Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis

Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility. [Display omitted] •Ruminococcus gnavus enriched in IBS-D patents produces phenethylamine and tryptamine•Phenethylamine and tryptamine stimulate serotonin biosynthesis in the gut via TAAR1•Monocolonizing mice with R. gnavus increases serotonin and induces IBS-D symptoms•TAAR1 inhibition alleviates IBS-D symptoms in mice transplanted with IBS-D microbiota Zhai et al. identify gut microbe Ruminococcus gnavus as a major factor that underlies gut motility disorder in IBS-D. Ruminococcus gnavus drives the development of IBS-D via the breakdown of dietary essential amino acids that stimulate serotonin biosynthesis in the gut.