Lithocholic Acid: A Translational Pathway to Metabolic Health in Type 2 Diabetes

Lithocholic acid (LCA) shows preclinical benefit for glycemic control in a diet‑plus‑streptozotocin mouse model of type 2 diabetes. C57BL/6 mice given daily oral gavage of LCA (50 mg/kg) for four weeks had significant reductions in fasting blood glucose and serum insulin and lower HOMA‑IR (p<0.05–0.01). Body‑weight gain trended lower and selected lipid and liver‑enzyme markers improved. These findings are supported by controlled in vivo work and complementary in vitro assays but derive from small groups (n=3–4 per arm) in an exploratory design.

The report extends prior bile acid–microbiome literature by mapping microbiome composition, bile‑acid profiling, and metabolic endpoints within a single experimental framework. Earlier studies often reported microbiota shifts, bile‑acid changes, and host metabolism separately; this integrated dataset links restoration of LCA‑related secondary bile acids directly to systemic glucose metrics and sets up receptor‑level hypotheses tested here.

At the receptor level, LCA exposure coordinated bile‑acid signaling with downstream microbial enrichment. The study observed increased Akkermansia muciniphila alongside ileal receptor changes—TGR5 upregulated and FXR downregulated—consistent with LCA‑driven shifts that raise TGR5 agonists while lowering intestinal FXR tone. Those receptor shifts coincided with enrichment of Akkermansia and other short‑chain fatty‑acid (SCFA)–producing taxa, creating a plausible mechanistic chain linking bile‑acid remodeling to improved glycemic endpoints.

Metabolically, LCA treatment raised total SCFAs—most prominently acetate—and improved markers of barrier integrity, including higher occludin transcripts and lower serum lipopolysaccharide‑binding protein. Fecal bile‑salt‑hydrolase and β‑glucuronidase activities were reduced. In vitro fermentations and single‑strain assays corroborated that physiologically relevant LCA concentrations selectively promote A. muciniphila growth and alter microbial bile‑acid metabolism, providing biological plausibility for the in vivo glucose and insulin effects.