Lithocholic Acid Improves Glucose Homeostasis by Activating the TGR5-GLP-1 Axis via Gut Microbiota-Derived Secondary Bile Acids: A Study Done on Diabetic Sprague-Dawley Rats.

Purpose: This study aimed to investigate the effects of lithocholic acid on glucose metabolism in streptozotocin -induced diabetic Sprague-Dawley (STZ-DM) rats and to explore its potential mechanisms. Methods: STZ-DM rats were randomly allocated into two groups (n=6 per group) and received LCA (50 mg/kg/d) or vehicle by daily gavage for 6 weeks. Longitudinal monitoring of body weight and fasting blood glucose was performed throughout the intervention, and oral glucose tolerance tests were conducted to evaluate glucose metabolic capacity. Fecal bile acid metabolomics and gut microbial community analyses were further conducted. Additionally, the transcriptional levels of ileal TGR5, FXR and GLP-1, as well as the key hepatic gluconeogenic genes G6PC and PCK1, were quantified by RT-qPCR at the mRNA level for mechanistic exploration. Results: LCA treatment reduced fasting glycemia and enhanced glucose tolerance, accompanied by a significant suppression of hepatic G6PC and PCK1 mRNA, with no significant impact on body weight. A marked elevation in fecal secondary bile acids was observed, showing a positive correlation with metabolic improvements. LCA supplementation enriched intestinal Clostridia, which correlated with secondary bile acid abundance and glucose homeostasis indicators. Meanwhile, ileal and hepatic TGR5 as well as ileal GLP-1 mRNA expression were upregulated following LCA administration. Conclusion: LCA is associated with improved glucose metabolism in STZ-DM rats, potentially through TGR5-GLP-1 activation and suppression of hepatic gluconeogenesis, in conjunction with Clostridium-enriched secondary bile acid production. However, this study only relies on mRNA expression data and lacks functional TGR5 receptor validation; the proposed correlative pathway requires further mechanistic verification to confirm causal effects.