Summary
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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵+ Co-first authors: Lixiang Zhai, Chunhua Huang, Ziwan Ning and Yijing Zhang
Abbreviations
- 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
