Aim: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite synthesized in host organisms from specific food constituents, such as choline, carnitine and betaine. During the last decade, elevated TMAO levels have been proposed as biomarkers to estimate the risk of cardiometabolic diseases. However, there is still no consensus about the role of TMAO in the pathogenesis of cardiovascular disease since regular consumption of TMAO-rich seafood (i.e., a Mediterranean diet) is considered to be beneficial for the primary prevention of cardiovascular events. Therefore, the aim of this study was to investigate the effects of long-term TMAO administration on mitochondrial energy metabolism in an experimental model of right ventricle heart failure.

Methods: TMAO was administered to rats at a dose of 120 mg/kg in their drinking water for 10 weeks. Then, a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) was administered to induce right ventricular dysfunction, and treatment with TMAO was continued (experimental groups: Control; TMAO; MCT; TMAO+MCT). After 4 weeks, right ventricle functionality was assessed by echocardiography, mitochondrial function and heart failure-related gene and protein expression was determined.

Results: Compared to the control treatment, the administration of TMAO (120 mg/kg) for 14 weeks increased the TMAO concentration in cardiac tissues up to 14 times. MCT treatment led to impaired mitochondrial function and decreased right ventricular functional parameters. Although TMAO treatment itself decreased mitochondrial fatty acid oxidation-dependent respiration, no effect on cardiac functionality was observed. Long-term TMAO administration prevented MCT-impaired mitochondrial energy metabolism by preserving fatty acid oxidation and subsequently decreasing pyruvate metabolism. In the experimental model of right ventricle heart failure, the impact of TMAO on energy metabolism resulted in a tendency to restore right ventricular function, as indicated by echocardiographic parameters and normalized organ-to-body weight indexes. Similarly, the expression of a marker of heart failure severity, brain natriuretic peptide, was substantially increased in the MCT group but tended to be restored to control levels in the TMAO+MCT group.

Conclusion: Elevated TMAO levels preserve mitochondrial energy metabolism and cardiac functionality in an experimental model of right ventricular heart failure, suggesting that under specific conditions TMAO promotes metabolic preconditioning-like effects.

目标：三甲胺N-氧化物（TMAO）是由肠道菌群衍生的代谢产物，是在宿主生物中由特定食物成分（例如胆碱，肉碱和甜菜碱）合成的。在过去的十年中，已经提出了升高的TMAO水平作为生物标记物，以评估心脏代谢疾病的风险。但是，关于TMAO在心血管疾病的发病机理中的作用仍未达成共识，因为经常食用富含TMAO的海鲜（即地中海饮食）被认为有利于心血管疾病的一级预防。因此，本研究的目的是在右心室心力衰竭的实验模型中研究长期TMAO给药对线粒体能量代谢的影响。

方法：将TMAO以120 mg / kg的剂量在大鼠的饮用水中给药10周。然后，单次皮下注射苦味碱（MCT）（60 mg / kg）引起右心功能不全，并继续用TMAO治疗（实验组：对照组； TMAO； MCT； TMAO + MCT）。4周后，通过超声心动图评估右心室功能，线粒体功能以及心力衰竭相关基因和蛋白质表达。

结果：与对照组相比，TMAO（120 mg / kg）给药14周可使心脏组织中TMAO的浓度增加14倍。MCT治疗导致线粒体功能受损，右心室功能参数降低。尽管TMAO治疗本身可降低线粒体脂肪酸氧化依赖性呼吸作用，但未观察到对心脏功能的影响。长期TMAO给药可通过保留脂肪酸氧化并随后减少丙酮酸代谢来预防MCT损伤的线粒体能量代谢。在右心室心力衰竭的实验模型中，如超声心动图参数和标准化的器官对体重指标所示，TMAO对能量代谢的影响导致恢复右心室功能的趋势。同样，

结论： 在右心室心力衰竭的实验模型中，升高的TMAO水平可保持线粒体能量代谢和心脏功能，这表明在特定条件下，TMAO可以促进类似代谢预处理的作用。