Mef2d EVs aggravate gut Bacteroides fragilis pathogenicity
Gut dysbiosis is tightly linked to type 2 diabetes (T2D) arterial calcification (AC), but the mechanism of gut dysbiosis remain poorly defined. Here, we found a T2D AC associated-gut Bacteroides fragilis (BF) was activated by M1 macrophage-derived extracellular vesicles (EVs). BF internalized macrophage EVs via membrane protein OprM-Jup interaction. Upon uptake, Mef2d which was riched in EVs translocated to the BF nucleoid, suppressed ArsR transcription and enhanced BF proliferation and trimethylamine N-oxide production in diabetic mice. Mechanistically, Mef2d suppressed the transcriptional activity of ArsR, an arsenic resistance regulator in BF. Overexpression of ArsR inhibited BF growth and trimethylamine synthesis, whereas ArsR knockdown exacerbated these phenotypes. Critically, ArsR overexpression abolished macrophage EV-driven BF activation. Our findings reveal a macrophage EV-BF signaling axis in which Mef2d-mediated ArsR suppression drives bacterial pathogenicity, offering a pharmacologically targetable axis for precision inhibitation of BF pathobiont virulence in diabetic complications.