Phenethylamine-producing gut bacteria induces diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis

Despite the strong association between gut microbial dysbiosis, serotonin (5-HT) dysregulation and diarrhea-predominant irritable bowel syndrome (IBS-D), the mechanism by which changes in the gut microbiota contribute to the pathogenesis of IBS-D, particularly the role of dysregulated 5-HT production, remains unclear. The present study identified Ruminococcus gnavus in the human gut microbiota as a key risk factor of IBS-D. R. gnavus was significantly enriched in IBS-D patients and exhibited positive correlation with serum 5- HT level and severity of diarrhea symptoms. We showed that R. gnavus induced diarrhea-like symptoms in mice by promoting microbial shunting of essential aromatic amino acids to aromatic trace amines including phenethylamine and tryptamine, thereby stimulating the biosynthesis of peripheral 5-HT, a potent stimulator for gastrointestinal transit. This study identify gut-microbial metabolism of dietary amino acids as a cause of IBS-D and lays a foundation for developing novel therapeutic target for the treatment of IBS-D. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * 5-HIAA : 5-Hydroxyindole acetic acid 5-HTP : 5-Hydroxytryptophan 5-HT : Serotonin CaMKII : Calmodulin-dependent protein kinase II EC : Enterochromaffin cells GI : Gastrointestinal IAA : 3-Indole acetic acid IBS : Irritable bowel syndrome IBS-D : Diarrhea-predominant irritable bowel syndrome PA : Phenylacetic acid PEA : Phenethylamine Phe : Phenylalanine PKA : Cyclic AMP-dependent protein kinase TAAR1 : Trace amine-associated receptor 1 TpA : Tryptamine TPH1 : Tryptophan hydroxylase 1 Trp : Tryptophan [1]: pending:yes