Earth is home to over 7 billion humans and 8.7 million different forms of life. Despite this rich biodiversity, from space our planet is merely a blue marble with swirls of green, white and brown. In the same way, although not visible to the naked eye, humans consist of multiple ecosystems, each ecosystem consisting of its own unique community of microbes. It is understandably very difficult to comprehend that the human body, just a fraction of the size of our planet, is a world in its own right, housing 100 trillion microbes in the gut alone.
The human microbiota benefits from a rich and continuous supply of nutrients from the human host and in return, the resident microorganisms contribute greatly to human physiology. The fact that such a mutualistic relationship occurs suggests that the benefits that these microorganisms bring to the host do indeed outweigh any potential pathogenic threat. This essay will discuss the vast advantages brought about by the microorganisms that live within us.
Fermentation of Indigestible Food
The human gastrointestinal tract is home to a complex microbial community that is characterised by its extensive diversity and complex interactions. The gastrointestinal microbiota consists largely of bacteria and it is predicted that 1000 bacterial species coexist in the gastrointestinal tract. Whereas humans do not possess the enzymes needed to digest certain dietary carbohydrates, some bacterial species are able to secrete the enzymes needed to break down these otherwise non-digestible substances, converting them into short chain fatty acids (SCFAs). It is evident that the three major SCFAs – acetate, propionate and butyrate – have a significant effect on the host’s physiology.
Acetate, propionate and butyrate passively diffuse across the colonic epithelium and are then utilised by various different organs. Butyrate is a significant energy source for human colonocytes (cells lining the colon) and interestingly, 70% of the colonic epithelium’s energy comes directly from butyrate . Without this energy source, colonocytes would undergo autophagy and die. Butyrate is perhaps most famously known for protecting against colorectal cancer. In a 2014 study, mice were colonised by mutant strains of the butyrate-producing bacterium, Butyrivibrio fibrisolvens. The mice showed an increase in colonic levels of butyrate and simultaneously, they developed fewer and less advanced colon tumours than those produced in mice lacking the bacterium. Tumour analysis of these mice showed greater expression of pro-apoptotic genes and a subsequent elevation in apoptotic markers in comparison to the control mice and the mice lacking the bacterium. These findings suggest that this bacterium’s fermentation of fibre into butyrate could potentially induce the apoptosis of colorectal cancer cells.
Acetate is the most abundant SCFA in the human body and is used in cholesterol metabolism and lipogenesis. In fact, acetate has been shown to make a larger carbon contribution to lipids than both propionate and butyrate. The SCFA is further believed to act as a vital metabolite in the growth of other bacteria. Propionate, on the other hand, is a significant hepatic gluconeogenic substrate and unlike acetate and butyrate, contributes carbon atoms directly to the synthesis of glucose. Gluconeogenesis (GNG) is a metabolic pathway that synthesises glucose or glycogen from certain non-carbohydrate organic substrates, supplying the need for plasma glucose in between meals. As well as stimulating gluconeogenesis, this SCFA has been linked to reduced stress behaviours.
Vitamins are inorganic compounds that are essential for the maintenance of good health and metabolism. Just as the human body does not have the enzymes needed to digest certain carbohydrates into SCFAs, humans do not have the enzymes needed to synthesise all the required vitamins. For the vitamins that humans can indeed synthesise, they are generally not produced in sufficient quantities Certain microorganisms of the human microbiota are however able to synthesise vitamins which can then be utilised by the host. Gastrointestinal microbiota such as Escherichia coli and Bacteroides fragilis synthesise vitamins including B1, B2, B5, B6, B12, folic acid and biotin. Perhaps the most well-known example is cobalamin (vitamin B12), a vitamin which acts as a coenzyme in DNA metabolism and is crucial to erythrocyte maturation. Enzymes needed for B12 synthesis found in neither plants nor animals, but rather in the bacteria living within the human body. Furthermore, it is thought that half of the daily Vitamin K requirement is supplied by gut bacteria.
It has been known for many years that the vast majority (around 80%) of the immune system is located in the gastrointestinal tract; remarkably, evidence has suggested that bacteria in the gut directly influences the immune system. The mucosal immune system is so specialised, in fact, that its functions are, for the most part, independent of the systemic immune system. The gastrointestinal microbiota is essential to the maturation of the immune system, which immediately begins to ‘learn’ to distinguish between pathogenic and commensal bacteria. Toll-like receptors (TLRs) are found on the membranes of non-immune cells and leukocytes; they are involved in this recognition and suppress inflammatory responses, stimulating immunological tolerance to the microbiota.
The gastrointestinal microbiota has been proved to modulate neutrophil function and migration and also to stimulate the differentiation of T lymphocytes into various helper T cells (Th) – including Th1, Th2 and Th17 – or into regulatory T cells (Tregs). Th17 cells secrete several pro-inflammatory cytokines, playing a critical role in host defence by attracting neutrophils and macrophages to infected tissues. Interestingly, the SCFA butyrate has been shown to induce the differentiation of Tregs and analysis has suggested that the luminal concentrations of SCFAs is positively correlated with the number of Tregs in the colon. Tregs are vital in controlling the immune response and the prevention of autoimmune diseases; people with Type 1 Diabetes Mellitus have a deficit of butyrate-producing bacteria in the gut providing some evidence for this butyrate-autoimmunity connection.
Furthermore, the host-commensal communication stimulates antimicrobial responses to foreign pathogens from the epithelium. This involves the release of antibacterial lectins – including alpha defensins and angiogenins – that help to decrease the number of pathogenic microbes in the body and thus prevent abnormal immune responses. For example, Bacteroides thetaiotaomicron (a bacterium commonly found in the human gastrointestinal tract) stimulates the production of antimicrobial peptides which in turn target pathogenic microorganisms.
Commensal viruses could potentially also protect the host from pathogenic infections from other viruses. Surprisingly, a virus in the same family as Zika and Dengue – known as pegivirus C (GBV-C) – is thought to mitigate the consequences of HIV infection. Several studies have shown that HIV patients containing this commensal virus tend to live longer than HIV-infected subjects without the virus The mechanism behind this is unknown, however it is thought that it involves blocking interactions between cell surface receptors found on helper T cells that are necessary for HIV virus replication.
Interestingly, one of the key ways in which the microbes in the gut protect the human body is by occupying spaces that could otherwise be colonised by harmful pathogens. This mechanism of colonisation resistance is not a new idea. Indeed, 50 years ago, work from Bohnhoff et al. demonstrated that antibiotic disruption of the microbiota results in increased susceptibility to salmonella infection. Though the phenomenon of colonisation resistance may seem simple, the mechanisms of microbiota-mediated colonisation are incredibly complex. A single slip-up, as Bohnhoff’s experiments suggest, will result in opportunistic bacteria exploiting this breakdown and expanding into the newly created niches.
Competition for nutrients in the gut is fierce and exogenous microorganisms are therefore unlikely to find an uncontested niche; they must compete with the established microorganisms for nutrients. Citrobacter rodentium (C. rodentium) is a mucosal pathogen of mice that shares many pathogenic mechanisms with several human intestinal diseases, including enteropathogenic Escherichia Coli (EPEC) infections, enterohemorrhagic E. coli (EHEC) infections and Crohn’s disease. C. rodentium is thus a very useful model in investigating human intestinal diseases. Such studies have found that commensals are often able to outcompete C. rodentium as both rely on structurally similar carbohydrates for growth. Therefore, pathogen colonisation is largely controlled by competition with metabolically similar commensal microorganisms.
The Microbiota-Gut-Brain Axis
The gut-brain axis is by definition a bidirectional link between the central nervous system (CNS) and the enteric nervous system (ENS). Several studies have suggested that there is a link between gut microbial composition and certain diagnoses; it is important to remember that though these studies may show strong correlations, there is not yet enough evidence to suggest causal relationships. Furthermore, it must be considered that much of the research into this topic involves studies on germ-free (GF) mice and it can be unreliable to extrapolate results to humans. However, work with GF mice has indicated the evolutionary importance of the microbiome and consequent effects in mammalian behaviour. Evidence from human studies has further made it clear that there is a correlation between cognitive function and the microbiome of the gut. In fact, the knowledge acquired from extensive research both on humans and GF mice has broadened the term ‘gut-brain axis’ to the ‘microbiota-gut-brain axis’.
The absence of microbial colonisation is associated with an altered expression and turnover of neurotransmitters in both the CNS and the ENS. Recent research has shown that the gastrointestinal microbiota stimulates human body cells to produce more serotonin and that 90% of serotonin is produced in the gut. Furthermore, some bacterial species are able to produce amino acids such as tyrosine and tryptophan that are small enough to pass through the blood-brain barrier. Inside the brain, tyrosine and tryptophan are then converted into dopamine and serotonin.
Serotonin is a significant signalling molecule within the gut-brain axis. Not only is it crucial for everyday intestinal functions such as coordinating contractions that transport food through the digestive tract, but also in sleep, appetite, mood, pain-sensitivity and general well-being. In a 2011 study, for instance, a French research group showed that a mixture of Lactobacillus helveticus and Bifidobacterium longum, given for 30 days, heavily improved healthy volunteer scores in a range of studies that assessed their mental health. The microbiota-gut-brain axis could thus potentially explain why studies have further indicated that probiotics improve the moods of patients with irritable bowel syndrome and chronic fatigue syndrome.
Other research has suggested that the microbiota-gut-brain axis may influence the development of CNS pathways involved in stress response. A well-known study led a decade ago by Nobuyuki Sudo involved restraining GF mice in a narrow tube for an hour, measuring their stress hormone output. The GF mice responded with significantly higher levels of adrenocorticotropic hormone and corticosterone in comparison to control mice. Moreover, by treating the mice with the bacterium Bifidobacterium infantis, more normal hormonal responses were induced. This was the first study to confirm a direct link between intestinal microbes and the hypothalamic-pituitary-adrenal (HPA) stress response.
Other Significant Microbiotas
The gastrointestinal tract is the most researched and recognised location of the human microbiome. Indeed, much of this essay has been discussing the advantages of the symbiotic relationship between the gastrointestinal microbiota and the host. Nonetheless, it is important not to underestimate the significance of other microbiotas. The vaginal microbial community is, for instance, incredibly complex and plays a crucial role in a woman’s reproductive health. The healthy vaginal microbiota is largely colonised by bacteria of the genus Lactobacillus; infection by pathogenic microorganisms is suppressed by the bacteria’s production of lactic acid and antimicrobial substances. Imbalances in the microbiota can result in bacterial vaginosis (BV), one of the most common gynaecological conditions affecting women around the world. Particularly interesting is the fact that weeks before a woman gives birth, the microbes in the birth canal begin to change. Scientists predict that this is to ensure that babies are born with the correct microbiome composition needed to grow and develop. These microbes are crucial in the growing infant. Inside breast milk, for example, are human milk oligosaccharides that are indigestible in the infant; they are in fact used to feed the microorganisms that are beginning to colonise the baby’s gastrointestinal tract. In turn, these microbes rapidly multiply and colonise niches that could otherwise be claimed by harmful pathogens.
The oral cavity is another significant microbiome, consisting of several microenvironments that harbour diverse beneficial bacterial populations, including the tongue, the hard and soft palate, teeth and gums. The warm and moist environment in the mouth enables the growth of many microorganisms, offering host-derived nutrients such as saliva, proteins and glycoproteins. A relatively newly discovered strain of bacteria, A12, has been shown to prevent tooth decay by targeting Streptococcus mutans, an anaerobic bacterium found to be a significant contributor to tooth decay. A12 produces hydrogen peroxide which subsequently targets the cell walls of S. mutans, inhibiting the harmful bacterium’s growth and replication. Secondly, A12 inhibits two intracellular signalling pathways of the pathogen, leaving the bacterium unable to settle into a biofilm due to the inability to send and receive chemical messages.
In conclusion, the microbiota-host relationships discussed throughout this article are the product of thousands of years of coevolution. Research has indicated that microorganisms serve many beneficial functions in the human body; they are involved in the fermentation of indigestible food, synthesis of vitamins and indeed protection against harmful pathogens. Although there is constant research into destroying microorganisms, it is of great value to consider whether such treatments are in fact harming beneficial microbiota, for it is certain that humans could not have evolved to their current sophistication without the microorganisms living within the human body.
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About the Author
Alina is a sixth form student studying in London, looking to study medicine at university. In her free time she enjoys playing tennis and netball, and is playing tennis at county level. Alina’s favourite subjects include biology, chemistry and maths.