Gastrointestinal microbiome and cholelithiasis: Current status and perspectives

Abstract

Cholelithiasis is a common digestive disease affecting 10% to 15% of adults. It imposes significant global health and financial burdens. However, the pathogenesis of cholelithiasis involves several factors and is incompletely elucidated. In addition to genetic predisposition and hepatic hypersecretion, the pathogenesis of cholelithiasis might involve the gastrointestinal (GI) microbiome, consisting of microorganisms and their metabolites. High-throughput sequencing studies have elucidated the role of bile, gallstones, and the fecal microbiome in cholelithiasis, associating microbiota dysbiosis with gallstone formation. The GI microbiome may drive cholelithogenesis by regulating bile acid metabolism and related signaling pathways. This review examines the literature implicating the GI microbiome in cholelithiasis, specifically gallbladder stones, choledocholithiasis, and asymptomatic gallstones. We also discuss alterations of the GI microbiome and its influence on cholelithogenesis.

Keywords: Bile acid; Bile microbiome; Cholesterol gallstone; Common bile duct stone; Gallstone; Gastrointestinal microbiome.

Figure 1

The underlying microbial mechanisms of gallstone formation. The gastrointestinal microbiome may drive cholelithogenesis by: (1) The fecal microbiome enriched in Desulfovibrionales led to an increase of 7α-dehydroxylation bacteria, thus converting primary bile acids (Bas) to secondary BAs. Attributed to the regulation of the FXR-CYP7A1 pathway, Desulfovibrionales increased taurodeoxycholic acid and decreased Tauro-β-muricholic acid, which was induced by the production of H₂S; (2) Lipopolysaccharide upregulated mucins via TACE/TGF-α/EGFR pathway and EP4/p38MAPK pathway; (3) Gram-positive bacteria contributed to the enriched expression of mucin 4 and subsequently modulated calcification; (4) Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa produced exogenous GUS to induce the hydrolysis of bilirubin diglucuronides, thus accelerating precipitation of calcium bilirubinate; and (5) Helicobacter spp. precipitated calcium via the urease activity. BA: Bile acids; CYP7A1: Cholesterol 7α-hydroxylase; EGFR: Epidermal growth factor receptor; EP4: E-prostanoid receptor 4; FXR: Farnesoid X receptor; GUS: β-glucuronidase; LPS: Lipopolysaccharide; MUC: Mucin; PGE2: Prostaglandin E2; PL: Phospholipase; TACE: Tumor necrosis factor-α converting enzyme; TβMCA: Tauro-β-muricholic acid; TDCA: Taurodeoxycholic acid; TGF: Transforming growth factor.