Microbiota regulates type 1 diabetes through Toll-like receptors - PubMed (original) (raw)

Microbiota regulates type 1 diabetes through Toll-like receptors

Michael P Burrows et al. Proc Natl Acad Sci U S A. 2015.

Abstract

Deletion of the innate immune adaptor myeloid differentiation primary response gene 88 (MyD88) in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D) results in microbiota-dependent protection from the disease: MyD88-negative mice in germ-free (GF), but not in specific pathogen-free conditions develop the disease. These results could be explained by expansion of particular protective bacteria ("specific lineage hypothesis") or by dominance of negative (tolerizing) signaling over proinflammatory signaling ("balanced signal hypothesis") in mutant mice. Here we found that colonization of GF mice with a variety of intestinal bacteria was capable of reducing T1D in MyD88-negative (but not wild-type NOD mice), favoring the balanced signal hypothesis. However, the receptors and signaling pathways involved in prevention or facilitation of the disease remained unknown. The protective signals triggered by the microbiota were revealed by testing NOD mice lacking MyD88 in combination with knockouts of several critical components of innate immune sensing for development of T1D. Only MyD88- and TIR-domain containing adapter inducing IFN β (TRIF) double deficient NOD mice developed the disease. Thus, TRIF signaling (likely downstream of Toll-like receptor 4, TLR4) serves as one of the microbiota-induced tolerizing pathways. At the same time another TLR (TLR2) provided prodiabetic signaling by controlling the microbiota, as reduction in T1D incidence caused by TLR2 deletion was reversed in GF TLR2-negative mice. Our results support the balanced signal hypothesis, in which microbes provide signals that both promote and inhibit autoimmunity by signaling through different receptors, including receptors of the TLR family.

Keywords: Toll-like receptors; commensal microbiota; type 1 diabetes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Distinct bacterial lineages reduce diabetes incidence in gnotobiotic MyD88-negative NOD mice. Bona fide insulitis (percentage of total islets) in 13-wk-old female MyD88+/+ or MyD88−/− mice in SPF and GF conditions and colonized with ASF, VSL3, or SFB. n = number of mice per group. P values for histopathology were determined by Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 2.

Non-TLR bacteria-sensing mechanisms do not protect from diabetes. (A) Diabetes incidence in NOD female caspase 1/11+/−, caspase 1/11−/− littermates, and MyD88−/− caspase 1/11+/−, MyD88−/− caspase 1/11−/− littermates. (B) Diabetes incidence in NOD female Ripk2+/−, Ripk2−/− littermates and MyD88−/− Ripk2+/−, MyD88−/− Ripk2−/− littermates. n = number of mice per group. P values for incidence were determined using Kaplan–Meier statistics. *P < 0.05, **_P_ < 0.01, ***_P_ < 0.001. ns, nonsignificant, _P_ > 0.05.

Fig. 3.

Signaling adaptor TRIF participates in microbiota-dependent protection from T1D. (A) Diabetes in NOD female TRIF+/−, TRIF−/− littermates and MyD88−/− TRIF+/−, MyD88−/− TRIF−/− littermates. (B) Bona fide insulitis (percentage of total islets) in diabetic or nondiabetic 30-wk-old female mice: NOD.MyD88+/+ TRIF+/− and NOD.MyD88+/+ TRIF−/− littermates, NOD.MyD88−/−TRIF+/+, as well as NOD.MyD88−/− TRIF+/− and NOD.MyD88−/− TRIF−/− littermates. (C) Full histopathology scores from mice shown in B. No insulitis (score 0), periinsulitis (score I), and insulitis (score II). (D) Representative images of islet histology in the nondiabetic 30-wk-old mice. n = number of mice per group. P values for incidence were determined using Kaplan–Meier statistics, for histopathology by Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. S1.

Histopathology scoring examples. Uninfiltrated islets (score 0), periinsulitis (score I), and insulitis (score II), which includes islets with variable degrees of destruction, are shown.

Fig. 4.

Antimicrobial TLR-dependent mechanisms favor T1D development in NOD mice. (A) Diabetes incidence in NOD SPF and GF female TLR2 +/− and TLR2−/− littermates. (B) Bona fide insulitis in diabetic or 30-wk-old nondiabetic female mice housed in SPF or GF conditions. NOD.TLR2+/− and NOD.TLR2−/− littermates were used in these experiments. (C) Full histopathology scores in mice shown in B. (D) Diabetes incidence in female NOD SPF and GF TLR4+/− and TLR4−/− littermates. The difference between SPF TLR4+/− (n = 21) and SPF TLR4−/− (n = 17) was significant (P = 0.04). The difference between GF TLR4+/− (n = 11) and GF TLR4−/− (n = 10) was not significant (P = 0.84). n = number of mice per group. P values for incidence were determined using Kaplan–Meier statistics, for histopathology by Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.

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Microbiota regulates type 1 diabetes through Toll-like receptors - PubMed (original) (raw)