TRIF deficiency protects non-obese diabetic mice from type 1 diabetes by modulating the gut microbiota and dendritic cells

Publication date: Available online 28 June 2018
Source:Journal of Autoimmunity
Author(s): Elke Gülden, Chen Chao, Ningwen Tai, James A. Pearson, Jian Peng, Monika Majewska-Szczepanik, Zhiguang Zhou, F. Susan Wong, Li Wen
The incidence of type 1 diabetes (T1D) is determined by both genetic and environmental factors. In recent years, the gut microbiota have been identified to be an important environmental factor that could modify diabetes susceptibility. We have previously shown that Myeloid differentiation primary response gene 88 (MyD88), a major adaptor protein downstream of most innate immune Toll-like receptor (TLR) signaling, is important for mediating diabetes susceptibility in the non-obese diabetic (NOD) mouse model of human T1D. Here we report the role of TIR-domain-containing adapter-inducing interferon-β (TRIF) in T1D development, as TRIF is an important adaptor protein downstream of TLR3 and TLR4 signaling. We found that TRIF-deficient (TRIF^−/-) NOD mice were protected from development of diabetes, but only when housed with TRIF-deficient (TRIF^−/-) NOD mice. When housed with TRIF-sufficient wild type (WT, i.e., TRIF^+/+) NOD mice, the mice developed diabetes. We further investigated the gut microbiota as a potential cause for the altered diabetes development. Interestingly, TRIF^−/−NOD mice had a different microbiota composition compared to WT NOD mice, only if they were housed with TRIF^−/−NOD mice. However, the composition of gut microbiota in the TRIF^−/−NOD mice was indistinguishable from WT NOD mice, if they were housed with WT NOD mice. The difference in the gut microbiota in TRIF^−/−NOD mice, due to cohousing, accorded with the diabetes development in TRIF^−/−NOD mice. Comparing the gut microbiota in TRIF^−/- and WT NOD mice, we identified changes in percentage of Sutterella, Rikenella and Turicibacter species. Moreover, bacteria from WT NOD mice induced significantly stronger inflammatory immune responses in vitro compared to those from TRIF^−/−NOD mice. Further immunological analysis revealed impaired function of dendritic cells and reduced T cell activation and proliferation in TRIF^−/−NOD mice. Our data show that TRIF-deficiency protects NOD mice from diabetes development through alteration of the gut microbiota and reduced immune cell activation; however, that protection is over-ridden upon exposure to WT NOD bacteria. Therefore exposure to different microbiota can modify disease susceptibility determined by genetic factors related to innate immunity.



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