Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling

• 成果类型: Article
• 署名作者: Yang, Yuanheng; Hao, Cong; Jiao, Tingying; Yang, Zidan; Li, Hui; Zhang, Yuqing; Zhang, Weiya; Doherty, Michael; Sun, Chuying; Yang, Tuo; Li, Jiatian; Wu, Jing; Zhang, Mengjiao; Wang, Yilun; Xie, Dongxing; Wang, Tingjian; Wang, Ning; Huang, Xi; Li, Changjun; Gonzalez, Frank J.; Wei, Jie; Xie, Cen; Zeng, Chao; Lei, Guanghua
• 署名单位: Central South University; Central South University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Fudan University; Central South University; Central South University; Central South University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; University of Nottingham; Nanjing University of Chinese Medicine; Central South University; Central South University; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Central South University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Central South University; Furong Laboratory; Central South University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11566
• DOI: 10.1126/science.adt0548
• 发表日期: 2025-04-04
• 关键词: acid; microbiota; diagnosis; HEALTH

摘要

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.