Lithocholic Acid Restores Gut Microbiota and Bile Acid Homeostasis to Improve Type 2 Diabetes

Background: Bile acids participate in several metabolic processes, and disturbances in their circulating profiles are commonly observed in type 2 diabetes. In a cohort of older adults, individuals with diabetes exhibited markedly lower concentrations of metabolites derived from lithocholic acid. These findings prompted further evaluation of the metabolic effects of lithocholic acid. Methods: We assessed the actions of lithocholic acid in a mouse model of diabetes induced by a high-fat diet and streptozotocin. Fasting glucose, insulin levels, lipid parameters, and measures of insulin resistance were evaluated. Gut microbial composition, short-chain fatty acids, fecal enzyme activities, intestinal barrier markers, and bile acid patterns were analyzed. In vitro assays examined the direct effects of lithocholic acid on A. muciniphila and bile acid metabolism. Results: Lithocholic acid supplementation lowered fasting glucose and insulin levels and improved insulin resistance. It shifted the gut microbial community toward a healthier structure, increased the abundance of A. muciniphila, and raised short-chain fatty acid concentrations. Fecal bile salt hydrolase and β-glucuronidase activity declined, and intestinal barrier markers improved. Lithocholic acid enhanced TGR5 expression and reduced FXR signaling in the ileum. In vitro, physiologically relevant concentrations promoted A. muciniphila growth and altered microbial bile acid metabolism. Conclusions: Lithocholic acid influences the interactions among gut microbes, bile acid pathways, and host metabolic regulation. These findings suggest that this compound may have value as a dietary component that supports metabolic health in type 2 diabetes.