Metabolic effects of Cordyceps militaris ethanol extract and cordycepin in mice with type 2 diabetes and hyperlipidaemia: gut microbial and bile acid-related changes.

Cordyceps militaris is an edible medicinal fungus with potential metabolic benefits, but its effects on type 2 diabetes mellitus accompanied by hyperlipidaemia (T2DM-HLP) remain incompletely understood. This study evaluated the effects of orally administered C. militaris ethanol extract (EAE; 2.0 g kg-1) and cordycepin (50 or 100 mg kg-1) in a T2DM-HLP mouse model over 6 weeks. Metabolic indices, serum transaminases, colon and liver histology, gut bacterial and fungal communities, serum metabolites, and FXR/TGR5-related molecular markers were assessed. Compared with the model group, EAE and 50 mg kg-1 cordycepin reduced serum lipid and transaminase levels to varying degrees and were associated with downward shifts in fasting blood glucose and oral glucose tolerance test curves. Histological alterations in the colon and liver were also less apparent in these two groups. Faecal 16S rDNA and ITS sequencing showed changes in the bacterial and fungal community structure, while untargeted serum metabolomics identified distinct metabolic profiles involving bile acids, fatty acids, amino acids, nucleotides, and redox-related metabolites. Enrichment analyses implicated bile secretion, primary bile acid biosynthesis, cholesterol metabolism, cAMP signalling, and amino acid metabolism. These changes were accompanied by increased colonic TGR5 and hepatic FXR immunoreactivity, increased hepatic Fxr, Nr0b2, and Ppara expression, and reduced Cyp7a1 expression. Responses to 100 mg kg-1 cordycepin were less consistent, indicating no simple dose-dependent relationship under the present conditions. Overall, EAE and cordycepin were associated with improved metabolic status and coordinated changes in the gut microbial composition, serum metabolism, and bile acid-related molecular readouts.