Plantago asiatica L. extract alleviates hyperuricemia-associated renal injury by modulating gut microbiota to inhibit NLRP3 inflammasome activation

BACKGROUND: Plantago asiatica L. (PTGA) is a widely used herbal medicine for the treatment of gout and hyperuricemia (HUA). Emerging evidence highlights the pivotal role of the gut microbiota in the pathogenesis of gout and HUA. However, existing research has failed to identify and verify the key mediator strains of PTGA that exert its role in lowering uric acid. METHODS: A hyperuricemia mouse model was established by intraperitoneal co-administration of hypoxanthine (100 mg/kg) combined with potassium oxonate (50 mg/kg) daily for 10 consecutive days. Serum uric acid (sUA) levels and renal function parameters were assessed using biochemical assay kits. 16S rRNA sequencing combined with non-targeted metabolomics was employed to characterize alterations in gut microbiota and intestinal metabolites. Western blotting was performed to examine the expression of intestinal and renal uric acid transporters, intestinal tight junction proteins, and NLRP3 inflammasome-related proteins. Finally, the mediate role of gut microbiota was verified through fecal microbiota transplantation (FMT) and oral supplementation with Lachnospiraceae bacterium. RESULTS: In the HUA model, elevated sUA levels (p < 0.01), activation of the renal NLRP3 inflammasome (p < 0.05), renal edema, and impaired renal function were accompanied by gut microbiota dysbiosis. PTGA extract markedly reduced sUA levels by approximately 70 % compared to the model group (p < 0.01), regulated uric acid transporter expression in both the intestine and kidney (p < 0.05), and reshaped gut microbiota composition. Moreover, PTGA enhanced intestinal uric acid catabolism of uric acid in the intestine. FMT and Lachnospiraceae bacterium supplementation experiments further confirmed the regulation of the gut microbiota is a key mediator of PTGA's therapeutic efficacy. CONCLUSION: This study demonstrates that PTGA exerts hypouricemic and renoprotective effects through modulation of the gut-kidney axis by enriching Lachnospiraceae, promoting intestinal uric acid catabolism, and suppressing renal NLRP3 inflammasome activation. These findings provide novel mechanistic insights into the gut microbiota-dependent therapeutic action of herbal medicine, distinguishing this work from previous studies focused solely on direct organ-level effects.