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Innate immunity and intestinal microbiota in the development of 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.

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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.

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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.


  1. 1

    Karvonen, M., Tuomilehto, J., Libman, I. & LaPorte, R. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. World Health Organization DIAMOND Project Group. Diabetologia 36, 883–892 (1993)

    CAS  Article  Google Scholar 

  2. 2

    Patterson, C. C., Dahlquist, G., Soltesz, G. & Green, A. Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia 44 (suppl. 3). B9–B16 (2001)

    Article  Google Scholar 

  3. 3

    Pozzilli, P., Signore, A., Williams, A. J. & Beales, P. E. NOD mouse colonies around the world–recent facts and figures. Immunol. Today 14, 193–196 (1993)

    CAS  Article  Google Scholar 

  4. 4

    McInerney, M. F., Pek, S. B. & Thomas, D. W. Prevention of insulitis and diabetes onset by treatment with complete Freund’s adjuvant in NOD mice. Diabetes 40, 715–725 (1991)

    CAS  Article  Google Scholar 

  5. 5

    Sadelain, M. W., Qin, H. Y., Lauzon, J. & Singh, B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 39, 583–589 (1990)

    CAS  Article  Google Scholar 

  6. 6

    Janeway, C. A. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989)

    CAS  Article  Google Scholar 

  7. 7

    Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006)

    CAS  Article  Google Scholar 

  8. 8

    Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

    CAS  Article  Google Scholar 

  9. 9

    Strober, W. Epithelial cells pay a Toll for protection. Nature Med. 10, 898–900 (2004)

    CAS  Article  Google Scholar 

  10. 10

    Wong, F. S. et al. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nature Med. 5, 1026–1031 (1999)

    CAS  Article  Google Scholar 

  11. 11

    Graser, R. T. et al. Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions. J. Immunol. 164, 3913–3918 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Amrani, A. et al. Perforin-independent beta-cell destruction by diabetogenic CD8+ T lymphocytes in transgenic nonobese diabetic mice. J. Clin. Invest. 103, 1201–1209 (1999)

    CAS  Article  Google Scholar 

  13. 13

    Haskins, K. & McDuffie, M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249, 1433–1436 (1990)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Lieberman, S. M. et al. Individual nonobese diabetic mice exhibit unique patterns of CD8+ T cell reactivity to three islet antigens, including the newly identified widely expressed dystrophia myotonica kinase. J. Immunol. 173, 6727–6734 (2004)

    CAS  Article  Google Scholar 

  15. 15

    Lieberman, S. M. et al. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 100, 8384–8388 (2003)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Hoglund, P. et al. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J. Exp. Med. 189, 331–339 (1999)

    CAS  Article  Google Scholar 

  17. 17

    Turley, S. J., Lee, J. W., Dutton-Swain, N., Mathis, D. & Benoist, C. Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc. Natl Acad. Sci. USA 102, 17729–17733 (2005)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Suzuki, T. et al. in Immune-deficient Animals in Biomedical Research (eds Rygaard, J. B. N., Graem, N. & Spang-Thomsen, M.) 112–116 (Karger, 1985)

    Google Scholar 

  19. 19

    Gray, D. H., Gavanescu, I., Benoist, C. & Mathis, D. Danger-free autoimmune disease in Aire-deficient mice. Proc. Natl Acad. Sci. USA 104, 18193–18198 (2007)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Kim, H. S. et al. Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27, 321–333 (2007)

    CAS  Article  Google Scholar 

  21. 21

    Dewhirst, F. E. et al. Phylogeny of the defined murine microbiota: altered Schaedler flora. Appl. Environ. Microbiol. 65, 3287–3292 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Rawls, J. F., Mahowald, M. A., Ley, R. E. & Gordon, J. I. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127, 423–433 (2006)

    CAS  Article  Google Scholar 

  25. 25

    Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006)

    CAS  Article  Google Scholar 

  26. 26

    Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)

    ADS  Article  Google Scholar 

  27. 27

    Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008)

    CAS  Article  Google Scholar 

  28. 28

    Funda, D. P., Fundova, P. & Harrison, L. C. Microflora-dependency of selected diabetes-preventive diets: germ-free and ex-germ-free monocolonized NOD mice as models for studying environmental factors in type 1 diabetes. Proc. 13th Int. Congr. Immunol. MS-11.4 16 (Brazilian Society for Immunology, Rio de Janeiro, 2007)

    Google Scholar 

  29. 29

    Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261–5267 (2007)

    CAS  Article  Google Scholar 

  30. 30

    Calcinaro, F. et al. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48, 1565–1575 (2005)

    CAS  Article  Google Scholar 

  31. 31

    Huber, T., Faulkner, G. & Hugenholtz, P. Bellerophon: a program to detect chimeric sequences in multiple sequence alignments. Bioinformatics 20, 2317–2319 (2004)

    CAS  Article  Google Scholar 

  32. 32

    Petkov, P. M. et al. An efficient SNP system for mouse genome scanning and elucidating strain relationships. Genome Res. 14, 1806–1811 (2004)

    CAS  Article  Google Scholar 

  33. 33

    Kanagawa, O., Militech, A. & Vaupel, B. A. Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice. J. Immunol. 168, 6159–6164 (2002)

    CAS  Article  Google Scholar 

  34. 34

    Takaki, T. et al. Requirement for both H-2Db and H-2Kd for the induction of diabetes by the promiscuous CD8+ T cell clonotype AI4. J. Immunol. 173, 2530–2541 (2004)

    CAS  Article  Google Scholar 

  35. 35

    Stratmann, T. et al. Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity. J. Clin. Invest. 112, 902–914 (2003)

    CAS  Article  Google Scholar 

  36. 36

    Dojka, M. A., Hugenholtz, P., Haack, S. K. & Pace, N. R. Microbial diversity in a hydrocarbon- and chlorinated-solvent-contaminated aquifer undergoing intrinsic bioremediation. Appl. Environ. Microbiol. 64, 3869–3877 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Weisburg, W. G., Barns, S. M., Pelletier, D. A. & Lane, D. J. 16S ribosomal DNA amplification for phylogenetic study. J. Bacteriol. 173, 697–703 (1991)

    CAS  Article  Google Scholar 

  38. 38

    Ludwig, W. et al. ARB: a software environment for sequence data. Nucleic Acids Res. 32, 1363–1371 (2004)

    CAS  Article  Google Scholar 

  39. 39

    Lozupone, C. & Knight, R. UniFrac: a new phylogenetic method for comparing microbial communities. Appl. Environ. Microbiol. 71, 8228–8235 (2005)

    CAS  Article  Google Scholar 

  40. 40

    Lozupone, C., Hamady, M. & Knight, R. UniFrac—an online tool for comparing microbial community diversity in a phylogenetic context. BMC Bioinformatics 7, 371 (2006)

    Article  Google Scholar 

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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).

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