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

doi:10.1126/science.adt0548

. 2025 Apr 4;388(6742):eadt0548.

doi: 10.1126/science.adt0548. Epub 2025 Apr 4.

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

Yuanheng Yang^#^{1

2}, Cong Hao^#¹, Tingying Jiao^#^{3

4}, Zidan Yang^#^{5

6

7}, Hui Li^#^{1

5

6}, Yuqing Zhang^{8

9}, Weiya Zhang^{10

11}, Michael Doherty^{10

11}, Chuying Sun¹², Tuo Yang^{5

6

13}, Jiatian Li¹, Jing Wu^{5

6}, Mengjiao Zhang¹², Yilun Wang^{1

5

6}, Dongxing Xie^{1

5

6}, Tingjian Wang^{5

6

14}, Ning Wang^{1

5

6}, Xi Huang^{15

16}, Changjun Li^{5

6

17}, Frank J Gonzalez¹⁸, Jie Wei^{1

5

6

19

20}, Cen Xie^{3

12}, Chao Zeng^{1

5

6

19

21}, Guanghua Lei^{1

5

6

21}

Affiliations

¹ Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
² Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China.
⁵ Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
⁶ Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China.
⁷ Bioinformatics Center, Xiangya Hospital, Central South University, Changsha, China.
⁸ Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ The Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.
¹¹ Pain Centre Versus Arthritis UK, Nottingham, UK.
¹² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
¹³ Health Management Center, Xiangya Hospital, Central South University, Changsha, China.
¹⁴ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
¹⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, China.
¹⁸ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁹ Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.
²⁰ Bioinformatics Center, Furong Laboratory, Changsha, China.
²¹ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

^# Contributed equally.

PMID: 40179178
DOI: 10.1126/science.adt0548

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

Yuanheng Yang et al. Science. 2025.

. 2025 Apr 4;388(6742):eadt0548.

doi: 10.1126/science.adt0548. Epub 2025 Apr 4.

Authors

Affiliations

¹ Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
² Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China.
⁵ Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
⁶ Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China.
⁷ Bioinformatics Center, Xiangya Hospital, Central South University, Changsha, China.
⁸ Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ The Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.
¹¹ Pain Centre Versus Arthritis UK, Nottingham, UK.
¹² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
¹³ Health Management Center, Xiangya Hospital, Central South University, Changsha, China.
¹⁴ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
¹⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, China.
¹⁸ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁹ Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.
²⁰ Bioinformatics Center, Furong Laboratory, Changsha, China.
²¹ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

^# Contributed equally.

PMID: 40179178
DOI: 10.1126/science.adt0548

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

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

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