Abstract
Recent evidence, including massive gene-expression analysis and a wide-variety of other multi-omics approaches, demonstrates an interplay between gut microbiota and the regulation of plasma lipids. Gut microbial metabolism of choline and l-carnitine results in the formation of trimethylamine (TMA) and concomitant conversion into trimethylamine-N-oxide (TMAO) by liver flavin monooxygenase 3 (FMO3). The plasma level of TMAO is determined by the genetic variation, diet and composition of gut microbiota. Multiple studies have demonstrated an association between TMAO plasma levels and the risk of atherothrombotic cardiovascular disease (CVD). We aimed to review the molecular pathways by which TMAO production and FMO3 exert their proatherogenic effects. TMAO may promote foam cell formation by upregulating macrophage scavenger receptors, deregulating enterohepatic cholesterol and bile acid metabolism and impairing macrophage reverse cholesterol transport (RCT). Furthermore, FMO3 may promote dyslipidemia by regulating multiple genes involved in hepatic lipogenesis and gluconeogenesis. FMO3 also impairs multiple aspects of cholesterol homeostasis, including transintestinal cholesterol export and macrophage-specific RCT. At least part of these FMO3-mediated effects on lipid metabolism and atherogenesis seem to be independent of the TMA/TMAO formation. Overall, these findings have the potential to open a new era for the therapeutic manipulation of the gut microbiota to improve CVD risk.
Highlights
Cardiovascular disease (CVD) accounts for approximately 17 million deaths worldwide each year and remains the main cause of mortality in the United States [1]
There is significant evidence supporting the hypothesis that gut microbiota-derived production of TMAO increases the risk of atherosclerotic CVD
The concentration of circulating TMAO is determined by several main factors, including the dietary habits, gut microbiota, flavin monooxygenase 3 (FMO3) activity and kidney function
Summary
Cardiovascular disease (CVD) accounts for approximately 17 million deaths worldwide each year and remains the main cause of mortality in the United States [1]. There is significant evidence supporting a role of the gut microbiota in cardiovascular health [10] and the onset and development of complex cardiometabolic diseases such as obesity, diabetes and metabolic syndrome [11,12]. The gut microbiota plays a critical role in plasma lipid levels, which was mainly found in plasma triglycerides and high-density lipoprotein (HDL) cholesterol levels [13]. Based on these studies, a link between microbiota, cardiometabolic diseases and CVD can be devised
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