Alteration in the balance of the community of microbes that reside in the body, especially within the gut, has been linked to a wide range of intestinal and extraintestinal diseases. While the causality for most of those conditions has yet to be established, the causal link between the microbiome and disease states has been shown for Helicobacter pylori-associated peptic ulceration and gastric cancer and Clostridioides difficile infection-associated diarrhea.
One of the most frequently studied therapeutic applications of microbiome science is the use of fecal microbiota transplantation (FMT) for recurrent C. difficile infection, first reported in 1958. FMT’s therapeutic benefits can be explained by an increased diversity of bacteria, viruses, fungi and archaea that can engraft into the recipient host and help improve the gut microbiota’s functional diversity. In addition, FMT is being tested in almost 300 clinical trials for a broad range of disease indications, including inflammatory bowel diseases, irritable bowel syndrome, acute pancreatitis, graft versus host disease, autoimmune diseases (e.g., multiple sclerosis), cancer, and even psychiatric conditions (e.g., epilepsy and Parkinson’s disease).
Although FMT has been shown to be effective and safe for C. difficile infection, safety concerns related to disorders linked to changes in the gut microbiota have been reported. For instance, in the light of the current COVID-19 pandemic, screening of donors for severe acute respiratory syndrome coronavirus 2 is recommended.
Beyond undefined fecal microbiota transplants, targeted formulations used to shape host microbiota (defined microbial consortia) are an alternative for overcoming issues of reproducibility and scalability. The most frequently studied formulations are probiotics, and a recent update of their clinical benefits can be found elsewhere (e.g., usprobioticguide.com and probioticchart.ca).
In addition to traditional probiotics, live microorganisms developed as therapeutic agents with defined clinical benefit claims (also called live biotherapeutics products or next-generation probiotics) are under investigation. Next-generation probiotics in particular include microorganisms that do not have a history of use as health-promoting agents to date, including genetically modified microorganisms, and will more likely follow a drug regulatory framework. Although the first next-generation probiotics focused on microorganism taxonomy, the most recent ones focus on the functional attributes of administered microorganisms.
The term probiotic implies that microorganisms should be alive at the time of ingestion. However, scientists have turned to compounds produced by microorganisms, released from food components or microbial constituents, including non-viable cells—also called postbiotics (and less frequently paraprobiotics, parapsychobiotics and ghost probiotics)—that have a potential to promote health and well-being when administered in adequate amounts. The case of heat-inactivated Akkermansia muciniphila to alleviate features of metabolic syndrome in overweight and obese subjects, for instance, is within the scope of a postbiotic.
Other strategies for modulating the gut microbiome include diet, prebiotics and the aforementioned postbiotics. Together with medication, diet is the factor that most affects gut microbiota composition and functional diversity, with microbial shifts apparent within just 24 hours, as well as in the long term. When it comes to prebiotics, they can be utilized by members of the host microbiota and/or by the co-administered live microbe. The flexibility of gut-dwelling bacteria in response to different types of fiber is also being studied as a way forward in developing personalized diets for tailoring the gut microbiota in the coming years.
It should also be acknowledged that not all diseases exhibit the same degree of gut microbiota alteration, and that may, in turn, affect the efficacy of selected strategies for modulating the gut microbiome. While C. difficile infection is an example of disease with profound gut microbiota changes, others only exhibit a subtle change in gut microbes. That makes it difficult to develop personalized predictions to dietary responses, diagnostics and therapeutics based on the gut microbiome. Moreover, multiple factors can affect the efficacy of procedures aimed at modulating the gut microbiota, including the means of gut microbiota modulation, preparative regimen and concurrent dietary intake, among others. Another caveat in the field is the current lack of a definition of what constitutes a healthy gut microbiota.
References:
Wargo JA. Modulating gut microbes. Science. 2020; 369(6509):1302-3. doi: 10.1126/science.abc3965.
O’Toole PW, Marchesi JR, Hill C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol. 2017; 2:17057. doi: 10.1038/nmicrobiol.2017.57.
David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505(7484):559-563. doi: 10.1038/nature12820.
Delzenne NM, Bindels LB. Food for thought about manipulating gut bacteria. Nature News and Views. 2019; 577:32-34. doi: 10.1038/d41586-019-03704-z.
Collado MC, Vinderola G, Salminen S. Postbiotics: facts and open questions. A position paper on the need for a consensus definition. Benef Microbes. 2019; 10(7):711-719. doi: 10.3920/BM2019.0015.
