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The gut ecosystem possesses a vast array of different microbial species, from bacteria and archaea to fungi and viruses. The colon alone contains upwards of 100 trillion bacteria, while the human body as a whole consists of around 40 trillion human cells.
In other words, there are more than two times as many bacteria in the colon as human cells in the entire body.
Thus, the microbiome is inextricably linked to the functioning of our bodies in both health and disease.
Because of the increasingly apparent correlations between the levels of certain species of bacteria and specific disease states, research aimed at exploring the factors that influence microbiome composition and how to leverage these factors is of paramount importance.
A review hot off the press in the prestigious journal Science entitled “The microbiome and gut homeostasis” outlines the parameters that can be used to define dysbiosis and homeostasiswhen it comes to the microbiome by exploring the role of host physiology and metabolism in microbiota composition.
Dysbiosis is broadly defined as a microbiome with one or more of the following features:
There are two broad categories of bacteria in the gut: facultative anaerobes and obligate anaerobes.
The high level of oxygen that is maintained in the lumen of the host’s small intestine favors the growth of facultative anaerobes, while the hypoxic (i.e. low oxygen) state of the epithelium in the colon supports the growth of obligate anaerobes.
Research probing the etiology of dysbiosis suggests that the control mechanisms established by the physiology of the host are weakened in the dysbiotic state. For example, in animal models of irritable bowel disease (IBD), gastric infection, and colorectal cancer, levels of oxygen are increased in the colonic environment, which boosts levels of facultative anaerobes while inhibiting the growth of native obligate anaerobes.
Similarly, the consumption of a Western diet rich in ultra-processed foods is associated with declines in host control mechanisms. Unlike a dysbiotic gut, a homeostatic gut is one in which host control mechanisms are successfully enforced (e.g., the maintenance of the oxygen gradient across the length of the gut).
Thus, a major goal of the research in this space is to characterize the host control mechanisms at play and develop methods to both assess and modulate these mechanisms.
Figure 1. The dysbiotic gut has weakened host control mechanisms that drive up levels of oxygen in the lumen, leading to the growth of aerobes in the colon and growth inhibition of anaerobes [1]
Although certain broad bacterial signatures are associated with benefit and harm, there is a vast interindividual variability in what constitutes a “healthy” homeostatic gut. For this reason, it has been challenging to identify specific bacteria as causal in health and disease. Thus, shifting the objective to instead characterizing parameters of the human body that are associated with health may provide an alternative lens by which to assess what a healthy microbiome looks like on an individual level.
As previously mentioned, the concentration of oxygen in the lumen decreases along the length of the gut. In mice, the luminal oxygen concentration is around 6% in the duodenum (i.e. the proximal-most portion of the intestines attached to the stomach), 1% in the ileum (i.e. the distal portion of the small intestine), and 0.6% in the cecum of the colon.
This oxygen gradient is accomplished by the colonic epithelium preventing the free diffusion of oxygen from the blood circulation into the lumen, whereas this diffusion is permissive in the small bowel.
The epithelial cells that line the ileum express enzymes that facilitate the production of nitrate, whereas the epithelial cells of the colon do not. The result is high levels of nitrate in the proximal gut which supports the growth of facultative anaerobes that thrive on both oxygen and nitrate. Meanwhile, the lack of expression of these enzymes in the distal gut favors the growth of the obligate anaerobes which require neither oxygen nor nitrate to produce energy.
Thus, host mechanisms that regulate the levels of oxygen and nitrate across the length of the gut directly control the differential composition of microbial communities.
In addition to oxygen and nitrate availability, diet is another major force that shapes microbiome composition. Prebiotics (i.e. indigestible carbohydrates like fibers and polyphenols) traverse the gut intact where they can serve as a food source for resident microbes.
These prebiotics are fermented in the colon, bolstering the growth of the obligate anaerobes therein, and supporting their production of secondary metabolites like short chain fatty acids (SCFAs).
In infancy, diet is relatively comparable across all individuals as breast milk is the primary source of nutrition. Human breast milk contains human milk oligosaccharides (HMOs) which preferentially feed a species of bifidobacteria called B. infantis(phylum: Actinobacteria).
As a result, up to 70% of the infant microbiome consists of B. infantis. Following weaning and the consumption of solid foods, B. infantisceases to be a major constituent of the gut microbiome as the repertoire of available prebiotics shifts from HMOs to other indigestible carbohydrates (e.g. FODMAPs and fibers). In this setting, colonization by Bacteroides and Clostridia (phylum: Firmicutes) is favored.
Figure 2. Microbiome composition from infancy to adulthood in comparison to a dysbiotic gut [1]
Thus, in the adult gut, Bacteroides and Clostridia-dominant microbiomes are considered homeostatic, while Actinobacteria-dominant microbiomes are homeostatic in infants. In the dysbiotic gut, the facultative anaerobes known as Proteobacteria occupy a larger niche.
There are multiple risk factors known to contribute to the development of dysbiosis:
A low fiber diet causes Prevotella species to be displaced by Bacteroides. Whereas Prevotella specialize in breaking down indigestible carbohydrates, Bacteroides feast on the glycans present in the mucus lining of the gut. As a result, the protective mucus barrier begins to erode, which can lead to gut inflammation and infection.
A high sugar diet results in simple sugars spilling over into the colon from the small intestine. As a result, levels of sugar-degrading Firmicutes increase which can also lead to degradation of the mucus barrier, facilitating an inflammatory environment.
A high fat diet can lead to increased production of reactive oxygen species in the colon that drive up inflammation and impair mitochondrial function. Because mitochondrial aerobic (oxygen-consuming) energy production is responsible for maintaining low oxygen levels in the colon, the high-fat-diet-induced mitochondrial impairment results in elevated levels of oxygen in the colonic lumen and increased production of nitrate, which both favor the growth of facultative anaerobes.
Increased levels of oxygen and nitrate in the colon are also observed following antibiotic treatment, infection with pathogens, ulcerative colitis, and colorectal cancer.
In the case of antibiotic use, the depletion of SCFA-producing obligate anaerobes in the colon results in elevations in luminal levels of oxygen and nitrate. This occurs because the burning of SCFAs by mitochondria within colon cells is one of the major mechanisms by which oxygen levels are kept low.
Today, stool testing is fairly popular among clinicians and consumers alike. However, assessment of gut microbial composition and gene expression is insufficient to determine the health status of one’s microbiome as it fails to consider the host influences.
Thus, in the future, markers of host status should be incorporated into microbiome testing approaches in order to paint a holistic picture. Specifically, assessment of oxygen and nitrate availability in the distal gut is imperative, as these electron acceptors facilitate the growth of facultative anaerobes that are not present in a homeostatic gut.
The mechanisms that drive control over oxygen and nitrate availability in the colon should be considered as an extension of the human immune system. Through this lens, failure to restrict the availability of these electron acceptors in the colonic environment is deemed immune dysfunction.
By considering host control over the microbiome as a primary determinant of colonic microbial composition, tools and strategies that leverage these host control mechanisms can be prioritized. For instance, it is now accepted that a major driver of dysbiosis is mitochondrial dysfunction within colon cells.
Thus, supplements and pharmaceuticals that boost mitochondrial function can feasibly be used to support mitochondria and help to restore hypoxia within the colonic environment.
Finally, continuing to conduct research exploring other host control mechanisms over the microbiome will provide us with additional levers upon which we can push to modulate the microbiome for targeted outcomes.
Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions.
Follow Dr. Cowan on Instagram: @dralexisjazmyn
Reference:
[1] Lee JY, Tsolis RM, Bäumler AJ. The microbiome and gut homeostasis. Science. 2022 Jul;377(6601):eabp9960. doi: 10.1126/science.abp9960. Epub 2022 Jul 1. PMID: 35771903.
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