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 outpatients with cholecystectomy, and gut microbiota alteration is correlated with it. However, how and to what extent changed fecal bacteria contributes to diarrhea are still unrevealed. Humanized gut microbiome mice model by fecal microbiota transplantation was established to explore the diarrhea-inducible effects of gut microbiota. The role of microbial bile acids (BAs) metabolites was identified by UPLC/MS and the underlying mechanisms were investigated with selective inhibitors and antagonists as probes. These mice transplanted with fecal microbiome of PCD patients (PCD mice) exhibited significantly enhanced gastrointestinal motility and elevated fecal water content, compared with these mice with fecal microbiome of NonPCD patients and HC. In analyzing gut microbiota, tryptophan metabolism was enriched in PCD microbiome. In addition, overabundant serotonin in serum and colon, along with elevated biosynthesis gene and reduced reuptake gene, and highly expressed 5-HT receptors (5-HTRs) in colon of PCD mice were found, but not in small intestine. Notably, diarrheal phenotypes in PCD mice were depleted by tryptophan hydroxylase 1 inhibitor (LX1606) and 5-HTRs selective antagonists (alosetron and GR113808). Furthermore, increased microbial secondary BAs metabolites of DCA, HDCA and LCA were revealed in feces of PCD mice and they were found responsible for stimulating 5-HT level in vitro and in vivo. Intriguingly, blocking BAs-conjugated TGR5/TRPA1 signaling pathway could significantly alleviate PCD. In conclusion, altered gut microbiota after cholecystectomy contributes to PCD by promoting secondary BAs in colon, which stimulates colonic 5-HT and increases colon motility.

KEYWORDS:

• PCD
• gut microbiota
• gastrointestinal motility
• 5-HT
• BAs

Acknowledgments

Great appreciations were owed to voluntary participants for their contributions in this study and PR Cai from Center for Traditional Chinese Medicine and Gut Microbiota Minhang Hospital, Fudan University for his excellent technical assistance. Besides, we also thank Xuan Tang from School of art, Donghua University for her assistance in designing graphical abstract. Great appreciations were owed to Shanghai Applied Protein Technology Co. Ltd for its efforts in tryptophan metabolism detection.

Author contributions

Ziping Zhang and Lishun Wang designed this study and Ziping Zhang provided the funds; Qimeng Chang recruited donors and collected fecal samples; Yayun Xu conducted animal and cell experiments, and wrote this article; Jianfa Wang and Hui Jing helped animal experiments, and Xubo Wu helped cell experiments; Shilong Zhang helped bioinformatic process; Longhua Rao and Zhiqiu Hu scored immunohistochemical slides and helped immunofluorescence staining.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data Availability statement

The 16S rRNA database were all deposited to the public platform of NCBI short-read archive with the BioProject number of PRJNA865451.https://submit.ncbi.nlm.nih.gov/subs/bioproject/SUB11888187/overview.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2168101

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Shanghai Municipal Commission of Health and Family Planning (201740238), Minhang District specific clinics construction project (2020MWTZB08), Shanghai Science Technology Commission (21142203300) and Minhang District Health Committee (2022MW27).