Innate immunity and intestinal microbiota in the development of Type 1 diabetes

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Abstract
The incidence of autoimmune diabetes in NOD (non-obese diabetic) mice, a lab model for type 1 diabetes, varies depending on the conditions in which they are kept. In particular, NOD mice exposed to killed mycobacteria and other microbial products are protected against the development of diabetes, suggesting the involvement of the rapid innate immune response. Experiments in NOD mice deficient in innate immunity — through the absence of the Toll-like receptor signal adaptor protein MyD88 — now show that both innate immunity and intestinal microbiota influence predisposition to diabetes. Germ-free MyD88-negative mice developed robust diabetes, yet in mice with a complement of gut microbes similar to the normal human gut, diabetes was reduced. This raises the prospect that live 'friendly' microbes, or microbial products might be therapeutic options for type 1 diabetes. The effect of deficiency of MyD88 on the generation of type 1 diabetes (T1D) has been investigated through the generation of congenic strains in the non-obese diabetic (NOD) mouse model. It is found that in specific pathogen-free conditions, MyD88-deficiency attenuates T1D, indicating that the interaction of intestinal microbes with the innate immune system is a critical factor in modifying susceptibility to type 1 diabetes. Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing β-cells. Its incidence has increased during the past several decades in developed countries1,2, suggesting that changes in the environment (including the human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility3 or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products4,5. Here we show that specific pathogen-free NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.