Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling
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 <i>Clostridium bolteae</i>, which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with <i>C. bolteae</i> 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.
Authors
- Chuying Sun
- Cen Xie (ORCID: https://orcid.org/0000-0002-4574-8456)
- Zidan Yang
- Yuqing Zhang (ORCID: https://orcid.org/0000-0001-7954-1149)
- Michael Doherty (ORCID: https://orcid.org/0000-0002-5763-8326)
- Mengjiao Zhang
- Cong Jing Hao
- Weiya Zhang (ORCID: https://orcid.org/0000-0003-1142-1460)
- Chao Zeng (ORCID: https://orcid.org/0000-0003-4889-5731)
- Jiatian Li (ORCID: https://orcid.org/0000-0002-1519-0615)
- Wang Ting-jian
- Ning Wang (ORCID: https://orcid.org/0000-0002-3801-6097)
- Xi Huang (ORCID: https://orcid.org/0000-0002-7177-7525)
- Frank J. Gonzalez (ORCID: https://orcid.org/0000-0002-7990-2140)
- Dongxing Xie (ORCID: https://orcid.org/0000-0003-2672-4544)
- Guanghua Lei (ORCID: https://orcid.org/0000-0003-2987-138X)
- Jie Wei (ORCID: https://orcid.org/0000-0003-3510-8241)
- Hui Li (ORCID: https://orcid.org/0000-0002-7184-592X)
- Yilun Wang (ORCID: https://orcid.org/0000-0002-9468-4110)
- Tuo Yang (ORCID: https://orcid.org/0000-0003-0738-4812)
- Jing Wu (ORCID: https://orcid.org/0000-0002-1112-4899)
- Changjun Li (ORCID: https://orcid.org/0000-0003-2718-0921)
- Yuanheng Yang
- Tingying Jiao (ORCID: https://orcid.org/0000-0002-8453-8291)
Institutions
- National Institutes of Health (US)
- Nanjing University of Chinese Medicine (CN)
- Harvard University (US)
- Central South University (CN)
- University of Nottingham (GB)
- University of Toronto (CA)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Hospital for Sick Children (CA)
- Massachusetts General Hospital (US)
- Shanghai Institute of Materia Medica (CN)
- Arthritis UK (GB)
- National Cancer Institute (US)
- Institute of Bioinformatics (IN)
- Center for Cancer Research (US)
- Xiangya Hospital Central South University (CN)
Publication Details
- Journal
- Science
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1126/science.adt0548
- Citations
- 71
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 74.22