Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis

作者：Yingchun Luo, Yun Zhang, Xuejie Han, Yue Yuan, Yun Zhou, Yunlong Gao, Hui Yu, Jiawei Zhang, Yiya Shi, Yu Duan, Xinbo Zhao, Sen Yan, Hongting Hao, Chenguang Dai, Shiqi Zhao, Jing Shi, Wenpeng Li, Song Zhang, Wei Xu, Ning Fang, Yongtai Gong, Yue Li · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104087 · 被引用次数：102 · 研究领域：Inflammasome and immune disorders、Atrial Fibrillation Management and Outcomes、Heme Oxygenase-1 and Carbon Monoxide

BACKGROUND: Cold exposure is one of the most important risk factors for atrial fibrillation (AF), and closely related to the poor prognosis of AF patients. However, the mechanisms underlying cold-related AF are poorly understood. METHODS: Various techniques including 16S rRNA gene sequencing, fecal microbiota transplantation, and electrophysiological examination were used to determine whether gut microbiota dysbiosis promotes cold-related AF. Metabonomics were performed to investigate changes in fecal trimethylamine (TMA) and plasma trimethylamine N-oxide (TMAO) during cold exposure. The detailed mechanism underlying cold-related AF were examined in vitro. Transgenic mice were constructed to explore the role of pyroptosis in cold-related AF. The human cohort was used to evaluate the correlation between A. muciniphila and cold-related AF. FINDINGS: We found that cold exposure caused elevated susceptibility to AF and reduced abundance of Akkermansia muciniphila (A. muciniphila) in rats. Intriguingly, oral supplementation of A. muciniphila ameliorated the pro-AF property induced by cold exposure. Mechanistically, cold exposure disrupted the A. muciniphila, by which elevated the level of trimethylamine N-oxide (TMAO) through modulation of the microbial enzymes involved in trimethylamine (TMA) synthesis. Correspondingly, progressively increased plasma TMAO levels were validated in human subjects during cold weather. Raised TMAO enhanced the infiltration of M1 macrophages in atria ...