Gut microbe-derived metabolite trimethylamine N-oxide accelerates fibroblast-myofibroblast differentiation and induces cardiac fibrosis

• Published in: Journal of molecular and cellular cardiology 2019-09, Vol.134, p.119-130
• Main Authors: Yang, Wenlong, Zhang, Shuning, Zhu, Jianbing, Jiang, Hao, Jia, Daile, Ou, Tiantong, Qi, Zhiyong, Zou, Yunzeng, Qian, Juying, Sun, Aijun, Ge, Junbo
• Format: Article
• Language: English
• Subjects: Cardiac fibrosis; Myocardial infarction; Trimethylamine N-oxide
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.07.004

Trimethylamine N-oxide (TMAO), a gut microbe-derived metabolite of dietary choline and other trimethylamine-containing nutrients, has been associated with poor prognosis in coronary heart disease. However, the role and underlying mechanisms of TMAO in the cardiac fibrosis after myocardial infarction (MI) remains unclear. We used mouse MI models and primary cardiac fibroblasts cultures to study the role of TMAO in the heart and in cardiac fibroblasts. C57BL/6 mice were fed a control diet, high choline (1.2%) or/and DMB diet or a diet containing TMAO (0.12%) starting 3 weeks before MI. DMB, a structural analogue of choline, inhibited microbial TMA lyases and reduced the level of TMAO in mice. Cardiac function was measured 7 days after MI using echocardiography. One week post MI, myocardial tissues were collected to evaluate cardiac fibrosis, and blood samples were evaluated for TMAO levels. The expression of TGF-β receptor, P-Smad2, α-SMA or collagen I in myocardial tissues and fibroblasts were analyzed by western blot or immunocytochemistry. We demonstrated that cardiac function and cardiac fibrosis were significantly deteriorated in mice fed either TMAO or high choline diets compared with the control diet, and DMB reversed the cardiac function damage of high choline diet (p