The contributory role of gut microbiota in cardiovascular disease

Abstract

Our group recently discovered that certain dietary nutrients possessing a trimethylamine (TMA) moiety, namely choline/phosphatidylcholine and L-carnitine, participate in the development of atherosclerotic heart disease. A meta-organismal pathway was elucidated involving gut microbiota-dependent formation of TMA and host hepatic flavin monooxygenase 3-dependent (FMO3-dependent) formation of TMA-N-oxide (TMAO), a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks. Collectively, these studies reveal that nutrient precursors, gut microbiota, and host participants along the meta-organismal pathway elucidated may serve as new targets for the prevention and treatment of CVD.

Figure 3. Examples of microbial enzymes that generate TMA, using choline or carnitine as substrates.

Thus far, 2 distinct microbial enzyme systems have been identified in vitro that can produce TMA from either choline or carnitine as substrate (75, 77). The choline-utilizing enzyme cutC (catalytic polypeptide) and its partner cutD (regulatory polypeptide) make a complex that selectively uses choline as substrate and releases TMA (choline TMA lyase activity). Similarly, a microbial oxygenase (CntA) complexes with the microbial reductase (CntB) to form an active complex that selectively uses carnitine as substrate and forms TMA (carnitine TMA lyase activity). In theory, inhibition of microbial choline and/or carnitine TMA lyases may serve as a potential therapeutic target for CVD through the reduction of microbial TMA and subsequent host TMAO formation.

Figure 2. Effects of gut microbiota–dependent TMAO production on cholesterol and sterol metabolism and atherosclerosis.

Compartments and processes through which microbiota-generated TMAO affects cholesterol and sterol metabolism and atherosclerosis. The microbiota metabolizes dietary L-carnitine and choline to form TMA and TMAO, influencing cholesterol and sterol metabolism in macrophages, liver, and intestine (39).

Figure 1. Nutrient/meta-organismal pathway associated with atherosclerosis and major adverse cardiovascular events.

Foods rich in cholesterol and fats are also often rich in the indicated dietary nutrients PC (lecithin), choline, and carnitine. Following ingestion, gut microbiota can use these nutrients as a carbon fuel source. While mammals do not have the enzyme, gut microbes have TMA lyases, which can cleave the C-N bond of these nutrients, releasing the TMA moiety as a waste product. Transport via the portal circulation brings the TMA to a cluster of hepatic enzymes, the FMOs (particularly FMO3), that efficiently oxidize TMA, thus forming TMAO. TMAO enters the circulation, where it is predominantly excreted by the kidneys. TMAO has been shown to affect cholesterol and sterol metabolism in animal models, enhancing macrophage cholesterol accumulation and atherosclerosis development. In multiple human studies, elevated TMAO has been independently associated with prevalent CVD and incident risks for MI, stroke, death, and revascularization. [O], oxidation.