Metaorganismal nutrient metabolism as a basis of cardiovascular disease

Abstract

Purpose of review: Atherosclerosis and associated cardiovascular disease (CVD) remains the leading cause of mortality in Western societies. It is well accepted that the consumption of foods abundant in saturated fats and cholesterol, like meats, egg yolk and high-fat dairy products, are associated with increased CVD risk. New evidence suggests that trimethylamine (TMA)-containing nutrients within these foods, including phosphatidylcholine, choline, and L-carnitine, can enter into a microbial metabolic pathway that promotes CVD. In this review, we highlight the role of gut microbiota-driven nutrient metabolism as a novel pathway promoting CVD.

Recent findings: Recent studies demonstrate a link between ingestion of dietary phosphatidylcholine, choline, and L-carnitine and CVD risk. At the center of this pathway is gut microbiota-dependent synthesis of a metabolic intermediate called TMA, and subsequent host-driven conversion of TMA to trimethylamine-N-oxide (TMAO). Microbiota-dependent generation of TMAO is associated with increased risk of incident major adverse cardiovascular events in humans, and provision of TMAO promotes atherosclerosis in mice.

Summary: Microbial metabolism of TMA containing nutrients can lead to formation of the proatherogenic compound TMAO. Recent insights into this diet-microbe-host interaction provide new clues surrounding the pathogenesis of atherosclerosis, and may serve as a framework for new CVD therapies.

FIGURE 1. Meta-organismal pathways linking dietary phosphatidylcholine or choline and l-carnitine and cardiovascular disease

Once ingested by the host, both the choline component of phosphatidylcholine (lecithin) and l-carnitine can be metabolized by gut microbiota to generate trimethylamine (TMA). The resulting bacterial metabolite TMA can then be converted to trimethylamine-N-oxide (TMAO) by the flavin monooxygenase family of enzymes (FMOs) in the host's liver. Elevated circulating TMAO levels are associated with increased risk of incident major adverse cardiovascular events including heart attack, stroke, and death in humans. Studies in mice have demonstrated that TMAO promotes atherosclerosis by dually increasing foam cell formation in the artery wall and decreasing reverse cholesterol transport. Collectively, this sequential nutrient metabolism pathway represents a new pathway for cardiovascular disease drug discovery efforts.