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

<b>Background:</b> 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. <b>Methods:</b> 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 <i>A. muciniphila</i> and bile acid metabolism. <b>Results:</b> 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 <i>A. muciniphila</i>, 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 <i>A. muciniphila</i> growth and altered microbial bile acid metabolism. <b>Conclusions:</b> 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.