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

L. pentosus JWN01 and L. plantarum JWN02 were isolated from healthy newborn skin as human-derived probiotic candidates representing an early-life human microbiome.

• The strains were isolated from healthy newborn skin, described as 'a relatively unperturbed, early-life human microbiome'.
• The rationale for human-derived strains was that most probiotic candidates are food-derived and not human-adapted.
• The two strains belong to the Lactiplantibacillus genus: L. pentosus (JWN01) and L. plantarum (JWN02).

Both probiotic strains showed robust survival under simulated gastrointestinal conditions and efficiently degraded uric acid precursors in vitro.

• In vitro testing confirmed robust survival under simulated gastrointestinal conditions.
• Both strains efficiently degraded UA precursors, specifically inosine and guanosine.
• These properties were characterized as prerequisites for their functional use as probiotics.

Oral supplementation with JWN01 and JWN02 for 12 weeks significantly reduced serum uric acid levels and improved renal function in Uox-/- mice.

• The model used was Uox-/- (uricase knockout) mice, which develop hyperuricemic nephropathy.
• Treatment duration was 12 weeks of oral supplementation.
• Serum UA levels were significantly reduced following probiotic intervention.
• Renal function parameters were improved following treatment.

Probiotic treatment regulated key urate transporters in both kidney and ileum of Uox-/- mice.

• Urate transporters regulated included ABCG2, GLUT9, and OAT1.
• Transporter regulation was observed in both kidney and ileum tissues.
• Modulation of these transporters is consistent with altered uric acid excretion via the gut-kidney axis.

JWN01 and JWN02 reinforced intestinal barrier integrity by upregulating tight junction proteins in Uox-/- mice.

• Tight junction proteins upregulated included Claudin-1, Occludin, and ZO-1.
• Upregulation of these proteins indicates improved intestinal barrier integrity.
• Intestinal barrier reinforcement is consistent with a gut-kidney axis mechanism of action.

Probiotic intervention alleviated renal fibrosis by inhibiting the TGF-β1/SMAD3 signaling pathway.

• Renal tubulointerstitial fibrosis is a hallmark of hyperuricemic nephropathy.
• The TGF-β1/SMAD3 signaling pathway was identified as the mechanistic target for anti-fibrotic effects.
• Both JWN01 and JWN02 treatment attenuated this fibrosis-associated signaling.

JWN01 and JWN02 administration reshaped gut microbial composition by decreasing potentially harmful genera and enriching beneficial taxa.

• Potentially harmful genera decreased included Mammaliicoccus, Staphylococcus, and Corynebacterium.
• Beneficial taxa enriched included Muribaculaceae, Lactiplantibacillus, and Akkermansia.
• Gut microbiome analysis confirmed the microbial reshaping effects of both strains.

Microbial shifts from probiotic treatment were accompanied by partial restoration of disturbed gut metabolites, including Coenzyme Q10 and p-cresol sulfate.

• Disturbed gut metabolites in HN were partially restored following JWN01 and JWN02 treatment.
• Specific metabolites identified included Coenzyme Q10 (beneficial) and p-cresol sulfate (potentially harmful uremic toxin).
• Metabolite changes are consistent with functional modulation of the gut-kidney axis.

Proteomic profiling of proximal tubules demonstrated that JWN01 and JWN02 suppressed pathological autophagy in hyperuricemic nephropathy.

• Pathological autophagy suppression was evidenced by reduced expression of ULK1, LC3A/B, and Beclin-1.
• P62 levels were increased following probiotic treatment, further indicating suppression of autophagic flux.
• Findings from proteomic profiling were subsequently validated.
• Suppression of pathological autophagy was identified as a novel mechanism of renal protection by these probiotics.

Inflammation-related biomarkers MSP and IBA1, elevated in hyperuricemic nephropathy, were reversed following probiotic treatment.

• MSP (macrophage-stimulating protein) and IBA1 were identified as potential inflammation-related biomarkers elevated in HN.
• Both biomarkers were reversed following JWN01 and JWN02 intervention.
• These biomarkers were identified through proteomic profiling of proximal tubules with subsequent validation.