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The Association between Trimethylamine N-Oxide and Its Predecessors Choline, L-Carnitine, and Betaine with Coronary Artery Disease and Artery Stenosis.

ABSTRACT: Background:Trimethylamine N-oxide (TMAO) and its predecessor products, choline, L-carnitine, and betaine, were reported to be associated with cardiovascular events risk. However, the association of TMAO and its predecessors with extent of artery stenosis in coronary artery disease (CAD) and in different gender is still unknown. Our aim is to investigate the association of plasma TMAO and its predecessors in CAD and extent of artery lesion in different gender. Methods:94 CAD patients and 75 healthy controls (CON) were enrolled. Fasting plasma TMAO, choline, L-carnitine, and betaine were detected using liquid chromatography-tandem mass spectrometry. Results:Elevated plasma TMAO but not choline, L-carnitine, or betaine was observed in CAD (1.46(0.8-2.32) ?M) and severe artery stenosis patients (S) (1.62(0.91-2.81) ?M) compared with controls and mild artery stenosis (M) (1.18(0.67-1.7) ?M in CON; 1.27(0.77-1.82) ?M in M, p < 0.05). TMAO was an independent risk factor of CAD and severe artery stenosis (CAD?:?OR?=?1.81, 95%CI: 1.07-3.09, p=0.03; S?:?OR?=?1.36, 95%CI: 1.01-1.84, p=0.04). TMAO was more sensitive in diagnosing CAD and severe artery stenosis from controls in men rather than in women by ROC analysis (AUC for men and women in CAD: 0.64 versus 0.57; AUC for men and women in S: 0.64 versus 0.58), while the combined four metabolites greatly improved diagnostic accuracy in women with CAD and severe artery stenosis (AUC in CAD: 0.64, AUC in S: 0.68). Conclusion:The associations of TMAO with CAD and severe artery stenosis were sex-related. TMAO alone was more powerful in determining CAD and artery stenosis in men than women, while a combination of TMAO, choline, L-carnitine, and betaine could be potential biomarkers for diagnosing CAD and artery stenosis in both men and women.

SUBMITTER: Guo F

PROVIDER: S-EPMC7443013 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Association between Trimethylamine N-Oxide and Its Predecessors Choline, L-Carnitine, and Betaine with Coronary Artery Disease and Artery Stenosis.

Guo Fei F Zhou Jun J Li Zhenyu Z Yu Zaixin Z Ouyang Dongsheng D

Cardiology research and practice 20200813

<h4>Background</h4>Trimethylamine N-oxide (TMAO) and its predecessor products, choline, L-carnitine, and betaine, were reported to be associated with cardiovascular events risk. However, the association of TMAO and its predecessors with extent of artery stenosis in coronary artery disease (CAD) and in different gender is still unknown. Our aim is to investigate the association of plasma TMAO and its predecessors in CAD and extent of artery lesion in different gender.<h4>Methods</h4>94 CAD patien ...[more]

PMID: 32855821

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Project description:BackgroundTrimethylamine N-oxide (TMAO), a compound derived from diet and metabolism by the gut microbiome, has been associated with several chronic diseases, although the mechanisms of action are not well understood and few human studies have investigated microbes involved in its production.ObjectivesOur study aims were 1) to investigate associations of TMAO and its precursors (choline, carnitine, and betaine) with inflammatory and cardiometabolic risk biomarkers; and 2) to identify fecal microbiome profiles associated with TMAO.MethodsWe conducted a cross-sectional analysis using data collected from 1653 participants (826 men and 827 women, aged 60-77 y) in the Multiethnic Cohort Study. Plasma concentrations of TMAO and its precursors were measured by LC-tandem MS. We also analyzed fasting blood for markers of inflammation, glucose and insulin, cholesterol, and triglycerides (TGs), and further measured blood pressure. Fecal microbiome composition was evaluated by sequencing the 16S ribosomal RNA gene V1-V3 region. Associations of TMAO and its precursors with disease risk biomarkers were assessed by multivariable linear regression, whereas associations between TMAO and the fecal microbiome were assessed by permutational multivariate ANOVA and hurdle regression models using the negative binomial distribution.ResultsMedian (IQR) concentration of plasma TMAO was 3.05 μmol/L (2.10-4.60 μmol/L). Higher concentrations of TMAO and carnitine, and lower concentrations of betaine, were associated with greater insulin resistance (all P < 0.02). Choline was associated with higher systolic blood pressure, TGs, lipopolysaccharide-binding protein, and lower HDL cholesterol (P ranging from <0.001 to 0.03), reflecting an adverse cardiometabolic risk profile. TMAO was associated with abundance of 13 genera (false discovery rate < 0.05), including Prevotella, Mitsuokella, Fusobacterium, Desulfovibrio, and bacteria belonging to the families Ruminococcaceae and Lachnospiraceae, as well as the methanogen Methanobrevibacter smithii.ConclusionsPlasma TMAO concentrations were associated with a number of trimethylamine-producing bacterial taxa, and, along with its precursors, may contribute to inflammatory and cardiometabolic risk pathways.

Project description:BackgroundCoronary artery stenosis induces heart diseases including acute coronary syndrome (ACS). Some studies reported the ceramide species are associated with the ACS and major adverse cardia and cerebrovascular events (MACE). However, few studies investigated the association between plasma ceramide levels and the severity of stenosis, together with the onset of diseases. This aim of the present study was to investigate the association betweencertain ceramide species, coronary artery stenosis and acute coronary syndrome.MethodsFive hundred fifty-three patients with definite or suspected CAD were recruited and received angiography. Subjects were assigned into 4 groups according to the severity of coronary artery stenosis. The measurements of 4 plasma ceramide species, namely, Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/24:1), Cer (d18:1/24:0) were carried out by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the ratio of Cer (d18:1/16:0), Cer (d18:1/18:0) and Cer (d18:1/24:1) to Cer (18:1/24:0), respectively, were calculated as index to evaluate the association between plasma ceramides levels and coronary artery stenosis. Multiple logistic regression analysis was used to establish the prognostic model for the prediction of ACS risk.ResultsAfter the adjustment by multiple clinical risk factors including age, gender, pre-existing myocardial/cerebral infarction, hemoglobin A1c% (HbA1c%), smoking and the diagnosis during index hospitalization, multiple logistic regression analysis showed that the high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c%, unstable angina (UAP) and acute myocardial infarction (AMI) diagnosis (compared with atherosclerosis) during index hospitalization were associated with more severe coronary artery stenosis. Furthermore, the prognostic model was established after adjustment of risk factors and the area under curve (AUC) of receiver operating characteristics (ROC) for the prognostic model was 0.732 and 95% CI was 0.642-0.822.ConclusionThe severity of coronary artery stenosis is associated with high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c% and AMI. Although the reported prognostic model showed a good discrimination, further investigation on long term MACE is needed to evaluate the role of ceramide for the prediction of MACE risk.

Project description:BACKGROUND:Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO (trimethylamine-N-oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge. METHODS AND RESULTS:We performed a double-blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan-donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6-choline and d3-carnitine (eg, labeled and unlabeled TMAO in plasma and 24-hour urine after oral ingestion of 250 mg of both isotope-labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan-donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan-donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18F-fluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells. CONCLUSIONS:Single lean vegan-donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation. CLINICAL TRIAL REGISTRATION:URL: http://www.trialregister.nl. Unique identifier: NTR 4338.

Project description:Fluctuations in osmolarity are one of the most prevalent stresses to which bacteria must adapt, both hypo- and hyperosmotic conditions. Most bacteria cope with high osmolarity by accumulating compatible solutes (osmolytes) in the cytoplasm to maintain the turgor pressure of the cell. Vibrio parahaemolyticus, a halophile, utilizes at least six compatible solute transporters for the uptake of osmolytes: two ABC family ProU transporters and four betaine-carnitine-choline transporter (BCCT) family transporters. The full range of compatible solutes transported by this species has yet to be determined. Using an osmolyte phenotypic microarray plate for growth analyses, we expanded the known osmolytes used by V. parahaemolyticus to include N,N-dimethylglycine (DMG), among others. Growth pattern analysis of four triple-bccT mutants, possessing only one functional BCCT, indicated that BccT1 (VP1456), BccT2 (VP1723), and BccT3 (VP1905) transported DMG. BccT1 was unusual in that it could take up both compounds with methylated head groups (glycine betaine [GB], choline, and DMG) and cyclic compounds (ectoine and proline). Bioinformatics analysis identified the four coordinating amino acid residues for GB in the BccT1 protein. In silico modeling analysis demonstrated that GB, DMG, and ectoine docked in the same binding pocket in BccT1. Using site-directed mutagenesis, we showed that a strain with all four residues mutated resulted in the loss of uptake of GB, DMG, and ectoine. We showed that three of the four residues were essential for ectoine uptake, whereas only one of the residues was important for GB uptake. Overall, we have demonstrated that DMG is a highly effective compatible solute for Vibrio species and have elucidated the amino acid residues in BccT1 that are important for the coordination of GB, DMG, and ectoine transport.IMPORTANCEVibrio parahaemolyticus possesses at least six osmolyte transporters, which allow the bacterium to adapt to high-salinity conditions. In this study, we identified several additional osmolytes that were utilized by V. parahaemolyticus We demonstrated that the compound DMG, which is present in the marine environment, was a highly effective osmolyte for Vibrio species. We determined that DMG is transported via BCCT family carriers, which have not been shown previously to take up this compound. BccT1 was a carrier for GB, DMG, and ectoine, and we identified the amino acid residues essential for the coordination of these compounds. The data suggest that for BccT1, GB is more easily accommodated than ectoine in the transporter binding pocket.

Dataset Information

The Association between Trimethylamine N-Oxide and Its Predecessors Choline, L-Carnitine, and Betaine with Coronary Artery Disease and Artery Stenosis.

Publications

The Association between Trimethylamine N-Oxide and Its Predecessors Choline, L-Carnitine, and Betaine with Coronary Artery Disease and Artery Stenosis.

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