Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57-63

Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nature (Impact Factor: 41.46). 04/2011; 472(7341):57-63. DOI: 10.1038/nature09922
Source: PubMed

ABSTRACT 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.

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Available from: Joseph A. DiDonato, Sep 27, 2015
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    • "As is such, some researchers in the fields of health and nutrition have begun to recommend daily supplementation of phosphatidylcholine as a way of slowing down senescence (Mci – Chu et al., 2001) and improving brain functioning and memory capacity (Chung et al., 1995). In addition to the increased caloric burden of a diet rich in fats like phosphatidylcholine, a recent report has linked the microbial catabolites of phosphatidylcholine with increased atherosclerosis through the production of choline, trimethylamine oxide and betaine (Wang et al., 2011). Phosphatidylethanolamine is found in all living cells, although in human physiology it is found particularly in nervous tissue such as the white matter of brain, nerves, neural tissue and in spinal cord. "
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    • "Increased plasma L-carnitine levels were detected in patients with cardiovascular abnormalities and were associated with increased cardiovascular risk (Koeth et al. 2013). Functional studies showed that TMAO inhibited RCT and promoted accumulation of cholesterol in macrophages through increasing cell surface expression of proatherogenic scavenger receptors CD36 and scavenger receptor A (SRA) (Wang et al. 2011b), reducing synthesis of bile acids from cholesterol, and decreasing expression of bile acid transporters in the liver (Koeth et al. 2013). Indeed, increased meat consumption could elevate the dose of L-carnitine and enhance TMAO production in the gut thereby contributing to higher cardiovascular risk. "
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    ABSTRACT: Inflammation and metabolic abnormalities are linked to each other. At present, pathogenic inflammatory response was recognized as a major player in metabolic diseases. In humans, intestinal microflora could significantly influence the development of metabolic diseases including atherosclerosis. Commensal bacteria were shown to activate inflammatory pathways through altering lipid metabolism in adipocytes, macrophages, and vascular cells, inducing insulin resistance, and producing trimethylamine-N-oxide. However, gut microbiota could also play the atheroprotective role associated with anthocyanin metabolism and administration of probiotics and their components. Here, we review the mechanisms by which the gut microbiota may influence atherogenesis.
    Frontiers in Microbiology 06/2015; 6:671. DOI:10.3389/fmicb.2015.00671 · 3.99 Impact Factor
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    • "The studies described here, along with previous reports linking TMAO to CVD risk in humans (Wang et al., 2011, 2014; Tang et al., 2013; Koeth et al., 2013), provide compelling evidence that the TMA/ FMO3/TMAO pathway is a central regulatory pathway that deserves further exploration. However, the ability of TMAO to promote atherosclerosis (Wang et al., 2011, 2014; Tang et al., 2013; Koeth et al., 2013) may be mutually exclusive from the ability of FMO3 inhibitors to reorganize cholesterol balance and hepatic inflammation. Our studies highlight the necessity to understand the repertoire of substrates that can be utilized by FMO3 and also open the possibility that FMO3 may have regulatory functions distinct from its enzymatic activity. "
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    ABSTRACT: Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here, we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT) and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic endoplasmic reticulum (ER) stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation.
    Cell Reports 01/2015; 66(3). DOI:10.1016/j.celrep.2014.12.036 · 8.36 Impact Factor
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