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. 2008 Oct 23;455(7216):1109-13.
doi: 10.1038/nature07336. Epub 2008 Sep 21.

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

Li Wen  1 , Ruth E Ley, Pavel Yu Volchkov, Peter B Stranges, Lia Avanesyan, Austin C Stonebraker, Changyun Hu, F Susan Wong, Gregory L Szot, Jeffrey A Bluestone, Jeffrey I Gordon, Alexander V Chervonsky
Affiliations

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

Li Wen et al. Nature. .

Abstract

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 countries, 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 facility or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products. 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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Figures

Figure 1
Figure 1. MyD88-negative (MyD88KO) mice are completely protected from development of type 1 diabetes
Incidence of diabetes in two independently derived NOD.MyD88KO and heterozygous NOD.MyD88KO/+ stocks (J-Jackson Laboratory and Y-Yale) (12 back-crosses to NOD). F, females; M, males. n, number of animals per group.
Figure 2
Figure 2. MyD88 deficiency leads to local tolerance to pancreatic antigens

  1. The overall reactivity of T cells from secondary lymphoid organs of MyD88-sufficient (solid bars) and MyD88-negative (open bars) NOD mice was calculated as a mean of the percentages of mice in the given group reacting to individual diabetes-associated peptides (see Supplemental Fig. 2c).

  2. The frequency of CD8+ T cells producing IFN-γ in response to peptide recognized by diabetogenic clone 8.3 was determined in the spleens, MLN and PLN of MyD88-sufficient (solid bars) and MyD88-negative (open bars) NOD mice. Error bars – s.e.m.

  3. Proliferation of CFSE-labeled BDC2.5 CD4+ T cells, depleted of CD25+ T cells, in the PLNs of SPF NOD and NOD.MyD88KO mice assayed on day 3 after i.v. injection. Representative CFSE dilution profiles are shown for BDC2.5+-gated cells in PLN (red) and control skin-draining lymph nodes (blue).

p values in all experiments were determined using unpaired Student's t test. Error bars – s.e.m. n, number of animals per group.
Figure 3
Figure 3. MyD88-negative NOD mice are protected from diabetes by the gut microbiota

  1. Diabetes incidence in SPF NOD.MyD88KO (J) females and control heterozygous NOD.MyD88KO/+ littermates treated with a broad-spectrum antibiotic from birth.

  2. Diabetes incidence in GF NOD.MyD88KO and control MyD88KO/+ mice. Incidence is shown for male mice; 100% of female NOD.MyD88KO and NOD.MyD88KO/+ female GF mice became diabetic (Supplemental Fig.1).

  3. Diabetes incidence in gnotobiotic male NOD.MyD88KO and control NOD.MyD88KO/+ mice colonized with a consortium of 6 bacterial strains (ASF 361,519,356,492,502, and 500; see Supplemental results for descriptions). The incidence of diabetes in gnotobiotic NOD.MyD88KO mice was significantly different from the incidence in GF NOD.MyD88KO animals (p<0.001), and in gnotobiotic NOD.MyD88KO/+ mice (p<0.05) (Kaplan Meier test).

  4. Histological scores of islet destruction in SPF, GF and ASF-colonized NOD.MyD88KO/+ and NOD.MyD88KO mice. Mice in all groups were males, except for the SPF NOD.MyD88KO group, which included both genders.

Figure 4
Figure 4. MyD88 deficiency leads to specific changes in the composition of intestinal microbiota

  1. Ratio of Firmicutes to Bacteroidetes in the cecal microbiota of NOD.MyD88KO/+ and NOD.MyD88KO mice who were or were not treated with Sulfatrim. Mean values per mouse ± s.e.m. Untreated NOD.MyD88KO mice had, on average, a significantly lower F/B ratio than all other mice combined (one-tailed t-test, t=-2.31, p=0.013). When comparing post-hoc the effect of sulfatrim in MyD88KO mice only, no significant difference in F/B ratios was observed (t= 0.85, p=0.20).

  2. Abundance of members of three different bacterial families in the cecal contents of NOD.MyD88KO/+ and NOD.MyD88KO mice (not treated with Sulfatrim). Mean values ± s.e.m. Each of the three families is enriched in NOD.MyD88KO mice (Lactobacilliaceae t=-1.54, p=0.07, Porphyromonadaceae t=2.1, p=0.03, Rikenellaceae t=2.74, p=0.007; one-tailed t-test).

  3. Clustering of mouse cecal bacterial communities using the unweighted UniFrac metric n=7,223 sequences. Diversity, not abundance of bacteria was taken into consideration. Top panel: Sulfatrim-treated litters. Bottom panel: Untreated litters. Line colors indicate families. Each label is a mouse: red labels are NOD.MyD88KO/+ (H); black labels are NOD.Myd88KO (K). The number is the common mother, S and N designate exposure to Sulfatrim or no Sulfatrim, respectively.

  4. Histological examination of the pancreata of 8 wk old males from SPF NOD, GF NOD, as well as GF NOD and GF NOD.MyD88KO exposed from birth to microbiota of an SPF NOD.MyD88KO female. The percentages (mean ±s.e.m.) of affected islets with no infiltration (open bars), periinsulitis (blue bars) and true infiltration (combined grades II and III) are shown. p values were obtained using unpaired Student's t test. n, number of animals per group.

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