Microbiota Reprogramming Driven by 7,8-Dihydroxyflavone Potentiates Xanthine Oxidase to Mitigate Hyperuricemia
Hyperuricemia (HUA), primarily driven by xanthine oxidase (XO)-mediated uric acid production, presents substantial challenges to both human health and livestock productivity. While conventional XO inhibitors are effective in mitigating HUA, they are often linked to severe adverse effects. In this study, we developed MiXO, an advanced high-throughput microbiome-based screening framework aimed at identifying natural products that inhibit uric acid (UA) production through microbiota-mediated XO inhibition. From a library of 131 compounds, 7,8-dihydroxyflavone (7,8-DHF) was identified as a primary candidate. In HUA mouse models, treatment with 7,8-DHF normalized serum UA levels and reduced hyperuricemia-associated pathological sequelae and renal dysfunction. Metagenomic and metabolomic analyses demonstrated that 7,8-DHF enhances the abundance of L. reuteri, which promotes the accumulation of the microbial co-metabolite catechin. Molecular docking simulations, along with subsequent in vivo validation, confirmed that catechin occupies the XO catalytic pocket, effectively providing a biochemical blockade of urate biosynthesis to alleviate hyperuricemia. Collectively, our findings establish MiXO as a robust platform for microbiome-targeted drug discovery and position 7,8-DHF as a versatile therapeutic candidate for mitigating HUA.