Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset

Frederico R C Costa, Marcela C S Françozo, Gabriela G de Oliveira, Aline Ignacio, Angela Castoldi, Dario S Zamboni, Simone G Ramos, Niels O Câmara, Marcel R de Zoete, Noah W Palm, Richard A Flavell, João S Silva, Daniela Carlos

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas. Additionally, STZ-injected wild-type (WT) diabetic mice displayed an altered gut microbiota compared with vehicle-injected WT mice, together with the translocation of bacteria to the PLNs. Interestingly, WT mice treated with broad-spectrum antibiotics (Abx) were fully protected from STZ-induced T1D, which correlated with the abrogation of bacterial translocation to the PLNs. Notably, when Abx-treated STZ-injected WT mice received the NOD2 ligand muramyl dipeptide, both hyperglycemia and the proinflammatory immune response were restored. Our results demonstrate that the recognition of bacterial products by NOD2 inside the PLNs contributes to T1D development, establishing a new putative target for intervention during the early stages of the disease.

Original languageEnglish
Pages (from-to)1223-39
Number of pages17
JournalJournal of Experimental Medicine
Volume213
Issue number7
DOIs
Publication statusPublished - 27 Jun 2016
Externally publishedYes

Keywords

  • Animals
  • Bacterial Translocation/genetics
  • Diabetes Mellitus, Experimental/genetics
  • Diabetes Mellitus, Type 1/genetics
  • Gastrointestinal Microbiome
  • Lymph Nodes/immunology
  • Male
  • Mice
  • Mice, Knockout
  • Nod2 Signaling Adaptor Protein/genetics
  • Pancreas/immunology

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