Trimethylamine N-oxide Supplementation Abolishes the Cardioprotective Effects of Voluntary Exercise in Mice Fed a Western Diet

Abstract

Excessive consumption of western diet (WD) induces obesity, resulting in cardiac dysfunction. Voluntary exercise ameliorates WD-induced obesity, but its effect on cardiac dysfunction remains unclear. Recent evidence suggests that elevated trimethylamine N-oxide (TMAO), a gut microbe-derived metabolite, can impair cardiac function in WD-induced obesity. We hypothesized that cardiac dysfunction in WD-induced obesity would be prevented by voluntary exercise but abolished by TMAO supplementation. Male CD1 mice fed a WD were assigned to sedentary, exercise or exercise with TMAO treatment for 8 weeks. Male CD1 mice fed a normal diet (ND) for 8 weeks were assigned to sedentary (control). Compared with ND-sedentary mice, WD-sedentary mice gained significantly more body weight and displayed metabolic abnormalities at the end of the experiment. Echocardiography showed significantly impaired cardiac systolic and diastolic function in WD-induced obese mice. Voluntary exercise partially attenuated weight gain and metabolic disorders, but completely prevented cardiac dysfunction in WD-induced obese mice. Molecular studies revealed that WD-sedentary mice had elevated plasma TMAO levels, along with increased myocardial inflammation and fibrosis, all of which were inhibited by voluntary exercise. Of note, concomitant administration of TMAO had no effects on body weight and metabolic disorders, but it abolished the beneficial effects of voluntary exercise on cardiac dysfunction, myocardial inflammation, and fibrosis in WD-induced obese mice. The results suggest that voluntary exercise prevents cardiac dysfunction in WD-induced obesity by inhibiting myocardial inflammation and fibrosis. Moreover, the cardioprotective effects of voluntary exercise in WD-induced obesity can be abolished by TMAO supplementation, which abrogates voluntary exercise-induced changes in myocardial inflammation and fibrosis.

TMAO: how gut microbiota contributes to heart failure

“…18,65 Additionally, Ma et al 66 demonstrated that TMAO upregulated vascular cell adhesion molecule (VCAM)-1 expression by activating protein kinase C (PKC)/NF-kB, which directly resulted in endothelial dysfunction that was characterized by reduced selfÀhealing capacity and increased monocyte adhesion. In a study to investigate whether inhibiting TMAO prevented myocardial inflammation, Zhang et al 67 discovered that TMAO might induce myocardial inflammation by elevating TNF-a levels and TMAO biogenesis and metabolism. Dietary nutrients (ie, choline) are biotransformed into TMA by TMA lyases (ie, cutC/D) in the gut.…”

Gut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide

“…An animal study showed that voluntary exercise normalizes the plasma TMAO levels and prevents cardiac dysfunction in western diet-induced obese mice. This effect was reversed by concomitant administration of TMAO and abrogated the beneficial effects [49].…”

Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome

“…Some clinical studies have reported TMAO levels to be higher with advanced left ventricular diastolic dysfunction in heart failure than in non-heart failure (Cannon and McMurray, 2014; Tang et al, 2014; Tang et al, 2015b). Several animal studies have suggested that elevated TMAO levels have a strong association with cardiac fibrosis and contribute to heart failure (Chen K. et al, 2017; Zhang et al, 2017; Li et al, 2018). However, the roles and mechanisms of TMAO-mediated cardiac fibrosis are not fully elucidated.…”