Feed the Gut

The Metabolic Matrix: Re-engineering ultraprocessed foods to feed the gut, protect the liver, and support the brain.

The Metabolic Matrix methods article (Harlan et al., 2023) proposes three key pillars – Support the Brain, Protect the Liver, and Feed the Gut – and serves as a novel guide to reengineering ultraprocessed foods in favor of improving metabolic health. The liver is a vital organ which plays a critical role in metabolism and in the storage, secretion, and detoxification of internal and external substances (Mega et al., 2021). There are 1-3 million xenobiotics, i.e., chemical substances, foreign to plant and animal life which gain access to the human body during the lifespan, and which may prove to be toxic. The liver plays a key role in preventing toxic liver damage from many of these substances and nutrition, is hypothesised to protect from a multitude of injuries which may lead to chronic liver disease and cirrhosis (Mega et al., 2021). The component Protect the Liver is detailed in our recently published methods paper and focused on 5 elements related to metabolic health namely: (i) reducing fructose and (ii) total sugar intake, (iii) ensuring adequate hydration, (v) minimising environmental toxins and (vi) reducing glycemic load.

This section aims to address questions concerning why our scientific team specifically selected the concept of protecting the liver.

Other sections of the website address the other two elements of the triage, Support the Brain and Protect the Liver.

Summary

The concept of feeding the gut has been the topic of rigorous investigation for approximately the past decade or so. The bi-directional relationship between the gut and brain has acquired a prominent place in current research, and the scientific understanding of the complex interplay between microbiome and a wide-range of human behaviours and emotions is fast emerging. Interestingly, however this is not a new association, but one that can be traced right back through medical history (Miller, 2018). Indeed, nineteenth century doctors and patients are likely very well aware that their stomachs and minds were somehow connected (Miller, 2018) and the concept of dis-ease of the mind correlates with dis-ease of the body is also an entire mind-body medicine entity (Brower, 2006).  The gut microbiota-brain axis research has given birth to an entire novel framework of science namely the field of psychobiotics  – considered a revolutionary advance (Hyland & Stanton, 2016). A popular book is The Psychobiotic Revolution which discusses the depths of the current mental health epidemic and deeply interconnected links between depression and gut health problems (Anderson et al., 2017). There is no doubt that gut microbiota is now established as a critical component in regulating brain activity, mood and behaviour (Berding et al., 2021). Furthermore, several communicative pathways between the gut and the brain have been identified including microbial metabolites, metabolic, immune, and neuronal some of which are manipulated via the diet (Berding et al., 2021; Palm et al., 2015). There is now no doubt that gut microbiota plays critical roles in influencing drug metabolism, protecting against pathogens, regulating endocrine and immune functions (Cho & Blaser, 2012). Indeed, the human intestine is host to a community of around 1, 000-1500 bacterial species called the microbiota which are predestined to evolve during the course of the human’s lifespan and generationally while being subjected to environmental change. Let’s discover more!

Gut Microbiota

The human body is host to trillions of microbes which include bacteria, fungi, viruses, archaea and eukaryotes (Marchesi & Ravel, 2015). Archaea are a group of single-celled prokaryotic microorganisms which are evolutionary distinct from bacteria and Eucarya and inhabit some of the most extreme environments of earth including the deep sea, hot springs, salt lakes and submarine volcanic sites. They are recognised as a third domain of life and do not have a cell nucleus or any other organelles inside their cell. Furthermore, the detection of anaerobic archaea has been confirmed in the human body in various regions including colonic, vaginal and oral microbial flora (Belay et al., 1988; Belay et al., 1990; Eckburg et al., 2003; Miller et al., 1982). Eukaryotes are organisms whose cells contain an organelle called a nucleus which contains the cells genetic material (DNA) and cellular structures which are bound by a biological membrane comprised of either a single layer or double layer of lipids and are typically interspersed with proteins. Eukaryotic cells also contain other organelles including energy-generating, mitochondria; the endoplasmic reticulum, which assists in the transport of proteins; and the Golgi apparatus, which organizes and compiles proteins and lipids for transport throughout the cell.

Around 1000 species of bacteria which reside in the human gut have now been identified creating a diverse and dense microbial community (microbiota) and on average, an individual is host to about 160 species (Simpson & Campbell, 2015). The key dominant gut microbial phyla incudes Actinobacteria, Verrucomicrobia, Proteobacteria, Firmicutes and Bacteroidetes (representing bacterial diversity) with the latter two representing 70%-90% of gut microbiota (Rinninella et al., 2019). These phyla are known to be manipulated directly via the diet. Clostridium, Lactobacillus, Bacillus, Enterococcus, and Ruminococcus exist within the Firmicutes phylum. The Bacteroidetes group for the most part comprises Bacteroides and Prevotella genera. In the Actinobacteria phylum, Bifidobacterium is the key genus (Rinninella et al., 2019).

Intestinal microbiota which becomes established in varying stages from early life (K. Aagaard et al., 2014; Ardissone et al., 2014) play a significant role in immunological, metabolic and nutritional processes (Ramakrishna, 2013) and alterations in their composition are implicated in a range of diseases and disorders including obesity (Cox et al., 2015), diabetes (Tilg & Moschen, 2014), inflammatory bowel disease (IBD) (Hold et al., 2014), ulcerative colitis (UC) (Hold et al., 2014) and a range of inflammatory disorders (Belkaid & Hand, 2014).

Foetal development and intestinal colonization

The traditionally held belief was that a foetus developed in a sterile uterine habitat and that initial intestinal colonisation took place from birth onward. However, additional studies have since disproved this notion and microorganisms have been detected and confirmed in the placenta, amniotic fluid and umbilical cord (Kjersti Aagaard et al., 2014; Pelzer et al., 2017). It is thought that the developing foetus first begins to colonise its own gastrointestinal tract absorbing amniotic fluid and the bacteria residing in the uterus. Additional evidence has emerged from the investigation of meconium (new-borns’ first stool made up of protein, fats, cells and bile which is passed in the first few hours and days post birth) and discovery of microorganisms (Walker et al., 2017). Childbirth, of course, exposes infants to the majority of microorganisms and the emergence of intestinal colonisation and microbiota. Furthermore, the type of delivery e.g., a natural (vaginal) birth versus a caesarean (“c”) section delivery governs the type of microorganisms the baby comes into contact with post-birth. For example, a natural childbirth is thought to assist in the development of greater diversity of microbiota than babies born by caesarean section (Jagodzinski et al., 2019; Nagpal & Yamashiro, 2018). Several studies suggest that initial colonization pattern is random and unordered and that both environmental influences and dietary patterns are key for alterations in composition (Savage et al., 2018). During the first stage of intestinal colonization in a child, the types of microorganisms are for a large part aerobic, such as Enterobacteria, staphylococci, and Streptococci, which have pathogenic potential. As the child grows and certainly during the first year of life, his or her intestinal community continues to change in responses to external variables such as antibiotic use and diet (Hill et al., 2017; Maiuolo et al., 2021). Research has demonstrated that there is an important distinction in the composition of an infant’s intestinal microbiota which transpires in direct relation to the type of milk, which he/she is fed, i.e., formula versus breast milk (Brahm & Valdes, 2017). Breast feeding is considered to be a protective factor for neurodevelopment and for the later development of a variety of inflammatory bowel conditions while the use of various types of milk formulated for children may increase the risk of intestinal disease creating gut dysbiosis and imbalances in diversity (Le Doare et al., 2018). Children who are breast fed have a more balanced formation of microbiota than formula-fed babies. This has  significant implications for the future health of the child in terms of immune responses and the reduced likelihood in developing autoimmune, allergic and inflammatory linked conditions (Vieira Borba et al., 2018). Breastmilk contains fats (lipids), proteins, and carbohydrates, in addition to endocannabinoids, immunoglobulins, and indigestible polysaccharides (often referred to as Human milk oligosaccharides or HMOs) (Urashima et al., 2012). Some of these polysaccharides serve as prebiotics selectively promoting the growth of beneficial gut bacteria most of which are Bifidobacteria which are indispensable to strengthening the primary barrier – acting as the first line of defence – between the immune system and the external environment (Herath et al., 2020). HMOs also are not digested by the pancreatic enzymes but travel to the colon intact where they support the growth of Bifidobacteria, Bacteroides and Lactobacillus (Senn et al., 2020; Thongaram et al., 2017). A final note, the use of antibiotic use has been found to significantly reduce strain diversity, resulting in less stable microbiota (Yassour et al., 2016); increase the probability of fungal overgrowth (Kligman, 1952) and may impact long-term health outcomes such as alter nutrient absorption (Krajmalnik-Brown et al., 2012), lower vitamin production (Krajmalnik-Brown et al., 2012), and increase risk of developing obesity (Dawson-Hahn & Rhee, 2019). Therefore reducing antibiotic therapy must be exercised for infants who do not actually require antibiotics  (Senn et al., 2020).

The Impact of Diet on Intestinal Microbiome & Short-Chain Fatty Acids (SCFAs)

One of the key foods for a healthy gut is dietary fibre which increases microbial diversity and increases the growth of beneficial bacteria which promote the growth of beneficial short-chain fatty acids (SCFA) such as butyrate, acetate and propionate (Simpson & Campbell, 2015). These SCFAs are the key metabolites produced in the colon by bacterial fermentation of dietary fibers and resistant starch (Silva et al., 2020). Both butyrate and propionate are common fatty acids produced in the large intestine of humans and are protective against the diet-induced development of obesity and insulin resistance (Lin et al., 2012) and furthermore are thought to play a role in neuro-immunoendocrine regulation (Silva et al., 2020). There is a body of evidence in both humans and animals supporting the notion that SCFAs exert critical physiological impacts of various organs including the brain (Dalile et al., 2019; Fung et al., 2017; Stilling et al., 2016), and in particular the links between gut dysbiosis and neurological and behaviour pathologies including Alzheimer’s (AD), Parkinson’s (PD) diseases, depression, and autism spectrum disorder (ASD) (Borre et al., 2014).

The Influence of Gut Microbiota on Brain Function

There are a number of pathways which are speculated to be involved in the crosstalk between gut microbiota and brain function, however the precise mechanisms are still unclear (Borre et al., 2014; Silva et al., 2020). Systemic inflammation is thought to be a key culprit and is either caused by infection or increased permeability of the intestine barrier. Essentially, inflammation can invoke an immune response and increase the production of cytokines impacting both the blood brain barrier and neurotransmitter function (Amor et al., 2014; Galea, 2021; Perry et al., 2003). Emerging research confirms that intestinal microbiota has the ability to synthesise neurotransmitters which have brain-based effects including dopamine, serotonin, norepinephrine, and δ-amino butyric acids (GABA) (Maiuolo et al., 2021). Bifidobacterium infantis, for example, has been demonstrated to increase tryptophan levels in blood plasma and promote serotonin transmission; Lactobacillus and Bifidobacterium are able to produce GABA; Escherichia, Bacillus, and Saccharomyces spp. can make noradrenaline; Candida, Streptococcus, Escherichia, and Enterococcus spp. can produce serotonin; Bacillus can generate dopamine; Lactobacillus can produce acetylcholine (Lyte, 2014). The vagus nerve is the key nerve of the parasympathetic component of the autonomic nervous system which controls a range of functions. Gut microbiotas generate reciprocated signals from the vagal nerve to the brain (Borre et al., 2014).

Depression

Depression is a common mood disorder which can be seriously debilitating and one of the key causes of social disability associated – when untreated – with an increased risk of morbidity and mortality including suicide. The monoamine theory of depression hypothesises that the cause is a result of depleting levels of key neurotransmitters, namely serotonin, norepinephrine and/or dopamine in the central nervous system (Delgado, 2000). Furthermore, this hypothesis postulates that symptoms of depression can be alleviated via the mechanistic actions of antidepressant medication (Delgado, 2000). However, rigorous scientific investigation has failed to produce robust and convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorder (Delgado, 2000). Furthermore, monoamine depletion does not appear to worsen depressive symptoms in unmedicated depressed individuals nor induce depression in healthy volunteers (Delgado, 2000). In addition, to the monoamine theory of depression, cognitive-behavioural therapies which are often the first line of treatment for depression have bene demonstrated to be ineffective in 50% of patients (Cuijpers et al., 2014; Leuzinger-Bohleber et al., 2019). Nutrition and physical exercise, which are both known to work in synergy to exert antidepressant and anxiolytic effects, can also increase the volume of beneficial microbial species (Mailing et al., 2019). Furthermore, in a similar fashion to exercise, butyrate appears to increase neuroplasticity and contain antidepressant effects by boosting serotonin levels (Monda et al., 2017).

Increasing evidence has demonstrated that healthy intestinal barrier function appears critical for crucial maintaining brain health (Di Meo et al., 2018). A common finding in individuals with depression is altered intestinal microbiota compositions (Barandouzi et al., 2020). For example, higher levels of both Actinobacteria and Fusobacteria phyla have been observed in individuals with depression, as well as inconsistencies in gut diversity and abundance (Barandouzi et al., 2020). Similarly, gut dysbiosis, is thought to play a key role in depression as well as alter memory, induce the stress response and anxiety-related behaviour and whilst the mechanisms of action are beyond the scope of this article, there is no doubt that these microscopic inhabitants play a significant role in human health and disease (Begum et al., 2022).

Experimental animal studies have shown that fecal microbiota transplantation from individuals with depression to microbiota-depleted rats results in both depression and anxiety-related behaviors (Kelly et al., 2016). Future research in the field of nutritional medicine must continue to further explore the modulation of gut microbiota as a potential adjunct treatment in depression. Greater insights into the gut-brain axis can result in a more in-depth understanding of the neuropathology underlying depressive (and anxiety) symptoms and disorders (Rosa et al., 2022).

 The Role of Microbiota on the Immune System

The symbiotic association between the host and gut microbiota is one which is mutually beneficial. The host provides the nourishment and a suitable environment for the microbiota, while the gut microbes supports the development and maturation of the intestinal host system (Obrenovich, 2018). Indeed, microbiota and probiotic agents are known to have direct impacts on the immune system (Borre et al., 2014; Power et al., 2014). Furthermore, there is bi-directional communication with the immune system and central nervous system (Dantzer, 2006). In fact, a lack of gut microbiota leads to a significant deficiency in terms of immune system functioning (Belkaid & Harrison, 2017). Deviation of the gut microbiome by environmental factors including a change in diet (high intake of junk, processed food, excess alcohol use) and antibiotic use can overtime increase the risk for pathogenic invasion resulting in atypical immune responses (Zheng et al., 2020).

Another signalling pathway in the gut–brain axis involves immunity through cytokines. Cytokines, which are protein-based, signalling molecules such as interleukin, interferon and growth factors. These substances which can impact the growth and activity of our immune and blood cells are produced in the intestine, and under certain conditions can flow into the bloodstream impacting brain regions such as the hypothalamus (El Aidy et al., 2014). The hypothalamus is an area of the brain associated with learning, memory and neurogenesis, i.e., the birth of new neurons. Essentially, cytokines regulate a range of inflammatory processes, mediate regular cellular processes in the body, including its response to disease and infection. Critically, processed foods and sugars increase the release of these inflammatory messengers creating inflammation and increasing risk for metabolic diseases including psychiatric conditions such as cytokine-induced depression (Felger & Lotrich, 2013; Himmerich et al., 2019; Zhang & An, 2007).

 The Role of Microbiota in Neurodevelopmental Conditions (ADHD and Autism)

Autistic Spectrum Disorders (ASD) is referred to as a cluster of complex neurodevelopmental disorders which caused by differences in the wiring of the brain impacting behaviour, learning and communication[1] . The etiology of both ADHD and ASD is described as predominately genetic or as having genetic anomalies with multifactorial environmental influences including inflammatory processes, nutritional insufficiencies and dysregulation of the immune system (Famitafreshi & Karimian, 2018). Although, distinct conditions, many features of both Autistic Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) overlap by between 30% and 50% (Davis & Kollins, 2012; Leitner, 2014). Some of these can include problems with focus, concentration and attention, social interaction, emotional dysregulation, verbal communication, impulsivity, varying degrees of restlessness and hyperactivity, avoiding eye contact, difficulties with aspects of learning, and restrictive and repetitive behaviours (Leitner, 2014). In addition, to the evidence demonstrating shared behavioural symptoms, research has also suggested that children with ADHD and/or Autism are over-represented in terms of fussy eating. For example, food selectivity and restricted eating are common behaviours with specific aversions to specific textures, tastes, colours odors, or other food characteristics, – as well as nutritional insufficiencies, food intolerances and food allergies (Cermak et al., 2010). The consequences of fussy eating behaviours include a wide-range of nutritional insufficiencies and a reduction in the quality of the food as well as altered composition of the intestinal microbiota (Berding & Donovan, 2016). In fact, gastrointestinal issues, in an estimated 23% to 70% of children with ASD experience abdominal pain, diarrhea, constipation, intestinal gas and flatulence are commonly reported (Berding & Donovan, 2016; Mulle et al., 2013).

Research has illustrated that microbiota are critical to maintain homeostasis during brain development and that microbial colonization coincides with critical neurodevelopmental stages. A body of scientific literature confirms that early life alterations of the development of gut microbiota can impact neurodevelopment (Borre et al., 2014). Studies have reported that the intestinal microbiota of children with ASD reveal sizeable and significant differences including a reduction of Bifidobacterium, which have led researchers to conclude that these neurological conditions are accompanied by lower levels of beneficial bacteria and elevated amounts of harmful bacteria (Iglesias-Vázquez et al., 2020). Scientists have hypothesised that an increase in Faecalibacterium detected in children with ASD, may be responsible for the progression of inflammatory processes, and alteration of the intestinal barrier. Furthermore, the observed reduction of Bifidobacterium leads to a reduction in levels of short-chain fatty acids (SCFAs) which is another common finding in neurodevelopmental conditions in children (Maiuolo et al., 2021). Interestingly, novel research in patients with ASD have undergone intestinal microbiota remodelling via bacterial transfer therapy and presented with reduced ASD symptomology highlighting this an area which warrants further exploration (Kang et al., 2017). Fortunately, there are specific treatments which can help heal the gut, restore the balance of microbiota, increase integrity of the intestinal barrier, and reduce, treat and prevent gut dysbiosis.

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[1] https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd