Triphala ameliorates hyperuricemia-associated nephropathy by modulating the gut microbiota-glycerophospholipid-TLR4 axis

Chebulic acid, gallic acid, and corilagin predominated among the seven quantified analytical markers in the TRP aqueous extract. • TRP acts as a potent microbiota modulator to ameliorate renal injury. • The lysophospholipid-TLR4 axis serves as one of the pathological drivers of HUA-associated chronic renal injury. • LPC 16:0 and LPC 18:1 trigger renal inflammation by activating the TLR4 pathway. Background Hyperuricemia (HUA) is a metabolic disorder with an escalating global prevalence, and its progression to HUA-associated nephropathy represents an important contributor to chronic kidney injury. Emerging evidence highlights a bidirectional relationship between uric acid and lipid metabolism, with dyslipidemia contributing to the pathological progression of HUA-related complications. Triphala (TRP), a classic Tibetan herbal formula with broad metabolic regulatory properties, was selected as a potential intervention for the complex metabolic disturbances associated with HUA. However, its therapeutic efficacy and the precise molecular mechanisms underlying its effects in HUA remain to be fully elucidated. Purpose This study aimed to investigate the protective effects of TRP on hyperuricemia-associated nephropathy and to elucidate the underlying mechanisms. Methods High-performance liquid chromatography (HPLC) was first employed to identify and quantify seven representative constituents in the TRP aqueous extract. To evaluate the efficacy of TRP, an HUA mouse model was established through the combined administration of intraperitoneal potassium oxonate injections and a yeast-containing diet. A multi-omics strategy integrating 16S rRNA sequencing, metabolomics and lipidomics elucidated TRP's impact on the gut microbiota and host metabolism. Critically, fecal microbiota transplantation (FMT), TLR4 blockade experiments, and in vitro assays were employed to evaluate the contribution of TRP-modulated microbiota and the LPC-TLR4 pathway to the protective effects of TRP. Results HPLC identified chebulic acid, gallic acid, and corilagin as the major representative constituents of TRP aqueous extract. TRP dose-dependently reduced serum uric acid, improved renal function by lowering serum creatinine (Cr) and blood urea nitrogen (BUN) levels, increased the fractional excretion of uric acid (FEUA), and alleviated tubular injury and fibrosis. These improvements were accompanied by normalized urate transporters (downregulated URAT1/GLUT9; restored OAT1/OAT3) and suppressed renal inflammatory cytokines. Multi-omics analysis revealed that TRP reversed HUA-induced dysbiosis by suppressing opportunistic pathogens (e.g., Parasutterella, Allobaculum ) and enriching beneficial genera (e.g., Bifidobacterium, Akkermansia ), specifically reducing pro-inflammatory LPC (e.g., LPC16:0, LPC18:1). TRP and FMT effectively inhibited the TLR4/MyD88/NF-κB signaling axis and reduced LPC accumulation within the kidney. In vitro experiments validated that these specific LPC directly trigger TLR4 expression and TNF-α release, confirming the potential role of the microbiota-driven lysophospholipid-TLR4 pathway in HUA-associated chronic renal inflammation. Conclusion TRP ameliorates HUA and renal inflammation by remodeling the gut microbiota to suppress the aberrant accumulation of pro-inflammatory lysophospholipids, thereby deactivating the TLR4-mediated inflammatory cascade. These findings establish the gut microbiota-glycerophospholipid metabolism-renal inflammation axis as a potential therapeutic target and validate TRP as a relevant strategy for targeting the gut microbiome to treat systemic metabolic disease. Download: Download high-res image (331KB) Download: Download full-size image