of a cross-sectional study of 164 patients with type 2 diabetes. Habitual food and nutrient intake were assessed and estimated by a self-administered diet history questionnaire. Intake of carbohydrate to fiber ratio was defined as carbohydrate (g)/fiber intake (g). Logistic regression analyses were performed to reveal the association between intake of carbohydrate to fiber ratio and metabolic syndrome (MetS). RESULTS: Intake of carbohydrate to fiber ratio has closely associated with metabolic parameters, including triglycerides (r = 0.21, p = 0.007) and high-density lipoprotein cholesterol (r = -0.23, p = 0.003). Intake of carbohydrate to fiber ratio was associated with MetS (OR 1.06 [95% CI 1.00-1.13], p = 0.047) after adjusting for covariates, whereas carbohydrate intake (1.00 [0.99-1.01], p = 0.752) or carbohydrate energy/total energy (1.00 [0.94-1.07], p = 0.962) was not associated with MetS. CONCLUSIONS: Intake of carbohydrate to fiber ratio was associated with MetS, whereas carbohydrate intake was not.

Hawkey, E. and J. T. Nigg (2014). “Omega-3 fatty acid and ADHD: blood level analysis and meta-analytic extension of supplementation trials.” Clin Psychol Rev 34(6): 496-505.

Interest in the value of omega-3 (n-3) fatty acid supplementation for treatment of ADHD remains high. No prior meta-analysis has examined whether ADHD is associated with alterations in blood lipid levels and meta-analyses of supplementation have reached conflicting conclusions. METHODS: We report two new meta-analyses. Study 1 examined blood levels of omega-3 fatty acids in relation to ADHD. Study 2 examined a larger sample of randomized intervention trials than previously reported. RESULTS: Study 1 included 9 studies (n=586) and found lower overall blood levels of n-3 in individuals with ADHD versus controls (g=0.42, 95% CI=0.26-0.59; p<.001). Study 2 included 16 studies (n=1408) and found that n-3 supplementation improved ADHD composite symptoms; using the best available rating and reporter (g=0.26, 95% CI=0.15-0.37; p<.001). Supplementation showed reliable effects on hyperactivity by parent and teacher report, but reliable effects for inattention only by parent report. CONCLUSIONS: Omega-3 levels are reduced in children with ADHD. Dietary supplementation appears to create modest improvements in symptoms. There is sufficient evidence to consider omega-3 fatty acids as a possible supplement to established therapies. However it remains unclear whether such intervention should be confined to children with below normal blood levels.

Hemamy, M., et al. (2021). “The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: a randomized controlled trial.” BMC Pediatr 21(1): 178.

BACKGROUND: Attention-Deficit / Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder, characterized by varying severity in attention deficit and hyperactivity. Studies have shown deficiencies in the serum level of magnesium and vitamin D in people with ADHD. The aim of this study is to determine the effect of vitamin D and magnesium supplementation on mental health in children with ADHD. METHODS: We conducted a randomized, double blind, placebo-controlled clinical trial of 66 children with ADHD. Participants were randomly allocated to receive both vitamin D (50,000 IU/week) plus magnesium (6 mg/kg/day) supplements (n = 33) or placebos (n = 33) for 8-weeks. Strengths and difficulties questionnaire was used to evaluate children’s mental health at baseline and the end of the study. RESULTS: After eight weeks of intervention, the serum levels of 25-hydroxy-vitamin D3 and magnesium increased significantly in the intervention group compared with the control group. Also, children receiving vitamin D plus magnesium showed a significant reduction in emotional problems (p = 0.001), conduct problems (p = 0.002), peer problems (p = 0.001), prosocial score (p = 0.007), total difficulties (p = 0.001), externalizing score (p = 0.001), and internalizing score (p = 0.001) compared with children treated with the placebo. CONCLUSION: Vitamin D (50,000 IU/week) and magnesium (6 mg/kg/day) co-supplementation for a duration of 8-weeks could improve the behavioral function and mental health of children with ADHD. However, further well-designed studies with a larger sample size are needed. TRIAL REGISTRATION: IRCT2016030326886N1 .

Hibbeln, J. R., et al. (2007). “Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study.” Lancet 369(9561): 578-585.

BACKGROUND: Seafood is the predominant source of omega-3 fatty acids, which are essential for optimum neural development. However, in the USA, women are advised to limit their seafood intake during pregnancy to 340 g per week. We used the Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the possible benefits and hazards to a child’s development of different levels of maternal seafood intake during pregnancy. METHODS: 11,875 pregnant women completed a food frequency questionnaire assessing seafood consumption at 32 weeks’ gestation. Multivariable logistic regression models including 28 potential confounders assessing social disadvantage, perinatal, and dietary items were used to compare developmental, behavioural, and cognitive outcomes of the children from age 6 months to 8 years in women consuming none, some (1-340 g per week), and >340 g per week. FINDINGS: After adjustment, maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ) (no seafood consumption, odds ratio [OR] 1.48, 95% CI 1.16-1.90; some, 1.09, 0.92-1.29; overall trend, p=0.004), compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor, communication, and social development scores. For each outcome measure, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome. INTERPRETATION: Maternal seafood consumption of less than 340 g per week in pregnancy did not protect children from adverse outcomes; rather, we recorded beneficial effects on child development with maternal seafood intakes of more than 340 g per week, suggesting that advice to limit seafood consumption could actually be detrimental. These results show that risks from the loss of nutrients were greater than the risks of harm from exposure to trace contaminants in 340 g seafood eaten weekly.

Holscher, H. D. (2017). “Dietary fiber and prebiotics and the gastrointestinal microbiota.” Gut Microbes 8(2): 172-184.

The gastrointestinal microbiota has an important role in human health, and there is increasing interest in utilizing dietary approaches to modulate the composition and metabolic function of the microbial communities that colonize the gastrointestinal tract to improve health, and prevent or treat disease. One dietary strategy for modulating the microbiota is consumption of dietary fiber and prebiotics that can be metabolized by microbes in the gastrointestinal tract. Human alimentary enzymes are not able to digest most complex carbohydrates and plant polysaccharides. Instead, these polysaccharides are metabolized by microbes which generate short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. This article reviews the current knowledge of the impact of fiber and prebiotic consumption on the composition and metabolic function of the human gastrointestinal microbiota, including the effects of physiochemical properties of complex carbohydrates, adequate intake and treatment dosages, and the phenotypic responses related to the composition of the human microbiota.

Hu, Y., et al. (2019). “Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants.” J Am Heart Assoc 8(19): e013543.

Background Whether marine omega-3 supplementation is associated with reduction in risk of cardiovascular disease (CVD) remains controversial. Methods and Results This meta-analysis included study-level data from 13 trials. The outcomes of interest included myocardial infarction, coronary heart disease (CHD) death, total CHD, total stroke, CVD death, total CVD, and major vascular events. The unadjusted rate ratios were calculated using a fixed-effect meta-analysis. A meta-regression was conducted to estimate the dose-response relationship between marine omega-3 dosage and risk of each prespecified outcome. During a mean treatment duration of 5.0 years, 3838 myocardial infarctions, 3008 CHD deaths, 8435 total CHD events, 2683 strokes, 5017 CVD deaths, 15 759 total CVD events, and 16 478 major vascular events were documented. In the analysis excluding REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), marine omega-3 supplementation was associated with significantly lower risk of myocardial infarction (rate ratio [RR] [95% CI]: 0.92 [0.86, 0.99]; P=0.020), CHD death (RR [95% CI]: 0.92 [0.86, 0.98]; P=0.014), total CHD (RR [95% CI]: 0.95 [0.91, 0.99]; P=0.008), CVD death (RR [95% CI]: 0.93 [0.88, 0.99]; P=0.013), and total CVD (RR [95% CI]: 0.97 [0.94, 0.99]; P=0.015). Inverse associations for all outcomes were strengthened after including REDUCE-IT while introducing statistically significant heterogeneity. Statistically significant linear dose-response relationships were found for total CVD and major vascular events in the analyses with and without including REDUCE-IT. Conclusions Marine omega-3 supplementation lowers risk for myocardial infarction, CHD death, total CHD, CVD death, and total CVD, even after exclusion of REDUCE-IT. Risk reductions appeared to be linearly related to marine omega-3 dose.

Ismail, A. A. A., et al. (2018). “Chronic magnesium deficiency and human disease; time for reappraisal?” Qjm 111(11): 759-763.

Numerous epidemiological, experimental and clinical studies over the last 30 years have consistently shown that chronic magnesium deficiency is associated with and/or exacerbates a number of major disorders (Table 1). Yet chronic magnesium deficiency is not widely recognized and a major reason for this failure is that serum magnesium levels do not accurately reflect body magnesium stores. Specifically, in chronic magnesium deficiency, serum magnesium levels are often within the normal reference range (usually lowest quartile) and may not progress to overt hypomagnesaemia. This raises serious questions namely (i) should chronic magnesium deficiency be considered in high-risk patients irrespective of serum magnesium, even when ‘normal’? and (ii) if recognized, should oral magnesium supplement be given to restore body stores? Appreciating the vital role of magnesium for normal cellular function and bone health may help in formulating a well-considered and justifiable approach to these questions. Pragmatic tests for assessing magnesium status in the adult are suggested and discussed.

Karaszewska, D. M., et al. (2021). “Marine Omega-3 Fatty Acid Supplementation for Borderline Personality Disorder: A Meta-Analysis.” J Clin Psychiatry 82(3).

OBJECTIVE: Several promising studies investigated marine omega-3 fatty acids (ie, fish oil) in borderline personality disorder (BPD), but overall effects remain unclear. The aim of this study was to obtain estimates of effectiveness of omega-3 fatty acids in BPD using meta-analysis, with a priori differentiation of affective, impulsive, and cognitive-perceptual symptom domains. DATA SOURCES: We performed a literature search in PubMed, EMBASE, PsycINFO, and MEDLINE, using terms related to BPD and omega-3 fatty acids. Publication date was not a restriction. STUDY SELECTION: We included randomized controlled trials (RCTs) that compared omega-3 fatty acids to placebo or any active comparator and pooled data using meta-analysis. Five studies were included in the meta-analysis, describing 4 RCTs testing effects of omega-3 fatty acids in 137 patients with BPD or BPD-related behavior. DATA EXTRACTION: Using a pre-piloted data extraction form, we obtained data including intervention dose, duration, and BPD symptom scale scores, differentiating affective, impulsive, and cognitive-perceptual symptom domains. RESULTS: Random effects meta-analysis showed an overall significant decreasing effect of omega-3 fatty acids on overall BPD symptom severity (0.54 standardized difference in means [SDM]; 95% CI = 0.91 to 0.17; Z = 2.87; P = .0041), without heterogeneity (I(2) = 0.00; Q = 2.63; P = .45). A priori differentiation of relevant symptom domains showed significant effects on affect dysregulation (0.74 SDM; 95% CI = 1.21 to 0.27; Z = 3.11; P = .002) and impulsive behavior (0.45 SDM; 95% CI = 0.84 to 0.059; Z = 2.26; P = .024). However, effects on cognitive-perceptual symptoms did not reach the significance threshold. CONCLUSIONS: Available data indicate that marine omega-3 fatty acids improve symptoms of BPD, particularly impulsive behavioral dyscontrol and affective dysregulation. Marine omega-3 fatty acids could be considered as add-on therapy.

Lewis, E. D., et al. (2019). “Regulatory role of vitamin E in the immune system and inflammation.” IUBMB Life 71(4): 487-494.

Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E in the immune system have typically focused on α-tocopherol; however, emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-α-alpha-tocopherol vitamin E on immune cell function as well as their potential clinical application. © 2018 IUBMB Life, 71(4):487-494, 2019.

Liao, Y., et al. (2019). “Efficacy of omega-3 PUFAs in depression: A meta-analysis.” Transl Psychiatry 9(1): 190.

We conducted this meta-analysis of double-blind randomized placebo-controlled trials to estimate the efficacy of omega-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in the improvement of depression. We applied a systematic bibliographic search in PubMed and EMBASE for articles published prior to 20 December 2017. This meta-analysis was performed using RevMan 5.3 and R 3.4.3, and means and standard deviations were calculated in fixed- or random-effects models based on the results of the Q-test. A sensitivity analysis was also conducted to evaluate the stability of the results, and publication bias was evaluated by a funnel plot and Egger’s linear regression analysis. Our search resulted in 180 articles; we analyzed 26 studies, which included 2160 participants. The meta-analysis showed an overall beneficial effect of omega-3 polyunsaturated fatty acids on depression symptoms (SMD = -0.28, P = 0.004). Compared with placebo, EPA-pure (=100% EPA) and EPA-major formulations (≥60% EPA) demonstrated clinical benefits with an EPA dosage ≤1 g/d (SMD = -0.50, P = 0.003, and SMD = -1.03, P = 0.03, respectively), whereas DHA-pure and DHA-major formulations did not exhibit such benefits.Current evidence supports the finding that omega-3 PUFAs with EPA ≥ 60% at a dosage of ≤1 g/d would have beneficial effects on depression. Further studies are warranted to examine supplementation with omega-3 PUFAs for specific subgroups of subjects with inflammation, severity of depression, and the dose response for both EPA and DHA supplementation.

Libuda, L., et al. (2020). “Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: results of a randomized controlled trial.” Eur J Nutr 59(8): 3415-3424.

PURPOSE: While observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depression, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an untreated vitamin D deficiency compared to an immediate vitamin D(3) supplementation on depression scores in children and adolescents during standard day and in-patient psychiatric treatment. METHODS: Patients with vitamin D deficiency [25(OH)D ≤ 30 nmol/l] and at least mild depression [Beck Depression Inventory II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640 IU vitamin D(3)/d) or placebo group (PG) in a double-blind manner. During the intervention period of 28 days, both groups additionally received treatment as usual. BDI-II scores were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence, Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes. RESULTS: At admission, 49.3% of the screened patients (n = 280) had vitamin D deficiency. Although the intervention led to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14 ng/ml; 95% CI 4.86-23.77; p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI - 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental ratings revealed pronounced improvements of depressive symptoms in the VG (- 0.68; 95% CI - 1.23 to - 0.13; p = 0.016). CONCLUSION: Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in- or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider clinician-rated depressive symptoms as primary outcome. TRIAL REGISTRATION: “German Clinical Trials Register” ( https://www.drks.de ), registration number: DRKS00009758.

Lynch, S., et al. (2018). “Biomarkers of Nutrition for Development (BOND)-Iron Review.” J Nutr 148(suppl_1): 1001s-1067s.

This is the fifth in the series of reviews developed as part of the Biomarkers of Nutrition for Development (BOND) program. The BOND Iron Expert Panel (I-EP) reviewed the extant knowledge regarding iron biology, public health implications, and the relative usefulness of currently available biomarkers of iron status from deficiency to overload. Approaches to assessing intake, including bioavailability, are also covered. The report also covers technical and laboratory considerations for the use of available biomarkers of iron status, and concludes with a description of research priorities along with a brief discussion of new biomarkers with potential for use across the spectrum of activities related to the study of iron in human health.The I-EP concluded that current iron biomarkers are reliable for accurately assessing many aspects of iron nutrition. However, a clear distinction is made between the relative strengths of biomarkers to assess hematological consequences of iron deficiency versus other putative functional outcomes, particularly the relationship between maternal and fetal iron status during pregnancy, birth outcomes, and infant cognitive, motor and emotional development. The I-EP also highlighted the importance of considering the confounding effects of inflammation and infection on the interpretation of iron biomarker results, as well as the impact of life stage. Finally, alternative approaches to the evaluation of the risk for nutritional iron overload at the population level are presented, because the currently designated upper limits for the biomarker generally employed (serum ferritin) may not differentiate between true iron overload and the effects of subclinical inflammation.

Maret, W. and H. H. Sandstead (2006). “Zinc requirements and the risks and benefits of zinc supplementation.” J Trace Elem Med Biol 20(1): 3-18.

The adult human contains 2-3g of zinc, about 0.1% of which are replenished daily. On this basis and based on estimates of bioavailability of zinc, dietary recommendations are made for apparently healthy individuals. Absent chemical, functional, and/or physical signs of zinc deficiency are assumed indicative of adequacy. More specific data are seldom available. Changing food preferences and availability, and new food preparation, preservation, and processing technologies may require re-evaluation of past data. Conservative estimates suggest that 25% of the world’s population is at risk of zinc deficiency. Most of the affected are poor, and rarely consume foods rich in highly bioavailable zinc, while subsisting on foods that are rich in inhibitors of zinc absorption and/or contain relatively small amounts of bioavailable zinc. In contrast, among the relatively affluent, food choice is a major factor affecting risk of zinc deficiency. An additional problem, especially among the relatively affluent, is risk of chronic zinc toxicity caused by excessive consumption of zinc supplements. High intakes of zinc relative to copper can cause copper deficiency. A major challenge that has not been resolved for maximum health benefit is the proximity of the recommended dietary allowance (RDA) and the reference dose (RfD) for safe intake of zinc. Present recommendations do not consider the numerous dietary factors that influence the bioavailability of zinc and copper, and the likelihood of toxicity from zinc supplements. Thus the current assumed range between safe and unsafe intakes of zinc is relatively narrow. At present, assessment of zinc nutriture is complex, involving a number of chemical and functional measurements that have limitations in sensitivity and specificity. This approach needs to be enhanced so that zinc deficiency or excess can be detected early. An increasing number of associations between diseases and zinc status and apparently normal states of health, where additional zinc might be efficacious to prevent certain conditions, point at the pharmacology of zinc compounds as a promising area. For example, relationships between zinc and diabetes mellitus are an area where research might prove fruitful. In our opinion, a multidisciplinary approach will most likely result in success in this fertile area for translational research.

Martinat, M., et al. (2021). “Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders.” Nutrients 13(4).

n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.

Means, R. T. (2020). “Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters.” Nutrients 12(2).

A normal pregnancy consumes 500-800 mg of iron from the mother. Premenopausal women have a high incidence of marginal iron stores or iron deficiency (ID), with or without anemia, particularly in the less developed world. Although pregnancy is associated with a “physiologic” anemia largely related to maternal volume expansion; it is paradoxically associated with an increase in erythrocyte production and erythrocyte mass/kg. ID is a limiting factor for this erythrocyte mass expansion and can contribute to adverse pregnancy outcomes. This review summarizes erythrocyte and iron balance observed in pregnancy; its implications and impact on mother and child; and provides an overview of approaches to the recognition of ID in pregnancy and its management, including clinically relevant questions for further investigation.

Mirza, F. G., et al. (2018). “Impact and management of iron deficiency and iron deficiency anemia in women’s health.” Expert Rev Hematol 11(9): 727-736.

Iron deficiency and iron deficiency anemia are highly prevalent among women throughout their lives. Some females are particularly vulnerable to iron deficiency/iron deficiency anemia, including those with heavy menstrual bleeding (HMB) and pregnant/postpartum women. Despite the high prevalence of iron deficiency/iron deficiency anemia in women, the condition is still underdiagnosed and therefore undertreated, with serious clinical consequences. Areas covered: The following review examines the impact of iron deficiency and iron deficiency anemia on clinical outcomes and quality of life in women from adolescence to post-menopause, paying particular attention to guidelines and current recommendations for diagnostic tests and management. Expert commentary: There are numerous adverse health consequences of an iron-deficient state, affecting all aspects of the physical and emotional health and well-being of women. Guidelines must be developed to help clinicians better identify and treat women at risk of iron deficiency or iron deficiency anemia, particularly those with HMB, or who are pregnant or postpartum. Replacement therapy with oral or intravenous iron preparations is the mainstay of treatment for iron deficiency/iron deficiency anemia, with red blood cell transfusion reserved for emergency situations. Each iron therapy type is associated with benefits and limitations which impact their use.

Padayatty, S. J. and M. Levine (2016). “Vitamin C: the known and the unknown and Goldilocks.” Oral Dis 22(6): 463-493.

Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron donor and acts as a cofactor for fifteen mammalian enzymes. Two sodium-dependent transporters are specific for ascorbic acid, and its oxidation product dehydroascorbic acid is transported by glucose transporters. Ascorbic acid is differentially accumulated by most tissues and body fluids. Plasma and tissue vitamin C concentrations are dependent on amount consumed, bioavailability, renal excretion, and utilization. To be biologically meaningful or to be clinically relevant, in vitro and in vivo studies of vitamin C actions have to take into account physiologic concentrations of the vitamin. In this paper, we review vitamin C physiology; the many phenomena involving vitamin C where new knowledge has accrued or where understanding remains limited; raise questions about the vitamin that remain to be answered; and explore lines of investigations that are likely to be fruitful.

Parikh, M., et al. (2019). “Dietary Flaxseed as a Strategy for Improving Human Health.” Nutrients 11(5).

Flaxseed is a rich source of the omega-3 fatty acid, alpha linolenic acid, the lignan secoisolariciresinol diglucoside and fiber. These compounds provide bioactivity of value to the health of animals and humans through their anti-inflammatory action, anti-oxidative capacity and lipid modulating properties. The characteristics of ingesting flaxseed or its bioactive components are discussed in this article. The benefits of administering flaxseed or the individual bioactive components on health and disease are also discussed in this review. Specifically, the current evidence on the benefits or limitations of dietary flaxseed in a variety of cardiovascular diseases, cancer, gastro-intestinal health and brain development and function, as well as hormonal status in menopausal women, are comprehensive topics for discussion.

Parletta, N., et al. (2016). “Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls.” PLOS ONE 11(5): e0156432.

BACKGROUND: There is evidence that children with Attention Deficit Hyperactivity Disorder (ADHD) and Autistic Spectrum Disorder (ASD) have lower omega-3 polyunsaturated fatty acid (n-3 PUFA) levels compared with controls and conflicting evidence regarding omega-6 (n-6) PUFA levels. OBJECTIVES: This study investigated whether erythrocyte n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower and n-6 PUFA arachidonic acid (AA) higher in children with ADHD, ASD and controls, and whether lower n-3 and higher n-6 PUFAs correlated with poorer scores on the Australian Twin Behaviour Rating Scale (ATBRS; ADHD symptoms) and Test of Variable Attention (TOVA) in children with ADHD, and Childhood Autism Rating Scale (CARS) in children with ASD. METHODS: Assessments and blood samples of 565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79) were analysed. One-way ANOVAs with Tukey’s post-hoc analysis investigated differences in PUFA levels between groups and Pearson’s correlations investigated correlations between PUFA levels and ATBRS, TOVA and CARS scores. RESULTS: Children with ADHD and ASD had lower DHA, EPA and AA, higher AA/EPA ratio and lower n-3/n-6 than controls (P<0.001 except AA between ADHD and controls: P = 0.047). Children with ASD had lower DHA, EPA and AA than children with ADHD (P<0.001 for all comparisons). ATBRS scores correlated negatively with EPA (r = -.294, P<0.001), DHA (r = -.424, P<0.001), n-3/n-6 (r = -.477, P<0.001) and positively with AA/EPA (r = .222, P <.01). TOVA scores correlated positively with DHA (r = .610, P<0.001), EPA (r = .418, P<0.001) AA (r = .199, P<0.001), and n-3/n-6 (r = .509, P<0.001) and negatively with AA/EPA (r = -.243, P<0.001). CARS scores correlated significantly with DHA (r = .328, P = 0.002), EPA (r = -.225, P = 0.038) and AA (r = .251, P = 0.021). CONCLUSIONS: Children with ADHD and ASD had low levels of EPA, DHA and AA and high ratio of n-6/n-3 PUFAs and these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders.

Pecoraro, L., et al. (2019). “Vitamin C: should daily administration keep the paediatrician away?” Int J Food Sci Nutr 70(4): 513-517.

Vitamin C is an organic compound that is almost ubiquitous in the daily diet of individuals. There are clear indications of supplementation when secondary deficiency is detected related with reduced dietary intake or reduced absorption. On the other hand, indications for supplementation concerning an increased need are controversial. Several authors have studied the role of vitamin C as an adjuvant in the treatment of diseases that may affect children and adolescents. These diseases affect all organs and systems: specifically, vitamin C supplementation could play a role in respiratory, neurological, psychiatric, oncohematological, nephrological, ophthalmological and nutritional disorders. In paediatric age, a significant benefit of vitamin C supplementation has been observed in depressive pathology, iron-deficiency anaemia and chronic renal failure related to haemodialysis. No evidence was found with vitamin C supplementation on mortality, cognitive performance, quality of life, eye diseases, infections, cardiovascular diseases and tumours. This evidence may be related to the fact that in developed countries, vitamin C is almost ubiquitous in the daily diet of each individual. In conclusion, studies on non-industrialised populations in which there could be a real benefit from such supplementation, have yet to be conducted.

Pope, S., et al. (2019). “Cerebral folate deficiency: Analytical tests and differential diagnosis.” J Inherit Metab Dis 42(4): 655-672.

Cerebral folate deficiency is typically defined as a deficiency of the major folate species 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) in the presence of normal peripheral total folate levels. However, it should be noted that cerebral folate deficiency is also often used to describe conditions where CSF 5-MTHF is low, in the presence of low or undefined peripheral folate levels. Known defects of folate transport are deficiency of the proton coupled folate transporter, associated with systemic as well as cerebral folate deficiency, and deficiency of the folate receptor alpha, leading to an isolated cerebral folate deficiency associated with intractable seizures, developmental delay and/or regression, progressive ataxia and choreoathetoid movement disorders. Inborn errors of folate metabolism include deficiencies of the enzymes methylenetetrahydrofolate reductase, dihydrofolate reductase and 5,10-methenyltetrahydrofolate synthetase. Cerebral folate deficiency is potentially a treatable condition and so prompt recognition of these inborn errors and initiation of appropriate therapy is of paramount importance. Secondary cerebral folate deficiency may be observed in other inherited metabolic diseases, including disorders of the mitochondrial oxidative phosphorylation system, serine deficiency, and pyridoxine dependent epilepsy. Other secondary causes of cerebral folate deficiency include the effects of drugs, immune response activation, toxic insults and oxidative stress. This review describes the absorption, transport and metabolism of folate within the body; analytical methods to measure folate species in blood, plasma and CSF; inherited and acquired causes of cerebral folate deficiency; and possible treatment options in those patients found to have cerebral folate deficiency.

Razzaque, M. S. (2018). “Magnesium: Are We Consuming Enough?” Nutrients 10(12).

Magnesium is essential for maintaining normal cellular and organ function. In-adequate magnesium balance is associated with various disorders, such as skeletal deformities, cardiovascular diseases, and metabolic syndrome. Unfortunately, routinely measured serum magnesium levels do not always reflect total body magnesium status. Thus, normal blood magnesium levels eclipse the wide-spread magnesium deficiency. Other magnesium measuring methods, including the magnesium loading test, may provide more accurate reflections of total body magnesium status and thus improve identification of magnesium-deficient individuals, and prevent magnesium deficiency related complications.

Reddy, P. and L. R. Edwards (2019). “Magnesium Supplementation in Vitamin D Deficiency.” Am J Ther 26(1): e124-e132.

BACKGROUND: Vitamin D and magnesium (Mg) are some of the most studied topics in medicine with enormous implications for human health and disease. Majority of the adults are deficient in both vitamin D and magnesium but continue to go unrecognized by many health care professionals. AREAS OF UNCERTAINTY: Mg and vitamin D are used by all the organs in the body, and their deficiency states may lead to several chronic medical conditions. Studies described in the literature regarding these disease associations are contradictory, and reversal of any of these conditions may not occur for several years after adequate replacement. One should consider the supplementation therapy to be preventative rather than curative at this time. DATA SOURCES: PubMed search of several reported associations between vitamin D and Mg with diseases. RESULTS: Vitamin D and Mg replacement therapy in elderly patients is known to reduce the nonvertebral fractures, overall mortality, and the incidence of Alzheimer dementia. CONCLUSIONS: Vitamin D screening assay is readily available, but the reported lower limit of the normal range is totally inadequate for disease prevention. Based on the epidemiologic studies, ∼75% of all adults worldwide have serum 25(OH)D levels of <30 ng/mL. Because of the recent increase in global awareness, vitamin D supplementation has become a common practice, but Mg deficiency still remains unaddressed. Screening for chronic magnesium deficiency is difficult because a normal serum level may still be associated with moderate to severe deficiency. To date, there is no simple and accurate laboratory test to determine the total body magnesium status in humans. Mg is essential in the metabolism of vitamin D, and taking large doses of vitamin D can induce severe depletion of Mg. Adequate magnesium supplementation should be considered as an important aspect of vitamin D therapy.

Reynolds, E. H. (2014). “The neurology of folic acid deficiency.” Handb Clin Neurol 120: 927-943.

The metabolism of folic acid and the metabolism of vitamin B12 are intimately linked such that deficiency of either vitamin leads to an identical megaloblastic anemia. The neurologic manifestations of folate deficiency overlap with those of vitamin B12 deficiency and include cognitive impairment, dementia, depression, and, less commonly, peripheral neuropathy and subacute combined degeneration of the spinal cord. In both deficiency states there is often dissociation between the neuropsychiatric and the hematologic complications. There is a similar overlap and dissociation between neurologic and hematologic manifestations of inborn errors of folate and vitamin B12 metabolism. Low folate and raised homocysteine levels are risk factors for dementia, including Alzheimer’s disease, and depression. Even when folate deficiency is secondary to psychiatric illness due to apathy or poor diet it may eventually aggravate the underlying disorder in a vicious circle effect. Clinical responses to treatment with folates are usually slow over weeks and months, probably due to the efficient blood-brain barrier mechanism for the vitamin, perhaps in turn related to the experimentally demonstrated excitatory properties of folate derivatives. The inappropriate administration of folic acid in the presence of vitamin B12 deficiency may lead to both neurologic and, later, hematologic relapse. Impaired maternal folate intake and status increases the risk of neural tube defects. Periconceptual prophylactic administration of the vitamin reduces, but does not eliminate the risk of neural tube defects even in the absence of folate deficiency. Folates and vitamin B12 have fundamental roles in central nervous system function at all ages, especially in purine, thymidine, neucleotide, and DNA synthesis, genomic and nongenomic methylation and, therefore, in tissue growth, differentiation and repair. There is interest in the potential role of both vitamins in the prevention of disorders of central nervous system development, mood, dementia, including Alzheimer’s disease, and aging.

Scaglione, F. and G. Panzavolta (2014). “Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.” Xenobiotica 44(5): 480-488.

1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid – it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency.

Shankar, A. H. and A. S. Prasad (1998). “Zinc and immune function: the biological basis of altered resistance to infection.” Am J Clin Nutr 68(2 Suppl): 447s-463s.

Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.

Shlisky, J., et al. (2022). “Calcium deficiency worldwide: prevalence of inadequate intakes and associated health outcomes.” Ann N Y Acad Sci 1512(1): 10-28.

Dietary calcium deficiency is considered to be widespread globally, with published estimates suggesting that approximately half of the world’s population has inadequate access to dietary calcium. Calcium is essential for bone health, but inadequate intakes have also been linked to other health outcomes, including pregnancy complications, cancers, and cardiovascular disease. Populations in low- and middle-income countries (LMICs) are at greatest risk of low calcium intakes, although many individuals in high-income countries (HICs) also do not meet recommendations. Paradoxically, many LMICs with lower calcium intakes show lower rates of osteoporotic fracture as compared with HICs, though data are sparse. Calcium intake recommendations vary across agencies and may need to be customized based on other dietary factors, health-related behaviors, or the risk of calcium-related health outcomes. The lack of standard methods to assess the calcium status of an individual or population has challenged efforts to estimate the prevalence of calcium deficiency and the global burden of related adverse health consequences. This paper aims to consolidate available evidence related to the global prevalence of inadequate calcium intakes and associated health outcomes, with the goal of providing a foundation for developing policies and population-level interventions to safely improve calcium intake and status where necessary.

Spedding, S. (2014). “Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws.” Nutrients 6(4): 1501-1518.

Efficacy of Vitamin D supplements in depression is controversial, awaiting further literature analysis. Biological flaws in primary studies is a possible reason meta-analyses of Vitamin D have failed to demonstrate efficacy. This systematic review and meta-analysis of Vitamin D and depression compared studies with and without biological flaws. The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search was undertaken through four databases for randomized controlled trials (RCTs). Studies were critically appraised for methodological quality and biological flaws, in relation to the hypothesis and study design. Meta-analyses were performed for studies according to the presence of biological flaws. The 15 RCTs identified provide a more comprehensive evidence-base than previous systematic reviews; methodological quality of studies was generally good and methodology was diverse. A meta-analysis of all studies without flaws demonstrated a statistically significant improvement in depression with Vitamin D supplements (+0.78 CI +0.24, +1.27). Studies with biological flaws were mainly inconclusive, with the meta-analysis demonstrating a statistically significant worsening in depression by taking Vitamin D supplements (-1.1 CI -0.7, -1.5). Vitamin D supplementation (≥800 I.U. daily) was somewhat favorable in the management of depression in studies that demonstrate a change in vitamin levels, and the effect size was comparable to that of anti-depressant medication.

Stark, A. H., et al. (2008). “Update on alpha-linolenic acid.” Nutr Rev 66(6): 326-332.

Consumption of omega 3 fatty acids is known to have health benefits. For many years, the importance of the only member of the omega 3 family considered to be essential, alpha-linolenic acid (ALA), has been overlooked. Current research indicates that ALA, along with its longer chain metabolites, may play an important role in many physiological functions. Potential benefits of ALA include cardioprotective effects, modulation of the inflammatory response, and a positive impact on both central nervous system function and behavior. Recommended levels for ALA intake have been set, yet the possible advantages of its consumption are just being revealed.

Takaya, J. (2021). “Calcium-Deficiency during Pregnancy Affects Insulin Resistance in Offspring.” Int J Mol Sci 22(13).

Prenatal malnutrition is known to affect the phenotype of the offspring through changes in epigenetic regulation. Growing evidence suggests that epigenetics is one of the mechanisms by which nutrients and minerals affect metabolic traits. Although the perinatal period is the time of highest phenotypic plasticity, which contributes largely to developmental programming, there is evidence of nutritional influence on epigenetic regulation during adulthood. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. This brief review aims to identify the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in the offspring. Those findings demonstrate that maternal Ca deficiency during pregnancy may affect the epigenetic regulation of gene expression and thereby induce different metabolic phenotypes. We aim to address the need for Ca during pregnancy and propose the scaling-up of clinical and public health approaches that improved pregnancy outcomes.

Talebi, S., et al. (2022). “The effect of zinc supplementation in children with attention deficit hyperactivity disorder: A systematic review and dose-response meta‑analysis of randomized clinical trials.” Crit Rev Food Sci Nutr 62(32): 9093-9102.

OBJECTIVE: The present systematic review and dose-response meta-analysis was conducted to quantify the efficacy of zinc supplementation on clinical symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. METHODS: Electronic databases including PubMed, Scopus, ISI web of science, and Google Scholar were searched until January 2021. Results were reported as standardized mean difference (SMD) with a 95% confidence interval (CI) using Hedges’s adjusted g method. RESULTS: six randomized clinical trials with 489 school-aged children were identified for the meta-analysis. Our findings showed a significant effect of zinc supplementation on ADHD total scores (SMD: -0.62 Hedges’ g; 95% CI: -1.24 to -0.002, p = 0.04) but not in hyperactivity scores (SMD: -0.93 Hedges’ g; 95% CI: -3.31 to 1.45, p = 0.44) and inattention scores (SMD: 0.21 Hedges’ g; 95% CI: -0.09 to 0.51, p = 0.17) compared to the control group. Besides, the dose-response analysis did not find any significant non-linear association between zinc supplementation dosage or duration on ADHD total scores. The certainty of the evidence was rated moderate to very low for all outcomes. CONCLUSION: Zinc supplementation may have beneficial effects in improving ADHD symptoms in children with ADHD. Future well-designed, large-scale randomized controlled trials are needed to establish the benefit of zinc supplementation for ADHD.

Ulatowski, L. M. and D. Manor (2015). “Vitamin E and neurodegeneration.” Neurobiol Dis 84: 78-83.

Alpha-tocopherol (vitamin E) is a plant-derived antioxidant that is essential for human health. Studies with humans and with animal models of vitamin E deficiency established the critical roles of the vitamin in protecting the central nervous system, and especially the cerebellum, from oxidative damage and motor coordination deficits. We review here the established roles of vitamin E in protecting cerebellar functions, as well as emerging data demonstrating the critical roles of alpha-tocopherol in preserving learning, memory and emotive responses. We also discuss the importance of vitamin E adequacy in seemingly unrelated neurological disorders.

Wiseman, E. M., et al. (2017). “The vicious cycle of vitamin a deficiency: A review.” Crit Rev Food Sci Nutr 57(17): 3703-3714.

Vitamin A deficiency (VAD) is a serious and widespread public health problem and the leading cause of preventable blindness in young children. It is also associated with increased rates of death from severe infections, especially in developing countries. Over the past 35 years, researchers have examined the numerous activities of vitamin A in different tissues of the human body. VAD can lead to a series of ocular symptoms, anemia, and weak resistance to infection, which can increase the severity of infectious diseases and the risk of death. Cell development, vision, growth, and normal metabolism are among the vital processes that are insufficiently supported in the presence of VAD. VAD leads to impaired tissue function especially during the developmental periods of infancy, childhood, pregnancy, and lactation. We describe a multidirectional model of VAD that demonstrates how VAD can have progressive, negative effects on vital processes of the human body throughout the life cycle. This model starts with impaired intake and its link to decreased absorption and digestion and includes outcomes such as malnutrition, inflammation, and improper growth processes, including possible mechanisms. Together, these clinical and biochemical manifestations contribute to the vicious cycle of VAD.

Wozniak, J., et al. (2022). “A Randomized, Double-Blind, Controlled Clinical Trial of Omega-3 Fatty Acids and Inositol as Monotherapies and in Combination for the Treatment of Pediatric Bipolar Spectrum Disorder in Children Age 5-12.” Psychopharmacol Bull 52(4): 31-51.

OBJECTIVES: The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children. METHODS: Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation. RESULTS: Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p < 0.05) and in CDRS mean scores in the combination treatment group (p < 0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score <12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores <2. CONCLUSION: The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.

Wu, Q., et al. (2015). “Protective effects of dietary supplementation with natural ω-3 polyunsaturated fatty acids on the visual acuity of school-age children with lower IQ or attention-deficit hyperactivity disorder.” Nutrition 31(7-8): 935-940.

OBJECTIVE: Little attention has been paid to the possible protective role of ω-3 polyunsaturated fatty acids (PUFAs) on the visual acuity of school-age children with lower IQs or attention-deficit hyperactivity disorder (ADHD). The aim of this study was to evaluate the effect of dietary ω-3 PUFAs on the visual acuity and red blood cell (RBC) fatty acid compositions of these children. METHODS: We randomly assigned 179 children with lower IQs or ADHD to receive ordinary eggs (control group, n = 90) or eggs rich in C18:3 ω-3, eicosapentaenoic acid (EPA, 20:5 ω-3) and docosahexaenoic acid (DHA, 22:6 ω-3) for 3 mo (study group, n = 89). Before and after the intervention, distance visual acuity was tested using an E chart and the RBC fatty acid composition was determined using capillary gas chromatography. RESULTS: Three months later, 171 children completed the follow-up with the exception of 8 children who were unavailable during follow-up. Both groups of children showed a significant improvement in visual acuity (P < 0.05), however, visual acuity in the study group was significantly better than that of the control group (P = 0.013). The C18:3 ω-3 (P = 0.009), DHA (P = 0.009) and ∑ω-3 (P = 0.022) levels of the intervention group were significantly higher than those of the control group, while the C20:4 ω-6 (P = 0.003), C22:4 ω-6 (P = 0.000), ∑ω-6 (P = 0.001), ∑ω-6/∑ω-3 (P = 0.000) and arachidonic acid/DHA (P = 0.000) of the study group were significantly lower than those of the control group. No significant differences in the levels of C18:2 ω-6 (P = 0.723), C20:2 ω-6 (P = 0.249), C20:3 ω-6 (P = 0.258), C20:5 ω-3 (P = 0.051), or C22:5 (P = 0.200) were found between the two groups. CONCLUSIONS: Dietary supplementation with ω-3 PUFAs improves both visual acuity and the RBC fatty acid profile in school-age children with lower IQs or ADHD.

Xie, F., et al. (2022). “Effect of vitamin D supplementation on the incidence and prognosis of depression: An updated meta-analysis based on randomized controlled trials.” Front Public Health 10: 903547.

BACKGROUND: There have been several controversies about the correlation between vitamin D and depression. This study aimed to investigate the relationship between vitamin D supplementation and the incidence and prognosis of depression and to analyze the latent effects of subgroups including population and supplement strategy. METHODS: A systematic search for articles before July 2021 in databases (PubMed, EMBASE, Web of Science, and the Cochrane Library) was conducted to investigate the effect of vitamin D supplementation on the incidence and prognosis of depression. RESULTS: This meta-analysis included 29 studies with 4,504 participants, indicating that the use of vitamin D was beneficial to a decline in the incidence of depression (SMD: -0.23) and improvement of depression treatment (SMD: -0.92). Subgroup analysis revealed that people with low vitamin D levels (<50 nmol/L) and females could notably benefit from vitamin D in both prevention and treatment of depression. The effects of vitamin D with a daily supplementary dose of >2,800 IU and intervention duration of ≥8 weeks were considered significant in both prevention and treatment analyses. Intervention duration ≤8 weeks was recognized as effective in the treatment group. CONCLUSION: Our results demonstrate that vitamin D has a beneficial impact on both the incidence and the prognosis of depression. Whether suffering from depression or not, individuals with low vitamin D levels, dose >2,800 IU, intervention duration ≥8 weeks, and all females are most likely to benefit from vitamin D supplementation.

Yuan, Q., et al. (2022). “The review of alpha-linolenic acid: Sources, metabolism, and pharmacology.” Phytother Res 36(1): 164-188.

α-linolenic acid (ALA, 18:3n-3) is a carboxylic acid composed of 18 carbon atoms and three cis double bonds, and is an essential fatty acid indispensable to the human body. This study aims to systematically review related studies on the dietary sources, metabolism, and pharmacological effects of ALA. Information on ALA was collected from the internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library, and Europe PMC using a combination of keywords including “pharmacology,” “metabolism,” “sources.” The following findings are mainly contained. (a) ALA can only be ingested from food and then converted into eicosapentaenoic acid and docosahexaenoic acid in the body. (b) This conversion process is relatively limited and affected by many factors such as dose, gender, and disease. (c) Pharmacological research shows that ALA has the anti-metabolic syndrome, anticancer, antiinflammatory, anti-oxidant, anti-obesity, neuroprotection, and regulation of the intestinal flora properties. (d) There are the most studies that prove ALA has anti-metabolic syndrome effects, including experimental studies and clinical trials. (e) The therapeutic effect of ALA will be affected by the dosage. In short, ALA is expected to treat many diseases, but further high quality studies are needed to firmly establish the clinical efficacy of ALA.

Zhang, Z., et al. (2018). “Dietary Intakes of EPA and DHA Omega-3 Fatty Acids among US Childbearing-Age and Pregnant Women: An Analysis of NHANES 2001-2014.” Nutrients 10(4).

BACKGROUND: The 2015–2020 Dietary Guidelines for Americans (DGA) recommend that the general population should consume about 8 ounces (oz.) per week of a variety of seafood, providing approximately 250 mg per day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and that pregnant and lactating women should consume 8–12 oz. per week of seafood. METHODS: We determined the usual intakes, percentage not meeting recommendations, and trends in EPA and DHA intakes among childbearing-age and pregnant women (15–44 years of age) using the NHANES cycles 2001–2002 through 2013–2014. RESULTS: For the childbearing-age women, the mean usual intake of seafood was 0.44 ± 0.02 oz. equivalent per day and 100% of the population was below the DGA recommendation. Mean usual intakes of EPA, DHA, and combined EPA and DHA from foods and dietary supplements combined were 26.8 ± 1.4, 62.2 ± 1.9, and 88.1 ± 3.0 mg per day, respectively. Over 95% of the sample did not meet the daily intakes of 250 mg EPA and DHA. Similar results were observed for pregnant women. After controlling for covariates, there were slight but significant increases in EPA and DHA intakes from foods and dietary supplements over the 14-year span among childbearing-age (p = 0.005) and pregnant women (p = 0.002). CONCLUSIONS: It was estimated that a majority of U.S. childbearing-age and pregnant women consumed significantly lower amounts of seafood than what the DGA recommends, which subsequently leads to low intakes of EPA and DHA; in addition, dietary supplement use has not eliminated the nutrient shortfall.

Supplementary Table H – Health criteria to achieve Tier I – Criterion: B6, B12, Cold Pressed Oils, Tryptophan

Refs 1-5: At least 0.75 mg of vitamin B6 (pyridoxine) per serving

(Ueland, McCann et al. 2017)
(Selhub, Byun et al. 2013)
(Wan, Zheng et al. 2022)
(Stach, Stach et al. 2021)
National Institutes of Health, US Department of Health & Human Services online article: https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional

Refs 6-10: At least 2 µg of vitamin B12 (cobalamin) per serving

National Institutes of Health, US Department of Health & Human Services online article: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/
(Stach, Stach et al. 2021)
(Rahman and Baumgartner 2019)
(Hossain, Amarasena et al. 2022)
(Mikkelsen and Apostolopoulos 2018)

Refs 11-15: Only cold-pressed plant-based oils

(Durazzo, Fawzy Ramadan et al. 2021)
(Fratianni, d’Acierno et al. 2021)
(De Santis, Cariello et al. 2019)
(Romani, Ieri et al. 2019)
(Prescha, Grajzer et al. 2014)

Refs 16-20: At least 88 mg of tryptophan per serving

(Kikuchi, Tanabe et al. 2021)
(Kałużna-Czaplińska, Gątarek et al. 2019)
(Gibson 2018)
(Dell’Osso, Carmassi et al. 2016)
(Agus, Planchais et al. 2018)

References:

Agus, A., et al. (2018). “Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease.” Cell Host Microbe 23(6): 716-724.

The gut microbiota is a crucial actor in human physiology. Many of these effects are mediated by metabolites that are either produced by the microbes or derived from the transformation of environmental or host molecules. Among the array of metabolites at the interface between these microorganisms and the host is the essential aromatic amino acid tryptophan (Trp). In the gut, the three major Trp metabolism pathways leading to serotonin (5-hydroxytryptamine), kynurenine (Kyn), and indole derivatives are under the direct or indirect control of the microbiota. In this review, we gather the most recent advances concerning the central role of Trp metabolism in microbiota-host crosstalk in health and disease. Deciphering the complex equilibrium between these pathways will facilitate a better understanding of the pathogenesis of human diseases and open therapeutic opportunities.

De Santis, S., et al. (2019). “Extra Virgin Olive Oil: Lesson from Nutrigenomics.” Nutrients 11(9).

Extra virgin olive oil (EVOO) consumption has a beneficial effect on human health, especially for prevention of cardiovascular disease and metabolic disorders. Here we underscore the peculiar importance of specific cultivars used for EVOO production since biodiversity among cultivars in terms of fatty acids and polyphenols content could differently impact on the metabolic homeostasis. In this respect, the nutrigenomic approach could be very useful to fully dissect the pathways modulated by different EVOO cultivars in terms of mRNA and microRNA transcriptome. The identification of genes and miRNAs modulated by specific EVOO cultivars could also help to discover novel nutritional biomarkers for prevention and/or prognosis of human disease. Thus, the nutrigenomic approach depicts a novel scenario to investigate if a specific EVOO cultivar could have a positive effect on human health by preventing the onset of cardiovascular disease and/or chronic inflammatory disorders also leading to cancer.

Dell’Osso, L., et al. (2016). “Depression, Serotonin and Tryptophan.” Curr Pharm Des 22(8): 949-954.

Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression have led to the appreciation of its complexity, although such study continues to support the role of 5-HT in this disorder. The aim of this review is to briefly summarize the available findings on 5-HT and depression, with a special focus on alterations in tryptophan (TRP) metabolism that can shift from 5-HT synthesis towards other, potentially neurotoxic, compounds, such as the tryptophan catabolite, quinolinic acid. The evidence that the TRP shunt may be promoted by stress hormones and proinflammatory cytokines strongly supports the notion that depression should now be considered a systemic disorder that can be triggered by different factors that ultimately target the 5-HT system in vulnerable individuals. In addition, such intriguing findings suggest biochemical targets for novel treatment options in depression.

Durazzo, A., et al. (2021). “Editorial: Cold Pressed Oils: A Green Source of Specialty Oils.” Front Nutr 8: 836651.

Fratianni, F., et al. (2021). “Fatty Acid Composition, Antioxidant, and in vitro Anti-inflammatory Activity of Five Cold-Pressed Prunus Seed Oils, and Their Anti-biofilm Effect Against Pathogenic Bacteria.” Frontiers in Nutrition 8.

Background/Aim: Sweet almond (Prunus amygdalus dulcis) oil is one of the most famous cold-pressed seed oils. However, other species of Prunus can provide oils with healthy properties. We analyzed the fatty acid (FA) composition, as well as the antioxidant, the in vitro anti-inflammatory properties, and the antibiofilm activity of five commercial vegetable cold-pressed seed oils of apricot, peach, plum, cherry, and black cherry.Methods: Gas Chromatography-Mass Spectrometry was performed for the analysis of FAs The antioxidant property of the oils was carried using different tests [2, 2-diphenyl-1-picrylhydrazyl (DPPH assay)], Ferric Reducing Antioxidant Power (FRAP), and the 2, 20 -azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS·+). The denaturation assay performed on bovine serum albumin (BSA) was used to evaluate the in vitro anti-inflammatory activity. The anti-biofilm activity was assessed using five pathogenic strains, namely, Acinetobacter baumannii, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Staphylococcus aureus, through the crystal violet test and the 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide (MTT), used to evaluate the metabolism of the microbial cells present within the biofilm.Results: Oleic acid and linoleic acids were the most abundant FAs. Black cherry seed oil exhibited the best antioxidant activity, but in general, the amount of oil needed to inhibit the activity of 1 ml of DPPH assay at 50% did not exceed 10 μg. The extract concentration for the 50% inhibition of the denaturation of the protein (IC50) did not exceed 4.4 μg. Linoleic and stearic acids affected the antioxidant activity of the oils; oleic acid, linolenic, and palmitoleic acids exhibited beneficial effects in preserving the BSA denaturation, as shown by the correlation data. The oils were able to inhibit the biofilm formation of the pathogens (up to 71.40% of inhibition) as well as act against their mature biofilm, although with different strengths, with values up to 61.54%. Concurrently, they also acted on the pathogen metabolism.Conclusion: The oils represent a valuable source of some healthy FAs. They showed potential antioxidant and anti-inflammatory in vitro activity, in addition, their potential effect on the biofilm can offer important ideas for research and reflection on their use as functional foods and/or ingredients.

Gibson, E. L. (2018). “Tryptophan supplementation and serotonin function: genetic variations in behavioural effects.” Proc Nutr Soc 77(2): 174-188.

The neurotransmitter serotonin has a role in affective disorders such as depression and anxiety, as well as sleep, cognitive function and appetite. This review examines the evidence that serotonin-related genotypes may moderate the behavioural effects of supplementation with the serotonin precursor amino acid l-tryptophan (TRP), on which synthesis of serotonin (or 5-hydroxytryptamine; 5-HT) depends. However, 95 % of serotonin is synthesised and used in the periphery, and TRP is also metabolised via non-5-HT routes such as the kynurenine pathway. Moreover, understanding of genotypes involved in regulation of serotonin raises questions over the generalisability of TRP effects on behaviour across individuals with varied serotonergic genotypes. To date, only differences between variants of the 5-HT transporter-linked promoter region (5-HTTLPR) have been investigated in relation to behavioural effects of TRP supplementation. Effects of 5-HTTLPR genotypes are usually compared between the alleles that are either high (L/L’) or low (S/S’) expressing of mRNA for the 5-HT transporter receptor. Yet, another key genetic variable is sex: in women, the S/S’ genotype predicts sensitivity to improved mood and reduced cortisol by TRP supplementation, during stressful challenges, whereas the L/L’ genotype protects against stress-induced mood deterioration. In men, the L/L’ genotype may confer risk of stress-induced increases in negative affect; there are insufficient data to assess effects on male S/S’ genotypes. However, better-powered studies to detect sex by genotype by stress by TRP interactions, as well as consideration of more genotypes, are needed before strong conclusions and recommendations for behavioural effects of TRP treatment can be reached.

Hossain, K. S., et al. (2022). “B Vitamins and Their Roles in Gut Health.” Microorganisms 10(6).

B vitamins act as coenzymes in a myriad of cellular reactions. These include energy production, methyl donor generation, neurotransmitter synthesis, and immune functions. Due to the ubiquitous roles of these vitamins, their deficiencies significantly affect the host’s metabolism. Recently, novel roles of B vitamins in the homeostasis of gut microbial ecology and intestinal health continue to be unravelled. This review focuses on the functional roles and biosynthesis of B vitamins and how these vitamins influence the growth and proliferation of the gut microbiota. We have identified the gut bacteria that can produce vitamins, and their biosynthetic mechanisms are presented. The effects of B vitamin deficiencies on intestinal morphology, inflammation, and its effects on intestinal disorders are also discussed.

Kałużna-Czaplińska, J., et al. (2019). “How important is tryptophan in human health?” Critical Reviews in Food Science and Nutrition 59(1): 72-88.

Kikuchi, A. M., et al. (2021). “A systematic review of the effect of L-tryptophan supplementation on mood and emotional functioning.” J Diet Suppl 18(3): 316-333.

L-tryptophan (TRP), one of the essential amino acids in humans, is a precursor of serotonin, and hence its intake is closely related to the suppression of depressed and anxious moods. We did a systematic review of RCTs to examine the effects of tryptophan intake on the mood of healthy adults by searching PubMed, the Cochrane Library, and Ichu-shi according to PRISMA guidelines. As a result, 11 RCTs met the criteria and were accepted. Four RCTs showed the effects of tryptophan intake on negative feelings and happy feelings in healthy individuals, with significant differences between the treatment and the control groups. This suggests that TRP intake may be an effective approach to decrease anxiety and increase positive mood in healthy individuals. On the other hand, the effectiveness of TRP for aggressive feelings was not recognized. Reviewing these 11 RCTs, we concluded that taking 0.14-3 g of TRP per day in addition to the usual meal can be expected to improve the mood of healthy individuals. In order to estimate the optimum amount of TRP intake more accurately, further studies need to be conducted with more appropriate settings of intake period, intake frequency, and intake method.

Mikkelsen, K. and V. Apostolopoulos (2018). “B Vitamins and Ageing.” Subcell Biochem 90: 451-470.

Vitamin B contributes to the overall health and wellbeing, including that of energy metabolism, methylation, synthesis and DNA repair and proper immune function. Deficiency in B vitamins has been linked to neurocognitive disorders, mitochondrial dysfunction, immune dysfunction and inflammatory conditions. In ageing populations B vitamin deficiency has been linked to cardiovascular disorders, cognitive dysfunction, osteoporosis and methylation disorders and can increase the risk of developing degenerative diseases, particularly cardiovascular disease, cognitive diseases and osteoporosis. Optimization of B vitamin status in the elderly may prove beneficial in the prevention of degenerative diseases. Here we discuss broadly the role of B vitamins in ageing.

Prescha, A., et al. (2014). “The Antioxidant Activity and Oxidative Stability of Cold-Pressed Oils.” Journal of the American Oil Chemists’ Society 91(8): 1291-1301.

Abstract In our study, we characterized the antioxidant activity and oxidative stability of cold-pressed macadamia, avocado, sesame, safflower, pumpkin, rose hip, Linola, flaxseed, walnut, hempseed, poppy, and milk thistle oils. The radical scavenging activity of the non-fractionated fresh oil, as well as the lipophilic and hydrophilic fractions of the oil was determined using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The fatty acid composition of the fresh and stored oils was analyzed by gas chromatography. The acid value, peroxide value, p-anisidine value and conjugated diene and triene contents in the fresh oils, as well as in those stored throughout the whole period of their shelf life, were measured by CEN ISO methods. The antioxidant activity of the oils expressed as Trolox equivalent antioxidant capacity (TEAC), ranged from 0.17 to 2.32 mM. The lipophilic fractions of the oils were characterized by much higher antioxidant activity than the hydrophilic ones. There were no significant changes in fatty acid composition and only slight changes in the oxidative stability parameters of the oils during their shelf life. Through the assessment of the relationship between antiradical activity and the oxidative stability of oils, it is proposed that a DPPH assay predicts the formation of oxidation products in cold-pressed oils—however, the correlations differ in fractionated and nonfractionated oils.

Rahman, S. and M. Baumgartner (2019). “B Vitamins: Small molecules, big effects.” J Inherit Metab Dis 42(4): 579-580.

Romani, A., et al. (2019). “Health Effects of Phenolic Compounds Found in Extra-Virgin Olive Oil, By-Products, and Leaf of Olea europaea L.” Nutrients 11(8).

Olea europaea L. fruit is a peculiar vegetal matrix containing high levels of fatty acids (98-99% of the total weight of extra-virgin olive oil, EVOO) and low quantities (1-2%) of phenolics, phytosterols, tocopherols, and squalene. Among these minor components, phenolics are relevant molecules for human health. This review is focused on their beneficial activity, in particular of hydroxytyrosol (HT), oleuropein (OLE), oleocanthal (OLC), and lignans found in EVOO, olive oil by-products and leaves. Specifically, the cardioprotective properties of the Mediterranean diet (MD) related to olive oil consumption, and the biological activities of polyphenols recovered from olive oil by-products and leaves were described. Recent European projects such as EPIC (European Prospective Investigation into Cancer and Nutrition) and EPICOR (long-term follow-up of antithrombotic management patterns in acute coronary syndrome patients) have demonstrated the functional and preventive activities of EVOO showing the relation both between cancer and nutrition and between consumption of EVOO, vegetables, and fruit and the incidence of coronary heart disease. The data reported in this review demonstrate that EVOO, one of the pillars of the MD, is the main product of Olea europaea L. fruits; leaves and by-products are secondary but precious products from which bioactive compounds can be recovered by green technologies and reused for food, agronomic, nutraceutical, and biomedical applications according to the circular economy strategy.

Selhub, J., et al. (2013). “Dietary vitamin B6 intake modulates colonic inflammation in the IL10-/- model of inflammatory bowel disease.” J Nutr Biochem 24(12): 2138-2143.

Pyridoxal-5-phosphate, the biologically active form of vitamin B6, is a cofactor for over 140 biochemical reactions. Although severe vitamin B6 deficiency is rare, mild inadequacy [plasma pyridoxal 5′-phosphate (PLP) <20 nmol/L] is observed in 19-27% of the US population. Plasma PLP concentrations are inversely related to markers of inflammation such as C-reactive protein. Furthermore, plasma PLP is diminished in those with inflammatory conditions and, in the case of inflammatory bowel disease (IBD), more so in those with active versus quiescent disease. Restricting B6 intake attenuates IBD pathology in mice; however, the effects of supplementation are unclear. We therefore sought to determine the effects of mild inadequacy and moderate supplementation of B6 on the severity of colonic inflammation. Weanling IL-10(-/-) (positive for Helicobacter hepaticus) mice were fed diets containing 0.5 (deficient), 6.0 (replete) or 24 (supplemented) mg/kg pyridoxine HCl for 12 weeks and then assessed for histological and molecular markers of colonic inflammation. Both low and high plasma PLP were associated with a significant suppression of molecular (TNFα, IL-6, IFN-γ, COX-2 and iNOS expression) and histological markers of inflammation in the colon. PLP is required for the breakdown of sphingosine 1-phosphate (S1P), a chemotactic lipid, by S1P lyase. Colonic concentrations of S1P and PLP were significantly and inversely correlated. If confirmed, vitamin B6 supplementation may offer an additional tool for the management of IBD. Although B6 is required in dozens of reactions, its role in the breakdown of S1P may explain the biphasic relationship observed between PLP and inflammation.

Stach, K., et al. (2021). “Vitamin B6 in Health and Disease.” Nutrients 13(9).

Vitamin B6 is a fascinating molecule involved in the vast majority of changes in the human body because it is a coenzyme involved in over 150 biochemical reactions. It is active in the metabolism of carbohydrates, lipids, amino acids, and nucleic acids, and participates in cellular signaling. It is an antioxidant and a compound with the ability to lower the advanced glycation end products (AGE) level. In this review, we briefly summarize its involvement in biochemical pathways and consider whether its deficiency may be associated with various diseases such as diabetes, heart disease, cancer, or the prognosis of COVID-19.

Ueland, P. M., et al. (2017). “Inflammation, vitamin B6 and related pathways.” Mol Aspects Med 53: 10-27.

The active form of vitamin B6, pyridoxal 5′-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions; there is a parallel reduction in liver PLP, but minor changes in erythrocyte and muscle PLP and in functional vitamin B6 biomarkers. Plasma PLP also predicts the risk of chronic diseases like cardiovascular disease and some cancers, and is inversely associated with numerous inflammatory markers in clinical and population-based studies. Vitamin B6 intake and supplementation improve some immune functions in vitamin B6-deficient humans and experimental animals. A possible mechanism involved is mobilization of vitamin B6 to the sites of inflammation where it may serve as a co-factor in pathways producing metabolites with immunomodulating effects. Relevant vitamin B6-dependent inflammatory pathways include vitamin B6 catabolism, the kynurenine pathway, sphingosine 1-phosphate metabolism, the transsulfuration pathway, and serine and glycine metabolism.

Wan, Z., et al. (2022). “Intermediate role of gut microbiota in vitamin B nutrition and its influences on human health.” Front Nutr 9: 1031502.

Vitamin B consists of a group of water-soluble micronutrients that are mainly derived from the daily diet. They serve as cofactors, mediating multiple metabolic pathways in humans. As an integrated part of human health, gut microbiota could produce, consume, and even compete for vitamin B with the host. The interplay between gut microbiota and the host might be a crucial factor affecting the absorbing processes of vitamin B. On the other hand, vitamin B supplementation or deficiency might impact the growth of specific bacteria, resulting in changes in the composition and function of gut microbiota. Together, the interplay between vitamin B and gut microbiota might systemically contribute to human health. In this review, we summarized the interactions between vitamin B and gut microbiota and tried to reveal the underlying mechanism so that we can have a better understanding of its role in human health.

Supplementary Table H2 – Environmental, sustainability and market criteria to achieve Tier I

Refs 1-4 Humane Farming

FACT online article about humane farming: https://www.foodanimalconcernstrust.org/nutritional-benefits
The Humane Farming Association: https://www.hfa.org
Compassion in world farming: https://www.ciwf.org.uk/research/solutions-for-humane-and-sustainable-agriculture
Humane Society International: https://www.hsi.org/issues/factory-farming

Refs 5-8 Organic Foods

(Mie, Andersen et al. 2017)
(Hurtado-Barroso, Tresserra-Rimbau et al. 2019)
(Brantsæter, Ydersbond et al. 2017)
Soil Association online article: The Benefits of Organic Farming: file:///Users/rachelvictoria/Downloads/the-benefits-of-organic-farming-april-2018%20(1).pdf and https://www.soilassociation.org/policy-reports

Refs 9-12: Non-GMO

(Salt 2023)
(Buchholzer and Frommer 2023)
The Non-GMO Project: https://www.nongmoproject.org/gmo-facts/what-is-gmo
Center for Food Safety: https://www.centerforfoodsafety.org/press-releases/3766/are-gmos-safe-no-consensus-in-the-science-scientists-say-in-peer-reviewed-statement

Refs 13-16: Recyclable or compostable packaging

Online article: https://wrap.org.uk/resources/guide/compostable-plastic-packaging-guidance
European bioplastics: https://www.european-bioplastics.org/faq-items/what-are-the-required-circumstances-for-a-compostable-product-to-compost
Food Standards Agency: https://www.food.gov.uk/sites/default/files/media/document/bio-based-materials-for-use-in-food-contact-applications_0.pdf
European Economic and Social Committee: https://www.eesc.europa.eu/sites/default/files/files/qe-03-20-534-en-n.pdf

Refs 17-19: Environmentally sourced

(Karwacka, Ciurzyńska et al. 2020)
(Xu, Sun et al. 2015)
(Russell 2014)

Refs 20:22: Meets UN Sustainable Development Goals (SDGs)

(Palmer 2015)
(Bexell and Jönsson 2017)
United nations: https://www.un.org/sustainabledevelopment/sustainable-development-goals

References:

Bexell, M. and K. Jönsson (2017). “Responsibility and the United Nations’ Sustainable Development Goals.” Forum for Development Studies 44(1): 13-29.

Brantsæter, A. L., et al. (2017). “Organic Food in the Diet: Exposure and Health Implications.” Annu Rev Public Health 38: 295-313.

The market for organic food products is growing rapidly worldwide. Such foods meet certified organic standards for production, handling, processing, and marketing. Most notably, the use of synthetic fertilizers, pesticides, and genetic modification is not allowed. One major reason for the increased demand is the perception that organic food is more environmentally friendly and healthier than conventionally produced food. This review provides an update on market data and consumer preferences for organic food and summarizes the scientific evidence for compositional differences and health benefits of organic compared with conventionally produced food. Studies indicate some differences in favor of organic food, including indications of beneficial health effects. Organic foods convey lower pesticide residue exposure than do conventionally produced foods, but the impact of this on human health is not clear. Comparisons are complicated by organic food consumption being strongly correlated with several indicators of a healthy lifestyle and by conventional agriculture “best practices” often being quite close to those of organic.

Buchholzer, M. and W. B. Frommer (2023). “An increasing number of countries regulate genome editing in crops.” New Phytologist 237(1): 12-15.

See also the Commentary on this article by Salt, 237: 7–8.

Hurtado-Barroso, S., et al. (2019). “Organic food and the impact on human health.” Crit Rev Food Sci Nutr 59(4): 704-714.

In the last decade, the production and consumption of organic food have increased steadily worldwide, despite the lower productivity of organic crops. Indeed, the population attributes healthier properties to organic food. Although scientific evidence is still scarce, organic agriculture seems to contribute to maintaining an optimal health status and decreases the risk of developing chronic diseases. This may be due to the higher content of bioactive compounds and lower content of unhealthy substances such as cadmium and synthetic fertilizers and pesticides in organic foods of plant origin compared to conventional agricultural products. Thus, large long-term intervention studies are needed to determine whether an organic diet is healthier than a diet including conventionally grown food products. This review provides an update of the present knowledge of the impact of an organic versus a conventional food diet on health.

Karwacka, M., et al. (2020). “Sustainable Development in the Agri-Food Sector in Terms of the Carbon Footprint: A Review.” Sustainability 12(16): 6463.

Mie, A., et al. (2017). “Human health implications of organic food and organic agriculture: a comprehensive review.” Environ Health 16(1): 111.

This review summarises existing evidence on the impact of organic food on human health. It compares organic vs. conventional food production with respect to parameters important to human health and discusses the potential impact of organic management practices with an emphasis on EU conditions. Organic food consumption may reduce the risk of allergic disease and of overweight and obesity, but the evidence is not conclusive due to likely residual confounding, as consumers of organic food tend to have healthier lifestyles overall. However, animal experiments suggest that identically composed feed from organic or conventional production impacts in different ways on growth and development. In organic agriculture, the use of pesticides is restricted, while residues in conventional fruits and vegetables constitute the main source of human pesticide exposures. Epidemiological studies have reported adverse effects of certain pesticides on children’s cognitive development at current levels of exposure, but these data have so far not been applied in formal risk assessments of individual pesticides. Differences in the composition between organic and conventional crops are limited, such as a modestly higher content of phenolic compounds in organic fruit and vegetables, and likely also a lower content of cadmium in organic cereal crops. Organic dairy products, and perhaps also meats, have a higher content of omega-3 fatty acids compared to conventional products. However, these differences are likely of marginal nutritional significance. Of greater concern is the prevalent use of antibiotics in conventional animal production as a key driver of antibiotic resistance in society; antibiotic use is less intensive in organic production. Overall, this review emphasises several documented and likely human health benefits associated with organic food production, and application of such production methods is likely to be beneficial within conventional agriculture, e.g., in integrated pest management.

Palmer, E. (2015). “INTRODUCTION: The Sustainable Development Goals Forum.” Journal of Global Ethics 11(1): 3-9.

Russell, D. A. M. (2014). “Sustainable (food) packaging – an overview.” Food Additives & Contaminants: Part A 31(3): 396-401.

Salt, D. E. (2023). “GMO or non-GMO? That is the question.” New Phytologist 237(1): 7-8.

This article is a Commentary on Buchholzer & Frommer (2023); 237: 12–15.

Xu, Z., et al. (2015). “Research Developments in Methods to Reduce the Carbon Footprint of the Food System: A Review.” Critical Reviews in Food Science and Nutrition 55(9): 1270-1286.