Protective Effects of Narirutin Against Exercise-Induced Fatigue in Mice: Insights from Integrated Microbiome, Metabolome, and Transcriptome Analysis

Exercise-induced fatigue is linked to oxidative stress, inflammation and intestinal dysbiosis. Narirutin (NAR), a natural flavonoid, lacks systematic evidence and mechanistic clarification against exercise fatigue. Herein, a forced exercise fatigue mouse model was constructed, and behavioral, biochemical, histological and multiomics analyses including 16S rRNA sequencing, untargeted metabolomics, transcriptomics and RT-qPCR were performed. Fecal microbiota transplantation (FMT) and antibiotic-mediated microbiota depletion further verified the causal role of gut microbiota. NAR dose-dependently improved exercise endurance, muscle strength, glycogen storage, oxidative status and inflammatory profiles. It restored gut microbial diversity, remodelled microbial composition and altered metabolic signatures. Multiomics integration indicated NAR regulated immune genes via the gut microbiota-metabolite-gene axis. FMT reproduced antifatigue effects, whereas antibiotic treatment eliminated NAR protection. This study demonstrates that NAR alleviates exercise-induced fatigue largely relying on intact gut microbiota, although microbiota-independent peripheral effects cannot be fully excluded. These findings support its exploitation as a natural antifatigue functional component.