Accumulation of microbial DNAs promotes to islet inflammation and beta cell abnormalities in obesity in mice

Obesity is associated with increased gut permeability, and microbial products that are leaked from the gut may contribute towards obesity-associated inflammation. Here the authors show that the leakage of gut extracellular vesicles containing microbial DNA leads to bacterial DNA accumulation in pancreatic beta-cells, promoting obesity-associated islet inflammation. Various microbial products leaked from gut lumen exacerbate tissue inflammation and metabolic disorders in obesity. Vsig4+ macrophages are key players preventing infiltration of bacteria and their products into host tissues. However, roles of islet Vsig4+ macrophages in the communication between microbiota and beta cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in beta cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into beta cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into beta cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in beta cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in beta cells and subsequently obesity-associated islet abnormalities.