Biological gender difference of bile acid metabolism in susceptibility to cholelithiasis in patients with nonalcoholic fatty liver disease

The incidence of gallstone disease (GSD) is often higher in female patients with nonalcoholic fatty liver disease (NAFLD) compared to their male counterparts; however, the underlying mechanisms remain unclear. This cross-sectional study aimed to investigate gender differences in susceptibility to GSD with a focus on the specificity of bile acid (BA) metabolism, while also considering the reciprocal influence between gut bacteria and BAs. A total of 16 female and 36 male NAFLD patients, identified as having a high risk of GSD, were included in the study. Serum and fecal BA profiles were analyzed, along with a correlation analysis of gut microbiota composition. Gender-specific divergence in hydrophobic BAs distribution was observed, with females exhibiting significantly higher serum retention. The concentrations of serum glycolithocholic acid, isolithocholic acid, and 12-ketolithocholic acid, as well as fecal lithocholic acid, were significantly higher in females than in males. Conversely, the levels of serum hyodeoxycholic acid, fecal 7-ketolithocholic acid (7-keto-LCA), chenodeoxycholic acid, glycocholic acid, and ursodeoxycholic acid were significantly lower in females. Additionally, the total abundance of Fusobacterium and Escherichia-Shigella in the gut microbiota was elevated in females. A statistically significant inverse correlation was observed in females between reduced fecal 7-keto-LCA levels and an increased abundance of butyrate-producing bacterial communities. Overall, BAs and gut microbiota exhibit gender dimorphism in NAFLD patients, which may be linked to the increased risk of secondary GSD in women.