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

Abstract

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.

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Figure 1: MyD88-negative (MyD88 KO ) mice are completely protected from development of type 1 diabetes.
Figure 2: MyD88 deficiency leads to local tolerance to pancreatic antigens.
Figure 3: MyD88-negative NOD mice are protected from diabetes by the gut microbiota.
Figure 4: MyD88 deficiency leads to specific changes in the composition of intestinal microbiota.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

16S rRNA sequences obtained from microbiota of SPF NOD and MyD88KO NOD mice treated and not-treated with antibiotic were deposited in GenBank under accession numbers EU450891EU458113.

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Acknowledgements

The authors are thankful to A. Putnam, T. Park, D. Schumann, M. Prokhorovich, W. Du, D. O’Donnell, M. Karlsson and S. Wagoner for help with experiments, and S. Dryden Perkins and M. Garcia for assistance with sequence analysis. This work was supported by the ADA grant 1-05-RA-142 to L.W.; JDRF grant 19-2006-1075 to L.W. and F.S.W.; Animal Genetic Core of Diabetes Endocrinology Research Center (NIH grant DK45735) to L.W.; NIH grants R37 AI46643 and P30 DK63720 as well as the JDRF 4-2005-1168 grant to J.A.B.; NIH grants DK30292 and DK70977, and a W. M. Keck Foundation award to J.I.G.; NIH grant DK063452 to A.V.C.; JDRF grants 2005-204 and 2007-353 to A.V.C.; and the NIH/NIDDK Digestive Disease Research Core Center grant DK42086.

Author Contributions L.W. designed and supervised experiments at Yale University; R.E.L. performed analysis of 16S rRNA sequences of the gut microbiota; P.Yu.V. analysed T1D development in germ-free and microbiota-colonized mice; P.B.S. performed ELISPOT analysis; L.A. and A.C.S. established and characterized mutant mouse strains at The Jackson Laboratory and at The University of Chicago; C.H., F.S.W. and L.W. characterized mutant mouse strains at Yale University; G.L.S. was involved in performance of regulatory-T-cell-based assays; J.A.B. designed and supervised the T cell assays; J.I.G. helped with design and interpretation of gut microbial ecology studies and oversaw the microbiota transfer experiments; A.V.C. conceived and designed the project, and wrote the manuscript with substantial critical contributions from L.W., R.E.L., F.S.W., J.A.B. and J.I.G.

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Correspondence to Alexander V. Chervonsky.

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Wen, L., Ley, R., Volchkov, P. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008). https://doi.org/10.1038/nature07336

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