Kluyveromyces marxianus XZ1 fermentation products alleviate hyperuricemia via the microbiota–SCFA–gut–kidney urate transporter axis

Hyperuricemia (HUA) is a systemic metabolic disorder closely linked to disrupted host-microbiota interplay. Current first-line drugs (e.g., allopurinol) primarily target urate synthesis but lack tissue-repair capabilities and cause long-term adverse effects. Although microbial metabolites circumvent the inflammatory risks of live probiotics, the urate-lowering mechanisms of Kluyveromyces marxianus fermentation metabolites remain largely uncharacterized. Here, we integrated in vitro bioassays, in vivo animal experiments, and multi-omics profiling to elucidate the anti-hyperuricemic efficacy of an ethyl acetate extract from K. marxianus XZ1. In vitro , the XZ1 extract exhibited significant antioxidant and xanthine oxidase (XOD) inhibitory activities. The cell-free extract exerted a dual-action mechanism: directly suppressing urate synthesis by inhibiting XOD and adenosine deaminase (ADA) activities, and enhancing systemic urate clearance through bidirectional regulation of renal and intestinal urate transporters (upregulating excretory ABCG2/OAT1 and downregulating reabsorptive URAT1/GLUT9). Integrated 16S rRNA sequencing and untargeted metabolomics revealed these systemic benefits are driven by gut microbiota remodeling, forming a “microbiota–short-chain fatty acid (SCFA)–gut–kidney urate transporter” regulatory axis. The intervention enriched SCFA-producing taxa, normalized fecal SCFA profiles, strengthened intestinal barrier integrity and reprogrammed host purine and redox metabolic networks. Collectively, K. marxianus XZ1 fermentation products lower uric acid and protect against HUA-induced multi-organ injury, inflammation, and oxidative stress. These findings highlight its potential as a safe, industrially stable, and multi-target functional food ingredient for early dietary intervention in asymptomatic hyperuricemia.