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1.
Molecules ; 26(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801417

RESUMO

Trimethylamine N-oxide (TMAO), as a gut-derived metabolite, has been found to be associated with enhanced risk for atherosclerosis and cardiovascular disease. We presented a method for targeted profiling of TMAO and betaine in serum and food samples based on a combination of one-step sample pretreatment and proton nuclear magnetic resonance spectroscopy. The key step included a processing of sample preparation using a selective solid-phase extraction column for retention of basic metabolites. Proton signals at δ 3.29 and δ 3.28 were employed to quantify TMAO and betaine, respectively. The developed method was examined with acceptable linear relationship, precision, stability, repeatability, and accuracy. It was successfully applied to detect serum levels of TMAO and betaine in TMAO-fed mice and high-fructose-fed rats and also used to determine the contents of TMAO and betaine in several kinds of food, such as fish, pork, milk, and egg yolk.


Assuntos
Betaína/análise , Análise de Alimentos/métodos , Metabolômica/métodos , Metilaminas/análise , Óxidos/química , Animais , Betaína/sangue , Betaína/metabolismo , Feminino , Masculino , Metilaminas/sangue , Metilaminas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar
2.
Nutrients ; 13(5)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922680

RESUMO

INTRODUCTION: Trimethylamine N-oxide (TMAO) may play a key mediator role in the relationship between the diet, gut microbiota and cardiovascular diseases, particularly in people with kidney failure. The aim of this review is to evaluate which foods have a greater influence on blood or urinary trimethylamine N-oxide (TMAO) levels. METHODS: 391 language articles were screened, and 27 were analysed and summarized for this review, using the keywords "TMAO" AND "egg" OR "meat" OR "fish" OR "dairy" OR "vegetables" OR "fruit" OR "food" in December 2020. RESULTS: A strong correlation between TMAO and fish consumption, mainly saltwater fish and shellfish, but not freshwater fish, has been demonstrated. Associations of the consumption of eggs, dairy and meat with TMAO are less clear and may depend on other factors such as microbiota or cooking methods. Plant-based foods do not seem to influence TMAO but have been less investigated. DISCUSSION: Consumption of saltwater fish, dark meat fish and shellfish seems to be associated with an increase in urine or plasma TMAO values. Further studies are needed to understand the relationship between increased risk of cardiovascular disease and plasma levels of TMAO due to fish consumption. Interventions coupled with long-term dietary patterns targeting the gut microbiota seem promising.


Assuntos
Alimentos , Metilaminas/sangue , Metilaminas/urina , Animais , Laticínios , Ovos , Humanos , Carne , Alimentos Marinhos
3.
J Neuroimmunol ; 354: 577526, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33647820

RESUMO

BACKGROUND: Over the recent years, the role of trimethylamine N-oxide (TMAO) as a gut-derived metabolite mediating cardiovascular disease pathogenesis has been under particularly intense scrutiny. The aim was to explore whether TMAO levels were associated with clinical severity or functional outcome in Chinese patients with ischemic stroke. METHODS: This is a single-center, prospective cohort study from Xiamen, China. We examined the relationship between fasting TMAO and 2 of its nutrient precursors, choline and betaine, vs. 3-month functional outcome and mortality in 351 first-ever patients with acute ischemic stroke. RESULTS: The median value of the plasma level of TMAO was 6.1 µM (IQR, 3.7-9.9 µM), which was higher than in those control cases (4.0; 2.4-5.9 µM). Patients with a poor outcome and nonsurvivors had significantly increased TMAO levels on admission (P < 0.001). Following adjustments for traditional risk factors, increased TMAO concentrations remained predictive of both poor outcome and mortality risks in stroke patients [e.g., quartiles 4 vs 1, odd ratio 5.65 (95% CI, 2.87-13.45), P < 0.001; and 5.84 (95% CI, 3.05-16.12), P < 0.001, respectively]. In multivariate analysis, TMAO was an independent predictor of functional outcome and mortality and improved the prognostic accuracy of the NIHSS to predict functional outcome (combined areas under the curve, 0.82; 95% CI 0.77-0.89, P = 0.003) and mortality (combined areas under the curve, 0.85; 95% CI: 0.80-0.90, P = 0.002). CONCLUSIONS: Fasting plasma concentrations of gut microbial TMAO are higher in patients with ischemic stroke and portend higher poor functional outcome events and mortality.


Assuntos
Microbioma Gastrointestinal/fisiologia , Metilaminas/sangue , Idoso , Biomarcadores/sangue , China , Colina , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
4.
Nutr Metab Cardiovasc Dis ; 31(1): 145-152, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500103

RESUMO

BACKGROUND AND AIMS: Healed plaque is a hallmark of previous regional plaque rupture or erosion. We hypothesized that the plasma level of trimethylamine N-oxide (TMAO) is related to healed culprit plaque in ST-segment elevation myocardial infarction (STEMI) patients. METHODS AND RESULTS: A prospective cohort of 206 patients with STEMI, who were examined by optical coherence tomography (OCT) was enrolled in our study. After exclusion, 156 patients were categorized into healed plaque (n = 54) and nonhealed plaque (n = 102) groups. Plasma TMAO levels were detected by stable isotope dilution liquid chromatography tandem mass spectrometry in these two groups. Increased age and low BMI were more common in patients with healed plaques than in those without healed plaques. Through OCT observation, plaque rupture (81.5% vs. 45.1%, p < 0.001), thin cap fibroatheroma (TCFA) and macrophages (42.6% vs. 20.6%, p = 0.004, 70.4% vs. 26.5%, p < 0.001, respectively) were more frequently seen in patients with healed plaques than in those without healed plaques. The TMAO level in patients with healed plaques was significantly higher than that in patients with nonhealed plaques (3.9 µM [2.6-5.1] vs. 1.8 µM [1.0-2.7], p < 0.001). Furthermore, the receiver operating characteristic curve showed that TMAO can be used as a potential biomarker to predict healed plaque presence with a cutoff value of 2.9 µM (AUC = 0.810, sensitivity: 72.2%, specificity: 81.4%). CONCLUSIONS: Healed plaque in STEMI patients is associated with a high level of plaque vulnerability and inflammation. A high level of plasma TMAO can be a useful biomarker to differentiate STEMI patients with healed culprit plaques.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Metilaminas/sangue , Placa Aterosclerótica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Tomografia de Coerência Óptica , Cicatrização , Idoso , Biomarcadores/sangue , Cromatografia Líquida , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Ruptura Espontânea , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Espectrometria de Massas em Tandem
5.
Am Heart J ; 234: 71-80, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33454370

RESUMO

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut-related metabolite, is associated with heart failure (HF) outcomes. However, TMAO is the final product of a complex metabolic pathway (ie, choline/carnitine) that has never been entirely investigated in HF. The present study investigates a panel of metabolites involved in the TMAO-choline/carnitine metabolic pathway for their associations with outcome in acute HF patients. METHODS: In total, 806 plasma samples from acute HF patients were analyzed for TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, γ-butyrobetaine, crotonobetaine, trimethylamine, betaine aldehyde, choline, and betaine using a developed liquid chromatography-tandem mass spectrometry method. Associations with outcome of all-cause mortality (death) and a composite of all-cause mortality and/or rehospitalization caused by HF (death/HF) at 30 days and 1 year were investigated. RESULTS: TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, and γ-butyrobetaine were associated with death and death/HF at 30 days (short term; hazard ratio 1.30-1.49, P≤ .021) and at 1 year (long term; hazard ratio 1.15-1.25, P≤ .026) when adjusted for cardiac risk factors. L-carnitine and acetyl-L-carnitine were superior for short-term outcomes whereas TMAO was the superior metabolite for association with long-term outcomes. Furthermore, acetyl-L-carnitine and L-carnitine were superior for in-hospital mortality and improved risk stratification when combined with current clinical risk scores (ie, Acute Decompensated HEart Failure National REgistry, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure, and Get With The Guidelines-Heart Failure; odds ratio (OR) ≥ 1.52, P≤ .020). CONCLUSIONS: Carnitine-related metabolites show associations with adverse outcomes in acute HF, in particular L-carnitine and acetyl-L-carnitine for short-term outcomes, and TMAO for long-term outcomes. Further studies are warranted to investigate the role and implications of carnitine metabolites including intervention in the pathogenesis of HF.


Assuntos
Carnitina/metabolismo , Colina/metabolismo , Microbioma Gastrointestinal , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Metilaminas/metabolismo , Acetilcarnitina/sangue , Acetilcarnitina/metabolismo , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Betaína/análogos & derivados , Betaína/sangue , Betaína/metabolismo , Carnitina/sangue , Colina/sangue , Feminino , Insuficiência Cardíaca/etiologia , Mortalidade Hospitalar , Humanos , Masculino , Metilaminas/sangue , Peptídeo Natriurético Encefálico/sangue , Fatores de Risco , Estatísticas não Paramétricas
6.
Nutrients ; 13(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477634

RESUMO

BACKGROUND: Due to the critical shortage of kidneys for transplantation, the identification of modifiable factors related to graft failure is highly desirable. The role of trimethylamine-N-oxide (TMAO) in graft failure remains undetermined. Here, we investigated the clinical utility of TMAO and its dietary determinants for graft failure prediction in renal transplant recipients (RTRs). METHODS: We included 448 RTRs who participated in the TransplantLines Cohort Study. Cox proportional-hazards regression analyses were performed to study the association of plasma TMAO with graft failure. Net Benefit, which is a decision analysis method, was performed to evaluate the clinical utility of TMAO and dietary information in the prediction of graft failure. RESULTS: Among RTRs (age 52.7 ± 13.1 years; 53% males), the baseline median TMAO was 5.6 (3.0-10.2) µmol/L. In multivariable regression analysis, the most important dietary determinants of TMAO were egg intake (Std. ß = 0.09 [95%CI, 0.01; 0.18]; p = 0.03), fiber intake (Std. ß = -0.14 [95%CI, -0.22, -0.05]; p = 0.002), and fish and seafood intake (Std. ß = 0.12 [95%CI, 0.03,0.21]; p = 0.01). After a median follow-up of 5.3 (4.5-6.0) years, graft failure was observed in 58 subjects. TMAO was associated with an increased risk of graft failure, independent of age, sex, the body mass index (BMI), blood pressure, lipids, albuminuria, and the Estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio per 1-SD increase of TMAO, 1.62 (95% confidence interval (CI): 1.22; 2.14, p < 0.001)). A TMAO and dietary enhanced prediction model offered approximately double the Net Benefit compared to a previously reported, validated prediction model for future graft failure, allowing the detection of 21 RTRs per 100 RTRs tested, with no false positives versus 10 RTRs, respectively. CONCLUSIONS: A predictive model for graft failure, enriched with TMAO and its dietary determinants, yielded a higher Net Benefit compared with an already validated model. This study suggests that TMAO and its dietary determinants are associated with an increased risk of graft failure and that it is clinically meaningful.


Assuntos
Dieta , Rejeição de Enxerto/epidemiologia , Transplante de Rim/estatística & dados numéricos , Metilaminas/sangue , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Sobrevivência de Enxerto/fisiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/cirurgia , Fatores de Risco , Alimentos Marinhos , Transplantados/estatística & dados numéricos
7.
Zhonghua Nan Ke Xue ; 26(2): 106-110, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33346411

RESUMO

Objective: To study of the regulatory effects of the lipid metabolic pathways of trimethylamine-N-oxide (TMAO), flavin-containingmonooxidase 3 (FMO3) and farnesoid X receptor (FXR) on compound stress-induced ED (CSED) rats and the mechanisms of Yimusake Tablets (YMSK) intervention. METHODS: Based on the results of metabonomics analysis, we determined the concentration of TMAO in the serum of the rats in the normal control (n = 30), the CSED model control (n = 30) and the YMSK intervention group (intragastrical administration of YMSK at 250 mg/kg once daily for 2-3 weeks after modeling, n = 30) by nuclear magnetic resonance (NMR) spectroscopy test. We also detected the expressions of the FMO3, FXR1 and FXR2 proteins in the liver tissue of the three groups of rats by Western blot. RESULTS: The serum TMAO level was significantly elevated in the CSED model control compared with that in the normal control group (ï¼»46.64 ± 5.16ï¼½ vs ï¼»34.98 ± 3.69ï¼½ µg/mL, P < 0.01) but remarkably decreased after YMSK intervention (ï¼»39.63 ± 4.81ï¼½ µg/mL) in comparison with that in the CSED model control group (P < 0.01). The rats in the CSED model control group, compared with the normal controls, showed significantly upregulated expressions of FMO3 (1.75 ± 0.90 vs 0.86 ± 0.62, P < 0.01),FXR1 (1.29 ± 0.38 vs 0.78 ± 0.25, P < 0.01) and FXR2 in the liver tissue (1.90 ± 0.63 vs 0.42 ± 0.27, P < 0.01), but all the three expressions were markedly decreased after YMSK intervention (FMO3: 1.05 ± 0.38, P < 0.05; FXR1: 1.07 ± 0.42, P < 0.05; FXR2: 1.04 ± 0.46, P < 0.01) as compared with those in the CSED model control group. CONCLUSIONS: The lipid metabolic pathways of TMAO, FMO3 and FXR underwent significant changes in the rat model of compound stress-induced ED, which could be improved by YMSK intervention, suggesting that YMSK may play an important role in protecting erectile function by regulating the lipid metabolic pathways of TMAO, FMO3 and FXR.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Disfunção Erétil/metabolismo , Metabolismo dos Lipídeos , Metilaminas/sangue , Oxigenases/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Disfunção Erétil/fisiopatologia , Masculino , Ratos
8.
Med J Aust ; 213(8): 374-379, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32959366

RESUMO

OBJECTIVE: Gut microbiota-produced trimethylamine N-oxide (TMAO) is a risk factor for cardiovascular events. However, conflicting findings regarding the link between plasma TMAO level and prognosis for patients with heart failure have been reported. We examined the association of plasma TMAO concentration with risk of major adverse cardiac events (MACEs) and all-cause mortality in patients with heart failure. STUDY DESIGN: Meta-analysis of prospective clinical studies. DATA SOURCES: We searched electronic databases (PubMed, EMBASE) for published prospective studies examining associations between plasma TMAO level and MACEs and all-cause mortality in adults with heart failure. DATA SYNTHESIS: Hazard ratios (HRs) with 95% confidence intervals for associations between TMAO level and outcomes were estimated in random effects models. In seven eligible studies including a total of 6879 patients (median follow-up, 5.0 years) and adjusted for multiple risk factors, higher plasma TMAO level was associated with greater risks of MACEs (TMAO tertile 3 v tertile 1: HR, 1.68; 95% CI, 1.44-1.96; per SD increment: HR, 1.26; 95% CI, 1.18-1.36) and of all-cause mortality (TMAO tertile 3 v tertile 1: HR, 1.67; 95% CI, 1.17-2.38; per SD increment: HR, 1.26; 95% CI, 1.07-1.48). Higher TMAO level was also associated with greater risk of MACEs after adjusting for estimated glomerular filtration rate (eGFR; six studies included); however, the heterogeneity of studies in which risk was adjusted for eGFR was significant (I2  = 76%). CONCLUSIONS: Elevated plasma TMAO level in patients with heart failure is associated with poorer prognoses. This association is only partially mediated by renal dysfunction.


Assuntos
Insuficiência Cardíaca/sangue , Transplante de Coração/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Metilaminas/sangue , Mortalidade , Causas de Morte , Microbioma Gastrointestinal , Insuficiência Cardíaca/complicações , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Insuficiência Renal/sangue , Insuficiência Renal/complicações
9.
Medicine (Baltimore) ; 99(27): e20794, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629663

RESUMO

BACKGROUND: Recently, trimethylamine N-oxide (TMAO) unexplained gut microbe has been proposed as a promising risk factor for atherosclerotic cardiovascular disease (CVD) pathogenesis and adverse events. The relationship of TMAO with coronary atherosclerotic burden has been evaluated in patients with stable coronary artery disease and ST-segment elevation myocardial infarction, but still needs to be explored in newly diagnosed non-ST-segment elevation myocardial infarction (NSTEMI) patients. MATERIAL AND METHODS: A prospective, single-center, SZ-NSTEMI trial (ChiCTR1900022366) is underway to investigate the relationship of TMAO with the severity and prognosis of coronary atherosclerosis in newly diagnosed NSTEMI patients who will undergo coronary angiography with primary percutaneous coronary intervention (pPCI). The primary endpoint of the study will be assessed the association of TMAO with coronary atherosclerotic severity quantify by the number of diseased coronary arteries and SYNTAX score after the coronary angiography. The secondary endpoints will be identified the TMAO as a prognostic biomarker for the short (1 month) and long-term (12 months) major cardiovascular and cerebrovascular events (MACCEs) rate including myocardial infarction, target vessel revascularization, stroke, heart failure, all-cause rehospitalization, and all-cause mortality after the pPCI. The blood samples will be collected from each patient before the procedure to measure the TMAO by isotope dilution high-performance liquid chromatography. In conclusion, SZ-NSTEMI will be the first cohort that will be investigated the association of TMAO with the severity and prognosis of coronary atherosclerotic burden in NSTEMI patients, aiming to identify TMAO as a predictor and a prognostic biomarker.


Assuntos
Aterosclerose/patologia , Doença da Artéria Coronariana/patologia , Metilaminas/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/patologia , Adolescente , Adulto , Idoso , Biomarcadores , Doenças Cardiovasculares/patologia , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
10.
J Food Sci ; 85(7): 2207-2215, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32572979

RESUMO

Trimethylamine-N-oxide (TMAO) is considered to have negative effect on human health. Different precursors of TMAO, such as choline, betaine, and L-carnitine, are commonly found in daily foods. The aim of the present study was to compare the ability of different precursors to be metabolized into TMAO, as well as the possible effect of chronic administration with TMAO precursors on TMAO production. The rate of TMAO generation after single gavage with different precursors was L-carnitine > choline >betaine. Moreover, the serum TMAO level of mice increased more than twofold after administration with choline for 3 weeks compared with L-carnitine and betaine groups, which was accompanied by the change of intestinal flora. After the gavage of choline chloride, the production for TMAO was 2.8 and 1.6 times higher in chronic choline-treated group compared with L-carnitine and betaine groups, respectively. In addition, administration with choline increased the lowest TMAO level after intraperitoneal injection of trimethylamine (TMA) hydrochloride among the three treated groups. These findings indicated that different TMAO precursors had different ability to form TMAO in vivo, and long-term dietary intervention would affect the metabolism of precursors to generate TMA and the TMA oxidation to form TMAO, suggesting that TMAO levels in vivo could be regulated by dietary intervention. PRACTICAL APPLICATION: Diverse TMAO precursors exhibited different ability to be converted into TMAO in vivo. The ability of choline to produce TMAO was stronger than that of betaine and L-carnitine. Long-term dietary intervention would affect the metabolism of precursors to generate TMA and the TMA oxidation to form TMAO, suggesting that TMAO levels in vivo could be regulated by adjustment of dietary structure.


Assuntos
Betaína/metabolismo , Carnitina/metabolismo , Colina/metabolismo , Metilaminas/sangue , Animais , Feminino , Microbioma Gastrointestinal , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
11.
Ann Vasc Surg ; 68: 497-504, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32599111

RESUMO

BACKGROUND: Acute aortic dissection (AAD) is the most devastating aortic pathology, and the incidence is increasing worldwide. However, the occurrence and development of AAD are unpredictable. A thorough understanding of the serum metabolic landscape through metabolomic analysis may help identify new biomarkers for AAD and offers new insights into its prevention and evaluation. METHODS: Nineteen patients with Stanford type A aortic dissection and 20 healthy individuals were enrolled in this study. We use global and targeted mass spectrometry-based metabolomics to investigate the serum metabolomics profiles, and the data were analyzed by principal component analysis and orthogonal partial least squares discriminant analysis. RESULTS: Initial untargeted metabolomics analysis revealed significant changes of lipids and polar metabolites in patients with AAD. Alterations of the phosphatidylcholine metabolic pathway were further observed by targeted metabolomics. Trimethylamine N-oxide (TMAO) levels were obviously increased in patients with AAD compared with controls (P < 0.005), whereas the levels of carnitine (P < 0.005), choline, and betaine (P < 0.05) were decreased. Furthermore, TMAO levels were associated with disease severity in AAD and correlated positively with C-reactive protein levels (r = 0.537, P = 0.018), IL-6 levels (r = 0.546, P = 0.016), D-dimer levels (r = 0.694, P = 0.001), and maximum aortic diameter on admission (r = 0.748, P = 0.002). CONCLUSIONS: Patients with AAD showed a predominant and consistent change of metabolites levels, especially the compounds in the phosphatidylcholine metabolic pathway. TMAO could potentially serve as a biomarker for the auxiliary diagnosis and evaluation of AAD.


Assuntos
Aneurisma Dissecante/sangue , Aneurisma Aórtico/sangue , Metabolômica , Metilaminas/sangue , Fosfatidilcolinas/sangue , Doença Aguda , Adulto , Aneurisma Dissecante/diagnóstico , Aneurisma Aórtico/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lipidômica , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Valor Preditivo dos Testes
12.
J Am Coll Cardiol ; 75(7): 763-772, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32081286

RESUMO

BACKGROUND: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with coronary atherosclerotic burden. No previous prospective study has addressed associations of long-term changes in TMAO with coronary heart disease (CHD) incidence. OBJECTIVES: The purpose of this study was to investigate whether 10-year changes in plasma TMAO levels were significantly associated with CHD incidence. METHODS: This prospective nested case-control study included 760 healthy women at baseline. Plasma TMAO levels were measured both at the first (1989 to 1990) and the second (2000 to 2002) blood collections; 10-year changes (Δ) in TMAO were calculated. Incident cases of CHD (n = 380) were identified after the second blood collection through 2016 and were matched to controls (n = 380). RESULTS: Regardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collection were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% confidence interval (CI): 1.05 to 2.38]; RR per 1-SD increment: 1.33 [95% CI: 1.06 to 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (95% CI: 1.08 to 2.96) for CHD as compared with those with consistently low TMAO levels. Further, we found that the ΔTMAO-CHD relationship was strengthened by unhealthy dietary patterns (assessed by the Alternate Healthy Eating Index) and was attenuated by healthy dietary patterns (p interaction = 0.008). CONCLUSIONS: Long-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.


Assuntos
Doença das Coronárias/epidemiologia , Metilaminas/sangue , Adulto , Estudos de Casos e Controles , Doença das Coronárias/sangue , Doença das Coronárias/microbiologia , Dieta Saudável , Feminino , Microbioma Gastrointestinal , Humanos , Incidência , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Am J Clin Nutr ; 111(6): 1226-1234, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32055828

RESUMO

BACKGROUND: Trimethylamine 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. OBJECTIVES: Our 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. METHODS: We 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. RESULTS: Median (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. CONCLUSIONS: Plasma 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.


Assuntos
Betaína/sangue , Doenças Cardiovasculares/sangue , Carnitina/sangue , Colina/sangue , Microbioma Gastrointestinal , Metilaminas/sangue , Adiposidade , Idoso , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biomarcadores/sangue , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Metilaminas/metabolismo , Pessoa de Meia-Idade
14.
Sci Rep ; 10(1): 2639, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060329

RESUMO

Plasma trimethylamine N-oxide (TMAO) is associated with coronary atherosclerotic plaque and cardiovascular disease risk, but associations between gut microbes in acute coronary syndrome (ACS) and post-ST-segment elevation myocardial infarction (post-STEMI) events are unknown. We investigated associations between gut microbial taxa and systemic TMAO levels and the possible TMAO contribution to incident post-STEMI cardiovascular events. PATIENTS AND METHODS: A total of 60 patients, including 30 with unstable angina pectoris (UAP), 30 post-STEMI and 30 healthy controls, were enrolled from June to November 2017. Metagenomic sequencing was performed and TMAO and IL-6 were detected. RESULTS: Minimal discriminators of gut microbial taxa (top 40) distinguished ACS patients from controls. Serum TMAO levels were positively associated with increased abundance of Aerococcaceae, Ruminococcaceae_UCG.005, Ruminococcaceae_UCC.014 and X. Eubacterium_fissicatena, and decreased abundance of Lachnospiraceae_FCS020 (P < 0.05). Elevated serum TMAO levels correlated independently with ACS (P < 0.05). Risk stratification for incident major adverse cardiovascular events (MACE) improved at one year in patients with serum TMAO levels ≦2.19 µM. Serum interleukin-6 levels were not significantly increased in patients with ACS and post-STEMI MACE. CONCLUSIONS: ACS and incident post-STEMI MACE may be associated with the gut bacteria choline metabolite TMAO. The specific gut microbial taxa identified in association with serum TMAO levels may be potential predictive biomarkers for accurate diagnosis of ACS onset.


Assuntos
Síndrome Coronariana Aguda/microbiologia , Microbioma Gastrointestinal , Infarto do Miocárdio com Supradesnível do Segmento ST/microbiologia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Metilaminas/sangue , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico
15.
BMC Endocr Disord ; 20(1): 3, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906930

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder, and its pathogenesis is still under debate. Trimethylamine-N-oxide (TMAO) is a small, organic compound generated by the gut microbiome with a hypothesized relation to insulin resistance (IR) and low-grade inflammation in PCOS. By comparing plasma TMAO levels in non-PCOS participants and PCOS patients without hyperandrogenism (HA), we aimed to determine whether plasma TMAO levels correlate with PCOS without HA and to analyze their relationship with low-grade inflammation and IR. METHODS: A total of 27 PCOS patients without HA and 23 non-PCOS participants were enrolled in this study and subdivided into "nonobese" and "obese" arms for each group. Levels of plasma TMAO were quantified, and basic clinical characteristics and plasma biomarkers of inflammation were assessed. RESULTS: First, plasma TMAO levels, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values were higher in PCOS patients without HA, especially in the obese subgroup. Second, the levels of the inflammatory factors interleukin (IL)-17A, IL-18 and interferon gamma (IFN-γ) were significantly increased in obese PCOS patients without HA. Third, plasma TMAO levels were associated with body mass index (BMI) in the normal-weight groups, and the obese groups had higher fasting plasma insulin (FINS) and HOMA-IR values. Finally, logistic regression showed that the plasma levels of TMAO and luteinizing hormone/follicle-stimulating hormone (LH/FSH) were independent predictors of PCOS and indicated an increased risk of PCOS. CONCLUSIONS: Elevated plasma TMAO levels may be associated with the pathogenesis of PCOS without HA and correlated with increased systemic inflammation. Further studies are needed to determine the suitability of TMAO as a predictive biomarker and to identify possible therapies for PCOS.


Assuntos
Biomarcadores/sangue , Hiperandrogenismo/fisiopatologia , Metilaminas/sangue , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/epidemiologia , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , China/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Resistência à Insulina , Prognóstico
16.
Neurology ; 94(7): e667-e677, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-31907287

RESUMO

OBJECTIVE: To investigate whether elevated plasma trimethylamine N-oxide (TMAO) levels are associated with initial stroke severity and infarct volume. METHODS: This cross-sectional study included 377 patients with acute ischemic stroke and 50 healthy controls. Plasma TMAO levels were assessed at admission. Stroke infarct size and clinical stroke severity were measured with diffusion-weighted imaging and the NIH Stroke Scale (NIHSS). Mild stroke was defined as an NIHSS score <6. RESULTS: Plasma TMAO levels were higher in patients with ischemic stroke than in healthy controls (median 5.1 vs 3.0 µmol/L; p < 0.001). Every 1-µmol/L increase in TMAO was associated with a 1.13-point increase in NIHSS score (95% confidence interval [CI] 1.04-1.29; p < 0.001) and 1.69-mL increase in infarct volume (95% CI 1.41-2.03; p < 0.001) after adjustment for vascular risk factors. At admission, 159 patients (42.2%) had experienced a mild stroke, and their plasma TMAO levels were lower compared to those with moderate to severe stroke (median 3.6 vs 6.5 µmol/L; p < 0.001). The area under the receiver operating characteristics curve of plasma TMAO level in predicting moderate to severe stroke was 0.794 (95% CI 0.748-0.839; p < 0.001), and the optimal cutoff value was 4.95 µmol/L. The sensitivity and specificity of TMAO levels ≥4.95 µmol/L for moderate to severe stroke were 70.2% and 79.9%, respectively. CONCLUSIONS: Patients with ischemic stroke had higher plasma TMAO levels compared to healthy controls. Higher plasma TMAO level at admission is an independent predictor of stroke severity and infarct volume in patients with acute ischemia.


Assuntos
Isquemia Encefálica/sangue , Metilaminas/sangue , Acidente Vascular Cerebral/sangue , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Isquemia Encefálica/diagnóstico por imagem , Estudos Transversais , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Dados Preliminares , Prognóstico , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico por imagem
18.
Nutrients ; 12(1)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963239

RESUMO

Trimethylamine-N-oxide (TMAO) can be produced by the gut microbiota from dietary substrates and is associated with cardiovascular disease. While dairy products contain TMAO precursors, the effect of fermented dairy on TMAO metabolism remains unclear. We used plasma and urine samples collected for two randomised cross-over studies to evaluate the effects of fermented dairy consumption on TMAO metabolism. In Study 1, thirteen healthy young men tested a yogurt and an acidified milk during postprandial tests and a two-week daily intervention. In Study 2, ten healthy adults tested milk and cheese during postprandial tests. TMAO and five related metabolites were measured in plasma and urine by LC-MS/MS and NMR. Faecal microbiota composition was assessed in Study 1 (16S rRNA metagenomics sequencing). Fermented milk products were associated with lower postprandial TMAO responses than non-fermented milks in urine (Study 1, p = 0.01; Study 2, p = 0.02) and in plasma, comparing yogurt and acidified milk (Study 1, p = 0.04). Daily consumption of dairy products did not differentially affect fasting TMAO metabolites. Significant correlations were observed between microbiota taxa and circulating or urinary TMAO concentrations. Fermentation of dairy products appear, at least transiently, to affect associations between dairy products and circulating TMAO levels.


Assuntos
Bactérias/metabolismo , Produtos Fermentados do Leite , Laticínios , Microbioma Gastrointestinal , Metilaminas/sangue , Metilaminas/urina , Período Pós-Prandial , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Estudos Cross-Over , Método Duplo-Cego , Fezes/microbiologia , Feminino , Humanos , Masculino , Suíça , Adulto Jovem
19.
Talanta ; 210: 120639, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987175

RESUMO

The application of dried blood spots in clinical research is becoming increasingly popular owing to its convenient collection, storage, and transportation compared to that of conventional biological samples. The potential of trimethylamine N-oxide and its related compounds as biomarkers for various cardiovascular diseases, such as atherosclerosis, stroke, thrombosis, and heart failure, was recently highlighted, which was the driving force behind the development of an analytical method to identify trimethylamine N-oxide and eight related compounds in dried blood spots. In the proposed method, a novel "on-spot reaction" approach was introduced to overcome the low loading efficiency of trimethylamine in dried blood spots. Upon the addition of 50 µL of blood onto the filter paper pretreated with dilute HCl, an acid-base neutralization reaction in the blood spots transformed the volatile trimethylamine to a salt. Next, a punched disc with a diameter of 6.0 mm was eluted by agitation with 20 mM ammonium formate for 10 min and derivatized with 1.0 M ethyl bromoacetate at 80 °C for 60 min. A surrogate analyte approach was employed for quantification of these endogenous compounds in the complex matrix. Analysis was carried out using zwitterionic hydrophilic interaction liquid chromatography-high-resolution mass spectrometry. The established method was validated and applied to monitor real samples from 30 clinical cases. The proposed new methodology based on dried blood spots could greatly improve the convenience, analytical sensitivity, and selectivity of cardiovascular disease testing.


Assuntos
Teste em Amostras de Sangue Seco , Metilaminas/sangue , Cromatografia Líquida , Humanos , Espectrometria de Massas
20.
PLoS One ; 15(1): e0227482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940332

RESUMO

Trimethylamine-N-oxide (TMAO)-a gut-microbiota metabolite-is a biomarker of cardiometabolic risk. No studies have investigated TMAO as an early biomarker of longitudinal glucose increase or prevalent impaired glucose regulation. In a longitudinal cohort study, 300 diabetes-free men and women (77%) aged 20-55 years (mean = 34±10) were enrolled at baseline and re-examined at 2-years to investigate the association between TMAO and biomarkers of diabetes risk. Plasma TMAO was measured using Ultra Performance Liquid Chromatography-Mass Spectrometry. After an overnight fast, FPG was measured longitudinally, HbA1C and insulin were measured only at baseline. Insulin resistance was defined using HOMA-IR. Multivariable generalized linear models regressed; i) FPG change (year 2 minus baseline) on baseline TMAO tertiles; and ii) HOMA-IR and HbA1c on TMAO tertiles. Multivariable relative risk regressions modeled prevalent prediabetes across TMAO tertiles. Mean values of 2-year longitudinal FPG±SE across tertiles of TMAO were 86.6±0.9, 86.7±0.9, 86.4±0.9 (p = 0.98). Trends were null for FPG, HbA1c, HOMA-IR, cross-sectionally. The prevalence ratio of prediabetes among participants in 2nd and 3rd TMAO tertiles (vs. the 1st) were 1.94 [95%CI 1.09-3.48] and 1.41 [95%CI: 0.76-2.61]. TMAO levels are associated with increased prevalence of prediabetes in a nonlinear fashion but not with insulin resistance or longitudinal FPG change.


Assuntos
Intolerância à Glucose/patologia , Resistência à Insulina , Metilaminas/sangue , Adulto , Biomarcadores/sangue , Glicemia/análise , Estudos Transversais , Feminino , Intolerância à Glucose/sangue , Hemoglobina A Glicada/análise , Humanos , Insulina/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/patologia , Prevalência , Fatores de Risco , Adulto Jovem
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