Gut Microbiome Dysbiosis Promotes Gallstone Formation via Bile Acid Metabolic Disorder: A Multiomics Study

Gallstone disease is a common global digestive disorder. This study intends to analyze gut microbiota-gallstone disease interactions, to inform disease mechanism and microbiota-targeted prevention and treatment strategies. Participants were recruited from health check-up populations, outpatients, and inpatients. Basic information and biological samples were collected: fecal samples for metagenomic sequencing, and serum samples for bile acid metabolism detection. A total of 62 gallstone patients and 62 healthy controls were enrolled in this study. Compared with the control group, gallstone patients exhibited increased level of bile salt hydrolase (BSH)-producing bacteria, including the genera Bacteroides, Enterococcus, Bifidobacterium, and the family Lactobacillaceae. Further KEGG analysis revealed that the significantly enriched signaling pathways in the gallstone patients were mainly related to bile acid biosynthesis, lipid and bile acid precursor metabolism. Subsequently, we found that in gallstone patients, the levels of hydrophobic bile acids, (e.g., lithocholic acid, LCA), was increased, while the levels of hydrophilic bile acids taurolithocholic acid (TLCA) were decreased. In the correlation analysis between differential bile acids and differential bacterial species, Bacteroides intestinalis was positively correlated with LCA, while Bacteroides fragilis was negatively correlated with TLCA. These results further confirm the role of BSH-active bacteria in bile acid dysregulation. This study proposes the "intestinal microbiota imbalance-bile acid metabolic disorder-gallbladder stone formation" axis, and confirms that gallstone patients exhibit intestinal dysbiosis, which leads to bile acid dysregulation. Furthermore, the accumulation of hydrophobic bile acids is identified as a key factor in gallbladder stone formation.