Lacticaseibacillus rhamnosus alleviates hyperuricemia by restricting intestinal nucleoside absorption

Hyperuricemia is a growing metabolic disorder, whereas current microbiota-based strategies primarily focus on urate degradation or excretion, leaving upstream regulation of nucleoside precursors largely unexplored. Here, we isolated a nucleoside-degrading probiotic strain, Lacticaseibacillus rhamnosus (L. rhamnosus), from traditional fermented dairy products and demonstrated its urate-lowering effect in a hyperuricemia rat model. The strain significantly reduced serum urate levels without altering renal urate transporter expression, suggesting a mechanism independent of renal excretion. Multi-omics and Caco-2 cell assays revealed that L. rhamnosus expresses intracellular nucleoside hydrolases that convert guanosine and inosine into poorly absorbed purine bases, thereby limiting intestinal nucleoside uptake and reducing hepatic substrate supply for urate synthesis. Two key hydrolases were functionally validated by gene cloning and enzymatic assays. In addition, L. rhamnosus reshaped gut microbial composition, modulated host metabolic pathways, and alleviated systemic inflammation. Collectively, this study identifies a previously uncharacterized substrate-restriction mechanism by which probiotics alleviate hyperuricemia, providing novel insight into microbiota-based strategies for dietary and therapeutic intervention in purine metabolism.