Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Cited from: Nature Volume: 472, Pages: 57–63 Date published: (07 April 2011)
Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—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 upregulation 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, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease

Abstract

The pathogenesis of CVD includes genetic and environmental factors. A known environmental risk factor for the development of CVD is a diet rich in lipids. A relationship between blood cholesterol and triglyceride levels and cardiovascular risk is well established. However, less is known about the role of the third major category of lipids, phospholipids, in atherosclerotic heart disease pathogenesis.

Another potential yet controversial environmental factor in the development or progression of atherosclerotic heart disease is inflammation due to infectious agents. Some studies have reported associations between coronary disease and pathogens such as cytomegalovirus (CMV), Helicobactor pylori, and Chlamydia pneumoniae1, 2, 3, 4. However, prospective randomized trials with antibiotics in humans have thus far failed to demonstrate cardiovascular benefit5, 6, 7 and studies with germ-free hyperlipidaemic mice confirm that infectious agents are not necessary for murine atherosclerotic plaque development8. Although a definite cause-and-effect relationship between a bacterial or viral pathogen and atherosclerosis in humans has not yet been established, the prospect of a role for microbes in atherosclerosis susceptibility remains enticing.

The intestinal microbiota (‘gut flora’), comprised of trillions of typically non-pathogenic commensal organisms, serve as a filter for our greatest environmental exposure—what we eat. Gut flora have an essential role, aiding in the digestion and absorption of many nutrients9. Animal studies have recently shown that intestinal microbial communities can influence the efficiency of harvesting energy from diet, and consequently influence susceptibility to obesity10. Metabolomics studies of inbred mouse strains have also recently shown that gut microbiota may have an active role in the development of complex metabolic abnormalities, such as susceptibility to insulin resistance and non-alcoholic fatty liver disease11. A link between gut-flora-dependent phospholipid metabolism and atherosclerosis risk through generation of pro-atherosclerotic metabolites has not yet been reported.

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