What question did this study set out to answer?

This research aims to identify metabolite biomarkers associated with gallstone disease and gallbladder cancer using metabolomics.

June 3, 2026

Plasma metabolomics identifies trimethylamine n-oxide as an accelerator of gallstone disease accompanied by early neoplastic alterations in mice

Puntos clave

This research aims to identify metabolite biomarkers associated with gallstone disease and gallbladder cancer using metabolomics.
Conducted LC-MS-based metabolomics on plasma samples from 14 healthy controls, 30 gallstone disease, and 56 gallbladder cancer patients.
Validated a 20-metabolite signature in 45 additional samples and focused on TMAO in an independent cohort (N=30).
Performed dietary interventions in female C57BL/6 mice, incorporating TMAO to observe effects on gallbladder disease progression.
Identified 172 significantly altered metabolites in the discovery cohort, with AUC values indicating high diagnostic accuracy for GSD (0.98) and CaGB (0.93).
TMAO levels were significantly elevated in GSD and CaGB patients (p<0.001), with AUC values indicating strong predictive value.
Mice fed TMAO with a lithogenic diet showed early onset gallstone formation and preneoplastic changes at 12 weeks, with associated alterations in bile acid regulatory expressions.

Resumen

India accounts for 10% of the global gallstone disease (GSD) and gallbladder cancer (CaGB) burden. CaGB’s poor prognosis necessitates early detection of biomarkers. We used targeted/untargeted plasma metabolomics in human and mouse models to identify metabolite biomarkers for gallbladder disease. Methods LC-MS-based metabolomics was performed on plasma samples in the discovery cohort (14 healthy controls, 30 GSD, and 56 CaGB). The identified metabolite signature was validated in 45 samples, and the candidate metabolite was further examined using targeted LC-MS in an independent cohort (N=30). Trimethylamine N-oxide (TMAO) emerged as a significant metabolite that was evaluated in female C57BL/6 mice fed a lithogenic diet. Results Untargeted metabolomics from the discovery cohort identified 172 significantly altered metabolites (p<0.05), with a 20-metabolite signature discriminating groups with high accuracy (AUC: GSD 0.98, CaGB 0.93; validation: GSD 0.87, CaGB 0.95). TMAO was significantly elevated in GSD and CaGB (p<0.001), with predictive values (AUC: GSD 0.96, CaGB 0.85). Targeted analysis confirmed two-fold higher plasma TMAO in patients (p<0.001). Female C57BL/6 mice fed on lithogenic diet (LD) with 0.3% TMAO (LD+TMAO) showed higher prevalence with early onset at 12 weeks. TMAO induced epithelial metaplasia, hyperplasia, and altered mRNA expression of bile acid regulators (ABCC3, FXR, TGR5), and IL-10. Immunohistochemistry in mouse gallbladder tissue showed increased FXR and reduced TGR5 expression, following TMAO treatment. Conclusion: TMAO is a key metabolite associated with GSD and CaGB. TMAO supplementation with lithogenic diet accelerated gallstone formation, accompanied by preneoplastic changes, and disrupted bile acid regulation

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