Cited by 160Gut microbiota and healthOsteoarthritis Treatment and MechanismsDrug Transport and Resistance Mechanisms

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

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Yang, Yuanheng, Hao, Cong, Jiao, Tingying, Yang, Zidan, Li, Hui, Zhang, Yuqing, Zhang, Weiya, Doherty, Michael +16 more·2025·Science

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.

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Crossref · 10.1126/science.adt0548

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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
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
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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