Fecal Microbiota Transplantation in the Treatment Strategy of Inflammatory Bowel Disease: Molecular Mechanisms, Clinical Evidence, and the Transition Toward Defined Microbial Therapeutics

Inflammatory Bowel Disease (IBD) comprises two clinically and pathologically distinct chronic intestinal inflammatory diseases, ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases result from a dysregulated mucosal immune response to the commensal gut microbiota in genetically predisposed individuals. Because gut dysbiosis is a constant feature of both diseases, Fecal Microbiota Transplantation (FMT) has recently been investigated as a potential therapeutic strategy to restore a balanced microbiota composition in patients with IBD. There are five placebo-controlled randomized controlled trials (RCTs) in UC and several meta-analyses, which showed that treatment with FMT using material from multiple donors can lead to clinical and endoscopic remission in patients with mild-to-moderate UC and may thus double to triple the rate of remission compared with placebo (number needed to treat [NNT] ≈ 3–5). In contrast, evidence for CD is limited and inconsistent, with one promising pilot study being contrasted with a large multicenter induction trial that was stopped for futility. This review provides an update of the current molecular understanding of FMT-induced recovery of mucosal barrier function and inflammation control in intestinal inflammation (α-diversity restoration and subsequent donor strain engraftment, production of short-chain fatty acids and secondary bile acids, tryptophan–AhR signaling, IL-10-mediated induction of Tregs vs. suppression of Th17 cells and restoration of epithelial barrier function). The review also summarizes the current clinical evidence for the use of FMT in IBD, its safety, and the current regulatory status. It also describes recent developments in FMT, including the use of defined bacterial consortia, ‘live biotherapeutic products’ (LBPs), and donor–recipient pairing. Collectively, FMT provides evidence of principle for manipulating intestinal microbial ecosystems to treat immune-mediated intestinal inflammation.