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1.
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
2.
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
3.
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
4.
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
5.
Heart Fail Clin ; 16(1): 23-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31735312

RESUMO

A novel pathophysiological model of interest is the association between heart failure (HF) and the gastrointestinal system, the 'gut hypothesis'. The choline and carnitine metabolic by-product, Trimethylamine N-oxide (TMAO) is one of the more prominent molecules associated with the link between HF and the gut. Indeed, TMAO levels are increased in HF populations and higher TMAO levels are associated with poor prognosis, whereas low TMAO levels either at baseline/follow up confer better prognosis. Considering that TMAO levels seem not to be affected by guideline-HF treatment, this model could represent a novel and independent therapeutic target for HF.


Assuntos
Microbioma Gastrointestinal/fisiologia , Insuficiência Cardíaca/metabolismo , Metilaminas/sangue , Volume Sistólico/fisiologia , Biomarcadores/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Prognóstico
6.
Artigo em Inglês | MEDLINE | ID: mdl-31850241

RESUMO

Objective: To characterize the gut microbiota in patients with preeclampsia (PE) compared with healthy controls. Methods: We analyzed and compared the microbiota communities in the feces of 48 PE patients with 48 age-, gestational weeks-, and pre-pregnancy body mass index-matched healthy controls using 16S rRNA gene sequencing, and also we tested fecal and plasma lipopolysaccharide (LPS) and plasma trimethylamine-N-oxide (TMAO) concentration levels in the two groups. Results: Compared with the control group, microbial alpha diversity was lower in the PE group, but there was no statistically significant difference between the two groups. At the phylum level, Firmicutes (51.64% PE vs. 59.62% Control, P < 0.05), Bacteroidetes (40.51% PE vs. 34.81% Control, P< 0.05), Proteobacteria (4.51% PE vs. 2.56% Control, P < 0.05), and Actinobacteria (2.90% PE vs. 1.77% Control, P < 0.05), exhibited significant differences between the PE group and the control group. LEfSe analysis found 17 differentially abundant taxa between the two groups. PICRUSt analysis found that in the KEGG pathways, the microbial gene functions related to LPS biosynthesis were higher in the fecal microbiome of the PE group. The fecal and plasma LPS concentrations and plasma TMAO concentrations of PE patients were higher than those of the healthy controls. Conclusion: PE patients had gut microbiota dysbiosis and increased plasma LPS and TMAO levels, which will lead to a better understanding of the relationship between the gut microbiota and PE.


Assuntos
Disbiose , Microbioma Gastrointestinal , Lipopolissacarídeos/sangue , Metilaminas/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/etiologia , Adulto , Biomarcadores , Estudos de Casos e Controles , Fezes/microbiologia , Feminino , Humanos , Metagenoma , Metagenômica/métodos , Gravidez , RNA Ribossômico 16S/genética
7.
Am J Med Sci ; 358(6): 422-428, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31666184

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Patients with AF are prone to forming cardiac thrombi. Elevated serum trimethylamine N-oxide (TMAO) levels are associated with increased thrombosis risk. No previous studies have examined the relationship between serum TMAO levels and thrombus formation in AF patients. MATERIALS AND METHODS: A total of 117 consecutive rheumatic heart disease patients with AF were enrolled. The patients were divided into 2 groups: patients with thrombi (n = 25) and patients without thrombi (n = 92). Platelet function tests were performed by light transmittance aggregometry. Serum TMAO, betaine and choline levels were quantified by liquid chromatography combined with tandem mass spectrometry. Results were compared between the 2 groups. The correlation between serum TMAO levels and thrombi formation was examined. RESULTS: No remarkable differences in demographic characteristics were found between the 2 groups. Serum TMAO levels were significantly higher in the thrombus group (4.55 UM [3.19-4.83] vs. 3.53 UM [2.96-4.25], P = 0.01). Enhanced platelet hyperreactivity was more likely in the thrombus group. Receiver operating characteristic analysis showed the diagnostic potential of serum TMAO levels to identify thrombus formation, with an area under the curve of 0.661 (P = 0.01, 95% confidence interval: 0.52-0.80). Binary regression analyses showed that serum TMAO had potent predictive power for thrombus formation (P < 0.01, 95% CI of 1.21-3.08). CONCLUSIONS: Elevated serum TMAO levels were predictive of thrombus formation in AF patients. Our results highlight the usefulness of serum TMAO levels in identifying individuals with increased susceptibility to thrombus formation, allowing development of precise thrombus prevention strategies.


Assuntos
Fibrilação Atrial/metabolismo , Microbioma Gastrointestinal , Metilaminas/metabolismo , Trombose/metabolismo , Feminino , Humanos , Masculino , Metilaminas/sangue , Pessoa de Meia-Idade , Agregação Plaquetária
8.
Artigo em Inglês | MEDLINE | ID: mdl-31661892

RESUMO

Acute kidney injury (AKI) is described as a relatively common complication of exercise. In clinical practice the diagnosis of AKI is based on serum creatinine, the level of which is dependent not only on glomerular filtration rate but also on muscle mass and injury. Therefore, the diagnosis of AKI is overestimated after physical exercise. The aim of this study was to determine changes in uremic toxins: creatinine, urea, uric acid, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), trimethylamine N-oxide (TMAO) and urinary makers of AKI: albumin, neutrophil gelatinase-associated lipocalin (uNGAL), kidney injury molecule-1 and cystatin-C (uCyst-C) after long runs. Sixteen runners, mean age 36.7 ± 8.2 years, (2 women, 14 men) participating in 10- and 100-km races were studied. Blood and urine were taken before and after the races to assess markers of AKI. A statistically significant increase in creatinine, urea, uric acid, SDMA and all studied urinary AKI markers was observed. TMAO and ADMA levels did not change. The changes in studied markers seem to be a physiological reaction, because they were observed almost in every runner. The diagnosis of kidney failure after exercise is challenging. The most valuable novel markers which can help in post-exercise AKI diagnosis are uCyst-C and uNGAL.


Assuntos
Lesão Renal Aguda/urina , Corrida/fisiologia , Proteínas da Fase Aguda , Adulto , Albuminúria , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Lipocalina-2/urina , Lipocalinas , Masculino , Metilaminas/sangue , Pessoa de Meia-Idade , Ureia/sangue , Ácido Úrico/sangue , Água
9.
Food Funct ; 10(11): 7174-7187, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31602443

RESUMO

The objective of this study was to investigate the effects of dietary intervention on intestinal microbiota-mediated change in short chain fatty acid (SCFA) profile and intestinal homeostasis. Sequencing of the 16S rDNA of gut bacteria, metagenomics, intestinal epithelial transcriptomics, and metabonomics were conducted. Results showed that the dietary interventions altered the microbiota composition of cecal digesta, microbiota-mediated metabolism, and the gene expression profile in intestinal epithelial cells. Compared with red meat-diet-fed mice, fiber-diet-fed mice presented a shift in the gut microbiome toward increased production of butanoate, which was accompanied by up-regulation of microbiota- and AMP-activated protein kinase (AMPK)-dependent gene expression and decrease in serum concentrations of trimethylamine N-oxide (TMAO), triglyceride (TG) and glucose (GLU). The results suggested a new regulatory mechanism via which butanoate and AMPK activation contributed to intestinal integrity and homeostasis by affecting metabolism, intestinal barrier function and transporter expression.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Bactérias/metabolismo , Fibras na Dieta/metabolismo , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Ácidos Graxos Voláteis/química , Feminino , Homeostase , Mucosa Intestinal/enzimologia , Mucosa Intestinal/microbiologia , Masculino , Metilaminas/sangue , Camundongos Endogâmicos C57BL , Triglicerídeos/sangue
10.
Nutrients ; 11(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547446

RESUMO

Higher dietary protein intake is increasingly recommended for the elderly; however, high protein diets have also been linked to increased cardiovascular disease (CVD) risk. Trimethylamine-N-oxide (TMAO) is a bacterial metabolite derived from choline and carnitine abundant from animal protein-rich foods. TMAO may be a novel biomarker for heightened CVD risk. The purpose of this study was to assess the impact of a high protein diet on TMAO. Healthy men (74.2 ± 3.6 years, n = 29) were randomised to consume the recommended dietary allowance of protein (RDA: 0.8 g protein/kg bodyweight/day) or twice the RDA (2RDA) as part of a supplied diet for 10 weeks. Fasting blood samples were collected pre- and post-intervention for measurement of TMAO, blood lipids, glucose tolerance, insulin sensitivity, and inflammatory biomarkers. An oral glucose tolerance test was also performed. In comparison with RDA, the 2RDA diet increased circulatory TMAO (p = 0.002) but unexpectedly decreased renal excretion of TMAO (p = 0.003). LDL cholesterol was increased in 2RDA compared to RDA (p = 0.049), but no differences in other biomarkers of CVD risk and insulin sensitivity were evident between groups. In conclusion, circulatory TMAO is responsive to changes in dietary protein intake in older healthy males.


Assuntos
Dieta Rica em Proteínas/efeitos adversos , Proteínas na Dieta/efeitos adversos , Metilaminas/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , Jejum/sangue , Microbioma Gastrointestinal , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Recomendações Nutricionais , Fatores de Risco
11.
Food Funct ; 10(10): 6484-6491, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31532423

RESUMO

Gut microbiota-dependent metabolites trimethylamine N-oxide (TMAO), trimethylamine (TMA) and dimethylamine (DMA) from dietary methylamines have recently gained much attention due to their high association with chronic kidney disease risk. Hence a simpler and faster performance liquid chromatography-tandem mass spectrometry method was developed and validated. The quantitative analysis was achieved within 6 min by using Agilent 6460C UPLC-MS/MS with 10% methyl alcohol isocratic elution and was more simple, convenient and rapid than that of previously reported methods. Furthermore, method verification results showed that the method correlation coefficient was 0.99978293, 0.99997514 and 0.98784721, and the detection limit was 0.121, 8.063 and 0.797 µg L-1, and the precision of the retention time and peak area of analytes was less than 0.331 and 3.280, respectively. The method was applied to simultaneously determine TMAO, TMA and DMA in the urine and serum from mice treated with normal, high l-carnitine, or high choline diet. Quantitative recoveries of TMAO, TMA and DMA were in the range of 94.2%-101.0%, and the RSD values were lower than 5.17%. The proposed UPLC-MS/MS-based assay should be of value for further evaluating TMAO as a risk marker and for examining the effect of dietary factors on TMAO metabolism.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dimetilaminas/análise , Metilaminas/análise , Espectrometria de Massas em Tandem/métodos , Animais , Dimetilaminas/sangue , Dimetilaminas/química , Dimetilaminas/urina , Masculino , Metilaminas/sangue , Metilaminas/urina , Camundongos
12.
Inflammation ; 42(6): 2257-2266, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31489527

RESUMO

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote inflammation in peripheral tissues and the central nervous system (CNS), contributing to the pathogenesis of various human diseases. Here, we examined whether the presence of high levels of circulating TMAO would influence central and peripheral inflammation and inflammatory hyperalgesia in a carrageenan (CG)-induced rat model of inflammation. Rats were treated with vehicle or TMAO in drinking water. After 2 weeks of treatment, rats received intraplantar injection of saline or CG into the hind paw. Acute nociception was unaltered in TMAO-treated rats that had elevated plasma TMAO. Following CG injection, TMAO-treated rats were significantly more sensitive to thermal and mechanical stimulation of the inflamed paw and displayed greater paw edema. Molecular studies revealed that CG injection induced increases in recruitment of neutrophils/macrophages in the paw and activation of microglia in the spinal cord, along with increased activation of nuclear factor (NF)-kB and production of proinflammatory mediators in both vehicle-treated rats and TMAO-treated rats. However, the increases in the above parameters were more pronounced in TMAO-treated rats. Moreover, TMAO treatment decreased protein levels of anti-inflammatory mediator regulator of G protein signaling (RGS)-10 in both saline-injected rats and CG-injected rats. These findings suggest that the presence of high levels of circulating TMAO downregulates anti-inflammatory mediator RGS10 in both peripheral tissues and the CNS, which may increase the susceptibility to inflammatory challenge-induced NF-kB activity, leading to greater increase in production of inflammatory mediators and consequent exacerbation of peripheral inflammation and inflammatory hyperalgesia.


Assuntos
Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Metilaminas/sangue , Animais , Carragenina , Edema , Mediadores da Inflamação/metabolismo , Metilaminas/farmacologia , NF-kappa B/metabolismo , Proteínas RGS/efeitos dos fármacos , Ratos
13.
Med Hypotheses ; 130: 109271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383335

RESUMO

Recent clinical studies show a positive correlation between elevated plasma TMAO and increased cardiovascular risk. However, the mechanism of the increase and biological effects of TMAO in the circulatory system are obscure. Plasma TMAO level depends mostly on the following three factors. First, the liver produces TMAO from TMA, a gut bacteria metabolite of dietary choline and carnitine. Second, plasma TMAO increases after ingestion of dietary TMAO from fish and seafood. Finally, plasma TMAO depends on TMAO and TMA excretion by the kidneys. Ample evidence highlights protective functions of TMAO, including the stabilization of proteins and cells exposed to hydrostatic and osmotic stresses, for example in fish exposed to hydrostatic stress (deep water) and osmotic stress (salty water). Osmotic stress and hydrostatic stresses are augmented in cardiovascular diseases such as hypertension. In hypertensive subjects a diastole-systole change in hydrostatic pressure in the heart may exceed 220 mmHg with a frequency of 60-220/min. This produces environment in which hydrostatic pressure changes over 100,000 times per 24 h. Furthermore, cardiovascular diseases are associated with disturbances in water-electrolyte balance which produce changes in plasma osmolarity. Perhaps, the increase in plasma TMAO in cardiovascular diseases is analogous to increased level of plasma natriuretic peptide B, which is both a cardiovascular risk marker and a compensatory response producing beneficial effects for pressure/volume overloaded heart. In this regard, there is some evidence that a moderate increase in plasma TMAO due to TMAO supplementation may be beneficial in animal model of hypertension-related heart failure. Finally, increased plasma TMAO is present in humans consuming seafood-rich diet which is thought to be health-beneficial. We hypothesize that increased plasma TMAO serves as a compensatory response mechanism which protects cells from hydrostatic and osmotic stresses.


Assuntos
Doenças Cardiovasculares/sangue , Metilaminas/sangue , Pressão Osmótica , Animais , Sistema Cardiovascular , Carnitina/metabolismo , Colina/metabolismo , Dieta , Humanos , Pressão Hidrostática , Rim/metabolismo , Fígado/metabolismo , Camundongos , Modelos Teóricos , Ratos , Fatores de Risco
14.
Cell Mol Neurobiol ; 39(8): 1201-1206, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31332666

RESUMO

Trimethylamine N-oxide (TMAO) has emerged as a newly identified gut microbiota-dependent metabolite contributing to a variety of diseases, such as diabetes, atherosclerosis, and cardiovascular diseases. The aim of our study was to determine whether a relatively high TMAO level is associated with an increased risk of poor outcome in ischemic stroke patients. From June 2018 to December 2018, we prospectively recruited acute ischemic stroke patients diagnosed within 24 h of symptom onset. The plasma TMAO level was measured at admission for all patients. Functional outcome was evaluated at 3 months after the stroke using the modified Rankin Scale (mRS) and then dichotomized as favorable (mRS 0-2) or unfavorable (mRS 3-6). A multivariate logistic regression analysis was conducted to evaluate the association between TMAO concentration and poor functional outcome and mortality at 3 months. Of the 225 acute ischemic stroke patients included in the analysis, the median TMAO concentration was 3.8 µM (interquartile range, 1.9-4.8 µM). At 3 months after admission, poor functional outcome was observed in 116 patients (51.6%), and 51 patients had died (22.7%). After adjusting for potential confounders, patients with TMAO levels in the highest quartile were more likely to have higher risks of poor functional outcome [compared with the lowest quartile, odds ratio (OR) 3.63; 95% confidence interval (CI) 1.34-9.82; P = 0.011] and mortality (OR 4.27; 95% CI 1.07-17.07; P = 0.040). Our data suggest that a high plasma TMAO level upon admission may predict unfavorable clinical outcomes in acute ischemic stroke patients.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Metilaminas/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Idoso , Feminino , Humanos , Modelos Logísticos , Masculino , Modelos Biológicos , Prognóstico , Resultado do Tratamento
15.
Biochim Biophys Acta Mol Basis Dis ; 1865(10): 2576-2585, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251986

RESUMO

Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation.


Assuntos
Cálculos Biliares/metabolismo , Metilaminas/metabolismo , Oxigenases/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/metabolismo , Colesterol/metabolismo , Dieta , Modelos Animais de Doenças , Feminino , Cálculos Biliares/patologia , Microbioma Gastrointestinal/fisiologia , Regulação da Expressão Gênica , Humanos , Lipoproteínas/metabolismo , Fígado/metabolismo , Masculino , Metilaminas/sangue , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Oxigenases/genética , RNA Mensageiro/metabolismo
16.
Mol Med Rep ; 20(1): 779-786, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180562

RESUMO

Myocardial infarction (MI) is a common cause of chronic heart failure (HF). Increasing evidence has revealed that trimethylamine N­oxide (TMAO), a gut­microbiota­derived metabolite, contributes to the pathogenesis of cardiovascular disease by promoting inflammation. Elevated levels of circulating TMAO have been reported in patients following MI and were associated with unfavorable outcomes. The present study examined whether reductions in circulating TMAO could attenuate the progression of HF in rats following MI. Sprague­Dawley rats underwent coronary ligation to induce MI or a sham operation. Echocardiography confirmed MI and cardiac dysfunction one day following coronary ligation. MI and sham rats were then treated with either vehicle (tap water) or 1.0% 3,3­dimethyl­1­butanol (DMB, a trimethylamine formation inhibitor) in tap water, for 8 weeks. At the end of the experiment, TMAO plasma levels were markedly elevated in vehicle­treated MI rats compared with vehicle­treated sham rats; however, TMAO plasma levels were reduced in DMB­treated MI rats compared with vehicle­treated MI rats. Both MI groups exhibited cardiac hypertrophy, lung congestion, left ventricular remodeling and impaired cardiac function, according to the results of anatomical analysis, echocardiography and left ventricular hemodynamics; however, these manifestations of MI­induced HF were significantly improved in DMB­treated MI rats compared with vehicle­treated MI rats. The plasma levels of the chemokine interleukin (IL)­8, and cardiac expression of IL­8 and its receptors were significantly increased in vehicle­treated MI rats compared with vehicle­treated sham rats; however, these were normalized in DMB­treated MI rats. In addition, elevated TMAO plasma level was positively correlated with increased IL­8 plasma level in MI groups. Notably, DMB treatment of sham rats also reduced plasma TMAO, but did not alter other parameters. These results indicated that reducing circulating TMAO may ameliorate the development of chronic HF following MI in rats, potentially by inhibiting IL­8 secretion. The results from the present study suggested that inhibition of TMAO synthesis may be considered as a novel therapeutic approach for the prevention and treatment of patients with chronic MI­induced HF.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hexanóis/uso terapêutico , Metilaminas/antagonistas & inibidores , Infarto do Miocárdio/tratamento farmacológico , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/microbiologia , Interleucina-8/sangue , Masculino , Metilaminas/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/microbiologia , Ratos , Ratos Sprague-Dawley
17.
Nutrients ; 11(6)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200429

RESUMO

L-carnitine supplementation elevates plasma trimethylamine-N-oxide (TMAO), which may participate in atherosclerosis development by affecting cholesterol metabolism. The aim of the current study was to determine the effect of increased plasma TMAO on biochemical markers in the blood following cessation of L-carnitine supplementation. The follow-up measurements were performed on subjects who completed 24 weeks of L-carnitine or placebo supplementation protocol. Blood samples were taken after finishing the supplementation and then 4 and 12 months following the supplementation withdrawal. Four months after cessation of L-carnitine supplementation, plasma TMAO concentration reached a normal level which was stable for the following eight months. During this period, no modifications in serum lipid profile and circulating leukocyte count were noted. TMAO implications in health and disease is widely discussed. The results of this study demonstrate no adverse effects of elevated plasma TMAO, induced by L-carnitine, on the measured parameters at 4 and 12 months after withdrawal of supplementation.


Assuntos
Carnitina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Metilaminas/sangue , Suspensão de Tratamento , Idoso , Aterosclerose/etiologia , Biomarcadores/sangue , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Contagem de Leucócitos , Lipídeos/sangue , Músculo Esquelético/efeitos dos fármacos , Fatores de Tempo
18.
Nutrients ; 11(6)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185686

RESUMO

Abstract: Vitamin D deficiency and obesity are two public health problems extensively exacerbated over the last years. Among the several mechanisms proposed to account for the complex interplay between vitamin D and obesity, one that has gained particular attention is related to the emerging role of obesity-related changes in gut microbiota and gut-derived metabolites, such as Trimethylamine-N-oxide (TMAO). Vitamin D deficiency and high circulating TMAO levels are associated with body weight and the severity of non-alcoholic fatty liver disease (NAFLD). Considering the link of obesity with vitamin D on the one hand and obesity with TMAO on the other hand, and the central role of the liver in both the vitamin D and TMAO metabolism, the aim of this cross-sectional observational study was first, to confirm the possible inverse association between vitamin D and TMAO across different body mass index (BMI) classes and second, to investigate if this association could be influenced by the presence of NAFLD. One hundred and four adult subjects (50 males and 54 females; 35.38 ± 7.49 years) were enrolled. The fatty liver index (FLI) was used as a proxy for the diagnosis of NAFLD. Vitamin D deficiency was found in 65 participants (62.5%), while 33 subjects (31.7%) had insufficient levels, and the remaining subjects had sufficient levels of vitamin D. Subjects with both vitamin D deficiency and FLI-NAFLD had the highest TMAO levels (p < 0.001). By stratifying the sample population according to the BMI classes, vitamin D levels decreased significantly along with the increase of plasma TMAO concentrations, with the lowest vitamin D levels and highest TMAO, respectively, in class III obesity. Vitamin D levels showed significant opposite associations with circulating levels of TMAO (r = -0.588, p < 0.001), but this association was no longer significant after the adjustment for FLI values. The highest values of TMAO were significantly associated with the severity of obesity (OR 7.92; p < 0.001), deficiency of vitamin D (OR 1.62; p < 0.001), and FLI-NAFLD (OR 3.79; p < 0.001). The most sensitive and specific cut-off for vitamin D to predict the circulating levels of TMAO was ≤19.83 ng/mL (p < 0.001). In conclusion, our study suggests that high TMAO levels are associated with vitamin D deficiency and NAFLD. Further studies are required to investigate if there is a causality link or whether all of them are simply the consequence of obesity.


Assuntos
Metilaminas/sangue , Obesidade/sangue , Deficiência de Vitamina D/sangue , Vitamina D/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/complicações , Fatores de Risco , Deficiência de Vitamina D/complicações , Adulto Jovem
19.
J Agric Food Chem ; 67(27): 7748-7754, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31203621

RESUMO

Choline and its metabolites have diverse and important functions in many physiological processes, especially for anabolic metabolism in growth and reproduction. Besides endogenous biosynthesis and direct choline supplement, choline esters in the diet are another source of choline in the body. Phenolic choline esters are a group of unique dietary choline esters rich in the seeds of Brassicaceae plants, among which sinapine is a choline ester of sinapic acid abundant in rapeseed. In this study, 40 nursery pigs were fed with rapeseed-derived feed ingredients (RSF) or soybean meal for 3 weeks (20 pigs/diet). The metabolic fate of sinapine-derived choline in RSF was examined by comparing the distribution of choline and its metabolites in digesta, liver, and serum samples by liquid chromatography-mass spectrometry analysis. The results showed that choline was released from extensive hydrolysis of sinapine in the small intestine. However, sinapine-derived choline did not increase the levels of choline and its major metabolites, including betaine, phosphocholine, and glycerophosphocholine, in the liver and serum. Instead, RSF feeding increased trimethylamine (TMA), the microbial metabolite of choline, in the large intestine and further increased trimethylamine N-oxide (TMAO), the oxidation metabolite of TMA, in the liver and serum. Overall, these results suggested that sinapine-derived choline from rapeseed feeding had limited influences on the post-absorption choline pool as a result of its low bioavailability but may serve as a major source of TMAO through microbial metabolism in nursery pigs. Improving the bioavailability of sinapine-derived choline might have the potential to modify the nutritional values and functionalities of rapeseed meal in swine feeding.


Assuntos
Brassica rapa/química , Colina/análogos & derivados , Colina/análise , Dieta/veterinária , Metilaminas/sangue , Sus scrofa/sangue , Ração Animal/análise , Animais , Disponibilidade Biológica , Colina/sangue , Colina/química , Colina/metabolismo , Colina/farmacocinética , Microbioma Gastrointestinal/fisiologia , Hidrólise , Fígado/química , Masculino
20.
Mol Nutr Food Res ; 63(17): e1900257, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31095863

RESUMO

SCOPE: Trimethylamine N-oxide (TMAO), the metabolite of choline generated by gut microbiota, is associated with nonalcoholic fatty liver disease (NAFLD) and could influence bile acid (BA) metabolism. However, whether TMAO aggravates liver steatosis by modulating BA metabolism and the related mechanisms has not been investigated. METHODS AND RESULTS: A case-control study including biopsy-proven NAFLD patients (n = 34) and controls (n = 14) is conducted to determine the correlation between TMAO and BA metabolism. Serum levels of total BA and the percentage of farnesoid X receptor (FXR)-antagonistic BA species are markedly higher in NAFLD patients than in the controls. Serum levels of TMAO positively correlated with the serum levels of total BA and hepatic mRNA expression of cholesterol 7 alpha hydroxylase (CYP7A1). In a murine model, it is found that 18 weeks administration of TMAO impairs liver function and increases hepatic triglyceride accumulation and lipogenesis in mice fed with a high-fat diet. TMAO increases BA synthesis and shifted hepatic BA composition toward FXR-antagonistic activity. Knockdown of CYP7A1 via small interfering RNA or activation of FXR by GW4064 blocks the effect of TMAO-induced lipogenesis in palmitic acid-treated HepG2 cells. CONCLUSION: TMAO aggravates liver steatosis by suppressing BA-mediated hepatic FXR signaling.


Assuntos
Ácidos e Sais Biliares/metabolismo , Metilaminas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Adulto , Animais , Ácidos e Sais Biliares/sangue , Estudos de Casos e Controles , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Metilaminas/sangue , Metilaminas/toxicidade , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Palmitatos/farmacologia , Transdução de Sinais/efeitos dos fármacos
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