Gallbladder Removal Fuels Colon Cancer via Gut Microbiome Disruption
New research reveals cholecystectomy reshapes gut bacteria and bile acids, suppressing FXR signaling and accelerating colorectal tumor growth.
Summary
A 2025 Nature Communications study demonstrates that cholecystectomy (gallbladder removal) worsens colorectal tumorigenesis by disrupting gut microbiota and bile acid metabolism. In mouse models and human samples, the procedure reduced beneficial Bifidobacterium breve while increasing Ruminococcus gnavus, elevating secondary bile acids like TUDCA/GUDCA. These shifts suppressed farnesoid X receptor (FXR) signaling, disrupted FXR's protective interaction with β-catenin, and accelerated colon tumor development. Fecal microbiota transplantation from cholecystectomy patients reproduced the tumor-promoting effect in mice. Critically, the FXR agonist obeticholic acid (OCA) reversed these harmful effects, pointing to the gut microbiota–bile acid–FXR axis as a viable preventive target for post-cholecystectomy colorectal cancer risk.
Detailed Summary
Cholecystectomy—surgical removal of the gallbladder—is one of the most common procedures worldwide, generally regarded as safe. However, epidemiological studies have long suggested an association between cholecystectomy and elevated colorectal cancer risk. Until now, the biological mechanism linking the two has remained poorly understood.
This study, published in Nature Communications (2025), used two established mouse colorectal cancer models (AOM/DSS carcinogen-induced and APC-min/+ transgenic) combined with human clinical samples to systematically trace the mechanistic chain from gallbladder removal to colon tumor promotion. Cholecystectomized mice in both models showed greater tumor burden, more advanced histological disease (higher proportions of adenocarcinoma and high-grade dysplasia), elevated tumor markers (CEA, CA19-9), and impaired intestinal barrier integrity compared to sham-operated controls. Dynamic histological analysis confirmed that tumorigenesis began significantly earlier following cholecystectomy.
Using metagenomic sequencing and targeted metabolomics, the researchers identified key microbiome and metabolite shifts. Cholecystectomy reduced Bifidobacterium breve and increased Ruminococcus gnavus in both mice and humans. These microbial changes drove elevated production of ursodeoxycholic acid conjugates—specifically tauroursodeoxycholic acid (TUDCA) in mice and glycoursodeoxycholic acid (GUDCA) in humans. Crucially, antibiotic depletion of gut bacteria abolished the cholecystectomy-associated tumor enhancement, confirming microbiota as the mediating factor. Fecal microbiota transplantation (FMT) from cholecystectomy patients or tumor-bearing cholecystectomized mice into germ-free recipient mice reproduced the accelerated tumorigenesis, as did co-housing experiments.
RNA sequencing and co-immunoprecipitation experiments revealed the molecular mechanism: the altered bile acid profile suppressed intestinal farnesoid X receptor (FXR) signaling. FXR normally interacts with and restrains β-catenin, a key oncogenic driver in colorectal cancer. Loss of FXR activity disrupted this FXR/β-catenin interaction, allowing β-catenin-driven proliferative and tumorigenic gene programs to proceed unchecked. Single bacterial colonization experiments with B. breve and R. gnavus, along with direct bile acid supplementation, confirmed their respective tumor-suppressing and tumor-promoting roles through this pathway.
Importantly, treatment with obeticholic acid (OCA), an FDA-approved FXR agonist, reversed the cholecystectomy-related enhancement of colorectal tumorigenesis in mice, offering a clinically actionable preventive strategy. The findings establish the gut microbiota–bile acid–FXR axis as the mechanistic bridge between cholecystectomy and colorectal cancer risk, and suggest that monitoring or modulating this axis in post-cholecystectomy patients could meaningfully reduce cancer incidence.
Key Findings
- Cholecystectomy significantly increased tumor number, size, and malignant grade in both AOM/DSS and APC-min/+ mouse models.
- Gallbladder removal depleted Bifidobacterium breve and expanded Ruminococcus gnavus, elevating TUDCA/GUDCA bile acid levels.
- FMT from cholecystectomy donors reproduced tumor promotion in recipient mice, confirming the microbiota as causal mediator.
- Altered bile acids suppressed FXR signaling, disrupting its protective interaction with β-catenin to accelerate tumorigenesis.
- FXR agonist obeticholic acid (OCA) rescued cholecystectomy-induced colorectal tumor exacerbation in mice.
Methodology
The study employed AOM/DSS carcinogen-induced and APC-min/+ transgenic mouse colorectal cancer models with surgical cholecystectomy, supported by metagenomic sequencing and targeted bile acid metabolomics from both mouse and human samples. Causality was established via antibiotic depletion, fecal microbiota transplantation (from human cholecystectomy patients and tumor-bearing mice), single bacterial colonization, co-housing experiments, bile acid supplementation, RNA-sequencing, and co-immunoprecipitation assays.
Study Limitations
The study is primarily mechanistic and conducted largely in mouse models, so direct causation in humans remains to be confirmed in prospective clinical trials. The exact timeline and magnitude of cancer risk elevation in human cholecystectomy patients were not quantified in this study. Long-term safety and efficacy of FXR agonist use specifically for cancer chemoprevention post-cholecystectomy has not been evaluated.
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