Nature 455, 1109-1113 (23 October 2008) | doi:10.1038/nature07336; Received 18 July 2008; Accepted 8 August 2008; Published online 21 September 2008

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

Li Wen1,7, Ruth E. Ley2,7,8, Pavel Yu. Volchkov3,7, Peter B. Stranges3,4, Lia Avanesyan3,4, Austin C. Stonebraker4, Changyun Hu1, F. Susan Wong5, Gregory L. Szot6, Jeffrey A. Bluestone6, Jeffrey I. Gordon2 & Alexander V. Chervonsky3,4

  1. Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
  2. Center for Genome Sciences, Washington University School of Medicine, St Louis, Missouri 63108, USA
  3. Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA
  4. The Jackson Laboratory, Bar Harbor, Maine 04609, USA
  5. Department of Cellular and Molecular Medicine, School of Medical Science, Bristol University, Bristol, BS8 1TD, UK
  6. Diabetes Center at the University of California San Francisco, San Francisco, California 94143, USA
  7. These authors contributed equally to this work.
  8. Present address: Department of Microbiology, Cornell University, Ithaca, New York 14850, USA.

Correspondence to: Alexander V. Chervonsky3,4 Correspondence and requests for materials should be addressed to A.V.C. (Email: achervon@bsd.uchicago.edu).

Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing beta-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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