Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Abstract

Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB

“…A previous report showed that TMAO enhanced uptake of cholesterol in peritoneal macrophages, a critical step in atherosclerosis 1. Although we did not observe TMAO inducing inflammation in macrophages, these observations could be due to differential regulation of receptor or signaling mechanisms across cell types.…”

“…TMAO is derived primarily from dietary choline and carnitine through the action of gut microbiota, which metabolize these constituents to trimethylamine (TMA) 1, 11, 12. TMA is absorbed in turn and travels via the portal circulation to the liver, where it is oxidized by flavin‐containing monoxygenases, primarily FMO3, to TMAO 1, 11, 12.…”

“…TMA is absorbed in turn and travels via the portal circulation to the liver, where it is oxidized by flavin‐containing monoxygenases, primarily FMO3, to TMAO 1, 11, 12. In studies in mice, supplementation with dietary choline, carnitine, precarnitine (γ‐butyrobetaine) , or even TMAO alone was sufficient to enhance macrophage cholesterol accumulation and atherogenic plaque formation, supporting a causal relationship 1, 2, 11. TMAO also has significant effects on cholesterol metabolism in the bile acid compartments 1, 11…”

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

“…PC is a major dietary source of choline in omnivores, which often is found in the Western diet, such as red meat, eggs, and meat products. Direct ingestion of PC was shown to result in a rise in choline, betaine, and TMAO levels 1, 3. Moreover, previous studies have report that elevated plasma TMAO levels predicted future risk of major adverse cardiovascular events and have a direct mechanistic link to development of cardiovascular disease 1, 2, 3, 4.…”

“…Our recent studies in animals and in humans suggested a role for gut microbiota in the pathogenesis of atherosclerosis 1, 2. Trimethylamine‐containing nutrients (eg, PC, choline, and l ‐carnitine) are metabolized by the gut microbiota to trimethylamine (TMA) and converted to TMAO 1.…”