Non-alcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM), posing a significant metabolic disorder with limited dietary intervention options. Cordycepin, a food‑derived nucleoside from the edible fungus Cordyceps militaris, exhibits hypoglycemic and hypolipidemic effects, but its role in T2DM combined with NAFLD remains unknown. Here, we established a mouse model of T2DM combined with NAFLD in male KM mice using high-fructose and high‑fat diet, and streptozotocin. Both cordycepin (COR) and Cordyceps militaris water extract (CWE) attenuated glucose intolerance, dyslipidemia, hepatic steatosis, liver injury, inflammatory response and oxidative stress, with cordycepin showing superior efficacy. Multi‑omics analysis revealed that cordycepin uniquely reshaped the gut microbiota by significantly enriching the c__Clostridia, including g__Acetatifactor, g__Anaerovorax, g__Monoglobus, s__Acutalibacter_muris, and further affected liver metabolism, which was characterized by enrichment of bile acid metabolism-related pathways. Targeted bile acid metabolomics demonstrated that cordycepin specifically promoted the production of cholic acid‑7‑sulfate (CA7S), a gut‑restricted secondary bile acid, through activation of the hepatic PXR/Sult2a1 pathway. Notably, integrated correlation analysis revealed a significant positive association between CA7S and c__Clostridia (e.g., g__Monoglobus, g__Lachnoclostridium, and g__Anaerovorax), suggesting that cordycepin enhances CA7S production by enriching these Clostridia members. And CA7S activated TGR5 to stimulate glucagon‑like peptide‑1 (GLP‑1) secretion, thereby improving glucose and lipid homeostasis. Therefore, these findings demonstrate that dietary cordycepin improves T2DM combined with NAFLD by modulating gut microbiota, particularly Clostridia, and affecting the PXR/Sult2a1/CA7S/GLP‑1 pathway, thereby exerting beneficial effects on glucose and lipid homeostasis.
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