<i>Limosilactobacillus fermentum</i> M5e Attenuates Hyperuricemia and Renal Injury via Dual Modulation of Gut Microbiota and Purine Metabolic Pathways

Hyperuricemia, associated with gout and chronic kidney disease, underscores the need for novel therapies. Recent studies suggest that the gut microbiota may play a role in the pathogenesis of HUA, with certain probiotics demonstrating potential in reducing urate levels. Notably, Limosilactobacillus fermentum M5e exhibits exceptional in vitro uric acid degradation, yet its in vivo mechanisms remain unexplored. This study investigates M5e's therapeutic efficacy and mechanisms in HUA mice. We established an HUA model and systematically evaluated M5e's effects on uric acid metabolism, inflammatory responses, and gut microbiota. M5e administration significantly reduced serum urate levels and markers of renal injury alongside the modulation of inflammatory cytokines. The strain also improved intestinal barrier integrity by upregulating tight junction proteins and restoring gut microbiota diversity. Mechanistically, M5e inhibited the activity of xanthine oxidase and adenosine deaminase while promoting fecal urate excretion without affecting renal clearance. The upregulation of ABCG2 and SLC2A9 transport proteins further corroborated their role in metabolic regulation. These findings establish L. fermentumM5e as a versatile therapeutic candidate capable of modulating urate metabolism, reducing systemic inflammation, and restoring gut microbiota homeostasis. The dual mechanisms of enzyme inhibition and transport regulation indicate novel pathways that differ from those of traditional urate-lowering medications. Future clinical studies are necessary to validate these preclinical results and evaluate long-term safety, especially for patients who are intolerant of existing treatments. This research advances probiotic-based interventions for metabolic disorders by elucidating strain-specific mechanisms that connect gut microbiota modulation to systemic urate regulation.