Resveratrol Ameliorates Hyperuricemia in Association with Remodeling of the Gut Microbiota–Metabolism Axis: An Integrated 16S rDNA Sequencing and Fecal Metabolomics Study

Hyperuricemia (HUA) is a chronic metabolic disorder whose prevalence continues to rise, whereas available urate-lowering drugs are limited by safety and tolerability concerns. Resveratrol (Res) exhibits urate-lowering activity, but its oral bioavailability is below 1%, prompting investigation of its potential interactions with the gut microbiota. Here, hyperuricemic mice induced by potassium oxonate plus high-fructose intake were treated with Res (20, 40, or 80 mg/kg) or benzbromarone (20 mg/kg), and 16S rDNA sequencing, PICRUSt2 functional prediction, untargeted fecal metabolomics, and multi-omics network analysis were integrated to characterize the underlying mechanisms. Res (80 mg/kg) significantly lowered serum uric acid, inhibited xanthine oxidase and adenosine deaminase activities, improved renal injury, suppressed pro-inflammatory cytokines, and up-regulated colonic barrier genes with reduced serum lipopolysaccharide. Res normalized inflated microbial richness, restored Akkermansia abundance, and PICRUSt2 prediction indicated down-regulation of the microbial purine-metabolism gene families XOD/XDH and UOX by 29.4% and 85.9%, respectively. Metabolomics identified 41 shared differential metabolites including eicosanoid lipid mediators and glycerophospholipids. Multi-omics exploratory network analysis suggested Akkermansia as a potential hub node associated with microbial remodeling, eicosanoid modulation, and host urate phenotypes, which may represent a “urate-production suppression plus microbiota–metabolism axis regulation” mode of action, providing preclinical evidence for Res as a candidate dietary intervention against HUA.