Lactiplantibacillus pentosus JWN01 and Lactiplantibacillus plantarum JWN02 attenuate renal fibrosis and pathological autophagy in hyperuricemic nephropathy via gut-kidney axis

Abstract

Hyperuricemic nephropathy (HN) is a worldwide metabolic disorder marked by uric acid (UA) imbalance and renal tubulointerstitial fibrosis, yet therapies that both lower UA and prevent fibrosis remain limited. Targeting the gut-kidney axis with probiotics is a promising strategy, but most candidates are food-derived and not human-adapted. We isolated two Lactiplantibacillus strains, Lactiplantibacillus pentosus JWN01 and Lactiplantibacillus plantarum JWN02, from the healthy newborn skin representing a relatively unperturbed, early-life human microbiome. In vitro, these two human-derived probiotic strains showed robust survival under simulated gastrointestinal conditions and efficiently degraded UA precursors (inosine, guanosine). In Uox^-/^- mice, oral supplementation with these probiotics for 12 weeks significantly reduced serum UA levels, improved renal function, and regulated key urate transporters, such as ABCG2, GLUT9, and OAT1, in kidney and ileum. The treatment also reinforced intestinal barrier integrity by upregulating tight junction proteins (Claudin-1, Occludin, ZO-1) and alleviated renal fibrosis by inhibiting the TGF-β1/SMAD3 signaling pathway. Gut microbiome analysis showed that JWN01 and JWN02 administration reshaped the microbial composition by decreasing potentially harmful genera (Mammaliicoccus, Staphylococcus, Corynebacterium) and enriching beneficial taxa (Muribaculaceae, Lactiplantibacillus, Akkermansia). This microbial shift was accompanied by partial restoration of disturbed gut metabolites, including Coenzyme Q10 and p-cresol sulfate. Proteomic profiling of proximal tubules, along with subsequent validation, demonstrated that intervention with JWN01 and JWN02 suppressed pathological autophagy-evidenced by reduced ULK1, LC3A/B, and Beclin-1 expression, and increased P62 levels. Notably, the potential inflammation-related biomarkers MSP and IBA1, elevated in HN, were reversed following probiotic treatment. Together, these findings indicate that L. pentosus JWN01 and L. plantarum JWN02 confer protective effects against HN through modulation of the gut-kidney axis, supporting their potential as functional probiotics for dietary management of hyperuricemia.

Keywords: Autophagy; Gut microbiota; Gut-kidney axis; Hyperuricemia; Probiotics; Proximal tubule proteomics; Renal fibrosis.