Microbiota regulates type 1 diabetes through Toll-like receptors

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 germfree (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.Toll-like receptors | commensal microbiota | type 1 diabetes

Cutting Edge: Commensal Microbiota Has Disparate Effects on Manifestations of Polyglandular Autoimmune Inflammation

“…These findings led to the conclusion that in the absence of signaling through MyD88-dependent innate immune receptors, the microbiota induces negative signaling reducing both anti-commensal and autoimmune reactivity (11,32). To test whether the same rules apply to development of sialitis in the absence of MyD88, we examined salivary glands lesions in MyD88 KO NOD mice.…”

Dissecting the interplay between intestinal microbiota and host immunity in health and disease: Lessons learned from germfree and gnotobiotic animal models

“…Results from a huge number of scientific investigations revealed a general impact of the commensal microbiota in host metabolism and in metabolic diseases including obesity, diabetes mellitus, cardiovascular disorders, kidney stones, or cancer [47–49]. Even the dysbiosis in the gut or the respiratory tract has been linked to alterations in immune responses and to disease development [50].…”

Microbiome and Gluten

“…These play a vital role in host defense, but dysregulation in TLR signaling can also confer risk to autoimmune diseases, such as CD [61] . It is known that gut microbes provide signals that can both promote and inhibit autoimmunity by signaling through the TLR family [62] . While TRIF signaling could act as a negative regulator of immunity, MyD88 signaling seems to act as a potent activator.…”