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

• DOI: 10.1016/j.chom.2022.11.006
• Publication Date: 2022-12-09T15:33:46Z
• Authors: Lixiang Zhai; Chunhua Huang; Ziwan Ning; Yijing Zhang; Min Zhuang; Wei Yang; Xiaolei Wang; Jingjing Wang; Lu Zhang; Haitao Xiao; Ling Zhao; Pallavi Asthana; Yan Y. Lam; Chi Fung Willis Chow; Jian-dong Huang; Shuofeng Yuan; Kui Ming Chan; Chun-Su Yuan; Johnson Yiu-Nam Lau; Hoi Leong Xavier ...; Zhao-xiang Bian
• Keywords: Irritable Bowel Syndrome; Diarrhea; 0301 basic medicine; Mice; Serotonin; 0303 health sciences; 03 medical and health sciences; Animals; 3. Good health

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.