Gut microbiota promotes cholesterol gallstone formation through the gut-metabolism-gene axis

Background: Gallstone disease, arising from the interplay between host metabolism and gut microbiota, represents a significant health concern. Dysbiosis of the gut microbiome and disruptions in circadian rhythm contribute to the pathogenesis of gallstones. This study conducted a comprehensive analysis of gut microbiota and metabolites derived from stool and serum samples of 28 patients with cholesterol gallstones (CGS) and 19 healthy controls, employing methodologies such as 16S rRNA sequencing, metaproteomics, metabolomics, and host genetic analysis. Additionally, a retrospective cohort study was utilized to assess the efficacy of probiotics or ursodeoxycholic acid (UDCA) in preventing CGS formation post-bariatric surgery. Results: In CGS patients, gut microbiota diversity shifted, with harmful bacteria rising and beneficial ones declining. The altered microbiota primarily affected amino acid, lipid, nucleotide, and carbohydrate metabolism. Metabolic abnormalities were noted in amino acids, glucose, lipids, and bile acids with decreased levels of ursodeoxycholic, glycosodeoxycholic, and glycolithocholic acids, and increased glycohyodeoxycholic and allocholic acids. Glutamine and alanine levels dropped, while phenylalanine and tyrosine rosed. Animal studies confirmed gene changes in gallbladder tissues related to bile acid, energy, glucose, and lipid metabolism. Importantly, UDCA and probiotics effectively reduced CGS risk post-bariatric surgery, especially when combined. Conclusions: Multi-omics can clarify CGS pathology, by focusing on the gut-metabolism-gene axis, paving the way for future studies on CGS prevention and treatment through gut microbiota or metabolic interventions.