A multi-component intervention enhances intestinal urate excretion and improves metabolic and immune homeostasis in diet-induced hyperuricemia

BACKGROUND: Although the intestine substantially contributes to daily urate clearance, intestinal urate-lowering strategies remain limited, particularly interventions that coordinately regulate transport, barrier integrity, inflammation, and microbial metabolism. METHODS: Modified Shuilu Erxian Decoction (MSLED) was characterized by UPLC-QE-Orbitrap-MS, and serum-exposed prototype constituents were identified using drug-containing plasma. Male Sprague-Dawley rats were exposed to a high-urate diet for 6 weeks to induce stable hyperuricemia (HUA); MSLED or benzbromarone was administered during the final 4 weeks. Serum biochemistry, histopathology, 24-h urinary and fecal urate excretion, intestinal luminal urate, intestinal barrier function, urate transporters, jejunal metabolomics and transcriptomics, and fecal 16S rRNA sequencing were assessed. RESULTS: MSLED reduced serum urate by up to 48.3% and mitigated renal and intestinal injury. MSLED increased fecal urate excretion and luminal urate, accompanied by higher intestinal ABCG2 abundance, lower GLUT9 abundance, and changes in epithelial staining distribution. MSLED also increased tight-junction protein staining and reduced circulating endotoxemia and pro-inflammatory cytokines. Multi-omics analyses indicated partial normalization of intestinal nucleotide metabolism and attenuation of inflammatory programs, particularly IL-17/MAPK-associated signaling. Fecal 16S rRNA sequencing revealed MSLED-associated shifts in microbial community composition that were associated with urate-related metabolic and inflammatory phenotypes. CONCLUSION: MSLED lowers serum urate in diet-induced HUA and is associated with enhanced intestinal urate elimination, improved epithelial barrier integrity, and coordinated metabolic-immune remodeling. These findings support intestinal urate handling as a potentially relevant therapeutic axis while indicating that renal transport, microbial causality, and direct transporter mechanisms require further functional validation.