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

Hongzhen Chen1; Xuekun Fu1,2; Xiaohao Wu3,4,5; Junyi Zhao1; Fang Qiu1,2; Zhenghong Wang6; Zhuqian Wang1,2; Xinxin Chen1; Duoli Xie1,2; Jie Huang1,2; Junyu Fan7; Xu Yang8; Yi Song6; Jie Li9; Dongyi He7; Guozhi Xiao3; Aiping Lu2,10,11; Chao Liang1,2,12

2024-05-23

10.1038/s41413-024-00336-6

Bone Research   影响因子和分区

2095-4700

2095-6231

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. (Figure presented.)

SCI

英语

第一 ; 共同第一 ; 通讯

2-s2.0-85194159137

人工提交

在线出版

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.Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou 510006, China
11.Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
12.State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850 Beijing, China

Hongzhen Chen,Xuekun Fu,Xiaohao Wu,et al. Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis[J]. Bone Research,2024,12(31).

Hongzhen Chen.,Xuekun Fu.,Xiaohao Wu.,Junyi Zhao.,Fang Qiu.,...&Chao Liang.(2024).Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis.Bone Research,12(31).

Hongzhen Chen,et al."Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis".Bone Research 12.31(2024).