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1.
Molecules ; 26(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33401401

RESUMO

There is a high level of interest in identifying metabolites of endogenously produced or dietary compounds generated by the gastrointestinal (GI) tract microbiota, and determining the functions of these metabolites in health and disease. There is a wealth of compelling evidence that the microbiota is linked with many complex chronic inflammatory diseases, including atherosclerosis. Macrophages are key target immune cells in atherosclerosis. A hallmark of atherosclerosis is the accumulation of pro-inflammatory macrophages in coronary arteries that respond to pro-atherogenic stimuli and failure of digesting lipids that contribute to foam cell formation in atherosclerotic plaques. This review illustrates the role of tryptophan-derived microbiota metabolites as an aryl hydrocarbon receptor (AhR) ligand that has immunomodulatory properties. Also, microbiota-dependent trimethylamine-N-oxide (TMAO) metabolite production is associated with a deleterious effect that promotes atherosclerosis, and metabolite indoxyl sulfate has been shown to exacerbate atherosclerosis. Our objective in this review is to discuss the role of microbiota-derived metabolites in atherosclerosis, specifically the consequences of microbiota-induced effects of innate immunity in response to atherogenic stimuli, and how specific beneficial/detrimental metabolites impact the development of atherosclerosis by regulating chronic endotoxemic and lipotoxic inflammation.


Assuntos
Aterosclerose , Células Espumosas , Microbioma Gastrointestinal/imunologia , Indicã , Metilaminas , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/microbiologia , Aterosclerose/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Espumosas/imunologia , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Indicã/imunologia , Indicã/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Metilaminas/imunologia , Metilaminas/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo
2.
Biomed Pharmacother ; 134: 111156, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33401080

RESUMO

Cardiac disorders contribute to one of the major causes of fatality across the world. Hypertensive patients, even well maintained on drugs, possess a high risk to cardiovascular diseases. It is, therefore, highly important to identify different factors and pathways that lead to risk and progression of cardiovascular disorders. Several animals and human studies suggest that taxonomical alterations in the gut are involved in the cardiovascular physiology. In this article, with the help of various experimental evidences, we suggest that the host gut-microbiota plays an important in this pathway. Short chain fatty acids (SCFAs) and Trimethyl Amine -n-Oxide (TMAO) are the two major products of gut microbiome. SCFAs present a crucial role in regulating the blood pressure, while TMAO is involved in pathogenesis of atherosclerosis and other coronary artery diseases, including hypertension. We prove that there exists a triangular bridge connecting the gap between dietary salt, hypertension and gut microbiome. We also present some of the dietary interventions which can regulate and control microbiota that can prevent cardiovascular complications.We strongly believe that this article would improve the understanding the role of gut microbiota in hypertension, and will be helpful in the development of novel therapeutic strategies for prevention of hypertension through restoring gut microbiome homeostasis in the near future.


Assuntos
Bactérias/metabolismo , Pressão Sanguínea , Microbioma Gastrointestinal , Hipertensão/etiologia , Intestinos/microbiologia , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Dieta Saudável , Dieta Hipossódica , Fibras na Dieta/uso terapêutico , Suplementos Nutricionais , Disbiose , Ácidos Graxos Voláteis/metabolismo , Humanos , Hipertensão/dietoterapia , Hipertensão/microbiologia , Hipertensão/fisiopatologia , Metilaminas/metabolismo , Medição de Risco , Fatores de Risco
3.
Crit Rev Food Sci Nutr ; 60(16): 2801-2823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32462890

RESUMO

The gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has been regarded as one of the potent risk factors of cardiovascular events and diabetes. However, its association with possible inflammatory mediators has not been revealed yet. In the current meta-analysis, we quantitatively summarized the results of studies regarding the association between TMAO and inflammation. Electronic databases including PubMed, ProQuest, Scopus, and Embase were systematically searched and a total of 586 manuscripts were retrieved. After removing 223 duplicates, 363 manuscripts were reviewed. All of the studies regarding the association between TMAO and inflammatory factors were included in the systematic review and eligible studies were included in to the meta-analysis. Accordingly, 13,783 number of participants were included and the results showed that being in the highest category of TMAO Accordingly was associated with 0.27 mg/L (weighted mean difference: 0.268; 95% confidence interval [CI]: 0.058-0.479; p = 0.013) increase in CRP concentrations compared with lowest category. The results of subgrouping and meta-regression revealed the location, CRP sample source, disease status, male percent, proportion of diabetes and smoking as the source of heterogeneity. Moreover, the dose-response meta-analysis revealed a non-linear association between increased TMAO concentrations and increased CRP concentrations (p for nonlinearity = 0.015). To our knowledge, this is first dose-response meta-analysis that summarized the results of studies about the association between circulating TMAO concentrations and inflammation risk.


Assuntos
Microbioma Gastrointestinal/fisiologia , Inflamação/metabolismo , Metilaminas/metabolismo , Humanos , Fatores de Risco
4.
J Med Chem ; 63(9): 4579-4602, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32282200

RESUMO

2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (Ki = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.


Assuntos
Ciclopropanos/farmacocinética , Agonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacocinética , Metilaminas/farmacocinética , Receptores de Dopamina D3/metabolismo , Animais , Sítios de Ligação , Encéfalo/metabolismo , Ciclopropanos/síntese química , Ciclopropanos/metabolismo , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/metabolismo , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/metabolismo , Desenho de Fármacos , Ligantes , Metilaminas/síntese química , Metilaminas/metabolismo , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor 5-HT2C de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
5.
Arterioscler Thromb Vasc Biol ; 40(5): 1239-1255, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32212854

RESUMO

OBJECTIVE: Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment. CONCLUSIONS: Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.


Assuntos
Bactérias/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Colina/farmacologia , Inibidores Enzimáticos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Liases/antagonistas & inibidores , Metilaminas/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Bactérias/enzimologia , Proteínas de Bactérias/metabolismo , Colina/análogos & derivados , Modelos Animais de Doenças , Fibrose , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Liases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/patologia
6.
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
8.
APMIS ; 128(5): 353-366, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32108960

RESUMO

The increasing prevalence of cardiovascular diseases cannot adequately be explained by traditional risk factors. Recently, accumulating evidence has suggested that gut microbiota-derived numerous metabolites are contributors to atherosclerotic events. Among them, the role of trimethylamine N-oxide (TMAO) in promoting atherosclerosis has gained attention. TMAO is reported to exert the proatherogenic effects by impacting on the traditional risk factors of atherosclerosis and is associated with high risk of cardiovascular events. Besides that, TMAO is involved in the complex pathological processes of atherosclerotic lesion formation, such as endothelial dysfunction, platelet activation and thrombus generation. In light of these promising findings, TMAO may serve as a potential target for atherosclerosis prevention and treatment, which is conceptually novel, when compared with existing traditional treatments. It is likely that regulating TMAO production and associated gut microbiota may become a promising strategy for the anti-atherosclerosis therapy.


Assuntos
Aterosclerose/metabolismo , Aterosclerose/microbiologia , Microbioma Gastrointestinal , Metilaminas/metabolismo , Animais , Humanos , Metilaminas/efeitos adversos , Fatores de Risco
9.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906370

RESUMO

l-Carnitine is an amino acid derivative widely known for its involvement in the transport of long-chain fatty acids into the mitochondrial matrix, where fatty acid oxidation occurs. Moreover, l-Carnitine protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Circulating carnitine is mainly supplied by animal-based food products and to a lesser extent by endogenous biosynthesis in the liver and kidney. Human muscle contains high amounts of carnitine but it depends on the uptake of this compound from the bloodstream, due to muscle inability to synthesize carnitine. Mitochondrial fatty acid oxidation represents an important energy source for muscle metabolism particularly during physical exercise. However, especially during high-intensity exercise, this process seems to be limited by the mitochondrial availability of free l-carnitine. Hence, fatty acid oxidation rapidly declines, increasing exercise intensity from moderate to high. Considering the important role of fatty acids in muscle bioenergetics, and the limiting effect of free carnitine in fatty acid oxidation during endurance exercise, l-carnitine supplementation has been hypothesized to improve exercise performance. So far, the question of the role of l-carnitine supplementation on muscle performance has not definitively been clarified. Differences in exercise intensity, training or conditioning of the subjects, amount of l-carnitine administered, route and timing of administration relative to the exercise led to different experimental results. In this review, we will describe the role of l-carnitine in muscle energetics and the main causes that led to conflicting data on the use of l-carnitine as a supplement.


Assuntos
Carnitina/análogos & derivados , Carnitina/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Carnitina/administração & dosagem , Carnitina/biossíntese , Carnitina/química , Carnitina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , Suplementos Nutricionais/efeitos adversos , Exercício Físico/fisiologia , Humanos , Metilaminas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Oxirredução
10.
J Biol Chem ; 295(10): 3362-3370, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-31988244

RESUMO

Ammonium transporters (AMT), methylamine permeases (Mep), and the more distantly related rhesus factors (Rh) are trimeric membrane proteins present in all domains of life. AMT/Mep/Rhs are highly selective membrane proteins required for ammonium uptake or release, and they efficiently exclude the similarly sized K+ ion. Previously reported crystal structures have revealed that each transporter subunit contains a unique hydrophobic but occluded central pore, but it is unclear whether the base (NH3) or NH3 coupled with an H+ are transported. Here, using expression of two plant AMTs (AtAMT1;2 and AMT2) in budding yeast, we found that systematic replacements in the conserved twin-histidine motif, a hallmark of most AMT/Mep/Rh, alter substrate recognition, transport capacities, N isotope selection, and selectivity against K+ AMT-specific differences were found for histidine variants. Variants that completely lost ammonium N isotope selection, a feature likely associated with NH4 + deprotonation during passage, substantially transported K+ in addition to NH4 + Of note, the twin-histidine motif was not essential for ammonium transport. However, it conferred key AMT features, such as high substrate affinity and selectivity against alkali cations via an NH4 + deprotonation mechanism. Our findings indicate that the twin-His motif is the core structure responsible for substrate deprotonation and isotopic preferences in AMT pores and that decreased deprotonation capacity is associated with reduced selectivity against K+ We conclude that optimization for ammonium transport in plant AMT represents a compromise between substrate deprotonation for optimal selectivity and high substrate affinity and transport rates.


Assuntos
Arabidopsis/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Histidina/metabolismo , Proteínas de Plantas/metabolismo , Compostos de Amônio/metabolismo , Animais , Proteínas de Transporte de Cátions/genética , Histidina/química , Íons/química , Cinética , Metilaminas/metabolismo , Mutagênese Sítio-Dirigida , Isótopos de Nitrogênio/química , Isótopos de Nitrogênio/metabolismo , Oócitos/metabolismo , Proteínas de Plantas/genética , Potássio/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Especificidade por Substrato , Xenopus laevis/crescimento & desenvolvimento
12.
Arterioscler Thromb Vasc Biol ; 40(3): 751-765, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31941382

RESUMO

OBJECTIVES: Vascular calcification is highly prevalent in patients with chronic kidney disease. Increased plasma trimethylamine N-oxide (TMAO), a gut microbiota-dependent product, concentrations are found in patients undergoing hemodialysis. However, a clear mechanistic link between TMAO and vascular calcification is not yet established. In this study, we investigate whether TMAO participates in the progression of vascular calcification using in vitro, ex vivo, and in vivo models. Approach and Results: Alizarin red staining revealed that TMAO promoted calcium/phosphate-induced calcification of rat and human vascular smooth muscle cells in a dose-dependent manner, and this was confirmed by calcium content assay. Similarly, TMAO upregulated the expression of bone-related molecules including Runx2 (Runt-related transcription factor 2) and BMP2 (bone morphogenetic protein-2), suggesting that TMAO promoted osteogenic differentiation of vascular smooth muscle cells. In addition, ex vivo study also showed the positive regulatory effect of TMAO on vascular calcification. Furthermore, we found that TMAO accelerated vascular calcification in rats with chronic kidney disease, as indicated by Mico-computed tomography analysis, alizarin red staining and calcium content assay. By contrast, reducing TMAO levels by antibiotics attenuated vascular calcification in chronic kidney disease rats. Interestingly, TMAO activated NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB (nuclear factor κB) signals during vascular calcification. Inhibition of NLRP3 inflammasome and NF-κB signals attenuated TMAO-induced vascular smooth muscle cell calcification. CONCLUSIONS: This study for the first time demonstrates that TMAO promotes vascular calcification through activation of NLRP3 inflammasome and NF-κB signals, suggesting the potential link between gut microbial metabolism and vascular calcification. Reducing the levels of TMAO could become a potential treatment strategy for vascular calcification in chronic kidney disease.


Assuntos
Inflamassomos/efeitos dos fármacos , Metilaminas/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteogênese/efeitos dos fármacos , Calcificação Vascular/induzido quimicamente , Adulto , Idoso , Animais , Antibacterianos/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos/metabolismo , Masculino , Metilaminas/metabolismo , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Artérias da Tíbia/efeitos dos fármacos , Artérias da Tíbia/metabolismo , Artérias da Tíbia/patologia , Técnicas de Cultura de Tecidos , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Calcificação Vascular/prevenção & controle
13.
Food Chem ; 309: 125683, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31670135

RESUMO

The ability of compounds of natural origin (black, white, red, and green tea extracts, phytic acid) to inhibit TMAO-demethylase enzyme was assayed. Black tea and phytic acid exerted the highest inhibiting activities, similar to the already known inhibitor sodium citrate. Hake minces incorporating these three compounds were prepared and stored frozen (150 days, -12 °C). TMAO-demethylase enzyme was partially inhibited (lower enzyme activity, reduction of formaldehyde accumulation). The study of physicochemical properties of the minces (salt-soluble proteins, water holding capacity, structural water associated with myofibrils) pointed to evident protein aggregation and loss of functionality when phytic acid was added, whereas black tea and sodium citrate did not have a negative effect. Consequently, the salt-ground mince with phytic acid showed worse viscoelastic properties than the others. In conclusion, black tea polyphenols and sodium citrate can be used as additives to inhibit TMAO-demethylase enzyme during frozen storage of fish minces.


Assuntos
Aldeído Liases/antagonistas & inibidores , Conservação de Alimentos/métodos , Gadiformes/metabolismo , Polifenóis/farmacologia , Alimentos Marinhos/análise , Aldeído Liases/metabolismo , Animais , Congelamento , Metilaminas/metabolismo , Chá/química
14.
BMJ Open Diabetes Res Care ; 7(1): e000718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798892

RESUMO

Introduction: Type 2 diabetes mellitus (T2D) confers high atherosclerotic cardiovascular disease (ASCVD) risk. The metabolite trimethylamine N-oxide (TMAO) derived via gut flora has been linked to excess ASCVD. Research design and methods: We analyzed data, biospecimens, and major adverse cardiovascular events (MACEs) from the prospective multicenter randomized Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to assess its value in 330 high-risk individuals with T2D without evident atherosclerotic disease at enrollment. Results: Incident cardiovascular events occurred in 165 cases; 165 controls matched by age, sex, and treatment arm experienced no incident events during follow-up. Cases and controls (mean age 64.5 years) had similar mean glycated hemoglobin (HbA1c) (8.2%) and mean 10-year ASCVD risk (23.5%); groups also had similar use of statins and antihypertensive medications at baseline and follow-up. Baseline plasma TMAO levels did not differ between groups after adjusting for ASCVD risk score, HbA1c, and estimated glomerular filtration rate, nor did TMAO distinguish patients suffering incident MACE from those who remained event-free. Conclusions: TMAO's prognostic value for incident ASCVD events may be blunted when applied to individuals with T2D with poor glycemic control and high baseline ASCVD risk. These results behoove further translational investigations of unique mechanisms of ASCVD risk in T2D.


Assuntos
Anti-Hipertensivos/uso terapêutico , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metilaminas/metabolismo , Idoso , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/prevenção & controle , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Resultado do Tratamento
15.
Nutrients ; 12(1)2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881690

RESUMO

Gut microbiota metabolization of dietary choline may promote atherosclerosis through trimethylamine (TMA), which is rapidly absorbed and converted in the liver to proatherogenic trimethylamine-N-oxide (TMAO). The aim of this study was to verify whether TMAO urinary levels may be associated with the fecal relative abundance of specific bacterial taxa and the bacterial choline TMA-lyase gene cutC. The analysis of sequences available in GenBank grouped the cutC gene into two main clusters, cut-Dd and cut-Kp. A quantitative real-time polymerase chain reaction (qPCR) protocol was developed to quantify cutC and was used with DNA isolated from three fecal samples collected weekly over the course of three consecutive weeks from 16 healthy adults. The same DNA was used for 16S rRNA gene profiling. Concomitantly, urine was used to quantify TMAO by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). All samples were positive for cutC and TMAO. Correlation analysis showed that the cut-Kp gene cluster was significantly associated with Enterobacteriaceae. Linear mixed models revealed that urinary TMAO levels may be predicted by fecal cut-Kp and by 23 operational taxonomic units (OTUs). Most of the OTUs significantly associated with TMAO were also significantly associated with cut-Kp, confirming the possible relationship between these two factors. In conclusion, this preliminary method-development study suggests the existence of a relationship between TMAO excreted in urine, specific fecal bacterial OTUs, and a cutC subgroup ascribable to the choline-TMA conversion enzymes of Enterobacteriaceae.


Assuntos
Proteínas de Bactérias/genética , Enterobacteriaceae/enzimologia , Microbioma Gastrointestinal/genética , Liases/genética , Metilaminas/urina , Adulto , Colina/metabolismo , DNA Bacteriano/genética , Enterobacteriaceae/classificação , Enterobacteriaceae/genética , Fezes/microbiologia , Feminino , Humanos , Masculino , Metilaminas/metabolismo , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
16.
Vopr Pitan ; 88(4): 25-33, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31722138

RESUMO

The aim of the study was to assess the impact of L-carnitine and phosphatidylcholine containing products on the production of the proatherogenic metabolite TMAO and gut microbiome changes in patients with coronary artery disease (CAD). Material and methods. The study consisted of 2 parts. In the first part, a comparison was made between the diet of patients with CAD (n=29) and healthy volunteers (n=30) over the age of 50 with respect to the frequency of intake of L-carnitine and phosphatidylcholine containing products. All participants underwent blood sampling and stool tests to assess the concentration of TMAO and the composition of fecal microflora. The second part of the study was dedicated to assessing the correlation between TMAO blood concentration in patients with CAD (n=89) and the frequency of intake of L-carnitine and phosphatidylcholine containing products. Results and discussion. Patients with CAD comparing to healthy people among the predecessor products of TMAO consumed red meat, dairy products more often, eggs and fish less often. TMAO concentration in patients with CAD was higher than in healthy volunteers (1036.4±748.2 vs 376.5±147.9 ng/ml, p=0.0001). Analysis of fecal microflora in patients with CAD revealed an increase number of bacteria from Verrucomicrobiaceae family (p<0.05) and Enterobacteriaceae family (p<0.05), of the Escherichia/Shigella genera (p<0.05), there was a trend to increased number of Ruminococcus (р=0.065), Clostridium XlV (b) genera (р=0.10). Correlation between TMAO concentration and frequency of red meat, eggs, and dairy products consumption was estimated in patients with CAD (r>0.525, р<0.05). Conclusion. Patients with CAD consume more precursors of TMAO, have higher blood TMAO concentrations compared to healthy volunteers. Fecal microflora of patients with CAD contains a greater number of gut bacteria related to trimethylamine producers compared to healthy volunteers. Reducing the number of L-carnitine and phosphatidylcholine containing products in the diet of patients with CAD may affect the decrease in the proatherogenic metabolite TMAO concentration.


Assuntos
Bactérias , Carnitina/administração & dosagem , Doença da Artéria Coronariana , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/microbiologia , Metilaminas/metabolismo , Fosfatidilcolinas/administração & dosagem , Idoso , Bactérias/classificação , Bactérias/metabolismo , Doença da Artéria Coronariana/dietoterapia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Sci Rep ; 9(1): 15901, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685846

RESUMO

Cardiovascular disease (CVD) remains the leading cause of death in chronic kidney disease (CKD) patients despite treatment of traditional risk factors, suggesting that non-traditional CVD risk factors are involved. Trimethylamine-N-oxide (TMAO) correlates with atherosclerosis burden in CKD patients and may be a non-traditional CVD risk factor. Serum TMAO concentrations are significantly increased in CKD patients, which may be due in part to increased hepatic flavin monooxygenase (FMO)-mediated TMAO formation. The objective of this work was to elucidate the mechanism of increased FMO activity in CKD. In this study, FMO enzyme activity experiments were conducted in vitro with liver microsomes isolated from experimental CKD and control rats. Trimethylamine was used as a probe substrate to assess FMO activity. The FMO activator octylamine and human uremic serum were evaluated. FMO gene and protein expression were also determined. FMO-mediated TMAO formation was increased in CKD versus control. Although gene and protein expression of FMO were not changed, metabolic activation elicited by octylamine and human uremic serum increased FMO-mediated TMAO formation. The findings suggest that metabolic activation of FMO-mediated TMAO formation is a novel mechanism that contributes to increased TMAO formation in CKD and represents a therapeutic target to reduce TMAO exposure and CVD.


Assuntos
Metilaminas/metabolismo , Oxigenases de Função Mista/metabolismo , Insuficiência Renal Crônica/patologia , Ativação Metabólica , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Modelos Animais de Doenças , Cinética , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Especificidade por Substrato
18.
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
19.
Curr Opin Microbiol ; 50: 64-70, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31693963

RESUMO

The gut microbiome has been implicated in the progression of cardiovascular diseases (CVD) including hypertension, dyslipidemia, atherosclerosis, thrombosis, heart failure, and ischemic stroke. Metabolomics studies in humans and diverse mouse populations have revealed associations between diet-derived gut bacterial metabolites, including trimethylamine-N-oxide, short-chain fatty acids, and intermediates of aromatic amino acid breakdown, with progression of CVD. Functional studies in animals fed diets of defined composition have been instrumental for establishing causal links between these metabolites, the microbes that produce them, dietary substrates and disease. The purpose of this review is to discuss recent progress in our understanding of how gut microbial metabolism of food influences the development of CVD and to outline experimental approaches that can be useful for addressing crucial knowledge gaps in the field. Together, this body of work supports the notion that the gut microbiomes mediate many of the effects of diet.


Assuntos
Bactérias/metabolismo , Doenças Cardiovasculares/microbiologia , Dieta , Microbioma Gastrointestinal , Metabolômica , Animais , Humanos , Metilaminas/sangue , Metilaminas/metabolismo , Camundongos
20.
Rev Endocr Metab Disord ; 20(4): 461-472, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31707624

RESUMO

The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism.


Assuntos
Microbioma Gastrointestinal/fisiologia , Metabolismo dos Lipídeos/fisiologia , Animais , Ácidos e Sais Biliares/metabolismo , Humanos , Lipídeos/sangue , Metilaminas/metabolismo
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