Alcalase-hydrolyzed casein peptides after simulated gastrointestinal digestion alleviate high-fat diet-induced metabolic dysfunction in mice

Background and aim High-fat diet (HFD)-induced metabolic dysfunction is associated with disturbances in gut microbial composition and hepatic lipid metabolism. This study investigated the metabolic effects of Alcalase-hydrolyzed casein peptides after simulated gastrointestinal digestion (MCPs) in HFD-fed mice and explored their potential association with gut microbiota and fecal metabolic alterations. Results MCP supplementation attenuated body weight gain, improved serum lipid profiles, and alleviated hepatic steatosis and injury in HFD-fed mice. In the colon, MCPs ameliorated histological damage and suppressed the mRNA and protein expression of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α. Gut microbiota analysis revealed increased relative abundances of Akkermansia, Bifidobacterium , and Lactobacillus and reduced abundance of Desulfovibrio following MCP supplementation. Fecal metabolomics identified alterations in bile acid- and lipid metabolism-related signatures, including increased levels of tauroursodeoxycholic acid (TUDCA) and reduced arachidonic acid metabolism-related metabolites. In the liver, MCPs downregulated. SREBP-1c/ACC/GPAT1 lipogenic signaling and enhanced Nrf2/HO-1-associated antioxidant responses. Correlation analysis revealed associations between microbial-metabolic alterations and host metabolic phenotypes. Conclusion Collectively, MCPs may alleviate HFD-induced metabolic dysfunction by modulating gut microbiota-associated metabolic profiles and improving intestinal and hepatic metabolic responses.