Mutual Modulation of Gut Microbiota and the Immune System in Type 1 Diabetes Models

Abstract

Objective Type 1 diabetes (T1D) has been associated with alterations of the gut microbiota. Here we investigate the cross-talk between the immune system and the intestinal microbiota in murine T1D. Design To evaluate the modulation of T1D by gut microbiota, non-obese diabetic (NOD) mice were cohoused with the 116C-NOD B-cell transgenic model. To further explore the influence of the adaptive immune system of NOD and 116C-NOD models on their fecal microbiota, we studied the immunodeficient variants NOD.RAG-2-/- and 116C-NOD.RAG-2-/-, as well as a non-T1D-prone mouse control. The role of B and T cells in modulating the gut microbiota composition was analyzed via intravenous injection of lymphocytes. Only female mice were studied. Results NOD cohoused with 116C-NOD exhibited a reduction of T1D incidence. This incidence decrease was associated with a shift from a Th1 to a Th17 immune response and was driven by intestinal microbiota changes. Moreover, T1D could be predicted by different gut bacterial signatures in each group of T1D-prone mice. The proliferation of segmented filamentous bacteria, known as immune modulatory organisms, was enabled by the absence of T lymphocytes in young NOD, 116C-NOD, and immunodeficient NOD.RAG-2-/- and 116C-NOD.RAG-2-/- at all ages. Conversely, Bifidobacterium colonization required the presence of lymphocytes and was boosted in a non-diabetogenic milieu. Finally, 116C-NOD B cells enriched the gut microbiota of 116C-NOD.RAG-2-/- in Adlercreutzia. Conclusion Together, these findings evidence the reciprocal modulation of gut microbiota and the immune system in rodent models of T1D.