Gut microbiota alteration after cholecystectomy contributes to post-cholecystectomy diarrhea via bile acids stimulating colonic serotonin

Abstract Post-cholecystectomy diarrhea (PCD) is highly prevalent among post-cholecystectomy outpatients and gut microbiota alteration is correlated with it. However, whether fecal bacteria alteration contributes to diarrhea are unrevealed. Herein, humanized gut microbiome mice model was established and PCD mice exhibited enhanced gastrointestinal motility and elevated fecal water content. In analyzing gut microbiota, tryptophan metabolism was enriched in PCD microbiome. Then, overabundant serotonin, along with elevated biosynthesis and reduced reuptake genes, and highly-expressed 5-HT receptors (5-HTR) in colon of PCD mice were found, but not in small intestine. Notably, diarrheal phenotypes in PCD mice were depleted by Tph1 inhibitor and 5-HTRs antagonists. Furthermore, increased PCD microbial secondary bile acids (BAs) metabolites of DCA, HDCA and LCA were revealed and were responsible for stimulating 5-HT. Intriguingly, blocking BAs-conjugated TGR5/TRPA1 signaling pathway alleviate PCD. Conclusively, altered gut microbiota after cholecystectomy induces PCD by promoting secondary BAs, which stimulates colonic 5-HT and increases colon motility.