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

Hong Gao, Zhenlong Luo, Yudong Ji, Kechun Tang, Zhongmou Jin, Crystal Ly, Dorothy D. Sears, Sushil Mahata and Wei Ying ()
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Hong Gao: University of California, San Diego
Zhenlong Luo: University of California, San Diego
Yudong Ji: University of California, San Diego
Kechun Tang: VA San Diego Healthcare System
Zhongmou Jin: University of California, San Diego
Crystal Ly: University of California, San Diego
Dorothy D. Sears: Arizona State University
Sushil Mahata: University of California, San Diego
Wei Ying: University of California, San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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 β cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in β cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into β cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into β cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in β cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in β cells and subsequently obesity-associated islet abnormalities.

Date: 2022
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DOI: 10.1038/s41467-022-28239-2

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