Link between gut microbial metabolites, epigenetics and the brain

Sibin Mathews

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Abstract: There is a growing body of evidence suggesting a role for the gut microbiota in regulating many important processes throughout the body. Two major advances demonstrate the involvement of the gut microbiota in regulating epigenetic modifications, as well as regulating brain activity. This perspective seeks to shed light on the importance of the gut microbiota by exploring the functions of the microbial metabolites produced, as well as exploring potential therapeutic avenues for diseases that are mediated by disruption of gut flora.

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Introduction

     The gut microbiota is composed of trillions of microorganisms and represents a metabolically active biomass of roughly two kilograms in the human body. Recent advances in medical research have only just begun to decipher the metabolic properties of the gut microbiota. Studies have shown an association between certain microbial profiles with illnesses such as ulcerative colitis, Crohn’s disease, and obesity. Moreover, evidence also supports the existence of a gut-brain axis, wherein microbial metabolites produced from bacterial fermentation are able to alter brain activity. Disruption of this axis may underlie diseases and disorders such as autism, anxiety, diabetes, and even osteoporosis. Because the exact link between the gut microbiota and these illnesses have yet to be explored in intervention studies, the underlying mechanisms that mediate the effects of the gut microbiota and their metabolic products are incomplete. As a result, the gut microbial metabolome is a good starting point because it has the potential to affect immune response, gut epithelial differentiation, and possibly the development of degenerative disorders through epigenetic modulation. The gut microbial metabolome can therefore have a profound influence on short- and long-term systemic physiological processes. Furthermore, the composition of the gut microbiota, as well as the diversity of their fermentation end products, represent a novel and potentially therapeutic strategy for many disorders1.

 

Gut Microbial Metabolites and Epigenetics

     It has been established that microbial metabolites can power beta-oxidation and other metabolic processes2. However, it is less known that these metabolites can also interact with the mammalian epigenetic machinery to modulate gene expression3. This level of epigenetic regulation happens through gut microbial metabolites that inhibit or modify the activity of enzymes and other host proteins that are known to control gene expression.  Some metabolites interact with histones and alter DNA methylation to manipulate the expression of host chromatin. Modifying gene expression results in downstream changes to a cell’s functionality, and can alter normal physiology. For example, short chain fatty acids (SCFA) are metabolites that can inhibit mammalian histone deacetylases (HDAC), resulting in an increase in the average acetylation of histones associated with DNA, which in turn affects gene expression. Specifically, the SCFAs butyrate and propionate are the most active HDAC inhibitors that affect histones, thereby altering gene expression by affecting the accessibility of DNA for transcription4. Other types of histone modification include methylation, ubiquitination, and phosphorylation at various amino acid residues of histone tails, which also can influence gene expression. Non-SCFA byproducts such as phenolic and sulfur compounds from microbial fermentation can also result regulate gene expression by inducing DNA methylation through changes in the levels of reactive oxygen species, niacin, and conjugated linoleic acids in cells.3

 

Gut microbial Metabolites and Early Development

     Changes in metabolite concentrations or even the bacterial species that produce the specific metabolites can drastically affect gene expression, especially during critical periods in early human development3. For example, infants delivered by caesarean section (C-section) have a substantially different gut microbial profile compared to those delivered vaginally, and this is thought to confer risk for diseases such as autism and autoimmune diseases. While inoculating C-section infants with the optimal human gut bacterial population seems like a pragmatic solution, recent epigenetic findings suggest that this may be harmful. Inoculating a newborn with the gut microbiota of an adult would influence the expression of certain genes, and result in an inappropriate developmental response for a newborn baby. In the pre- and post-natal period, the body undergoes sequential development of cells and tissue, and may be vulnerable to epigenetic changes from gut microbial metabolites. Some organs such as the heart, for example, are protected from these epigenetic changes, as they develop before delivery, and before post-natal gut metabolite changes can exert any changes. However, as other organs are still undergoing cell differentiation even after labor, those organs are susceptible to epigenetic changes from microbial metabolites. Future treatments may include specific infant microbiome inoculation cocktails that serve to improve the gut microbial profiles of babies that have undergone delivery complications that alter their gut microbiota from those of vaginally-delivered babies5.

Infants fed on formula milk constitute another population that may be susceptible to microbial metabolite-induced epigenetic disruptions. Breast-fed infant microbiota consist predominantly of bifidobacteria and ruminococci, which produce various metabolites with beneficial effects, including appropriate regulation of DNA methylation. While formula milk matches the essential amino acids of breast milk, it lacks the human milk oligosaccharides (HMO) of breast milk. Remarkably, human breast milk contains as many as 130 different oligosaccharides which reach the newborn colon intact. These HMOs serve as prebiotics that selectively allow growth of certain commensal bacteria 6. Furthermore, formula milk contains more protein to compensate for poorer quality of protein, and as a result, a greater amount of protein reaches the newborn colon. This in turn selects for proteolytic bacteria instead of carbohydrate-fermenting bacteria, resulting in different downstream microbial metabolites and different epigenetic effects. Formula-fed infants have been shown to have a higher proportion of firmicutes, which includes genera such as lactobacilli, clostridia, and streptococci. The byproducts of metabolism produced by these species are generally not as prevalent in breast-fed infants. As a result, these vital differences at critical stages in development could play a role in certain diseases and disorders that are prominent in C-section and formula-fed infants 7.

 

Gut Microbial Metabolites and the Brain

     The gut microbiota produces SCFA through fiber and carbohydrate metabolism, which in turn influences epigenetic modulation. Functionally diverse, the microbiota has also been implicated in regulating behavior through endocrine and neural pathways. There is a growing body of evidence suggesting the existence of a possible gut microbiota-brain axis through epigenetic regulation. For example, gut microbiota has been shown to regulate the blood–brain barrier permeability in mice 8. In a recent study, germ-free mice monocolonized with Clostridium tyrobutyricum and treated with the SCFA sodium butyrate showed increased expression of occludin and claudin-5 in the frontal cortex, striatum, and hippocampus compared to a control group of germ-free mice. The decreased expression of occludin and claudin-5 is linked to decreased integrity of tight junctions that are essential for maintaining proper blood–brain barrier function. Thus, the gut bacterial metabolites may play a role in some neurological diseases3.

     Even stress has been shown to be regulated by the gut microbiota and its metabolites. Clostridium sporogenes and Ruminococcus gnavus have the metabolic ability to decarboxylate tryptophan to tryptamine, which induces the release of serotonin by enterochromaffin cells. This increases the availability of serotonin in the colon for uptake by the enteric nervous system in conditions of stress 3. Additionally, the microbial metabolites of L. rhamnosus have been shown to increase the expression of gamma-aminobutyric acid (GABA) and decrease expression of GABA receptors in the hippocampus though the vagus pathway. This has been linked to reduced stress-induced anxiety and depression-related behaviors as illustrated in Figure 1.

 

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Treatment Options

     Current treatments to mitigate the effects of gut dysbiosis include prebiotics, probiotics, and more recently, fecal transplants.  Recent studies on the effectiveness of prebiotics have shown that phylogenetically distant bacterial species competitively break down the same prebiotics to produce different end-product metabolites that result in their own regulation. For example, resistant starch intake has been shown to selectively stimulate certain firmicutes and bifidobacteria (such as R. bromii and B. adolescentis) which in turn produce butyrate 9. This increase in butyrate showed significant immunomodulatory effects, such as an increase in levels of the anti-inflammatory cytokine interleukin-10, and also an increase in splenic regulatory T cells, both resulting in a marked reduction in colonic inflammation. Furthermore, butyrate has also been shown to play a vital role in regulating mucin production and cellular permeability in vitro 10. Similarly, products of fructan fermentation (FF) have been shown to affect the mucus lining through gene regulation. Specifically, FF products in adult animal models have shown an increased microvilli height as well as an increase in cryptal depth, which could potentially increase nutrient absorption and mucus secretion. Despite the protective effects of butyrate and FF products, more research into the interconnected epigenetic mechanism of these metabolites is warranted2.

     Probiotics are also used to recolonize beneficial bacteria to reduce colonic inflammation. However, the oral route of administration dampens the potency due to stomach acid that kills most of the bacteria before it arrives at the colon. As a result, fecal transplants have gained attention. Fecal transplants work by transplanting a healthy individual’s fecal matter into the patient’s colon. The bacteria of the healthy individual will then colonize the patient’s colon and improve the gut microbiota profile of the patient11.

Conclusion

     Our gut microbiota is indispensable for the fermentation of otherwise indigestible dietary components such as starch and cellulose. The microbial metabolites produced as a result of this fermentation may one day work as a therapy for a myriad of disorders and diseases. However, more research is necessary to understand the variety of healthy gut microbiota profiles. Individual variation in phenotype and gut microbiota make research studies and thus therapeutic strategies more difficult12. Additionally, studying the bacterial metabolite-epigenetic and brain regulation axis is complex due to difficulties in studying long-lasting physiological and health consequences in animal and human models. Any possible intervention needs to start with advances in mapping the functions of the various microbial species in the colon before progressing to the effects of the microbial metabolites themselves.1

 

 

References

 

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