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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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Self-citationFeng, H., Nan, J., Wu, R. Y., Zhang, B., Liu, Q., Ma, T., Zhang, Z., Hu, Y., Xie, J., & Yang, Y. (2026) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-026-00960-6 · Cited by 1
“However, these interventions fail to reverse disease progression or repair damaged cartilage [14], highlighting the urgent need for disease-modifying therapies.”
Self-citationYu, T., Liu, Z., Liu, Y., Gao, M., Guo, F., Liu, Y., Xiong, J., Jiang, Y., & Yan, S. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.158363 · Cited by 1
Wang, W., Fortuna, R., Mayengbam, S., Seerattan, R. A., Mu, C., Rios, J. L., Abughazaleh, N., Vaghef‐Mehrabany, E., Tuplin, E. W. N., Hart, D. A., et al. (2026) · Gut Microbes · doi:10.1080/19490976.2026.2679516 · Cited by 1
“2 In mice, farnesoid X receptor (FXR) inhibition and/or intra-articular injection of the GLP-1 receptor agonist liraglutide mitigate cartilage degradation.”
InfluentialHeading Toward a Different Future: The Microbiome, Dysbiosis, Microbial Translocation, and Beyond
He, M., Ferrini, A., Chisari, E., Kolhoff, F. K., Sehgal, P., & Parvizi, J. (2026) · Journal of Bone and Joint Surgery · doi:10.2106/jbjs.25.01100 · Cited by 1
Jiang, Y., Qin, W., Wei, L., Liao, Y., & Wei, G. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1862397 · Cited by 1
“Accumulating studies have verified that gut microbiota participates in the initiation and progression of OA (12, 13).”
The oral–gut microbiome axis in systemic bone-related diseases
Zhang, Z., Sun, L., Lou, F., & Xiao, J. (2026) · Oral Science and Homeostatic Medicine · doi:10.26599/oshm.2026.9610069 · Cited by 1
Immunomodulatory mechanisms of bile acids in autoimmune diseases along the gut-liver axis
Zhang, S., Xiong, X., Wei, S., Meng, R., An, H., & Chen, L. (2026) · Autoimmunity Reviews · doi:10.1016/j.autrev.2026.104183 · Cited by 1
Makarczyk, M. J., Zhang, Y., Aguglia, A. M., Bartholomew, O., Hines, S. E., Li, K., Sinkar, S., Liu, S., Duvall, C. L., & Lin, H. (2025) · eLife · doi:10.7554/elife.106224.2 · Cited by 1
Self-citationMakarczyk, M. J., Zhang, Y., Aguglia, A. M., Bartholomew, O., Hines, S. E., Li, K., Sinkar, S., Liu, S., Duvall, C. L., & Lin, H. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.18.643933
Self-citationMicrobiome variations in osteoarthritis reflect aging and metabolic factors, not the diseasePreprint
Bevc, K., Malfertheiner, L., Neuenschwander, S., Tran, V. D. T., Pagni, M., Pantiukh, K., Jaagura, M., Niiranen, T., Knight, R. D., Salomaa, V. V., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.24.661261
“Interestingly, one study also reported a lower abundance of Clostridium boltae and suggests that this alters microbial bile acid formation and affects OA progression 30 .”
Exploring the interactions of gut microbiome and metabolites in polycystic ovary syndrome: a review
Li, J., Jia, Y., Xu, H., Bing, H., Ling, Q., Wang, S., Wang, Y., Zhang, X., & Zhao, L. (2025) · Microbiological Research · doi:10.1016/j.micres.2025.128309 · Cited by 1
Self-citationMetformin for Treatment of Knee Osteoarthritis in Patients With Overweight or Obesity
Yen, H., Fu, S., & Chiang, C. (2025) · JAMA · doi:10.1001/jama.2025.10717
Makarczyk, M. J., Zhang, Y., Aguglia, A. M., Bartholomew, O., Hines, S. E., Li, K., Sinkar, S., Liu, S., Duvall, C. L., & Lin, H. (2025) · eLife · doi:10.7554/elife.106224.3
Self-citationHong, L., Zhu, X., Zhu, J., Chen, N., & Bao, W. (2025) · Transboundary and Emerging Diseases · doi:10.1155/tbed/2422900
“…in fl uence osteoarthritis progression and intestinal far-nesoid X receptor is a viable therapeutic target to ameliorate osteoarthritis by increasing intestinal L cell-secreted glucagon-like peptide 1, which uncovered the existence of a functional and targetable gut-joint axis in human [12].”
Wen, H., Li, J., Yin, J., Hu, Y., Wang, R., Li, H., & Zhou, S. (2025) · Journal of Future Foods · doi:10.1016/j.jfutfo.2025.12.005
Self-citationGuan, S., & Mei, Y. (2026) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.70535
The local-mechanical and systemic-metabolic dialogue: A new dawn in osteoarthritis treatment
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“Two seminal studies published in 2025, one in Cell by Zhu et al. 4 and another in Science by Yang et al., 5 have risen to this challenge.”
Wang, W., Fortuna, R., Mayengbam, S., Seerattan, R. A., Mu, C., Rios, J. L., Abughazaleh, N., Mehrabany, E. V., Tuplin, E. W. N., Hart, D. A., et al. (2026) · medRxiv · doi:10.64898/2026.01.21.26344540
Advanced Biomaterials Revolutionize Gout Therapy: From Uric Acid Degradation to Pain Alleviation
Cao, J., Gong, F., Han, Z., Qiao, X., Cui, X., & Cheng, L. (2026) · Advanced Functional Materials · doi:10.1002/adfm.202530174
“Conversely, dysbiosis of the microbiota may affect the production of these beneficial metabolites, negatively impact bone health, and trigger various types of bone inflammation [148, 149].”
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“Recent advances in antibody engineering enable precise, instructive modulation of immune cells— particularly macrophages— in vivo [29–34].”
Intra-articular GLP-1 analogues: A new disease-modifying strategy for osteoarthritis?
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“A reduced abundance of E. bolteae has been documented in patients with osteoarthritis, and its colonization has been shown to alleviate disease progression via the gut FXR-joint GLP-1 axis [46].”
Bjerkhaug, A. U., Jakobsson, J. E., Ahmed, A. S., Carlsson, H., Erngren, I., Al-Grety, A., Farinotti, A. B., Svensson, C. I., Kultima, K., & Kosek, E. (2026) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2026.101227
“Given the availability of FDA-approved drugs that modulate bile acid metabolism (e.g., UDCA, FXR agonists/antagonists, and GLP-1R agonists), these insights may inform future personalized treatment strategies for OA that integrate metabolic and microbiota-focused approaches (Yang et al., 2025).”
InfluentialPekary, A. E., & Sattin, A. (2026) · Research Square · doi:10.21203/rs.3.rs-9162755/v1
Targeting Bifidobacterium animalis alleviates high-fluoride exposure-induced kidney injury in mice
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“Microbiome research increasingly follows a discovery-to-validation pipeline: microbiome profiling identifies candidate taxa, which are then tested in vivo using defined strains to evaluate effects beyond the gut (Gui et al. 2024; Routy et al. 2018; Yuan et al. 2019; Yang et al. 2025).”
ASSOCIATION BETWEEN HAND SYNOVITIS AND ALL-CAUSE MORTALITY: A GENERAL POPULATION-BASED STUDY
Liu, K., Weng, Q., Zhang, Y., Zhang, W., Doherty, M., Yang, T., Yang, Z., Chen, Q., Su, C., Wang, Y., et al. (2026) · Arthritis Care & Research · doi:10.1002/acr.80141
Self-citationZhang, Y., Gao, B., Zhu, X., Chen, Y., Huang, C., & Wang, G. (2025) · Archives of Clinical Rheumatology · doi:10.33696/rheumatology.1.004
Self-citationBeaulieu, M. L., Patel, N. B., & Wojtys, E. M. (2026) · Osteoarthritis and Cartilage Open · doi:10.1016/j.ocarto.2026.100807
“Notably, a recently published PTOA study provides a more specific mechanistic example of gut-joint axis [53].”
Yang, Y., Liu, X., Wang, M., Zhu, X., Yang, B., Cao, J., Song, Y., & Jiang, G. (2026) · Environment & Health · doi:10.1021/envhealth.5c00852
Self-citation
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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