Male microbiota protects female BWF1 mice from lupus and death by restoring CD103DC function possibly via metabolite(s) production (THER5P.914)

Abstract

Abstract Alterations in microbiota composition are associated with autoimmune diseases. Little is known about the effect of microbial metabolite production on disease development. CD103 dendritic cells (CD103DC) induce regulatory T cells (iTregs) in the periphery. We have found that lupus-resistant male BWF1 mice exhibit increased disease incidence/mortality when treated with anti-CD103 antibody. Female CD103DC exhibit lower tolerogenic function than male cells in vitro and in vivo (i.e., oral tolerance) possibly due to a defect in the retinoic acid synthesis pathway. We also found that microbiota composition differed significantly between female and male BWF1 mice, and transfer of male microbiota decreased autoantibody production in female BWF1 mice. Here we report that transfer of male microbiota prevents kidney disease and dramatically increases survival of female BWF1 mice which correlates with enhanced female CD103DC function in both in vitro and in vivo assays, and increased iTregs. Furthermore, our preliminary study suggests that treatment with anti-CD103 antibody prevents male microbiota-mediated protection. Finally, metabolomic analysis of feces from female and male BWF1 mice revealed significant quantitative differences in 17 metabolites, including one that exhibits retinoid X receptor agonist activity. Taken together, these data suggest that male microbiota may protect against lupus through the production of metabolite(s) that enhance the retinoic acid synthesis pathway.