A role for gut flora in cardiovascular disease: you are what they eat
Wang and colleagues writing in this week’s Nature, report that gut flora contribute to cardiovascular disease (CVD) by metabolising dietary phospatidylcholine (1). Phosphatidylcholine (PC), as Wang et al. highlight, is plentiful in eggs, milk, liver, red meat, poultry, shell fish and fish.
Plasma samples from 50 cardiac evaluation volunteers who developed CVD within the next 3 years and 50 age and sex matched controls (without CVD in the next 3 years) were compared using mass spectrometry. 18 analytes were significantly more abundant in the CVD group. The concentrations of 3 of these analytes correlated closely, suggesting that they could represent biochemical intermediates of a single biological pathway. Using NMR, one of these analytes was shown to be TMAO, a choline breakdown product and, with further NMR studies, the other 2 peaks were identified as choline and betaine (a product of an alternative catabolic pathway for choline). A large cohort study of 1,876 volunteers showed a dose- dependent relationship between choline, betaine and TMAO and subsequent CVD. These experiments suggested that choline, or its derivates, might contribute to the pathogenesis of CVD.
To dissect the role of choline in CVD pathogenesis, Choline or TMAO- supplemented chow was fed to Apoe-/- mice. Apoe-/- animals are prone to atherosclerosis. Choline or TMAO chow resulted in accelerated atherosclerotic plaque formation in a dose-dependent manner. The generation of TMAO from PC required gut flora in two different systems – antibiotic-mediated clearance of gut flora and experiments using germ-free mice. Foamy macrophages, isolated from atherosclerotic plaques, showed in increased expression of scavenger receptors with choline/TMAO-supplemented chow. TMAO might promote the development of foam cells, an important cellular component of atherosclerotic plaques.
Wang et al. demonstrate, for the first time, the importance of gut flora in the development of atherosclerosis. A non-absorbed inhibitor of bacterial choline metabolism could be a potent anti- atherosclerosis agent.
1. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011 Apr;472(7341):57-63.