How Gut Bacteria Influences Genetic Expression

Over the last few decades scientists have discovered that humans exist in a symbiotic relationship with microbes that outnumber us by a factor of about 10:1. These microbes, which are collectively referred to as our microbiome, are responsible for several key functions including providing protection against pathogenic invasion, synthesizing vitamins and neurotransmitters, detoxifying harmful compounds, reacting to and modifying the action of several drugs, and even providing between 5 and 10% of our energy requirements (1).

Microbial dysbiosis, which refers to a microbiome that has an abundance of pathogenic or virulent species and/or a shortage of commensal or protective species, drives excessive inflammation and has been implicated in a variety of diseases including inflammatory bowel disease, irritable bowel syndrome, a variety of autoimmune diseases, diabetes, heart disease, and cancer (2). 

Recently, research has uncovered several ways through which these bacteria exert their effects and one of the key mechanisms is through modulation of our gene expression (3). This is done primarily via metabolites that are produced from the breakdown of components of our food and an emerging field of study called metabolomics is working to better understand these metabolites and their function (4).

This phenomenon of altering gene expression, without changing the underlying genetic code, is referred to as epigenetics and it takes place via three primary mechanisms: methylation, histone modification, and non-coding RNAs (5).

DNA methylation involves “tagging” of the DNA at specific sites which can increase or decrease gene expression. Each of our genes codes for a specific protein and methylation effectively turns up or down the ability of that gene to be turned into those proteins (6).

Histone modification

Histones are proteins that DNA wraps around, like thread wraps around a spool, which allows parts of the DNA to be exposed or not exposed. When histone tails are modified that regulates the portions of the DNA that is exposed and determines whether a gene is coded into a protein or not (7)

Non-coding RNA are copies of genes that do not get coded into proteins. It was originally thought that these non-coding RNA served no function, but we now understand that they are important regulators of gene expression (8). 

The Microbiome and Gene Expression

Microbial metabolites include fatty acids, vitamins, and choline metabolites along with several other compounds that can modify gene expression. The two most well-studied metabolites produced by our microbiome are folate (vitamin B9) and butyrate.

Folate is a B-vitamin that contributes to the generation of SAM, a methyl donor that supports DNA methylation. DNA methylation is incredibly important in the colon and rectum as it helps to activate tumor suppressor genes that counteract cancer cell proliferation and protect against the development of cancer (9).

Most people know that dietary folate is important for human health, but few people know that it can be produced by our microbiome. In vivo and in vitro studies have shown that several Bifidobacterium species and Lactobacillus Plantarum are able to produce folate endogenously (10). In a pilot study that included 23 participants, supplementation with the species B. adolescentis DSM 18350, B. adolescentis DSM 18352, and Bifidobacterium pseudocatenulatum DSM 1835 for 30 days led to increases in fecal folate content, with B. adolecentis 13852 exerting the largest effect (11).

Given the rapid turnover rate of colonocytes, scientists believe that increasing microbial production of folate may be a superior method for increasing methylation in the colonocytes compared to using supplemental folate, as bacterial production can provide a continuous rather than transient dose of folate.  

Butyrate is a short chain fatty acid (SCFA) that is a by-product of bacterial fermentation of carbohydrates, and to a lesser extent protein, that is produced mostly in the proximal colon. Butyrate is the major energy source for the coloncytes and it is involved in modulating immune and inflammatory responses in the colon and for maintaining intestinal barrier function (12).

Several of the positive effects of butyrate production are mediated through its ability to inhibit histone deacytlase (HDAC) activity.  Butyrate exerts anti-inflammatory activity through inhibition of HDAC which supresses nuclear factor-kappa B (NF-kB), a proinflammatory mediator, and inducing the production of Treg immune cells. Butyrate has also been found to suppress cancer cell proliferation and induce programmed cell death through inhibition of non-coding RNA transcription, specifically miR-92a (13).

Several species of bacteria have been shown to produce butyrate including Faecalibacterium prausnitzii (clostridial cluster IV) and Anaerostipes, Eubacterium, and Roseburia species (clostridial cluster XIVa) (14). Growth and proliferation of these species are further supported by the consumption of prebiotic fibers including inulin-type fructans (ITF) and arabinoxylan-oligosaccharides (AXOS) as well as resistant starches and they are inhibited by consumption of a high fat diet (15). 

Supplementation with the butyrate producing species B. pullicaecorum 25-3 T, F. prausnitzii, Roseburia hominis, Roseburia inulinivorans, Anaerostipes caccae, and Eubacterium hallii, was shown to increase butyrate production by 11% in active Chron’s patients after 48 hours (16). In another study, small, but significant increases in butyrate production was found in healthy subjects who were supplemented with a 4 strain probiotic that included Lactobacillus acidophilus NCIMB 30175, Lactobacillus plantarum NCIMB 30173, Lactobacillus rhamnosus NCIMB 30174 and Enterococcus faecium NCIMB 30176) (17). 

Interestingly, prebiotic fiber supplementation might have a larger impact on fecal butyrate production than probiotics. In a 2003 study of patients with Ulcerative Colitis, supplementation with 60 grams of oat bran increased fecal butyrate by 36% (18). While another study showed that supplementation with type III resistant starches via 48 grams daily of modified potato starch in healthy subjects increased fecal butyrate by 50% (19). In the latter study, researchers found that this effect was dependent on baseline butyrate production and the abundance of butyrate producing species which indicates that the combination of supplementation with butyrate producing probiotics along with prebiotics, may have a synergistic effect on fecal butyrate production.

The MIcrobiome, Metabolome and the Future of Medicine 

Advancements in better understanding how to optimize health and prevent disease relies on gaining a better understanding of the complex interaction between our microbiome and our own physiology. Scientists are working hard to better understanding how these microbes and their metabolites communicate with our genetic expression and are working to develop strategies to alter the microbiome in ways that can help prevent disease and improve human health. 

Currently, probiotic and prebiotic supplementation along with nutritional changes that support a healthy microbial profile have shown promise. Continued research in this field may offer more effective and precise therapeutic options for altering the microbiome and metabolome in ways that enhance human health and prevent chronic illness.