Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) modulates T1DM susceptibility by gut microbiota

•The innate immune molecule Nod2 regulates susceptibility to autoimmune diabetes in NOD mice.•Nod2 expression and housing partners alter the composition of gut microbiota that affect diabetes development.•Gene-determined and housing-dependent altered microbiota modify T and B cell responses.•Immunological phenotypes are dependent on the composition of gut microbiota.

Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) is an innate immune receptor. To investigate the role of Nod2 in susceptibility to the autoimmune disease, type 1 diabetes mellitus (T1DM), we generated Nod2−/− non-obese diabetic (NOD) mice. The Nod2−/−NOD mice had different composition of the gut microbiota compared to Nod2+/+NOD mice and were significantly protected from diabetes, but only when housed separately from Nod2+/+NOD mice. This suggested that T1DM susceptibility in Nod2−/−NOD mice is dependent on the alteration of gut microbiota, which modulated the frequency and function of IgA-secreting B-cells and IL-10 promoting T-regulatory cells. Finally, colonizing germ-free NOD mice with Nod2−/−NOD gut microbiota significantly reduced pro-inflammatory cytokine-secreting immune cells but increased T-regulatory cells. Thus, gut microbiota modulate the immune system and T1D susceptibility. Importantly, our study raises a critical question about the housing mode in the interpretation of the disease phenotype of genetically-modified mouse strains in T1DM studies.