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

ABSTRACT: 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.

SUBMITTER: Li YY

PROVIDER: S-EPMC8284907 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Li Yang-Yang YY Pearson James A JA Chao Chen C Peng Jian J Zhang Xiaojun X Zhou Zhiguang Z Liu Yu Y Wong F Susan FS Wen Li L

Journal of autoimmunity 20170604

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 mi ...[more]

PMID: 28592385

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Project description:BackgroundWithin one week following peroral high dose infection with Toxoplasma (T.) gondii, susceptible mice develop non-selflimiting acute ileitis due to an underlying Th1-type immunopathology. The role of the innate immune receptor nucleotide-oligomerization-domain-2 (NOD2) in mediating potential extra-intestinal inflammatory sequelae including the brain, however, has not been investigated so far.Methodology/principal findingsFollowing peroral infection with 100 cysts of T. gondii strain ME49, NOD2-/- mice displayed more severe ileitis and higher small intestinal parasitic loads as compared to wildtype (WT) mice. However, systemic (i.e. splenic) levels of pro-inflammatory cytokines such as TNF-α and IFN-γ were lower in NOD2-/- mice versus WT controls at day 7 p.i. Given that the immunopathological outcome might be influenced by the intestinal microbiota composition, which is shaped by NOD2, we performed a quantitative survey of main intestinal bacterial groups by 16S rRNA analysis. Interestingly, Bifidobacteria were virtually absent in NOD2-/- but not WT mice, whereas differences in remaining bacterial species were rather subtle. Interestingly, more distinct intestinal inflammation was accompanied by higher bacterial translocation rates to extra-intestinal tissue sites such as liver, spleen, and kidneys in T. gondii infected NOD2-/- mice. Strikingly, intracerebral inflammatory foci could be observed as early as seven days following T. gondii infection irrespective of the genotype of animals, whereas NOD2-/- mice exhibited higher intracerebral parasitic loads, higher F4/80 positive macrophage and microglia numbers as well as higher IFN-γ mRNA expression levels as compared to WT control animals.Conclusion/significanceNOD2 signaling is involved in protection of mice from T. gondii induced acute ileitis. The parasite-induced Th1-type immunopathology at intestinal as well as extra-intestinal sites including the brain is modulated in a NOD2-dependent manner.

Dataset Information

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

Publications

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

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