Screening of urate-lowering probiotic candidates and their effect on alleviating hyperuricemia in mice through nucleoside transport and FoxO pathway.

Hyperuricemia (HUA) is a metabolic condition arising from disrupted homeostasis between uric acid (UA) synthesis and elimination. Prolonged administration of current therapeutic agents frequently leads to undesirable side effects, underscoring the necessity for safer adjunctive or alternative interventions. This work screened urate-lowering probiotic candidate strains and evaluated their efficacy in HUA. First, 16 probiotic candidate strains were comprehensively evaluated in vitro based on nucleoside/purine degradation capacity and xanthine oxidase (XOD) inhibitory activity. Limnosilactobacillus reuteri GOLDGUT-CCFM1040 (C1040) and Bifidobacterium animalis GOLDGUT-BB21 (BB21) strains with optimal overall performance were selected as the final candidates. In a HUA mouse model, administration of C1040 or BB21 observably decreased serum UA concentrations, suppressed the activities of hepatic XOD and serum PNP, mitigated renal inflammatory responses and fibrosis, as well as enhanced renal function. The transcriptomic analysis combined with RT-qPCR and Western blot results confirmed that C1040 and BB21 exerted their beneficial effects by modulating key gene expression within the FoxO signaling pathway in the kidney. Furthermore, probiotic intervention reshaped the gut microbiota composition, enhanced intestinal barrier integrity, and downregulated the nucleoside transporter ENT1 to reduce the absorption of exogenous purine nucleosides. These findings provide an important theoretical basis for developing novel probiotic-based intervention strategies for HUA.