Adam Saleh

Introduction: Ulcerative Colitis (UC) is a chronic idiopathic inflammatory disorder of the colon with continuous inflammation beginning in the rectum and ascending proximally. The disease can present clinically with varying severity of diarrhea and blood in stool, urgency, and tenesmus¹. The pathogenesis of UC likely has contributions from various factors including genetics, environment, and gut microbiota composition². Microbiota alterations associated with the development of UC include enteric infections, antibiotic use, high dietary intake of total fats, PUFAs, and proteins^3–5. Fecal Microbiota Transplant (FMT) is an experimental form of therapy defined by the transfer of healthy donor stool to the patient. Methods: A significant percentage of research being done to identify FMT mechanisms of action has been focused on correlations between bacterial and viral populations present in responders and non-responders. In this review, the mechanisms behind these prevalent correlations are presented to suggest a multifactorial mechanism for FMT induction of remission. Results:  UC patients at baseline have been shown to have a reduced number of bacteria from Clostridium cluster IV and XIVa when compared to their healthy counterparts. Clostridium Clusters IV,XIVa also have been shown to be associated with positive response to FMT in multiple studies with mean relative abundance shifting towards donor levels after FMT therapy⁶. The mechanism through which Clostridium Clusters IV and XIVa affect inflammation was demonstrated in murine models where they successfully suppressed colitis through the induction of IL-10-producing regulatory T (Treg) cells in dextran sodium sulfate (DSS) mice models^7–9. Additionally, the enteric virome for patients with UC shows an increased species richness defined by the number of taxa present¹⁰. There is an increase in bacteriophages with the most prominent change being in the population of Caudovirales in the intestinal microbiota^10–12. These Caudovirales bacteriophages are present in increased levels in patients that do not respond to FMT. When murine models were exposed to Caudovirales bacteriophaghes, a larger proportion of cells exhibited an activated phenotype with more IFN-gamma and IL-17a producing T cells¹¹. Conclusions: The mechanism through which FMT is capable of inducing remission likely involves multiple bacterial and viral species such as Caudovirales bacteriophages and Clostridium Clusters IV and IVa. This review suggests that there is sufficient data available to begin targeted therapy in conjunction with FMT to help improve FMT response. Additionally, prescreening should be performed on the patients and donors and evaluated for Caudovirales and Clostridum Clusters IV and IVa levels.

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