Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA.DOI: http://dx.doi.org/10.7554/eLife.01202.001

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Maternal immune activation (MIA) contributes to behavioral abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring1-4. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing Autism Spectrum Disorder (ASD)5-7. We recently demonstrated that interleukin-17a (IL-17a) produced by Th17 cells, CD4+ T helper effector cells involved in multiple inflammatory conditions, is required in pregnant mice to induce behavioral as well as cortical abnormalities in the offspring exposed to MIA8. However, it is unclear if other maternal factors are required to promote MIA-associated phenotypes. Moreover, underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here, we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote Th17 cell differentiation. Pregnant mice that had been colonized with the mouse commensal segmented filamentous bacteria (SFB) or human commensal bacteria that induce intestinal Th17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells (DCs) from pregnant, but not from non-pregnant, females upon exposure to MIA secrete IL-1β/IL-23/IL-6 and stimulate T cells to produce IL-17a. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce Th17 cells may increase the risk for neurodevelopmental disorders in offspring of pregnant mothers undergoing immune system activation due to infections or autoinflammatory syndromes.

The intestinal microbiota have critical roles in immune system and metabolic homeostasis, but they must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents1-6. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis7. We hypothesized that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. We demonstrate that, at steady state, the microbiota inhibit the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph node (MLN). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria trafficked to the MLN in a CCR7-dependent manner and induced both T cell responses and IgA production. Trafficking was carried out by CX3CR1hi mononuclear phagocytes, an intestinal cell population previously reported to be non-migratory8. These findings define a central role for commensals in regulating the migration to the MLN of CX3CR1hi mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.