Gut Microbiota Dysbiosis in High-Risk Individuals For Rheumatoid Arthritis Triggers Mucosal Immunity Perturbation and Promotes Arthritis in Mice

Abstract

Background: Intestinal microbial dysbiosis in patients with rheumatoid arthritis (RA) is associated with enhanced inflammation in the joint. Recent studies indicate intestinal microbiota changes prior to clinical signs of arthritis in the joints. However, it remains undefined whether gut microbiota dysbiosis is triggering the initiation and progression of RA during the preclinical stages. Here, we describe the gut microbiome characteristics in preclinical high-risk individuals for RA, and investigate their consequences on the mucosal immunes system and involvement in the pathogenesis of arthritis.Results: 16S rRNA sequencing was performed on faeces from human participants, comprising preclinical high-risk for RA individuals (Pre-RA, n=53), who were anti-citrullinated protein antibodies positive, established RA patients (RA, n=30) and healthy individuals (HCs, n=38). Pre-RA individuals showed lower fecal microbial diversity comparing with HCs. The bacterial community structure dynamically shifted from HCs to Pre-RA individuals and to RA patients, with the relative abundance changes of genera including Bacteroides, Ruminiclostridium_5, and Streptococcus. To further decipher the effect of these gut microbiota alterations in mucosal immune response, we transplanted pooled human fecal samples from each group into antibiotics pre-treated mice. The inoculation of faeces from the Pre-RA group increased fluorescent-labelled dextran uptake, decreased ZO-1 gene expression in the intestine, and changed typical microvilli structure of the small intestine of the recipient mice. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer’s patches were also increased in mice following fecal microbiota transplantation (FMT) from Pre-RA and RA compared to HC group. We also applied the collagen induced arthritis (CIA) mice model to test the effect of FTM from Pre-RA individuals on arthritis severity. Importantly, we revealed that the FMT from Pre-RA and RA group similarly enhanced clinical CIA symptom in recipient mice as compared with HC-FMT mice.Conclusions: Gut microbial dysbiosis is already present in high-risk individuals for RA with autoimmune signature. FMT from preclinical individuals triggers the intestinal barrier dysfunction and changed mucosal immunity further contributing to arthritis development.

The Role of Nutritional Factors and Intestinal Microbiota in Rheumatoid Arthritis Development

“…Modern utilization of 16S and “shotgun” sequencing allowed comparison of healthy-control gut flora with microbiota from RA patients ( Table 1 ). The subsequent findings have not been completely consistent across the literature, but a repeated feature has been the increase of Prevotella species in early RA [ 47 , 48 , 49 , 50 ], associated to a relative decrease in the Bacteroides genus [ 48 , 51 ]. The overrepresentation of Prevotella species is usually no longer found in established and treated RA patients [ 52 , 53 , 54 ].…”

“…Beyond P. copri or C. aerofaciens isolates, the “whole” pre-RA or RA-derived microbiota also worsen arthritis when transferred to mice models [ 47 , 51 , 53 ]. For instance, Prevotella species have been found invading the mucus layer in irritable bowel disease models [ 73 ] or in human colonic cancer related studies [ 74 , 75 ].…”

Role of Intestinal Dysbiosis and Nutrition in Rheumatoid Arthritis

“…The 16S next-generation sequencing (NGS) allows for rapid comparison of gut flora from healthy controls to RA patients. Prevotella copri ( P. copri ) is patients’ main bacterial population associated with dysbiosis [ 55 , 56 ]. A first-degree human gut microbiome study from Rodriguez et al showed that patients with preclinical auto-antibody positive RA had marked differences in gut microbial populations compared to healthy controls, namely an increase in Prevotellacaea , specifically Prevotella spp.…”