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Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling
Open accessAbstract
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.
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“Gut dysbiosis has been implicated in RA-associated immune activation, whereas modulation of microbial BA metabolism and glucagon-like peptide-1 secretion has emerged as a potential therapeutic route in OA [130].”
From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [130]
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Metadata
- Authors
- Yang, Y., Hao, C., Jiao, T., Yang, Z., Li, H., Zhang, Y., Zhang, W., Doherty, M., Sun, C., Yang, T., Li, J., Wu, J., Zhang, M., Wang, Y., Xie, D., Wang, T., Wang, N., Huang, X., Li, C., Gonzalez, F. J., Wei, J., Xie, C., Zeng, C., & Lei, G.
- Affiliations
- Central South University (CN)
- Chinese Academy of Sciences (CN)
- Harvard University (US)
- University of Nottingham (GB)
- Nanjing University of Chinese Medicine (CN)
- University of Toronto (CA)
- National Institutes of Health (US)
- Corresponding author
- Yang, Yuanheng
- Hao, Cong
- Jiao, Tingying
- Yang, Zidan
- Li, Hui
- Wei, Jie
- Xie, Cen
- Zeng, Chao
- Lei, Guanghua
- ORCID
- Venue
- Science
- Published
- 2025-04-04
- Volume
- 388
- Issue
- 6742
- Pages
- eadt0548-eadt0548
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4409176469
- Cited by
- 160
- References
- 91
- Citations by year
- 2026: 110 · 2025: 50
- FWCI
- 47.42
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (82 372 474, 2022YFC2505500, 81930071, 2022YFC3601900)
- Peking University
- Xiangya Hospital, Central South University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- osteoarthritis, gut-joint axis, glucagon-like peptide-1, farnesoid X receptor, glycoursodeoxycholic acid, bile acid metabolism, gut microbiota, Clostridium bolteae, ursodeoxycholic acid, GLP-1 receptor, joint replacement, microbiota-targeted therapy
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Clostridium, Female, Humans, Male, Mice, Inbred C57BL, Osteoarthritis, Ursodeoxycholic Acid, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Mice, Glucagon-Like Peptide 1
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