Background Role of environmental factors in predisposition to develop rheumatoid arthritis (RA) have gained interest due, in part, to the studies showing an association of gut microbiota with immune homeostasis. Although the etiology of RA is unknown, recent studies on the role of gut microbiota in inflammatory adaptive immune response have led to the concept that interaction between the host microbiome and genetic factors influences autoimmunity. We have recently shown an association of Collinsella aerofaciens with RA
Objectives In this study, we aimed to determine how human gut commensals modulate arthritis phenotype in humanized mice expressing RA-susceptible HLA-DQ8.
Methods DQ8 mice following immunization with type II collagen develop arthritis and antigen-specific cellular and humoral response. DQ8 mice orally gavaged with RA-associated Collinsella aerofaciens and non-associated Prevotella histicola on alternate days for one week and were induced for arthritis. Gavage with microbes continued for 4 weeks. Mice were monitored for onset and progression of arthritis. Th17 regulatory network and cells involved in regulation were analyzed. DQ8 mice were gavaged with fecal homogenates supernatants from arthritis-resistant mice, induced for arthritis and monitored for disease.
Results Mice gavaged with C. aerofaciens enhanced disease severity while P. histicola protected mice from arthritis. While treatment with P. histicola reduced intestinal permeability by increasing expression of tight junction proteins, C. aerofaciens had a complete opposite effect. Suppression of arthritis by P histicola was dependent on an increase in the numbers of CD103+ dendritic cells, myeloid suppressors, CD11b+Gr-1, and T regulatory cells, CD4+CD25+FoxP3+, in the gut as well as systemically. This led to reduction in TH17 response while increasing IL-10. On the other hand, C. aerofaciens gavage increased expression of IL-17 and regulatory chemokines as compared to controls. DQ8 mice gavaged with intestinal microbes of arthritis-resistant mice developed arthritis with lower incidence and had skewed Th17/Th2 response.
Conclusions Our studies suggest that gut commensals influence immune response in and away from the gut. Commensals and their products may provide novel targets for therapeutic strategies in arthritis.
Acknowledgements Funds were provided by the Department of Defense and Mayo Center of Individualized Medicine
Disclosure of Interest None declared
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