Free Choline, but Not Phosphatidylcholine, Elevates Circulating Trimethylamine-N-oxide and This Response Is Modified by the Gut Microbiota Composition in Healthy Men (original) (raw)
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Nutrients, 2020
Background: Trimethylamine-N-oxide (TMAO), a choline-derived gut microbiota-dependent metabolite, is a newly recognized risk marker for cardiovascular disease. We sought to determine: (1) TMAO response to meals containing free versus lipid-soluble choline and (2) effects of gut microbiome on TMAO response. Methods: In a randomized, controlled, double-blinded, crossover study, healthy men (n = 37) were provided meals containing 600 mg choline either as choline bitartrate or phosphatidylcholine, or no choline control. Results: Choline bitartrate yielded three-times greater plasma TMAO AUC (p = 0.01) and 2.5-times greater urinary TMAO change from baseline (p = 0.01) compared to no choline and phosphatidylcholine. Gut microbiota composition differed (permutational multivariate analysis of variance, PERMANOVA; p = 0.01) between high-TMAO producers (with ≥40% increase in urinary TMAO response to choline bitartrate) and low-TMAO producers (with <40% increase in TMAO response). High-TMAO...
Nutrients
Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which, upon absorption by the host is converted into trimethylamine-N-oxide (TMAO) in the liver. A high accumulation of both components is related to cardiovascular disease, inflammatory bowel disease, non-alcoholic fatty liver disease, and chronic kidney disease. However, the relationship between the microbiota production of these components and its impact on these diseases still remains unknown. In this review, we will address which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., the genotype) and diet affect TMA production, and the colonization of these microbes and the reversal of dysbiosis as a therapy for these diseases.
International Journal of Molecular Sciences
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 promot...
The American journal of clinical nutrition, 2016
Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment. We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans. A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured. Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhom...
Nutrients
Gut microbiota-derived metabolites have recently attracted considerable attention due to their role in host-microbial crosstalk and their link with cardiovascular health. The MEDLINE-PubMed and Elsevier’s Scopus databases were searched up to June 2022 for studies evaluating the association of baseline circulating levels of trimethylamine N-oxide (TMAO), secondary bile acids, short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), tryptophan and indole derivatives, with risk of cardiovascular disease (CVD). A total of twenty-one studies were included in the systematic review after evaluating 1210 non-duplicate records. There were nineteen of the twenty-one studies that were cohort studies and two studies had a nested case–control design. All of the included studies were of high quality according to the “Newcastle–Ottawa Scale”. TMAO was positively associated with adverse cardiovascular events and CVD/all-cause mortality in some, but not all of the included studies. Bile ...
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Nature, 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.
Nutrients
TMAO is elevated in individuals with cardiometabolic diseases, but it is unknown whether the metabolite is a biomarker of concern in healthy individuals. We conducted a cross-sectional study in metabolically healthy adults aged 18–66 years with BMI 18–44 kg/m2 and assessed the relationship between TMAO and diet, the fecal microbiome, and cardiometabolic risk factors. TMAO was measured in fasted plasma samples by liquid chromatography mass spectrometry. The fecal microbiome was assessed by 16S ribosomal RNA sequencing and recent food intake was captured by multiple ASA24 dietary recalls. Endothelial function was assessed via EndoPAT. Descriptive statistics were computed by fasting plasma TMAO tertiles and evaluated by ANOVA and Tukey’s post-hoc test. Multiple linear regression was used to assess the relationship between plasma TMAO and dietary food intake and metabolic health parameters. TMAO concentrations were not associated with average intake of animal protein foods, fruits, vege...
Trimethylamine N-oxide: heart of the microbiota–CVD nexus?
Nutrition Research Reviews, 2020
We critically review potential involvement of trimethylamine N-oxide (TMAO) as a link between diet, the gut microbiota and CVD. Generated primarily from dietary choline and carnitine by gut bacteria and hepatic flavin-containing mono-oxygenase (FMO) activity, TMAO could promote cardiometabolic disease when chronically elevated. However, control of circulating TMAO is poorly understood, and diet, age, body mass, sex hormones, renal clearance, FMO3 expression and genetic background may explain as little as 25 % of TMAO variance. The basis of elevations with obesity, diabetes, atherosclerosis or CHD is similarly ill-defined, although gut microbiota profiles/remodelling appear critical. Elevated TMAO could promote CVD via inflammation, oxidative stress, scavenger receptor up-regulation, reverse cholesterol transport (RCT) inhibition, and cardiovascular dysfunction. However, concentrations influencing inflammation, scavenger receptors and RCT (≥100 µm) are only achieved in advanced heart...
The Gut Microbiome and Cardiovascular Disease
Cureus, 2021
Cardiovascular disease (CVD) is currently the leading cause of death worldwide. Although many well-known conditions cause CVD, recent research has suggested that alterations to the gut microbiome may also promote CVD. The gastrointestinal tract houses trillions of bacteria, some of which in large numbers are considered to be part of a healthy gut microbiome profile. These "good" bacteria have the ability to process and digest complex carbohydrates into short-chain fatty acids (SFCA). These SCFA serve as signaling molecules, immune-modulating molecules, and sources of energy. However, with gut dysbiosis, there is an overgrowth of certain bacteria and these bacteria overly produce phosphatidylcholine, choline, and carnitine into the waste product trimethylamine-N-oxide (TMAO). Elevated TMAO levels are associated with an increased risk of atherosclerosis, myocardial infarction, thrombosis, and stroke. Therefore, introducing therapeutic interventions that alter a dysbiotic gut profile back to a healthy gut microbiome may be the key to reducing the incidence of cardiovascular disease in some conditions. The purpose of this review is to critically examine and consolidate the relevant information bearing on this concept. Our goal is to provide the informational framework for the possible use of microbiome modification as an optional therapeutic modality.