Abstract BACKGROUND Hyperuricemia, a major risk factor for gout and kidney disease, requires safe and effective dietary strategies beyond conventional pharmacotherapy. This study investigated the multi‐target effects of the food‐grade probiotic Limosilactobacillus reuteri RE225 on hyperuricemia. It was evaluated in vitro for xanthine oxidase (XOD) inhibition and nucleoside degradation, and in vivo in hyperuricemic mice gavaged daily with low or high doses of RE225 (1 × 10 6 or 1 × 10 9 CFU). Serum uric acid (UA), XOD activity, inflammatory cytokines, intestinal permeability markers – fluorescein isothiocyanate–dextran (FITC‐dextran), lipopolysaccharide (LPS), and d ‐lactate – and renal TLR4/NF‐ κ B signaling were quantified. Fecal metagenomics and Kyoto Encyclopedia of Genes and Genomes ortholog (KO) profiling were used to assess microbiota structure and function. RESULTS Limosilactobacillus reuteri RE225 dose‐dependently inhibited XOD and degraded more than 50% of nucleosides in vitro . In vivo , RE225 reduced serum urate, restored intestinal barrier function, suppressed inflammation, and downregulated renal TLR4/NF‐ κ B signaling. Metagenomic analysis showed that L. reuteri RE225 reversed UA‐induced loss of microbial richness and evenness, enriched Faecalibaculum and Erysipelotrichaceae , and shifted functional profiles from proliferation‐ and inflammation‐related modules (K02315, K02970, and K03496) toward carbohydrate utilization and genetic stability pathways (K01784 and K07491). CONCLUSION Limosilactobacillus reuteri RE225 shows promise as a dietary intervention for the management of hyperuricemia. © 2026 Society of Chemical Industry.
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