Quercetin ameliorates hyperuricemic nephropathy through improving gut dysfunctions and decreasing gut bacteria-derived uremic toxins.

Background: Hyperuricemia (HUA) is closely associated with gut dysbiosis, yet the role of microbial metabolism in hyperuricemic nephropathy (HN) remains poorly understood. Quercetin has shown urate-lowering and nephroprotective effects, but its therapeutic mechanisms, particularly in modulating the gut microbiome and microbial metabolism, remain elusive.

Purpose: This study investigates the therapeutic effects of quercetin on HN and explores its role in regulating host-microbial co-metabolism.

Methods: A spontaneous HUA rat model (Uox-/- rats) was used to evaluate the therapeutic effect of quercetin. Multi-omics analyses, including gut microbiome profiling, peripheral untargeted metabolome, and targeted quantification of gut bacteria-derived uremic toxins, were performed. An integrated network analysis was conducted to uncover potential host-microbe metabolic interactions.

Results: Quercetin treatment significantly reduced serum uric acid, creatinine, and blood urea nitrogen, ameliorated renal inflammation, fibrosis and oxidative stress, and improved gut dysbiosis and intestinal barrier dysfunction. Notably, high-dose quercetin downregulated Blautia, a key gut bacterium associated with uremic toxin production, and suppressed microbial phenylalanine metabolism, leading to decreased levels of gut bacteria-derived nephrotoxic metabolites (e.g., 3-phenyllactic acid, hippuric acid, and N-acetyl-l-phenylalanine). These uremic toxins were positively correlated with markers of kidney injury and proinflammatory cytokines. Mechanistically, quercetin modulated microbial enzymatic pathways involved in phenylalanine metabolism, thereby disrupting the formation of nephrotoxic metabolites and alleviating renal damage.

Conclusions: This study provides multi-omics evidence that quercetin ameliorates HN by regulating gut dysfunctions and decreasing gut bacteria-derived uremic toxins through host-microbial co-metabolism. These findings highlight the therapeutic potential of microbiota-targeted interventions in HUA-associated kidney diseases.