Microbiota regulates type 1 diabetes through Toll-like receptors | Academic Article individual record

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.

author list (cited authors)
Burrows, M. P., Volchkov, P., Kobayashi, K. S., & Chervonsky, A. V.
publication date
  • Adaptor Proteins, Vesicular TransportAnimalsAnti-Infective AgentsBacteriaDiabetes Mellitus, Type 1Germ-Free LifeIslets Of LangerhansMice, Inbred C57BLMice, Inbred NODMicrobiotaMyeloid Differentiation Factor 88PhylogenyToll-Like ReceptorsCommensal MicrobiotaType 1 Diabetes