Pinfang Kang, Dimin Wang, Peng Teng, Wenjie Diao, Yi Zhao, Qing Chen, Ying Tang, CHEN Ziyi, Meiyang Xu, Zhengyu Sun, Wenjuan Wu, Hongju Wang, Jinjin Meng, Weidong Li, Bi Tang, Liang Ma
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. Atrial fibrillation involves systemic inflammatory activation that remodel the atrial endocardium. Here, the authors show that gut microbiota activate PLCy2 positive monocytes, promoting endothelial-to-mesenchymal transition and atrial fibrillation through a microbiota–monocyte–endocardial axis.