Dietary Dihydromyricetin Supplementation Enhances Antioxidant Capacity and Modulates Jejunal Barrier Function, Cecal Microbiota, and Hepatic Metabolism in Mice

Background: Dihydromyricetin (DHM) is a food-derived flavonoid enriched in vine tea and has been reported to possess antioxidant and metabolism-regulating properties. This study was designed to characterize the multi-level nutritional responses to dietary DHM supplementation, with emphasis on hepatic redox-inflammatory status, jejunal barrier-related phenotypes, cecal microbiota remodeling, hepatic metabolomic alterations, and homocysteine (Hcy) metabolism-related markers in mice. Methods: Forty-eight healthy mice were assigned to a basal-diet control group or diets containing 50, 100, or 200 mg/kg DHM for 4 weeks. Growth performance, serum biochemistry, antioxidant parameters, hepatic antioxidant-related expression, hepatic inflammatory cytokines, jejunal morphology and tight junction proteins, cecal 16S rRNA profiles, hepatic metabolomics, and Hcy metabolism-related markers were assessed. Results: Dietary DHM improved serum and hepatic antioxidant status, as reflected by increased T-AOC and GSH-Px activity and decreased MDA concentrations (p < 0.05). DHM also modulated the hepatic cytokine profile, with decreased TNF-α concentration (p < 0.05) and increased IL-10 concentration (p < 0.01). DHM increased hepatic Nrf2 protein abundance, HO-1 protein abundance, and Gclc mRNA expression (p < 0.05). DHM also improved jejunal villus architecture, as indicated by increased villus height, decreased crypt depth, and an increased villus height-to-crypt depth ratio (p < 0.05). Jejunal Occludin and ZO-1 protein expression were increased in the DHM-treated groups (p < 0.05). Cecal microbiota analysis showed increased richness and diversity indices and altered microbial community structure. Hepatic metabolomics revealed changes involving vitamin B6 metabolism, purine metabolism, the pentose phosphate pathway, and α-linolenic acid metabolism. Serum Hcy levels decreased (p < 0.05), accompanied by increased hepatic BHMT and MTHFR protein abundance (p < 0.01). Conclusions: Dietary DHM supplementation improved hepatic redox status and supported a less pro-inflammatory cytokine profile in mice, accompanied by enhanced jejunal barrier-related phenotypes, cecal microbiota remodeling, hepatic metabolic alterations, and Hcy metabolism-related responses. These findings provide a multi-level nutritional evaluation of DHM and suggest its potential relevance for supporting intestinal barrier integrity and hepatic metabolic homeostasis under basal physiological conditions.