The role of gut microbiota, short-chain fatty acids, and bile acids in the development of gallstone disease

Background. Gallstone disease remains one of the most common pathologies of the hepatobiliary system.

Objective. The purpose of this review is to systematize current data on the pathogenesis of gallstone disease, the role of bile acids and short-chain fatty acids, and gut microbiota in the development of systemic inflammation leading to the formation of cholesterol gallstones.

Results. The pathogenesis of cholesterol gallstone formation involves several factors, the most significant of which include genetic predisposition, imbalance between bile components (such as cholesterol, bile acids, and phospholipids), motility disorders of the biliary tract, and systemic inflammation. Bile acids play a key role in stabilizing the physicochemical and colloidal properties of bile. Disruptions in gut microbiota lead to insufficient production of hydrophilic ursodeoxycholic acid and increased absorption of toxic primary bile acids. In contrast, ursodeoxycholic acid exhibits a wide range of pleiotropic effects, including modulation of the bile acid pool, acting as a cytoprotective, immunomodulatory, and choleretic agent. The gallbladder microbiota closely interacts with the gut microbiota. Shortchain fatty acids, produced by gut microbiota, inhibit pathogenic bacteria, stimulate the immune system to mount a specific response, and mitigate inflammatory reactions. They serve as universal "signaling" molecules involved in intra- and intercellular communication. One mechanism involves interaction with nuclear acetyl-CoA, regulating the expression of genes responsible for pro-inflammatory cytokine production. Due to their small size, short-chain fatty acids passively diffuse through cell membranes or are actively transported via sodium-coupled transporters, entering the cytoplasm and even the nucleus of eukaryotic cells. There, they inhibit histone deacetylase activity, regulating acetylation and thus epigenetically dependent gene expression related to cell proliferation, differentiation, epithelial integrity, and immune response.

Conclusion. Short-chain fatty acids and bile acids are key molecules in regulating the "gut-liver-gallbladder" axis, which may be crucial for developing new therapeutic approaches for biliary tract diseases.

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