Background:The early treatment of rheumatoid arthritis (RA) is associated with better outcomes. In recent years, studies in our understanding of the preclinical events in RA help to define the “at-risk” populations who might go on to develop RA. Emerging evidence indicate that initiating events may occur at mucosal surfaces including oral cavity, lung and gut influenced by the local microbiome. Therefore, identifying the microbiome characteristics in prospective cohorts of at-risk individuals enables risk prediction or prevention of RA.Objectives:Here, we undertook this study to clarify the intestinal microbiota changes in individuals at high risk for RA. Meanwhile, we performed fecal transplantation study to investigate whereby the intestinal dysbiosis in the pre-RA population contributes to RA initiation and development, and provide a new prevention strategy for the treatment of this disease.Methods:42 high-risk for RA individuals (Pre-RA), who were defined as having a positive serum antibody for anti-cyclic citrullinated peptide (CCP), 31 RA patients and 38 healthy individuals (HC) were recruited in this study. The V3-V4 region of 16S ribosomal RNA of fecal samples from these individuals were sequenced. We evaluated the gut permeability and the gut barrier dysfuction using HE staining and RT-PCR in mice receiving fecal transplantation (FMT). Flow cytometry was applied to measure the proportions of T cell subsets in immune organs. The disease severity of collagen-induced arthritis (CIA) was also evaluated after the mice receiving FMT.Results:Alpha diversity analysis showed a comparable community richness and a lower community diversity of the intestinal microbiota in Pre-RA compared to HC (Fig 1A). At the family level, the abundance ofBacteroidaceaegradually decreased from HC to Pre-RA individuals and to RA patients (Fig 1B). On the contrary, the enriched abundances ofStreptococcaceae, Lactobacillus, Lactococcus, Weissellaandunclassified_o_Lactobacillaleswere observed in RA patients (Fig 1B). There was different intestinal microbiota construction between groups based on principal coordinate analysis (PCoA). The intestinal microbiota communities dynamically shifted from HC to Pre-RA and to RA patients (Fig.1C). Fecal transplantation study showed that gut microbiota from Pre-RA group (P) significantly increased the fluorescence intensity (Fig 2A), accompanied with a significantly decreased ZO-1 gene expression (Fig 2B), and injured epithelial microvilli of the small intestine (Fig 2C). Moreover, the percentages of Th17 cells in the mesenteric lymph nodes (mLN) and peyer patches (PP) were also significantly increased in P and R groups (Fig 2D, E). Importantly, in CIA models, the joints redness and swelling in the mice receiving Pre-RA faeces occurred earlier and were more severe compared to HC-transplanted mice (Fig 2F, G and H).Figure 1.Figure 2.Conclusion:The intestinal microbiota changed gradually during disease progression of human rheumatoid arthritis. The gut microbiota from Pre-RA individuals can trigger the gut barrier dysfunction and intestinal mucosal immunity imbalance, which may further contribute to the arthritis initiation and development.References:[1]Brusca, S. B., Abramson, S. B. & Scher, J. U. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity.Curr Opin Rheumatol26, 101-107, doi:10.1097/bor.0000000000000008 (2014).[2]Rogers, G. B. Germs and joints: the contribution of the human microbiome to rheumatoid arthritis.Nat. Med.21, 839-841, doi:10.1038/nm.3916 (2015).[3]Holers, V. M.et al.Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction.Nature reviews. Rheumatology, doi:10.1038/s41584-018-0070-0 (2018).Acknowledgments:The work of the authors is supported by National Natural Science Foundation of China (Grant Number: 81770101, 81403041) and Outstanding interdisciplinary project of West China Hospital, Sichuan University (Grant Number: ZYJC18024).Disclosure of Interests:None declared
Intestinal Dysbiosis and Rheumatoid Arthritis: A Link between Gut Microbiota and the Pathogenesis of Rheumatoid Arthritis