August 11, 2022 10 min read
The microbes living in and on our bodies, collectively known as the microbiome, are becoming increasingly recognized as major influencers of both health and disease. The most densely populated area of the body is the gastrointestinal tract, namely the colon, which houses upwards of 100 trillion bacteria. The populations of bacteria are far from fixed, however.
Diet and environmental exposures greatly influence the density and diversity of bacteria in the gut.
Our diets serve as the primary food source for these microbes, with changes in diet composition dramatically shifting bacterial populations. Diets rich in prebiotics, like fibers and polyphenols, are associated with significantly greater bacterial diversity—a marker of microbiome health. Prebiotics are indigestible molecules that reach to the colon where they serve as a bacterial food source.
Both low fiber diets and environmental exposures like antibiotic use are associated with reduced density and diversity of the microbiota. Given the importance of antibiotics in the context of severe infection, the identification of strategies that can restore the microbiome post-exposure is of paramount importance.
In a review article hot off the press at Nature Reviews Microbiology entitled “Microbiome-based therapeutics”, the authors outline five primary clinical approaches currently implemented to facilitate microbiome restoration, modulation, and mimicry. These strategies are:
In clinical research, FMT is emerging as a potential treatment for multiple diseases, and research already supports its use in the treatment of C. difficile infections, inflammatory bowel disease (IBD), and infection with antibiotic-resistant strains of bacteria (also known as multidrug-resistant organisms). FMT involves the transplantation of the community of microorganisms in the feces of a healthy donor into a recipient. There are two sources of material for an FMT.
In addition to the two options for source material, there are also multiple routes of administration that can influence treatment efficacy. The routes of administration fall into two broad categories: upper gastrointestinal tract and lower gastrointestinal tract.
Upper gastrointestinal tract delivery involves the administration of small amounts of concentrated material to a patient, and also exposes the small intestine to the microbes being administered. The two routes of upper gastrointestinal tract delivery are:
Lower gastrointestinal tract delivery can involve the administration of large amounts of material directly to the colon. The three routes of lower gastrointestinal tract delivery are:
Patients eligible for an FMT exhibit dysregulated gut ecosystems including an inability of the microbiota to prevent pathogen colonization, low levels of bacterial diversity, changes to the population of immune cells that reside in the gut mucosa, and altered levels of key metabolites in the gut such as short chain fatty acids (SCFAs) and bile acids. FMTs facilitates improvements in bacterial diversity, while also restoring healthy SCFA and bile acid production, and inciting favorable changes to the characteristics of local immune cells.
Figure 1. Features of the microbiome pre- and post-FMT 
The efficacy of FMT has been demonstrated in humans, where fecal matter from healthy people was transferred into patients with recurring C. difficile-induced colitis (i.e. colon inflammation). C. difficile-induced colitis occurs when the microbiota loses the ability to suppress the growth of pathogenic bacteria in the gut—a function that all healthy, diverse microbiomes exhibit. Strikingly, FMT has up to a 90% success rate for patients suffering from this form of colitis, out-performing the previous standard-of-care treatment (i.e. antibiotics) by a landslide.
A strong correlation between microbiome composition and IBD has been reported in the literature. Given this relationship, FMT is being explored as a treatment for this condition. The research suggests that the composition of the donor microbiome is the primary determinant of treatment efficacy, and clinical remission is achieved by roughly 20% of IBD patients receiving an FMT. Interestingly, FMT is also being studied in the context of hepatic steatosis (i.e. fatty liver), where a clinical trial suggested that patients receiving an FMT exhibited reductions in liver inflammation.
Research in both the clinic and the laboratory now support the connection between the microbiome, diabetes, and obesity. In a study that administered fecal matter from lean individuals into individuals with insulin resistance, improvements in insulin sensitivity were observed for six weeks following the FMT. This efficacy corresponded to enhancements in the levels of Akkermansia muciniphila quantified in the microbiome.
Although specific species of bacteria in the gut have been identified as beneficial, boosting the levels of these key microbes is not as straightforward as simply consuming a probiotic. This is because there are various factors that must be considered to ensure a given species can thrive in the gut including:
Thus, the development of effective symbiotic microbial consortia (i.e. formulations containing multiple bacterial species that synergize to promote human health) is largely dependent on our ability to understand the complex interactions that occur between different members of the gut ecosystem. The development of effective consortia requires a deep understanding of the major commensal species in the gut and how they interact with one another.
Of the bacteria that inhabit the gut, bacteria from the phyla Firmicutes and Bacteroidetes are the most abundant, while Proteobacteria, Verrrucomicrobia, and Actinobacteria comprise smaller subsets of the ecosystem. Research has identified key functions of multiple species within each phylum.
The phylum Firmicutes includes species in the following orders:
In particular, a great deal of research has been conducted on species within the orders Lactobacillales and Clostridiales, and their roles as members of the microbiome have been examined.
The functions of Lactobacillales include:
Indeed, Lactobacillales are some of the most commonly sold probiotics on the market. Interestingly, however, a 2018 study published in the journal Cell reported that the consumption of Lactobacillus-containing probiotics can actually be harmful in the context of post-antibiotic use as the ability of these bacteria to stimulate the production of antimicrobials by the gut leads to impairments in microbiome reconstitution following antibiotics .
The functions of Clostridiales include:
Interestingly, the levels of one species in this order, Ruminococcus gnavus, is positively associated with IBD symptoms, while other species show a correlation to obesity. In other words, the relationship of Clostridiales with gut health is not as simple as “good” or “bad”, and is instead context dependent.
Bacteroidetes, which constitutes between 5 and 60% of the gut microbiome, is split into four primary families:
Bacteroidetes engage in complex and important behaviors in the gut including:
Because some Bacteroidetes can inhibit the growth of other microbes as a competitive advantage, this presents a challenge when trying to design a symbiotic bacterial consortia with bacteria from this phyla such as B. fragilis.
The only species of Verrucomicrobia currently identified as a member of the human gut microbiome is Akkermansia muciniphila, which resides in the mucus layer of the gut and feeds on mucus protein polysaccharides. This species holds a great deal of therapeutic promise as its levels are closely associated with metabolic health and favorable body composition, and boosting levels of A. muciniphila in the obese and metabolically ill confers improvements in these conditions. Moreover, the administration of heat pasteurized A. muciniphilato obese patients has been shown to improve insulin sensitivity and decrease fasting insulin levels without adverse effects. This suggests that A. muciniphilaneed not be alive to trigger some of the benefits to metabolic health. In addition to these effects, A. muciniphila also:
Thus, although this bacterium presents an important therapeutic opportunity, its association with certain neurological diseases means that its abundance is not necessarily beneficial across all contexts.
Within the phylum Actinobacteria are species of the genus Bifidobacterium. Bifidobacteriumare among the most popular probiotics on the market and their abundance in the gut is associated with a range of health benefits including:
Bifidobacterium are particularly abundant in the infant gut, as their growth and colonization is specifically promoted by the presence of human milk oligosaccharides (HMOs) in breast milk. HMOs serve as a potent food source for these bacteria, and infants who are not breast fed have lower levels of Bifidobacteria in their gut and are more susceptible to developing diseases of inflammation later in life including asthma, allergies, and autoimmunity .
As we develop our understanding of the nutrient preferences of different members of the microbiota, we open the door for strategic dietary and supplemental recommendations geared towards cultivating certain groups of bacteria over others. Current research has already revealed the effects of certain dietary components on the composition of the microbiota. For example:
In addition to the types of foods influencing the microbiota, how a food is prepared is also an important consideration as, for example, cooking plants increases starch and fiber digestibility. In other words, less polysaccharides will reach to the microbiome to serve as a food source.
Moreover, prebiotic supplements also have the ability to create meaningful shifts in the composition of the gut microbiome. For example, HMOs and polyphenols (i.e. the pigments present in brightly colored fruits and vegetables) have proven efficacy in boosting levels of both Bifidobacteria and Akkermansia. As the research continues developing, more dietary components and nutraceuticals will be identified and synthesized that can modulate the growth of key species of bacteria in the gut for targeted health outcomes.
As the name implies, engineered symbiotic bacteria are bacteria that are normally found in a healthy microbiome that are genetically altered to confer additional benefits. For example, bacteria like E. coli and Lactococcus lactis have previously been used to deliver recombinant proteins (i.e. proteins that these bacteria do not naturally express). However, these bacteria do not persist in the gut without continual supplementation.
Conversely, recent research has been focused on the production of engineered strains of Bacteroidales that have the ability to synthesize tryptamine and, in doing so, promote mucin secretion from goblet cells (i.e. mucus producing cells) in the gut. This engineered probiotic was shown to help prevent colitis in rodent models. Additional work is underway to express the enzymes required for the breakdown of complex polysaccharides into other commensal microbes to give them a selective growth advantage. These enzymes are naturally expressed to a high degree in some species of Bacteroidetes.
An alternative to seeding bacteria of interest into the gut is to directly introduce bacterially-derived proteins and metabolites (post-biotics). Many bacterially-produced factors are known to exert potent effects on both other bacteria in the surrounding ecosystem as well as on host physiology and metabolism. For example, the SCFAs produced by certain species of bacteria upon fiber fermentation not only serve as food sources for other species of commensals, but also modulate immune cell function, promote satiety, and can enhance cognition.
The direct delivery of bacterially-derived factors may be particularly prudent in certain clinical contexts such as in immunocompromised patients, as the administration of live probiotics can lead to systemic infections in these individuals. However, challenges exist in developing drug delivery mechanisms that will allow these key microbiota-derived metabolites to mimic their natural location in the gut, as well as understanding the appropriate local concentrations needed to exert the intended effects.
From the administration of multiple synergistic species of bacteria and engineered strains, to dietary manipulation and direct supplementation with microbially-derived metabolites and proteins, various strategies for manipulating and mimicking the effects of the microbiome are being explored to confer health benefits. As technology develops and our understanding of bacteria-bacteria and bacteria-host interactions becomes more nuanced, our ability to leverage the microbiome for targeted clinical outcomes will improve. Although dietary and supplemental strategies confer less targeted effects, they currently possess the highest level of safety making them prudent first-in-line options for microbiome modulation.
Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions.
Follow Dr. Cowan on Instagram: @dralexisjazmyn
 Sorbara MT, Pamer EG. Microbiome-based therapeutics. Nat Rev Microbiol. 2022 Jun;20(6):365-380. doi: 10.1038/s41579-021-00667-9. Epub 2022 Jan 6. PMID: 34992261.
 Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, Horn M, Cohen Y, Moor AE, Zeevi D, Korem T, Kotler E, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Pevsner-Fischer M, Shapiro H, Sharon I, Halpern Z, Segal E, Elinav E. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018 Sep 6;174(6):1406-1423.e16. doi: 10.1016/j.cell.2018.08.047. PMID: 30193113.
 Henrick B et al. Bifidobacteria-mediated immune system imprinting early in life. Cell. 2021; 184(15).
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