Characterization of the microbiome in association with reduced diabetes incidence in AhR deficient NOD mice

AhR activation by the ligands TCDD and Cl-BBQ leads to potent immunosuppression and prevents hyperglycemia in NOD mice. In addition to exogenous treatment, AhR can be activated by endogenous ligands that control inflammation. AhR −/− mice on the C57Bl6 background have enhanced inflammatory responses following infectious or allergenic exposure in comparison to AhR wild type mice. We generated AhR−/− mice on the NOD background and hypothesized they would display an increased incidence of diabetes. Surprisingly, the opposite finding was observed; in the absence of AhR, female NOD mice have a significantly reduced onset of diabetes in comparison to wild type mice. A similar trend was observed between knockout and wild type male mice. While immune cell composition was unchanged in the pancreatic LN, an increase in the percentage of F4/80 + macrophages and CD25 + Foxp3+ T cells was observed in mesenteric LN of NOD.AhR −/− mice. Changes in gene expression in the ileum of NOD.AhR −/− mice included reduced Gzmb, Il10 and Lcn2. Commensal bacteria (including SFB and Akkermansia) have been identified that influence diabetes incidence in the NOD mouse model. It has been shown that microbial biproducts can activate AhR, and in turn, AhR activation (or lack thereof) can impact the microbiome. Thus, we hypothesize that NOD.AhR −/− mice have altered microbiota and that these changes contribute to the reduction in diabetes incidence. Initial observations demonstrated changes in fecal consistency and an increase in SFB associated with AhR deficiency. Current studies are focused on determining if shifts in the microbiome are directly associated with the reduction of diabetes incidence in NOD.AhR −/− mice.