Nonlethal Inhibition of Gut Microbial Trimethylamine N‐oxide Production Improves Cardiac Function and Remodeling in a Murine Model of Heart Failure

Background Patients at increased risk for coronary artery disease and adverse prognosis during heart failure exhibit increased levels of circulating trimethylamine N‐oxide (TMAO ), a metabolite formed in the metabolism of dietary phosphatidylcholine. We investigated the efficacy of dietary withdrawal ofTMAO as well as use of a gut microbe‐targeted inhibitor ofTMAO production, on cardiac function and structure during heart failure.Methods and Results Male C57BLK /6J mice were fed either control diet, a diet containingTMAO (0.12% wt/wt), a diet containing choline (1% wt/wt), or a diet containing choline (1% wt/wt) plus a microbial choline trimethylamine lyase inhibitor, iodomethylcholine (0.06% wt/wt), starting 3 weeks before transverse aortic constriction. At 6 weeks after transverse aortic constriction, a subset of animals in theTMAO group were switched to a control diet for the remainder of the study. Left ventricular structure and function were monitored at 3‐week intervals. Withdrawal ofTMAO from the diet attenuated adverse ventricular remodeling and improved cardiac function compared with theTMAO group. Similarly, inhibiting gut microbial conversion of choline toTMAO with a choline trimethylamine lyase inhibitor, iodomethylcholine, improved remodeling and cardiac function compared with the choline‐fed group.Conclusions These experimental findings are clinically relevant, and they demonstrate thatTMAO levels are modifiable following long‐term exposure periods with either dietary withdrawal ofTMAO or gut microbial blockade ofTMAO generation. Furthermore, these therapeutic strategies to reduce circulatingTMAO levels mitigate the negative effects of dietary choline andTMAO in heart failure.