IDDF2022-ABS-0035 Pathogenetic Role of GUT Microbiota Shunting of Dietary Phenylalanine to Phenethylamine in Diarrhea-Predominant Irritable Bowel Syndrome

Background Irritable bowel syndrome, including the diarrhea-predominant subtype (IBS-D), is a prevalent disorder on a global scale. The pathogenesis of IBS-D involves changes in gastrointestinal motility and intestinal secretion, both of which were shown to be modulated by increased serotonin synthesis in the gut. While there is anecdotal evidence that gut microbiota may contribute to serotonin biosynthesis, the pathogenetic and molecular pathways involved are largely unknown. Knowledge of the molecular axis involved may allow the identification of novel bacterial and molecular targets for the development of better therapeutic options for IBS-D. Methods We applied metagenomics and metabolomics analysis to study the changes in gut microbiota and gut microbial metabolites. We conducted in vitro, ex vivo, and in vivo studies to examine the effects and underlying mechanisms of gut bacteria and their metabolites on 5-HT production and gastrointestinal transit. Results Herein, we identified a human gut bacterium Ruminococcus gnavus as a major factor that underlies the motility disorder in IBS-D. We showed that R. gnavus is highly enriched in IBS-D patients and positively correlated with the severity of diarrheal symptoms (IDDF2022-ABS-0035 Figure 1. The enrichment of Ruminococcus gnavus in IBS-D patients and its positive correlation with serum 5-HT level and diarrhea symptoms). Monocolonization of R. gnavus induces IBS-D-like symptoms including increased gastrointestinal transit and colonic secretion in pseudo-germ-free mice by stimulating the production of peripheral 5-HT (IDDF2022-ABS-0035 Figure 2. Monoassociation of Ruminococcus gnavus induces IBS-D-like symptoms and elevation of PEA level in pseudo-germ-free mice). Metabolically, we discovered that phenethylamine (PEA) derived from R. gnavus-mediated metabolism of dietary aromatic amino acids directly stimulates the 5-HT biosynthesis in intestinal enterochromaffin cells and this is mediated by its activation of a G-protein coupled receptor (TAAR1), thereby contributing to elevated GI transit and colonic secretion in IBS-D (IDDF2022-ABS-0035 Figure 3. PEA activates 5-HT production accelerate GI transit and increase colonic secretion in vitro and in vivo) (IDDF2022-ABS-0035 Figure 4. PEA stimulates 5-HT production via a TAAR1-dependent mechanism). More importantly, pharmacological inhibition of TAAR1 activation alleviates IBS-D-like symptoms in mice transplanted with fecal microbiota from IBS-D patients, a preclinical model of IBS-D (IDDF2022-ABS-0035 Figure 5. In vivo pea production by IBS-D associated bacteria enhance 5-HT synthesis and induce diarrhea like symptoms). Conclusions Our studies provide a deeper understanding of how gut microbial metabolites derived from dietary amino acids affect 5-HT-dependent control of gut motility and have identified potential pathways predominantly mediated via the PEA/TAAR1 signaling axis for prophylactic and therapeutic treatments for IBS-D (IDDF2022-ABS-0035 Figure 6. Pathogenic role of gut microbiota-derived PEA in IBS-D).