Islet Vsig4+ macrophages can block the infiltration of intestinal mEVs into β cells through a C3-mediated mechanism, whereas prolonged obesity causes a remarkable decrease in Vsig4+ macrophage population, allowing the spread of intestinal mEVs and microbial DNA enrichment within β cells of both obese mice and patients with obesity. The gene discussed is VSIG4; the disease is obesity disorder.