Luo Yubin, Tong Yanli, Wu Liang, Niu Haitao, Li Yanhong, Su Lin Chong, Wu Yuxi, Bozec Aline, Zaiss Mario M, Qing Pingying, Zhao Hua, Tan Chunyu, Zhang Qiuping, Zhao Yi, Tang Huairong, Liu Yi
Department of Rheumatology and Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
School of Medicine, Jinan University, Guangzhou, China.
Arthritis Rheumatol. 2023 Oct;75(10):1736-1748. doi: 10.1002/art.42616. Epub 2023 Sep 21.
In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis.
Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice.
Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice.
Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis.
在本研究中，我们旨在解析类风湿关节炎（RA）高危个体的肠道微生物群（GM）和血清代谢特征，并研究GM对黏膜免疫系统的致病作用及其在关节炎发病机制中的参与情况。
收集了38名健康个体和53名抗瓜氨酸化蛋白抗体（ACPA）阳性的RA高危个体（RA前期）的粪便样本，53名RA前期个体中有12人在随访的5年内发展为RA。通过16S核糖体RNA测序确定健康对照组与RA前期个体之间或RA前期亚组之间肠道微生物组成的差异。还探索了血清代谢物谱及其与GM的相关性。此外，对接受健康对照组或RA前期组GM的抗生素预处理小鼠进行肠道通透性、炎性细胞因子和免疫细胞群体评估。还应用胶原诱导性关节炎（CIA）来测试RA前期个体的粪便微生物群移植（FMT）对小鼠关节炎严重程度的影响。
RA前期个体的粪便微生物多样性低于健康对照组。健康对照组与RA前期个体之间的细菌群落结构和功能存在显著差异。虽然RA前期亚组之间的细菌丰度在一定程度上存在差异，但未观察到明显的功能差异。RA前期组血清中的代谢物与健康对照组血清中的代谢物有显著差异，氨基酸和脂质代谢的KEGG通路富集。此外，RA前期组的肠道细菌增加了FMT小鼠的肠道通透性以及小肠和Caco-2细胞中紧密连接蛋白1的表达。此外，与健康对照组相比，接受RA前期粪便的小鼠肠系膜淋巴结和派尔集合淋巴结中的Th17细胞也增加。与健康对照组FMT小鼠相比，关节炎诱导前肠道通透性和Th17细胞活化的变化增强了RA前期FMT小鼠的CIA严重程度。
RA高危个体中已出现肠道微生物失调和代谢组改变。临床前期个体的FMT引发肠道屏障功能障碍并改变黏膜免疫，进一步促进关节炎的发展。
