The dietary polyphenol Resveratrol attenuates High-Fat Diet-induced testicular dysfunction via modulating the Gut-Microbiota-Testis metabolic axis

Resveratrol, a dietary polyphenol from grapes and berries, was evaluated for its protection against high-fat diet (HFD)-induced testicular dysfunction via the gut-microbiota-testis axis. In mice, resveratrol improved sperm quality and systemic metabolism. It reshaped gut microbiota (enriching Bifidobacterium) and normalized testicular metabolites, including the antioxidant 1,4-dithiothreitol and membrane-stabilizing heptadecanoic acid. Crucially, network pharmacology predicted specific targets, TNF-α, IL-1β, PTGS2, HRAS, and the TCA cycle enzyme SDHB, which led us to hypothesize and validate that resveratrol enhances mitochondrial TCA cycle activity (upregulating SDHB, ACO2, CS, MDH2). Concurrently, it suppressed the NF-κB pathway and promoted repair processes. Molecular docking confirmed stable binding to these targets. This work demonstrates that dietary resveratrol alleviates testicular impairment, a mechanism pinpointed through computational prediction, supporting its role as a nutritional intervention for male subfertility.