Qu-zhuo-tong-bi decoction exerts gouty arthritis therapy by skewing macrophage polarization through butanoate metabolism

BACKGROUND: Qu-zhuo-tong-bi decoction (QZTBD), a traditional Chinese medicine (TCM), has demonstrated efficacy in the treatment of gouty arthritis. However, to date, the precise pharmacological mechanisms remain unclear. PURPOSE: The study aims to ascertain the therapeutic effects and the underlying mechanisms of QZTBD in the treatment of gouty arthritis. METHODS: The efficacy and safety of different doses of QZTBD were investigated in Uox-KO mice. Candidate active ingredients were identified using UHPLC-MS/MS. The potential therapeutic pathways of the active ingredients were predicted through network pharmacology. The mechanisms of QZTBD in alleviating gouty arthritis were explored via comprehensive analyses of gut microbiota, combined with RT-qPCR, western blot, immunofluorescence, ELISA, flow cytometry, and Seahorse assay. Fecal microbiota transplantation (FMT), bacterial culture experiment, butyrate-producing bacteria (BPB) and butyrate administration, and 2-DG intervention were conducted to explore the roles of BPB and butanoate metabolism in gout progression and therapeutic mechanisms of QZTBD. In vitro studies further validated the regulatory effects of butyrate and QZTBD on macrophage polarization through glycolysis modulation. RESULTS: 18.0 g/kg/d of QZTBD effectively alleviated the symptoms of gouty arthritis with excellent hepatic and renal safety. UHPLC-MS/MS analysis and network pharmacology revealed that QZTBD exerts its effects on butanoate metabolism during gouty arthritis inflammation. QZTBD treatment increased the abundance of BPB, the levels of serum and colon butyrate, and the expression levels of Buk and But. The transplantation of QZTBD-treated microbiota reproduced the therapeutic effects of QZTBD. M1 macrophage polarization was suppressed after QZTBD intervention. The administration of BPB and butyrate attenuated gouty arthritis and orchestrated macrophage polarization. Inhibition of glycolysis regulated the phenotype of macrophage and attenuated inflammatory processes. In vitro analysis unveiled that QZTBD and butyrate modulated glycolysis to regulate macrophage polarization, thereby alleviating gouty arthritis. CONCLUSION: QZTBD targeted butanoate metabolism to regulate macrophage polarization, thereby effectively alleviating intestinal inflammation and restoring immune homeostasis in gouty arthritis. These findings establish a mechanistic foundation for developing precision therapeutic strategies leveraging QZTBD to combat gouty arthritis.