Gut microbiota-activated PLCγ2 monocytes drive atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia, conferring risks of stroke and heart failure. Monocyte activation-associated inflammation is implicated in AF, yet the recruitment of monocytes and their role in atrial remodeling remain unclear. Here we show that monocytes from AF patients upregulate phospholipase C gamma 2 (PLCG2). In a combined AF male mouse model, phospho-PLCγ2⁺ monocytes are recruited to the atria, where they trigger endothelial‑to‑mesenchymal transition (EndMT) through the secreted phosphoprotein 1 (SPP1)-integrin α9β1 signaling axis. Monocyte-specific deletion of PLCG2 blocks atrial recruitment of these monocytes and reduces AF. Depletion of the gut microbiota with antibiotics reduces the number of phospho-PLCγ2⁺ monocytes in the atria, suppresses EndMT, and attenuates AF inducibility, and these effects are reversed by fecal microbiota transplantation (FMT). Mechanistically, gut microbiota-derived bacterial membrane vesicles activate spleen tyrosine kinase (Syk)/PLCG2 signaling in monocytes. These findings establish a gut microbiota-monocyte-EndMT axis, wherein monocyte-endocardial crosstalk drives AF.