Yiyangzi Ma1, Ruru Guo2, Yiduo Sun3, Xin Li4, Lun He4, Zhao Li5, Gregg J Silverman6, Guobing Chen4, Feng Gao4, Jiali Yuan7, Qiang Wei8, Mengtao Li9, Liangjing Lu10, Haitao Niu11. 1. School of Medicine and Institute of Laboratory Animal Sciences, Jinan University; Guangzhou Key Laboratory of Germ-free Animals and Microbiota Application, Guangzhou 510632, China; Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China. 2. Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China. 3. Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China; Department of Rheumatology，The First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU), Hangzhou 310003, China. 4. School of Medicine and Institute of Laboratory Animal Sciences, Jinan University; Guangzhou Key Laboratory of Germ-free Animals and Microbiota Application, Guangzhou 510632, China. 5. Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China; Beijing Hospital, National Center of Gerontology, Beijing 100730, China. 6. Division of Rheumatology, New York University School of Medicine, New York, NY 10016, USA. 7. School of Basic Medicine, Yunnan University of Traditional Chinese Medicine, China. 8. Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, China. 9. Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China. Electronic address: mengtao.li@cstar.org.cn. 10. Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China. Electronic address: luliangjing@renji.com. 11. School of Medicine and Institute of Laboratory Animal Sciences, Jinan University; Guangzhou Key Laboratory of Germ-free Animals and Microbiota Application, Guangzhou 510632, China; Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China. Electronic address: htniu@jnu.edu.cn.
Abstract
BACKGROUND: The etiology of systemic lupus erythematosus (SLE) is multifactorial. Recently, growing evidence suggests that the microbiota plays a role in SLE, yet whether gut microbiota participates in the development of SLE remains largely unknown. To investigate this issue, we carried out 16 s rDNA sequencing analyses in a cohort of 18 female un-treated active SLE patients and 7 female healthy controls, and performed fecal microbiota transplantation from patients and healthy controls to germ-free (GF) mice. RESULTS: Compared to the healthy controls, we found no significant different microbial diversity but some significantly different species in SLE patients including Turicibacter genus and other 5 species. Fecal transfer from SLE patients to GF mice caused GF mice to develop a series of lupus-like phenotypic features, including increased serum autoimmune antibodies, imbalanced cytokines, altered distribution of immune cells in mucosal and peripheral immune response, and upregulated expression of genes related to SLE in recipient mice that received SLE fecal microbiota transplantation (FMT). Moreover, the metabolism of histidine was significantly altered in GF mice treated with SLE patient feces, as compared to those which received healthy fecal transplants. CONCLUSIONS: Overall, our results describe a causal role of aberrant gut microbiota in contributing to the pathogenesis of SLE. The interplay of gut microbial and histidine metabolism may be one of the mechanisms intertwined with autoimmune activation in SLE.
BACKGROUND: The etiology of systemic lupus erythematosus (SLE) is multifactorial. Recently, growing evidence suggests that the microbiota plays a role in SLE, yet whether gut microbiota participates in the development of SLE remains largely unknown. To investigate this issue, we carried out 16 s rDNA sequencing analyses in a cohort of 18 female un-treated active SLE patients and 7 female healthy controls, and performed fecal microbiota transplantation from patients and healthy controls to germ-free (GF) mice. RESULTS: Compared to the healthy controls, we found no significant different microbial diversity but some significantly different species in SLE patients including Turicibacter genus and other 5 species. Fecal transfer from SLE patients to GF mice caused GF mice to develop a series of lupus-like phenotypic features, including increased serum autoimmune antibodies, imbalanced cytokines, altered distribution of immune cells in mucosal and peripheral immune response, and upregulated expression of genes related to SLE in recipient mice that received SLE fecal microbiota transplantation (FMT). Moreover, the metabolism of histidine was significantly altered in GF mice treated with SLE patient feces, as compared to those which received healthy fecal transplants. CONCLUSIONS: Overall, our results describe a causal role of aberrant gut microbiota in contributing to the pathogenesis of SLE. The interplay of gut microbial and histidine metabolism may be one of the mechanisms intertwined with autoimmune activation in SLE.