Abstract
Type 2 diabetes (T2D) is a metabolic disease characterized by increased inflammation, NOD-like receptors (NLRs) activation and gut dysbiosis. Our research group has recently reported that intestinal Th17 response limits gut dysbiosis and LPS translocation to visceral adipose tissue (VAT), protecting against metabolic syndrome. However, whether NOD2 receptor contributes intestinal Th17 immunity, modulates dysbiosis-driven metabolic tissue inflammation, and obesity-induced T2D remain poorly understood. In this context, we observed that mice lacking NOD2 fed a high-fat diet (HFD) display severe obesity, exhibit greater adiposity, and more hepatic steatosis compared to HFD-fed wild-type (WT) mice. In addition, they develop increased hyperglycemia, worsening of glucose intolerance, and insulin resistance. Notably, the deficiency of NOD2 causes a deviation from M2 macrophage and regulatory T cells (Treg) to M1 macrophage and mast cells into VAT compared to WT mice fed HFD. An imbalance was also observed in Th17/Th1 cell populations, with reduced IL-17 and IL-22 gene expression in the mesenteric lymph nodes (MLNs) and ileum, respectively, of NOD2-deficient mice fed HFD. 16S rRNA sequencing indicates lower richness, alpha diversity, and a depletion of Allobaculum, Lactobacillus, and enrichment with Bacteroides genera in these mice compared to HFD-fed WT mice. These alterations were associated with disrupted tight-junctions expression, augmented serum LPS, and bacterial translocation into VAT. Overall, NOD2 activation is required for a protective Th17 over Th1 immunity in the gut, which seems to decrease gram-negative bacteria outgrowth in gut microbiota, attenuating the endotoxemia, metainflammation, and protecting against obesity-induced T2D.
Highlights
Type 2 diabetes (T2D) is a chronic inflammatory disease characterized by hyporesponsiveness to insulin and glucose intolerance resulting in alterations of β-cell function, structure, or both
There were no differences in food intake, Nucleotidebinding oligomerization domain-containing protein 2 (NOD2)−/− mice displayed augmented visceral and total fat accumulation and an increased adiposity index compared to WT mice under the high-fat diet (HFD) (Figures 1D,F)
We observed a significant decline in forkhead box P3 (Foxp3) expression in visceral adipose tissue (VAT) of NOD2−/− mice fed HFD compared to NOD2−/− mice fed control diet (CTD) (Figure 2F)
Summary
T2D is a chronic inflammatory disease characterized by hyporesponsiveness to insulin and glucose intolerance resulting in alterations of β-cell function, structure, or both. It was proposed that obesity progression shifts macrophage phenotype (to the M1 over the M2 phenotype) in adipose tissue, contributing to the development of insulin resistance and T2D. An additional mechanism by which the microbiome contributes to metabolic disorders appears to be by initiating a systemic inflammation Intestinal phagocytes, such as dendritic cells and macrophages, capture intestinal bacterial antigens through a process known as bacterial translocation, causing a “low grade bacteremia” mediated by both CD14 and NOD1 receptors in diabetic mice [10]. NOD2 receptor activation contributes to intestinal Th17 response, which can limit gut microbiota dysbiosis and disruption of intestinal barrier. These mechanisms reduce LPS translocation to the VAT, attenuate metainflammation and obesity-induced T2D
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