Cholecystectomy-related gut microbiota dysbiosis exacerbates colorectal tumorigenesis

Bo Tang, Shengpeng Li, Xin Li, Jialin He, An Zhou, Lingyi Wu, Xu Xiao, Sumin Wang, Hongfei Jiang, Jincheng Jian, Zhanjie Hou, Yusong Ge, Yuanyuan Lei, Jianchun Zhou, Dianji Tu, Cheng Lu (), Min Yang () and Shiming Yang ()
Additional contact information
Bo Tang: Army Medical University
Shengpeng Li: Army Medical University
Xin Li: Army Medical University
Jialin He: Army Medical University
An Zhou: Army Medical University
Lingyi Wu: Army Medical University
Xu Xiao: Army Medical University
Sumin Wang: Army Medical University
Hongfei Jiang: Army Medical University
Jincheng Jian: Army Medical University
Zhanjie Hou: Army Medical University
Yusong Ge: Army Medical University
Yuanyuan Lei: Army Medical University
Jianchun Zhou: Army Medical University
Dianji Tu: Army Medical University
Cheng Lu: Army Medical University
Min Yang: Army Medical University
Shiming Yang: Army Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Cholecystectomy represents the most prevalent biliary surgical procedure for gallbladder abnormalities. Growing evidence suggests that cholecystectomy is associated with an elevated risk of colorectal cancer. However, the underlying mechanism remains elusive. Here we show that cholecystectomy exacerbates colorectal tumorigenesis in both AOM/DSS and APCmin/+ mice models. Metagenomic sequencing and targeted metabolomics show that cholecystectomy leads to a decrease of Bifidobacterium breve (B. breve) and an increase of Ruminococcus gnavus (R. gnavus), along with increased levels of glycoursodeoxycholic acid (GUDCA) in human and tauroursodeoxycholic acid (TUDCA) in mice. Fecal microbiota transplantation, single bacterial colonization and bile acid supplementation demonstrate that cholecystectomy-related gut microbiota perturbations promote the production of TUDCA and facilitate colorectal tumorigenesis. RNA-sequencing and co-immunoprecipitation reveal that the compromised bile acid metabolism inhibits farnesoid X receptor (FXR) signaling, disrupts the FXR/β-catenin interaction, and ultimately exacerbates colorectal tumorigenesis. Significantly, FXR agonist obeticholic acid (OCA) averts cholecystectomy-related colorectal tumorigenesis. The gut microbiota holds a crucial position in cholecystectomy-induced colorectal tumorigenesis, and modulation of the gut microbiota-bile acid-FXR axis represents a promising preventive strategy.

Date: 2025
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DOI: 10.1038/s41467-025-62956-8

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