Cholecystectomy-related gut microbiota dysbiosis exacerbates colorectal tumorigenesis.

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 APC^min/+ 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.