DIETARY FIBER-INDUCED ODORIBACTER METABOLITES PROMOTE MUCOSAL HEALING IN COLITIS

Background: Fecal microbiota transplantation (FMT) is an emerging therapy for the treatment of ulcerative colitis (UC). Our group recently identified Odoribacter splanchnicus (O.sp) in UC patients with clinical response to FMT, but the potential role of dietary supplements in regulating microbial metabolism to promote mucosal healing in FMT is not well defined.
Hypothesis: We aim to test the hypothesis that dietary fiber promotes O.sp-derived metabolites that promote healing in colitis.
Methods: Gnotobiotic and genetic mouse models were used to evaluate the role of dietary fiber and O.sp in experimental colitis induced by dextran sodium sulfate (DSS). Untargeted metabolomics and bacterial transcriptomics were used to define fiber-induced metabolites. Single-cell RNA-sequencing and flow cytometry were performed to define the target cell populations.
Results: High-fiber diet promoted healing in O.sp-monocolonized mice following DSS-induced colitis. The enhanced healing was T cell- and IL10-independent. Flow cytometry and single cell analysis revealed an alteration of immune cells and mesenchymal cells in the colon of O.sp-colonized mice, including increases in IgA-positive plasma cells, macrophages and PDGFRa+ telocytes. Transcriptional analysis showed that high-fiber diet upregulates TGFb expression in macrophages and BMP expressions in telocytes. Bacterial transcriptomics revealed a fiber-dependent induction of pseudoaminic acid biosynthesis. Metabolic increase in purine derivatives, amino acids, and glycolysis-related pathways in O.sp-monocolonized mice fed high-fiber diet directly impact in vitro cultures of organoids.
Conclusions: High-fiber diet regulates Odoribacter transcription and metabolism to promote innate and adaptive mechanisms of mucosal healing in colitis. We have initiated an ongoing clinical trial (NCT03998488) to evaluate the impact of high-fiber diet on the clinical efficacy of FMT in UC.