Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling
Yuanheng Yang, Cong Jing Hao, Tingying Jiao, Zidan Yang, Hui Li, Yuqing Zhang, Weiya Zhang, Michael Doherty, Chuying Sun, Tuo Yang, Jiatian Li, Jing Wu, Mengjiao Zhang, Yilun Wang, Dongxing Xie, Tingjian Wang, Ning Wang, Xi Huang, Changjun Li, Frank J. Gonzalez, Jie Wei, Cen Xie, Chao Zeng, Guanghua Lei
Abstract
Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)—the receptor of GUDCA—alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of Clostridium bolteae , which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with C. bolteae and Food and Drug Administration–approved UDCA alleviated osteoarthritis through the gut FXR–joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota–GUDCA–intestinal FXR–GLP-1–joint pathway offers a potential strategy for osteoarthritis treatment.