After Gallbladder Removal: How Microbes and Bile Acids Push the Gut Toward Cancer

Gallbladder removal (cholecystectomy) has long been considered “safe routine.” But a new study in Nature Communications reveals a biological pathway that helps explain why some patients have an increased risk of colorectal cancer (CRC) after the surgery. The key story: after cholecystectomy, the microbiota and bile acid profile change; this suppresses the FXR signaling pathway, “unties the hands” of β-catenin - and accelerates tumorigenesis in the colon. Moreover, the FXR agonist obeticholic acid (OCA) “breaks” this cascade in mouse models.

Background of the study

Cholecystectomy is one of the most common abdominal surgeries in the world, and for a long time it was considered "metabolic neutral": remove the "reservoir" of bile - and we live on. But epidemiological observations hinted at something else: in some people, the risk of colorectal cancer (CRC) increases years after the operation. Why this happens remained unclear. Biologically plausible candidates for the role of "mediator" seemed to be bile acids and intestinal microbiota: removal of the gallbladder changes the rhythm and composition of bile entering the intestine, and therefore the ecology of the microbial community, on which inflammation, the barrier and local signaling pathways in the epithelium depend.

Bile acids are not just “emulsifiers” of fats, but hormone-like molecules that interact with the nuclear receptor FXR and through it regulate proliferation, immune response, and barrier proteins. Shifts in their pool after cholecystectomy can theoretically “mute” FXR and thereby clear the way for proliferative cascades - primarily β-catenin-dependent transcription. In parallel, the change in bile selects species resistant to bile salts (for example, Ruminococcus gnavus ) and suppresses more “tender” commensals (like Bifidobacterium breve ), which further pulls the metabolite profile towards conjugated bile acids (GUDCA/TUDCA) with different signaling effects.

Until this paper, the puzzle had not fit together: there were associations and disparate mechanistic pieces, but a direct “bridge” from surgery—via microbiota and bile acids—to accelerated colon carcinogenesis was missing. The Nature Communications authors connect the dots: they show that cholecystectomy increases tumorigenesis in mice, that the microbiota and altered bile acid pool in patients after surgery reproduce this effect when transferred to a model, and that the key link is the suppression of the FXR signal with the breakdown of its complex with β-catenin. Moreover, pharmacological activation of FXR with the agonist obeticholic acid disrupts the cascade and attenuates tumor growth in the model.

The practical context remains muted: the human cohort is small and the mouse models do not fully mimic human CRC. But the cholecystectomy → dysbiosis/bile acids → ↓FXR → ↑β-catenin pathway provides an explanation for long-standing epidemiological signals and outlines testable targets, from screening and microbiome interventions to FXR-targeted chemoprevention in clinical trials.

The most important thing in brief

• In two mouse oncomodels (AOM/DSS and APC^min/+), cholecystectomy increased tumorigenesis: more foci, higher proportion of high-grade dysplasia and adenocarcinoma. Barrier function was impaired (↓ZO-1, Occludin), inflammation increased (↑IL-1β, TNF-α).
• In humans after surgery (n=52) and in parallel mouse models, Bifidobacterium breve declined and Ruminococcus gnavus increased - two strains with opposite effects on tumorigenesis.
• The pool of bile acids changed: in patients ↑conjugated forms; GUDCA (in humans) and TUDCA (in mice) were especially prominent.
• Transplantation of feces from cholecystectomized patients into mice increased the number and "malignancy" of tumors; co-housing and solitary colonization confirmed the role of microbiota.
• Mechanism: GUDCA/TUDCA accumulation → FXR inhibition → FXR/β-catenin complex breakdown → β-catenin/TCF4 upregulation → MYC → CRC acceleration. FXR agonist (OCA) “removes” the effect.

After gallbladder removal, bile enters the intestines differently - fractionally and more frequently. This feeds bile-resistant microbes (like R. gnavus ) and suppresses "tender" ones (like B. breve ). Some bacteria use 7β-HSDH to produce TUDCA/GUDCA, while others, like B. breve, deconjugate bile acids through BSH. The result is that the shifted "cocktail" of bile acids suppresses FXR (the nuclear receptor for bile acids in the intestine/liver), and the β-catenin pathway gains an advantage.

How it was tested (step by step)

• AOM/DSS and APC^min/+: more tumors/severe lesions after surgery; confirmed by colonoscopy, histology, Ki-67, barrier proteins and CEA/CA19-9 markers.
• Antibiotics → FMT: After flora "zeroing", fecal transplantation from cholecystectomy patients caused more severe carcinogenesis than from healthy donors.
• Single colonization: B. breve reduced and R. gnavus increased tumorigenesis; resistance of R. gnavus to bile salts was confirmed in vitro.
• Metagenomics and metabolomics: in humans ↓α-diversity; signal species - B. breve (down) and R. gnavus (up). In feces/serum - shift to GUDCA/TUDCA and ↑proportion of conjugated acids.
• Enzyme biochemistry: BSH ( B. breve ) and 7β-HSDH ( R. gnavus ) activity are associated with GUDCA/TUDCA levels; pharmacological inhibitors and addition of the acids themselves altered the severity of the model.
• Molecular: RNA-seq and co-IP showed that GUDCA/TUDCA disrupt the FXR/β-catenin complex, enhancing transcription of β-catenin targets; OCA counteracts this.

The clinical note is cautious. In a small human cohort (52 post-surgery vs 45 controls), there were 2 cases of CRC during follow-up at 4 and 6 years after cholecystectomy - the difference was not statistically significant, but the mechanistic "road map" of microbes and bile acids explains why the risk of CRC after surgery appeared higher in larger meta-analyses.

What this might mean for practice (without “self-medication” for now):

• For patients after cholecystectomy, follow standard CRC screening guidelines (age/risk appropriate colonoscopy) and discuss individual factors with your physician.
• Researchers and clinicians should consider the microbiota-bile acids-FXR axis as a target for prevention/therapy; FXR agonists (eg, OCA) have shown protective effects in mice, but RCTs are needed in humans.
• Dietary/microbiome approaches (strain-specific probiotics like B. breve ) seem logical, but there is no evidence to recommend them yet.

Limitations that the authors honestly talk about

• The human part is small; the differences in CRR did not reach significance.
• Mouse models (AOM/DSS, APC^min/+) do not fully replicate human CRC.
• Species differences in bile acids (in humans, glycine- forms are more common, in mice, taurine- forms) complicate the transfer of conclusions.
• Intervention points (probiotics, enzyme inhibitors, FXR agonists) require clinical trials for safety and efficacy.

Summary

The work neatly puts together the puzzle: after gallbladder removal, dysbiosis + bile acid shift → FXR suppression → accelerated growth of intestinal tumors. This is not a reason for panic, but a reason for proper screening and new clinical studies on modulation of the "microbiota-bile acids-FXR" axis.

Source: Tang B. et al. Cholecystectomy-related gut microbiota dysbiosis exacerbates colorectal tumorigenesis. Nature Communications (published 16 August 2025). https://doi.org/10.1038/s41467-025-62956-8