Choline Diet and Its Gut Microbe–Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload–Induced Heart Failure

Abstract

Background Trimethylamine N-oxide (TMAO), a gut microbe dependent metabolite of dietary choline and other trimethylamine containing nutrients, is both elevated in the circulation of patients suffering from heart failure (HF) and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerate atherosclerotic lesion development in ApoE deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the LDL receptor knockout mouse. Methods and Results C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks prior to surgical TAC. Mice were studied for 12 weeks following TAC. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post-TAC myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac BNP, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction (LVEF) were significantly (p < 0.05, each) worse in mice fed either TMAO or choline supplemented diets compared to the control diet. In addition, myocardial fibrosis was also significantly greater (p < 0.01, each) in the TMAO and choline groups relative to controls. Conclusions Heart failure severity is significantly enhanced in mice fed diets supplemented in either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that further studies are warranted examining whether gut microbiota and the dietary choline -> TMAO pathway contribute to increased heart failure susceptibility.

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

“…Similar to our observations in angiotensin-II treated germ-free mice, showing increased cardiac fibrosis, macrophage and neutrophil accumulation, and increased cardiomyocyte area together with increased end-organ damage and angiotensin-II induced hypertension in the conventionally-raised controls [65], myocardial fibrosis was significantly enhanced in mice on a choline-rich or TMAO supplemented diet in the transverse aortic constriction model [113].…”

“…In addition to its role in promoting atherosclerotic lesion development, choline-rich diet or TMAO were demonstrated to exacerbate pressure overload-induced heart failure in mice that were subjected to a transverse aortic constriction [113]. Similar to our observations in angiotensin-II treated germ-free mice, showing increased cardiac fibrosis, macrophage and neutrophil accumulation, and increased cardiomyocyte area together with increased end-organ damage and angiotensin-II induced hypertension in the conventionally-raised controls [65], myocardial fibrosis was significantly enhanced in mice on a choline-rich or TMAO supplemented diet in the transverse aortic constriction model [113].…”

Metabolomic Analysis in Heart Failure

“…63 In addition, elevation of TMAO level is a risk factor for development of HF in both diabetic and non-diabetic individuals. 64 In a murine LV pressure overload model, a diet enriched in TMAO or choline was shown to promote cardiac systolic dysfunction, together with severe cardiac fibrosis, 65 indicating a causative role of TMAO in promoting HF pathology. In addition, it is reported that TMAO contributes to progression of atherosclerotic plaque by reducing reverse cholesterol transport.…”

Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment

“…Several studies have found that elevated serum TMAO is associated with increased incidence of myocardial infarction, HF, and cardiovascular mortality [35–40]. The mechanisms underlying these adverse associations between TMAO and cardiovascular have been partially described.…”