肠道阿克曼菌-循环脂多糖及高糖-心房肌NLRP3炎性小体通路在寒冷相关性心房颤动发生中的作用及机制

寒冷可增加心房颤动（房颤）发病率，但确切机制不清楚。我们前期研究发现：寒冷暴露大鼠房颤易感性显著增加，肠道菌群改变，循环脂多糖和血糖水平升高，心房肌NLRP3炎症小体表达增加并激活；将寒冷暴露大鼠的粪菌移植至室温大鼠体内，其房颤易感性增加、循环脂多糖和血糖升高、心房肌NLRP3炎症小体活化；脂多糖和高糖联合孵育使心房肌细胞和心房成纤维细胞NLRP3炎症小体显著上调并活化。我们还观察到，冬季人群和寒冷暴露大鼠肠道阿克曼菌数量均明显减少，有报道该菌减少可导致循环脂多糖和血糖升高。我们提出假设：在寒冷环境刺激下，肠道阿克曼菌减少，导致循环脂多糖和血糖水平升高，通过上调并激活心房肌NLRP3炎症小体，引起心房重构，促进房颤发生。本项目将从在体和细胞水平阐明“阿克曼菌-循环脂多糖和血糖-心房肌NLRP3炎症小体”通路在寒冷相关性房颤发生中的作用及分子机制，从肠道菌群角度揭示寒冷相关性房颤发病新机制。

Cold can increase the incidence of atrial fibrillation (AF), but the exact mechanism remains unknown. Our previous results found that: the susceptibility of atrial fibrillation in cold-exposed rats increased significantly, the gut microbiome changed, circulating lipopolysaccharide and blood glucose levels increased, and atrial NLRP3-inflammasome was increased and activated. The fecal microbiota translation in room temperature rats by utilizing fecal samples collected from cold-induced rats increased the susceptibility of atrial fibrillation, and increased levels of circulating lipopolysaccharide and blood glucose, and activation of atrial NLRP3-inflammasome. Combined incubation of lipopolysaccharide and high glucose could induce the activation of NLRP3-inflammasome in atrial myocytes and atrial fibroblasts. We also observed that the number of Akkermansia muciniphila of human in winter and of cold-exposed rats were significantly reduced. It has been reported that the reduction of Akkermansia muciniphila can contribute to the increased levels of circulating lipopolysaccharide and blood glucose. We propose a hypothesis: under the cold environment, the intestinal Akkermansia muciniphila reduces, resulting in increased levels of circulating lipopolysaccharide and blood glucose which upregulate and activate the atrial NLRP3-inflammasome. It causes atrial remodeling and promotes the occurrence of atrial fibrillation. This project will clarify the role and molecular mechanism of the intestinal Akkermansia-lipopolysaccharide and high glucose-atrial NLRP3 pathway in the occurrence of cold-induced atrial fibrillation in vivo and in vitro. It will reveal the mechanism and pathogenesis of cold-induced atrial fibrillation from the perspective of intestinal flora.