Microbiome
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It is generally assumed that humans are the most complex organisms ever to have existed on this planet. However, if we base this assertion on the complexity of the human genome, which is the entirety of distinct functioning genes contained with the human species, this clearly is not so.
The most striking discovery of the Human Genome Project is that the human genome contains only 26,000 distinct functioning genes (1,2). By way of comparison, Oryza sativa - that is to say, rice - boasts 46,000 such genes (3). Based on this comparison, humans are less complex than rice. This is known as the genome-complexity conundrum; many complex species seem to possess rather simple genomes, and many simple species seem to possess rather complex genomes.
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The microbiome contains 90% of the cells and over 99% of the distinct functioning genes in the human body. |
The existence of the microbiome resolves the genome-complexity conundrum in that it increases the number of distinct functioning genes from 26,000 to well over 4 million for a typical human being, with nearly all those genes located not in human cells but in bacteria and viruses. The cataloguers of the Human Genome Project have a wee bit more work to do if they want to finish the job that they started.
With such a colossal gene inventory, the microbiome is clearly vital. So, what does it do?
Immune Tolerance
The human immune system is critical for existence; without it, various damaged human cells and pathogenic microbes would rapidly infiltrate and destroy the human body. Yet the immune system must be educated so that it can distinguish its foes (damaged human cells and pathogenic microbes) from its friends (healthy human cells and resident microbes) (7). The major point of contact between the human immune system and the outside world occurs at the interface of the gut; the gut is the school where the immune system learns to distinguish pathogenic microbes from resident microbes, where it learns to destroy the former yet tolerate the latter.
Tolerance to healthy human cells and resident microbes is governed by specialized cells of the immune system called T regulatory cells; these cells suppress or “calm down” various components of the immune system. In turn, the actions of T regulatory cells are governed by various resident microbes such as Bacteroides, Lactobacillus, and Bifidobacterium species (8). Therefore while T regulatory cells may supervise the immune system, their roles are reversed in the gut's school of immune tolerance, where they become students to the teachings of the resident microbes.
The mechanism by which Bacteroides, Lactobacillus, and Bifidobacterium influence T regulatory cells appears to involve the production of short chain fatty acids, microbial products such as acetate, propionate, and butyrate that are derived from the metabolism of dietary fibre (8). In addition to their influence on immunity, short chain fatty acids also influence metabolism (1) - they provide 70% of the energy needs for colon epithelial cells (9), stimulate tight junctions (10,11) to make the gut less “leaky” to toxins, reduce local inflammation thus protecting against colitis and colon cancer (8,12), and even regulate systemic inflammation thus protecting against metabolic conditions such as obesity and type II diabetes (10).
Evidence from animal studies shows just how critical it is for T regulatory cells to be exposed to the short chain fatty acids produced by resident microbes. Mice that are made to be “germ-free” in a laboratory have fewer lymph nodes, fewer lymphocytes, and a deficient T regulatory cell response (4,13) resulting in a heightened, inappropriate allergic response (8,14); these abnormalities can be reversed if the mice are colonized with the correct bacteria.
Dysbiosis
While it is not possible to make germ-free humans in a laboratory it is certainly known that people with dysbiosis, broadly defined as a microbiome that is somehow “different” to that found in healthy people, are much more likely to suffer from conditions associated with abnormal immune tolerance such as asthma, ulcerative colitis, Crohn’s disease, Celiac disease, and multiple sclerosis, all of which have been rapidly rising over the last 50 years (8). By examining the microbiomes of people afflicted by these conditions it is possible to identify two major characteristics of a dysbiotic microbiome.
First, dysbiosis is characterized by reduced microbiome diversity. Healthy microbiomes contain an average of around 160 species of bacteria (6,15). In contrast, the dysbiotic microbiomes in people with asthma, ulcerative colitis, and Crohn’s disease lack this degree of diversity (8,10). Reduced diversity likely results from insufficient exposure to environmental microbes at a young age; for example, it is well documented that children with asthma have significantly lower microbial diversities early in life compared to children without asthma (16). Thus, exposure to environmental microbes early in life is probably important for preventing conditions associated with abnormal immune tolerance such as asthma.
Second, dysbiosis is characterized by an inappropriate microbiome balance. Healthy microbiomes are mostly composed of species from five phyla – species from Bacteroidetes and Firmicutes each make up 30% of the microbiome, and species from Actinobacteria, Proteobacteria, Verrucomicrobia make up the rest of it (1,4). In the case of ulcerative colitis, twin studies reveal that the microbiome of the twin with the ulcerative colitis contains more species from Actinobacteria and Proteobacteria compared to that of their healthy sibling (17). Moreover, the microbiome of children with Celiac disease contains less Bifidobacterium species compared to that of children without Celiac disease (1). Furthermore, the microbiome of people with multiple sclerosis contains an increased proportion of Methanobrevibacter and Akkermansia species and a lower proportion of Butyricimonas species compared to that of people without multiple sclerosis (18). Thus, maintaining the appropriate balance of residential microbes throughout life is probably important for preventing conditions associated with abnormal immune tolerance such as ulcerative colitis, Celiac disease, and multiple sclerosis.
It is essential to remember that these human studies are associative in nature; they cannot prove that a causative link exists between dysbiosis and abnormal immune tolerance. However, given the known role of the microbiome in educating T regulatory cells in the gut’s school of immune tolerance, the findings from human studies are highly suggestive.
Rebiosis
If a dysbiotic microbiome is mainly characterized by reduced diversity and an inappropriate balance of residential microbes then the obvious way to conduct a restoration or rebiosis of the microbiome is to increase diversity and repair the balance. Ultimately, the goal of rebiosis is to make the immune system more tolerant so that it is less likely to create abnormal immune responses against the body’s own healthy human cells and resident microbes.
The most direct way to increase diversity and repair the balance is to replace a person’s dysbiotic microbiome with a healthy one using a fecal microbiota transplant, a procedure in which the stool from a healthy donor is transplanted into the gut of an unhealthy recipient (8). Although this procedure sounds somewhat dubious, the results are quite excellent as exemplified by patients with antibiotic-induced Clostridium difficile infections. The standard treatment for the severe diarrhea and colitis induced by these infections is to give the patient even more antibiotics in the form of vancoymycin or metronidazole, a strategy that results in a high recurrent infection rate of 25% (8). Alternatively, giving the patient one or two fecal microbiota transplants drops this recurrent infection rate down to a paltry 2% (8, 19). Thus, replacing a dysbiotic microbiome with a healthy one is clearly both feasible and effective.
For those not interested in fecal microbiota transplants there may be other, more natural ways to increase diversity and repair the balance of the microbiota. They involve limiting antibiotic use, restricting energy intake, and eliminating processed food consumption; the evidence for the latter two methods is still preliminary.
Since antibiotics are unable to differentiate between pathogenic and resident microbes, they may destroy the pathogenic bacteria while at the same time killing vast swathes of resident microbes. Widespread reductions in microbiome diversity and residential microbe community loss occur in as little as three days after commencing common antibiotics such as amoxicillin, vancomycin, ciprofloxacin, and cephalosporins (8,20). These reductions and losses can be easily avoided by limiting antibiotic use only to potentially life-threatening situations in which they are absolutely required.
Interestingly, a 2013 a study involving 49 overweight or obese subjects showed that these individuals were significantly more likely to have a lower microbiome gene count compared to lean individuals (21). Furthermore, a 35% reduction in energy intake for just six weeks enriched the gene counts in these overweight and obese individuals; in other words, eating less increased microbiome diversity. It is therefore tantalizing to speculate that restricting energy intake even further through intermittent fasting protocols could provide even further benefit, although this has not yet been studied to my knowledge.
In addition, it is well known from animal studies that diets high in refined foods and low in fibre are associated with a lack of microbiome diversity (15). By eliminating processed food consumption and returning to a high fibre diet, this loss of diversity is largely recoverable. It is tempting to speculate that a ketogenic diet bolstered by fibre-laden vegetables and healthy fats could provide even further benefit, although again this has not yet been studied to my knowledge.
Finally, there may be other methods that can increase diversity and repair the balance of the microbiome. Many people are aware of probiotics, microbes that are believed to provide health benefits when consumed, and prebiotics, non-digestible substances that stimulate the growth and activity of beneficial bacteria. While the evidence supporting the use of probiotics and prebiotics is scant at this point in time, some individuals have taken things much further by compiling comprehensive microbiome diets which can be extremely successful in some people (22). The concept of a microbiome diet is intriguing and definitely warrants further attention in the years ahead.
To wrap this up, as many as 90% of all cells in humans are residential microbes in the gut, and their collective microbiome contains over 99% of the distinct functioning genes in the human body. Given these facts, the microbiome does not receive anywhere near the amount of scientific and medical attention that it should. However, perhaps that time is coming; perhaps there will be a day when doctors order microbiome analyses as frequently as they currently order blood tests.
Until that day, go easy on the antibiotics.
Solace.
References
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(2) Venter JC, Adams, MD, Myers EW et al. 2001. The sequence of the human genome. Science 291, 1304-1351.
(3) Jacquemin J, Ammiraju JS, Haberer G et al. 2014. Fifteen million years of evolution in the Oryza genus shows extensive gene family expansion. Molecular Plant 7, 642-656.
(4) Glenn JD, Mowry EM. 2016. Emerging Concepts on the Gut Microbiome and Multiple Sclerosis. Journal of Interferon & Cytokine Research 36 (6), 347-357.
(5) Savage DC. 1977. Microbial ecology of the gastrointestinal tract. Annual Review of Microbiology 31, 107-133.
(6) Qin J, Li R, Raes J, Arumugam M et al. 2010. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65.
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(17) Lepage P, Hasler R, Spehlmann ME et al. 2011. Twin Study Indicates Loss of Interaction Between Microbiota and Mucosa of Patients with Ulcerative Colitis. Gastroenterology 141, 227-236.
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(21) Cotillard A, Kennedy SP, Kong LC, Layec S. 2013. Dietary intervention impact on gut microbial gene richness. Nature 500, 585-590.
(22) Kellman R. 2014. The Microbiome Diet: The Scientifically Proven Way to Restore Your Gut Health and Achieve Permanent Weight Loss. Da Capo Press.
