心肌纤维化是导致心衰、死亡的重要病变，机制不明，治疗困难。氧化三甲胺（TMAO）是肠道菌群相关代谢产物，也是新的心血管疾病风险因子，但其在心肌纤维化中的作用及机制尚未完全阐明。我们和其他课题组研究发现：心衰患者TMAO水平增高，TMAO诱导小鼠心肌纤维化和心肌成纤维细胞活化，伴随溶酶体激活与炎症反应。我们推测：TMAO通过激活心肌成纤维细胞溶酶体释放组织蛋白酶CathepsinB，进一步活化NLRP3炎症小体，诱发炎症反应，从而促进心肌纤维化。本项目将运用基因敲除、慢病毒转染等手段，从在体与离体水平（1）确证TMAO是促进心肌纤维化的重要病理因子；（2）阐明TMAO诱导NLRP3活化及相关炎症反应的作用机制；（3）揭示Cathepsin B介导TMAO促心肌纤维化的作用。本项目的实施将深化我们对肠道菌群诱导心肌纤维化的认识，为从肠道菌群角度探讨心脏疾病的防治策略提供理论和实验依据。

Myocardial fibrosis is a heavy disease leading to heart failure and death. Its mechanism is unknown and its treatment is difficult. Intestinal microflora-related metabolite trimethylamine (TMAO) is a new risk factor of cardiovascular disease, but its role and mechanism in myocardial fibrosis has not been fully elucidated. We and other research groups have found that the TMAO levels were elevated in patients with heart failure; TMAO induced myocardial fibrosis and activation of cardiac fibroblasts in mice, accompanied by lysosomal activation and inflammatory response. Thus we speculate that TMAO can further activate NLRP3 inflammasome and induce inflammation by activating lysosome to release Cathepsin B, finally promoting myocardial fibrosis. In this study, by using gene knockout, gene overexpression and lentiviral transfection stratagem, from the in vivo and ex vivo levels, we planned to (1) confirm that TMAO is an important pathological factor to promote myocardial fibrosis; (2) elucidate underlying mechanism of TMAO-induced NLRP3 inflammasome activation and related inflammatory response; (3) reveals the role of Cathepsin B in mediating TMAO-induced myocardial fibrosis. The implementation of this project will deepen our understanding of intestinal microflora-induced myocardial fibrosis, and provide theoretical and experimental basis for the prevention and treatment of heart disease from the perspective of intestinal flora.