2. Academic Validation
  3. Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

  • Bone Res. 2024 May 23;12(1):31. doi: 10.1038/s41413-024-00336-6.
Hongzhen Chen # 1,  Xuekun Fu # 1 2,  Xiaohao Wu # 3 4 5,  Junyi Zhao 1,  Fang Qiu 1 2,  Zhenghong Wang 6,  Zhuqian Wang 1 2,  Xinxin Chen 1,  Duoli Xie 1 2,  Jie Huang 1 2,  Junyu Fan 7,  Xu Yang 8,  Yi Song 6,  Jie Li 9,  Dongyi He 7,  Guozhi Xiao 10,  Aiping Lu 11 12 13,  Chao Liang 14 15 16
Affiliations

Affiliations

  • 1 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China.
  • 2 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
  • 3 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China.
  • 4 Division of Immunology and Rheumatology, Stanford University, Stanford, CA, 94305, USA.
  • 5 VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
  • 6 Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 7 Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 8 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 9 Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China.
  • 10 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China. xiaogz@sustech.edu.cn.
  • 11 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China. aipinglu@hkbu.edu.hk.
  • 12 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, 510006, China. aipinglu@hkbu.edu.hk.
  • 13 Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. aipinglu@hkbu.edu.hk.
  • 14 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China. liangc@sustech.edu.cn.
  • 15 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China. liangc@sustech.edu.cn.
  • 16 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China. liangc@sustech.edu.cn.
  • # Contributed equally.
PMID: 38782893 DOI: 10.1038/s41413-024-00336-6
Abstract

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the Others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

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