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    Trimethylamine N-oxide (TMAO) in human health. Gatarek Paulina,Kaluzna-Czaplinska Joanna EXCLI journal Due to numerous links between trimethylamine-N-oxide (TMAO) and various disorders and diseases, this topic is very popular and is often taken up by researchers. TMAO is a low molecular weight compound that belongs to the class of amine oxides. It is formed by the process of oxidation of trimethylamine (TMA) by the hepatic flavin monooxygenases (FMO1 and FMO3). TMAO is mainly formed from nutritional substrates from the metabolism of phosphatidylcholine/choline, carnitine, betaine, dimethylglycine, and ergothioneine by intestinal microflora in the colon. Its level is determined by many factors, such as age, gender, diet, intestinal microflora composition, kidney function, and also liver flavin monooxygenase activity. Many studies report a positive relationship between the level of TMAO concentration and the development of various diseases, such as cardiovascular diseases and cardiorenal disorders, including atherosclerosis, hypertension, ischemic stroke, atrial fibrillation, heart failure, acute myocardial infarction, and chronic kidney disease, and also diabetes mellitus, metabolic syndrome, cancers (stomach, colon), as well as neurological disorders. In this review, we have summarized the current knowledge on the effects of TMAO on human health, the relationship between TMAO and intestinal microbiota, the role of TMAO in different diseases, and current analytical techniques used in TMAO determination in body fluids. 10.17179/excli2020-3239
    Analysis of changes in intestinal flora and intravascular inflammation and coronary heart disease in obese patients. Li Xv,Li Chuantao Experimental and therapeutic medicine Changes in intestinal flora in obese patients and intravascular C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and coronary heart disease (CHD) were analyzed. A total of 75 cases of obese patients were divided into obesity (OB) alone (n=40) and OB with CHD group (n=35). There was no statistically significant difference in age, sex, pre-existing basic diabetes, history of hypertension, and body mass index (P>0.05). Results showed that total bacterial load of CHD was obviously higher than that of OB group. The uric acid decomposed by intestinal flora (IFUA) and blood uric acid levels in CHD were higher than those in OB group, but the fecal uric acid level was lower than that of OB group (P<0.05). Levels of inflammatory factors in CHD, were significantly higher than those in OB group (P<0.05). Correlation analyses showed that the intestinal flora total load and CRP were positively correlated (r=0.793, P<0.001). Intestinal flora and Gensini score were also positively related to total load (r=0.893, P=0.893). Furthermore, CRP and Gensini score were positively related (r=0.796, P<0.796). IFUA and Gensini score were positively related to (r=0.647, P<0.001). Over-reaction in the flammation system in obese patients may lead to intestinal flora disorder, disturbance and also increased levels of IFUA and inflammatory factors. 10.3892/etm.2018.5987
    Interactions between the Gut Microbiome, Lung Conditions, and Coronary Heart Disease and How Probiotics Affect These. Wassenaar Trudy M,Juncos Valentina A,Zimmermann Kurt International journal of molecular sciences The importance of a healthy microbiome cannot be overemphasized. Disturbances in its composition can lead to a variety of symptoms that can extend to other organs. Likewise, acute or chronic conditions in other organs can affect the composition and physiology of the gut microbiome. Here, we discuss interorgan communication along the gut-lung axis, as well as interactions between lung and coronary heart diseases and between cardiovascular disease and the gut microbiome. This triangle of organs, which also affects the clinical outcome of COVID-19 infections, is connected by means of numerous receptors and effectors, including immune cells and immune-modulating factors such as short chain fatty acids (SCFA) and trimethlamine-N-oxide (TMAO). The gut microbiome plays an important role in each of these, thus affecting the health of the lungs and the heart, and this interplay occurs in both directions. The gut microbiome can be influenced by the oral uptake of probiotics. With an improved understanding of the mechanisms responsible for interorgan communication, we can start to define what requirements an 'ideal' probiotic should have and its role in this triangle. 10.3390/ijms22189700
    Correlations of changes in inflammatory factors, glucose and lipid metabolism indicators and adiponectin with alterations in intestinal flora in rats with coronary heart disease. Peng Y,Zhang N,Li W-J,Tan K,Zhou Y,She C,Chen H-N European review for medical and pharmacological sciences OBJECTIVE:The aim of this study was to explore the correlations of changes in inflammatory factors, glucose and lipid metabolism indicators and adiponectin with alterations in intestinal flora in rats with coronary heart disease. MATERIALS AND METHODS:A total of 30 male specific pathogen-free rats were randomly assigned into two groups, including: blank group (n=15) and coronary heart disease group (n=15). The rats in the coronary heart disease group were given high-fat diets and pituitrin to establish the model of coronary heart disease. Meanwhile, rats in the blank group were administered with an equal volume of double-distilled water. The alterations in the intestinal flora of rats were detected in the two groups, respectively. In addition, the changes in the levels of inflammatory factors, glucose and lipid metabolism indicators, adiponectin, creatine kinase (CK) and its isoenzyme, as well as troponin, were also examined. RESULTS:Statistically, significant differences in the levels of glucose and lipid metabolism indicators low-density lipoprotein (LDL) (p=0.040), total cholesterol (TC) (p=0.039), high-density lipoprotein (HDL) (p=0.044), triglyceride (TG) (p=0.000) and blood glucose (p=0.046) were observed between the rats in the coronary heart disease group and blank group. The content of all the glucose and lipid metabolism indicators (except HDL) in coronary heart disease group was significantly higher than the blank group (p<0.05). The rats in the coronary heart disease group had evidently higher levels of CK (p=0.000) and its isoenzyme (p=0.019), as well as troponin (p=0.021), than those in the blank group. The level of serum adiponectin in rats in coronary heart disease group was distinctly lower than that in the blank group, showing statistically significant differences (p<0.05). Besides, the levels of the inflammatory factors interleukin (IL)-2 (p=0.011), transforming growth factor (TGF)-β (p=0.048), tumor necrosis factor-α (TNF-α) (p=0.025) and IL-6 (p=0.038) in rats in the coronary heart disease group were dramatically higher than those in blank group. Rats in coronary heart disease group had remarkably more Actinobacteria, Desulfovibrio, Aristipus and Escherichia coli in the intestine. Meanwhile, the abundance of Flavobacterium, Burkhofer and some probiotics increased significantly in the intestine of rats in blank group (p<0.05). The changes in the abundance of Actinobacteria, Desulfovibrio, Aristipus and Escherichia coli in the intestine of rats were probably correlated with increased levels of glucose and lipid metabolism indicators, inflammatory factors and adiponectin in coronary heart disease group. Moreover, the abundance of intestinal probiotics such as Bifidobacterium and Lactobacillus in rats in coronary heart disease group was notably lower than that in blank group (p<0.05). The decline in the abundance of such intestinal probiotics as Bifidobacterium and Lactobacillus was correlated with the changes in the levels of glucose and lipid metabolism indicators, inflammatory factors and adiponectin. In addition, decreased levels of probiotics weakened normal physiological functions of the intestine and promoted disease progression. CONCLUSIONS:Inflammatory factors, glucose and lipid metabolism indicators and adiponectin have evident changes in rats with coronary heart disease, which may be correlated with the alterations in the intestinal flora. 10.26355/eurrev_202010_23231
    Trimethylamine oxide: a potential target for heart failure therapy. Lv Shichao,Wang Yunjiao,Zhang Wanqin,Shang Hongcai Heart (British Cardiac Society) Heart failure (HF) is a clinical syndrome in the late stage of cardiovascular disease and is associated with high prevalence, mortality and rehospitalisation rate. The pathophysiological mechanisms of HF have experienced the initial 'water-sodium retention' mode to 'abnormal hemodynamics' mode, and subsequent to 'abnormal activation of neuroendocrine' mode, which has extensively promoted the reform of HF treatment and updated the treatment concept. Since the Human Microbiome Project commencement, the study on intestinal microecology has swiftly developed, providing a new direction to reveal the occurrence of diseases and the mechanisms behind drug effects. Intestinal microecology comprises the gastrointestinal lumen, epithelial secretion, food entering the intestine, intestinal flora and metabolites. Choline and L-carnitine in the diet are metabolised to trimethylamine (TMA) by the intestinal micro-organisms, with TMA being absorbed into the blood. TMA then enters the liver through the portal vein circulation and is oxidised to trimethylamine oxide (TMAO) by the hepatic flavin-containing mono-oxygenase (FMO) family, especially FMO3. The circulating TMAO levels are associated with adverse outcomes in HF (mortality and readmission), and lower TMAO levels indicate better prognosis. As HF progresses, the concentration of TMAO in patients gradually increases. Whether the circulating TMAO level can be decreased by intervening with the intestinal microflora or relevant enzymes, thereby affecting the prognosis of patients with HF, has become a research hotspot. Therefore, based on the HF intestinal hypothesis, exploring the treatment strategy for HF targeting the TMAO metabolite of the intestinal flora may update the treatment concept in HF and improve its therapeutic effect. 10.1136/heartjnl-2021-320054
    Intestinal Flora Dysbiosis Aggravates Cognitive Dysfunction Associated With Neuroinflammation in Heart Failure. Yu Wei,Gao Dapeng,Jin Wen,Wang Zijian,Li Yan,Peng Xiaowei,Cong Yushuang,Li Chenglong,Zhao Ayang,Liu Shuai,Qi Sihua Journal of cardiac failure BACKGROUND:Cognitive dysfunction after heart failure (HF) is characterized by neuroinflammation, which plays an important role in the occurrence and development of cognitive dysfunction. Recent studies have shown that an intestinal flora imbalance may also trigger neuroinflammation in Alzheimer's disease. The present study was designed to reveal that intestinal flora dysbiosis caused by HF aggravates neuroinflammation-associated cognitive impairment. METHODS AND RESULTS:Adult male Sprague-Dawley rats were fed daily for 2 weeks with probiotics or placebo until the day of surgery. HF was then triggered by 8 weeks of sustained coronary artery occlusion. 16S rDNA sequencing was used to confirm intestinal flora dysbiosis after HF and demonstrate that the changes paralleled intestinal pathology scores. The permeability of the blood-brain barrier was increased after HF, and such an increase in permeability may increase the levels of inflammatory cytokines caused by intestinal flora disorders. The changes in the intestinal flora caused by probiotics significantly reduced the level of neuroinflammation. In addition, probiotic administration considerably improved the impaired spatial memory in HF rats. CONCLUSIONS:We conclude that intestinal flora dysbiosis plays a potential role in aggravating the impaired cognition associated with neuroinflammation and that these effects may be attenuated by probiotics. 10.1016/j.cardfail.2020.02.002
    Gut microbiome - A potential mediator of pathogenesis in heart failure and its comorbidities: State-of-the-art review. Mamic Petra,Chaikijurajai Thanat,Tang W H Wilson Journal of molecular and cellular cardiology Gut microbiome (GMB) has been increasingly recognized as a contributor to development and progression of heart failure (HF), immune-mediated subtypes of cardiomyopathy (myocarditis and anthracycline-induced cardiotoxicity), response to certain cardiovascular drugs, and HF-related comorbidities, such as chronic kidney disease, cardiorenal syndrome, insulin resistance, malnutrition, and cardiac cachexia. Gut microbiome is also responsible for the "gut hypothesis" of HF, which explains the adverse effects of gut barrier dysfunction and translocation of GMB on the progression of HF. Furthermore, accumulating evidence has suggested that gut microbial metabolites, including short chain fatty acids, trimethylamine N-oxide (TMAO), amino acid metabolites, and bile acids, are mechanistically linked to pathogenesis of HF, and could, therefore, serve as potential therapeutic targets for HF. Even though there are a variety of proposed therapeutic approaches, such as dietary modifications, prebiotics, probiotics, TMAO synthesis inhibitors, and fecal microbial transplant, targeting GMB in HF is still in its infancy and, indeed, requires further preclinical and clinical evidence. In this review, we aim to highlight the role gut microbiome plays in HF pathophysiology and its potential as a novel therapeutic target in HF. 10.1016/j.yjmcc.2020.12.001
    High-Choline Diet Exacerbates Cardiac Dysfunction, Fibrosis, and Inflammation in a Mouse Model of Heart Failure With Preserved Ejection Fraction. Shuai Wei,Wen Jingyi,Li Xiuli,Wang Dan,Li Yunde,Xiang Jian Journal of cardiac failure BACKGROUND:Trimethylamine N-oxide, a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, has been associated with a poor prognosis for patients with cardiovascular disease. However, the role and underlying mechanisms of trimethylamine N-oxide in the cardiac function of patients with heart failure with preserved ejection fraction (HFpEF) have not been elucidated. METHODS AND RESULTS:C57BL/6 mice were fed a normal diet, high-choline (1.2%) diet, and/or 3-dimethyl-1-butanol diet 3 weeks before the operation (uninephrectomy followed by a continuous saline or aldosterone infusion). Mice were assessed for 4 weeks after the operation. Echocardiographic and hemodynamic measurements were performed. Blood samples were evaluated for choline, trimethylamine N-oxide, and inflammatory factor levels. Left ventricular tissues were collected to assess myocardial fibrosis and inflammation. Left ventricular hypertrophy, pulmonary congestion, and diastolic dysfunction were markedly exacerbated in HFpEF mice fed high-choline diets compared with mice fed the control diet. Myocardial fibrosis and inflammation were markedly increased in HFpEF mice fed high-choline diets compared with animals fed the control diet. Additionally, 3,3-dimethyl-1-butanol DMB markedly ameliorated cardiac diastolic dysfunction, myocardial fibrosis and inflammation in the choline-fed HFpEF mice. CONCLUSIONS:A high-choline diet exacerbates cardiac dysfunction, myocardial fibrosis, and inflammation in HFpEF mice, and 3,3-dimethyl-1-butanol ameliorates the high-choline diet-induced cardiac remodeling. 10.1016/j.cardfail.2020.04.017
    3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice. Wang Guangji,Kong Bin,Shuai Wei,Fu Hui,Jiang Xiaobo,Huang He The Journal of nutritional biochemistry Trimethylamine N-oxide (TMAO) is closely related to cardiovascular diseases, particularly heart failure (HF). Recent studies shows that 3,3-dimethyl-1-butanol (DMB) can reduce plasma TMAO levels. However, the role of DMB in overload-induced HF is not well understood. In this research study, we explored the effects and the underlying mechanisms of DMB in overload-induced HF. Aortic banding (AB) surgery was performed in C57BL6/J mice to induce HF, and a subset group of mice underwent a sham operation. After surgery, the mice were fed with a normal diet and given water supplemented with or without 1% DMB for 6 weeks. Cardiac function, plasma TMAO level, cardiac hypertrophy and fibrosis, expression of inflammatory, electrophysiological studies and signaling pathway were analyzed at the sixth week after AB surgery. DMB reduced TMAO levels in overload-induced HF mice. Adverse cardiac structural remodeling, such as cardiac hypertrophy, fibrosis and inflammation, was elevated in overload-induced HF mice. Susceptibility to ventricular arrhythmia also significantly increased in overload-induced HF mice. However, these changes were prevented by DMB treatment. DMB attenuated all of these changes by reducing plasma TMAO levels, hence negatively inhibiting the p65 NF-κB signaling pathway and TGF-β1/Smad3 signaling pathway. DMB plays an important role in attenuating the development of cardiac structural remodeling and electrical remodeling in overload-induced HF mice. This may be attributed to the p65 NF-κB signaling pathway and TGF-β1/Smad3 signaling pathway inhibition. 10.1016/j.jnutbio.2020.108341
    TMAO: how gut microbiota contributes to heart failure. Zhang Yixin,Wang Yuan,Ke Bingbing,Du Jie Translational research : the journal of laboratory and clinical medicine An increasing amount of evidence reveals that the gut microbiota is involved in the pathogenesis and progression of various cardiovascular diseases. In patients with heart failure (HF), splanchnic hypoperfusion causes ischemia and intestinal edema, allowing bacterial translocation and bacterial metabolites to enter the blood circulation via an impaired intestinal barrier. This results in local and systemic inflammatory responses. Gut microbe-derived metabolites are implicated in the pathology of multiple diseases, including HF. These landmark findings suggest that gut microbiota influences the host's metabolic health, either directly or indirectly by producing several metabolites. In this review, we mainly discuss a newly identified gut microbiota-dependent metabolite, trimethylamine N-oxide (TMAO), which appears to participate in the pathologic processes of HF and can serve as an early warning marker to identify individuals who are at the risk of disease progression. We also discuss the potential of the gut-TMAO-HF axis as a new target for HF treatment and highlight the current controversies and potentially new and exciting directions for future research. 10.1016/j.trsl.2020.08.007
    A cross-talk between gut microbiome, salt and hypertension. Naqvi Salma,Asar Turky Omar,Kumar Vikas,Al-Abbasi Fahad A,Alhayyani Sultan,Kamal Mohammad Amjad,Anwar Firoz Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 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. 10.1016/j.biopha.2020.111156
    Microbiota-Mediated Immune Regulation in Atherosclerosis. Eshghjoo Sahar,Jayaraman Arul,Sun Yuxiang,Alaniz Robert C Molecules (Basel, Switzerland) 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--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. 10.3390/molecules26010179
    Role of Gut Microbiota and Their Metabolites on Atherosclerosis, Hypertension and Human Blood Platelet Function: A Review. Duttaroy Asim K Nutrients Emerging data have demonstrated a strong association between the gut microbiota and the development of cardiovascular disease (CVD) risk factors such as atherosclerosis, inflammation, obesity, insulin resistance, platelet hyperactivity, and plasma lipid abnormalities. Several studies in humans and animal models have demonstrated an association between gut microbial metabolites such as trimethylamine--oxide (TMAO), short-chain fatty acids, and bile acid metabolites (amino acid breakdown products) with CVD. Human blood platelets are a critical contributor to the hemostatic process. Besides, these blood cells play a crucial role in developing atherosclerosis and, finally, contribute to cardiac events. Since the TMAO, and other metabolites of the gut microbiota, are asociated with platelet hyperactivity, lipid disorders, and oxidative stress, the diet-gut microbiota interactions have become an important research area in the cardiovascular field. The gut microbiota and their metabolites may be targeted for the therapeutic benefit of CVD from a clinical perspective. This review's main aim is to highlight the complex interactions between microbiota, their metabolites, and several CVD risk factors. 10.3390/nu13010144
    Fluorescent assay for quantitative analysis of trimethylamine N-oxide. Zhang Wen,Sun Jiao,Wang Fang,Liu Jiang,Han Ying,Jiang Miao,Tang Dongqi Analytical methods : advancing methods and applications Trimethylamine N-oxide (TMAO), a gut microbial metabolite involved in cardiovascular and kidney diseases, has great potential as a biomarker, thus making TMAO quantification of great significance. The current assay methods are mainly established on mass spectrometry. However, the classic enzymatic approach is absent, which may be because there is no appropriate single-enzyme reaction. Here, we prepared TMAO demethylase and formaldehyde dehydrogenase and found that these two bacterial enzymes catalyze an efficient coupled reaction that produces NADH from TMAO conversion. With the participation of another enzyme, diaphorase, the multienzymatic coupling system was constructed, which realizes the output of fluorescence signals from TMAO input using resazurin as a probe, thus laying the foundation for fluorescent assay. Through optimization, the sensitivity and specificity were improved. A pretreatment procedure was developed to eliminate formaldehyde that pre-exists with TMAO to avoid an interference effect. Our assay is suitable for quantifying serum TMAO in the range of 2.05-50 μM, covering actual levels in clinical samples, and exhibits a high degree of accordance with mass spectrometry. Therefore, the established fluorometric microplate assay is facile, sensitive and accurate and may enable low-cost and high-throughput analysis of TMAO in clinical laboratory diagnosis. 10.1039/d0ay02353a
    Determination of Trimethylamine -oxide and Betaine in Serum and Food by Targeted Metabonomics. He Mingshuai,Yu Heshui,Lei Peng,Huang Shengjie,Ren Juanning,Fan Wenjing,Han Lifeng,Yu Haiyang,Wang Yuefei,Ren Ming,Jiang Miaomiao Molecules (Basel, Switzerland) Trimethylamine -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 3.29 and 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. 10.3390/molecules26051334
    Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis. Yang Jae Jeong,Shu Xiao-Ou,Herrington David M,Moore Steven C,Meyer Katie A,Ose Jennifer,Menni Cristina,Palmer Nicholette D,Eliassen Heather,Harada Sei,Tzoulaki Ioanna,Zhu Huilian,Albanes Demetrius,Wang Thomas J,Zheng Wei,Cai Hui,Ulrich Cornelia M,Guasch-Ferré Marta,Karaman Ibrahim,Fornage Myriam,Cai Qiuyin,Matthews Charles E,Wagenknecht Lynne E,Elliott Paul,Gerszten Robert E,Yu Danxia The American journal of clinical nutrition BACKGROUND:Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. OBJECTIVES:To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia. METHODS:Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant. RESULTS:After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses. CONCLUSIONS:In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation. 10.1093/ajcn/nqaa430
    Gut microbiota-derived metabolites and risk of coronary artery disease: a prospective study among US men and women. Liu Gang,Li Jun,Li Yanping,Hu Yang,Franke Adrian A,Liang Liming,Hu Frank B,Chan Andrew T,Mukamal Kenneth J,Rimm Eric B,Sun Qi The American journal of clinical nutrition BACKGROUND:Accumulating evidence has suggested that human gut microbiota metabolize certain dietary compounds and subsequently produce bioactive metabolites that may exert beneficial or harmful effects on coronary artery disease (CAD) risk. OBJECTIVES:This study examined the joint association of 2 gut microbiota metabolites, enterolactone and trimethylamine N-oxide (TMAO), that originate from intake of plant-based foods and animal products, respectively, in relation to CAD risk. METHODS:A prospective nested case-control study of CAD was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in the Nurses' Health Study II and the Health Professionals Follow-up Study. Plasma concentrations of enterolactone and TMAO, as well as choline and L-carnitine, were assayed among 608 CAD case-control pairs. RESULTS:A high enterolactone and low TMAO profile was associated with better diet quality, especially higher intake of whole grains and fiber and lower intake of red meats, as well as lower concentrations of plasma triglycerides and C-reactive protein. Participants with a high enterolactone/low TMAO profile had a significantly lower risk of CAD: the multivariate-adjusted OR was 0.58 (95% CI: 0.38, 0.90), compared with participants with a low enterolactone/high TMAO profile. No significant interaction between enterolactone and TMAO on CAD risk was observed. Neither TMAO nor enterolactone alone were associated with CAD risk in pooled analyses. In women, a higher enterolactone concentration was significantly associated with a 54% lower CAD risk (P trend = 0.03), although the interaction by sex was not significant. CONCLUSIONS:Our results show that a profile characterized by high enterolactone and low TMAO concentrations in plasma is linked to a healthful dietary pattern and significantly associated with a lower risk of CAD. Overall, these data suggest that, compared with individual markers, multiple microbiota-derived metabolites may facilitate better differentiation of CAD risk and characterization of the relations between diet, microbiota, and CAD risk. 10.1093/ajcn/nqab053
    Association of Urinary and Plasma Levels of Trimethylamine N-Oxide (TMAO) with Foods. Lombardo Mauro,Aulisa Giovanni,Marcon Daniele,Rizzo Gianluca,Tarsisano Maria Grazia,Di Renzo Laura,Federici Massimo,Caprio Massimiliano,De Lorenzo Antonino Nutrients 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. 10.3390/nu13051426
    Mitochondrial DNA copy number and trimethylamine levels in the blood: New insights on cardiovascular disease biomarkers. Bordoni Laura,Petracci Irene,Pelikant-Malecka Iwona,Radulska Adriana,Piangerelli Marco,Samulak Joanna J,Lewicki Lukasz,Kalinowski Leszek,Gabbianelli Rosita,Olek Robert A FASEB journal : official publication of the Federation of American Societies for Experimental Biology Among cardiovascular disease (CVD) biomarkers, the mitochondrial DNA copy number (mtDNAcn) is a promising candidate. A growing attention has been also dedicated to trimethylamine-N-oxide (TMAO), an oxidative derivative of the gut metabolite trimethylamine (TMA). With the aim to identify biomarkers predictive of CVD, we investigated TMA, TMAO, and mtDNAcn in a population of 389 coronary artery disease (CAD) patients and 151 healthy controls, in association with established risk factors for CVD (sex, age, hypertension, smoking, diabetes, glomerular filtration rate [GFR]) and troponin, an established marker of CAD. MtDNAcn was significantly lower in CAD patients; it correlates with GFR and TMA, but not with TMAO. A biomarker including mtDNAcn, sex, and hypertension (but neither TMA nor TMAO) emerged as a good predictor of CAD. Our findings support the mtDNAcn as a promising plastic biomarker, useful to monitor the exposure to risk factors and the efficacy of preventive interventions for a personalized CAD risk reduction. 10.1096/fj.202100056R
    Microbiota-derived Trimethylamine N-oxide Predicts Cardiovascular Risk After STEMI. Matsuzawa Yasushi,Nakahashi Hidefumi,Konishi Masaaki,Sato Ryosuke,Kawashima Chika,Kikuchi Shinnosuke,Akiyama Eiichi,Iwahashi Noriaki,Maejima Nobuhiko,Okada Kozo,Ebina Toshiaki,Hibi Kiyoshi,Kosuge Masami,Ishigami Tomoaki,Tamura Kouichi,Kimura Kazuo Scientific reports Trimethylamine N-oxide (TMAO), a metabolite derived from the gut microbiota, is proatherogenic and associated with cardiovascular events. However, the change in TMAO with secondary prevention therapies for ST-segment elevation acute myocardial infarction (STEMI) remains unclear. The purpose of this study was to investigate the sequential change in TMAO levels in response to the current secondary prevention therapies in patients with STEMI and the clinical impact of TMAO levels on cardiovascular events We included 112 STEMI patients and measured plasma TMAO levels at the onset of STEMI and 10 months later (chronic phase). After the chronic-phase assessment, patients were followed up for cardiovascular events. Plasma TMAO levels significantly increased from the acute phase to the chronic phase of STEMI (median: 5.63 to 6.76 μM, P = 0.048). During a median period of 5.4 years, 17 patients experienced events. The chronic-phase TMAO level independently predicted future cardiovascular events (adjusted hazard ratio for 0.1 increase in log chronic-phase TMAO level: 1.343, 95% confidence interval 1.122-1.636, P = 0.001), but the acute-phase TMAO level did not. This study demonstrated the clinical importance of the chronic-phase TMAO levels on future cardiovascular events in patients after STEMI. 10.1038/s41598-019-48246-6
    Trimethylamine N-oxide (TMAO): a new attractive target to decrease cardiovascular risk. Swanepoel Ione,Roberts April,Brauns Chelsea,Chaliha Devahuti R,Papa Veronica,Palmer Raymond D,Vaccarezza Mauro Postgraduate medical journal Cardiovascular disease (CVD) is one of the greatest disease burdens and takes the lives of many each year. There are many risk factors both modifiable and non-modifiable which contribute to the onset and progression of the disease. Trimethylamine N-oxide (TMAO) in recent years has been found to have a correlation with CVD onset. Those with increased levels of the metabolite have a markedly increased risk of future development of cardiometabolic disorders.This literature review aimed to critique past studies undertaken to find a consensus of the significance of the interrelationship between TMAO and cardiovascular risk. A definite link between TMAO levels and a CVD outcome was found. The majority of the literature stated the relationship with evidence; however, there is still some uncertainty as to why and how the correlation occurs. Further study needs to be done to further dissect and understand the relationship between TMAO and CVD risk. 10.1136/postgradmedj-2021-139839
    Gut microbiota-derived trimethylamine-N-oxide: A bridge between dietary fatty acid and cardiovascular disease? He Mengxue,Tan Chin-Ping,Xu Yong-Jiang,Liu Yuanfa Food research international (Ottawa, Ont.) Cardiovascular disease (CVD) is a serious disease that endangers human health and is one of the leading causes of death. Recent studies have reported that gut microbiota plays an important role in the development of CVD, especially its metabolite trimethylamine-N-oxide (TMAO). Dietary precursors, such as choline, L-carnitine, phosphatidylcholine and betaine were metabolized to trimethylamine (TMA) under the action of gut microbiota, and subsequently oxidized by hepatic flavin monooxygenases (FMOs) to form TMAO. Dietary fat is one of three major nutrients in food, has been found to have a positive or negative effect on the development of CVD. Multiple clinical and experimental evidences suggested that dietary fatty acids (FAs) can affect TMAO production through gut microbiota and/or FMO3 enzyme activity. This article summarizes the existing gut microbiota-mediated reduction of TMA, discusses the molecular mechanism of dietary FAs in the pathobiology of CVD from the view of TMAO. Therefore, this review provides new insight into the association of dietary FAs and CVD, paving the way for dietary FAs therapy for CVD. 10.1016/j.foodres.2020.109812
    Trimethylamine/Trimethylamine-N-Oxide as a Key Between Diet and Cardiovascular Diseases. He Siyu,Jiang Hong,Zhuo Caili,Jiang Wei Cardiovascular toxicology Trimethylamine (TMA) is a gut microbiota-derived metabolite which comes from diets rich of choline, betaine or L-carnitine and could be further converted to Trimethylamine-N-oxide (TMAO) in the liver. As the function of gut microbiota and its metabolites being explored so far, studies suggest that TMAO may be a potential risk factor of cardiovascular diseases independent of other traditional risk factors. However, the precise role of TMAO is controversial as some converse results were discovered. In recent studies, it is hypothesized that TMA may also participate in the progression of cardiovascular diseases and some cytotoxic effect of TMA has been discovered. Thus, exploring the relationship between TMA, TMAO and CVD may bring a novel insight into the diagnosis and therapy of cardiovascular diseases. In this review, we discussed the factors which influence the TMA/TMAO's process of metabolism in the human body. We have also summarized the pathogenic effect of TMA/TMAO in cardiovascular diseases, as well as the limitation of some controversial discoveries. 10.1007/s12012-021-09656-z
    Trimethylamine N-Oxide (TMAO), Diet and Cardiovascular Disease. Thomas Minu S,Fernandez Maria Luz Current atherosclerosis reports PURPOSE OF REVIEW:The association between plasma Trimethylamine N-Oxide (TMAO), diet and risk for cardiovascular disease (CVD) is still not fully understood. While epidemiologic research shows a causal relationship between plasma TMAO concentrations and CVD risk, the role of dietary precursors in determining plasma concentrations of TMAO and biomarkers for CVD is inconclusive. RECENT FINDINGS:Studies in diverse populations show that plasma TMAO concentrations are positively associated with inflammation, endothelial dysfunction, type-2 diabetes, central adiposity and hypertension. Most recent studies utilizing challenges of dietary choline have not shown increases in plasma chronic TMAO concentrations while studies with carnitine have shown increases in plasma TMAO but in some cases, no alterations in plasma lipids or biomarkers of oxidative stress were observed. TMAO is an important plasma metabolite that through several mechanisms can increase the risk of CVD. The correlations between dietary choline and carnitine on chronic plasma TMAO levels and risk for CVD requires further investigation. 10.1007/s11883-021-00910-x
    Impact of trimethylamine N-oxide (TMAO) metaorganismal pathway on cardiovascular disease. Zhao Yongzhong,Wang Zeneng Journal of laboratory and precision medicine Host-microbes interaction plays a crucial role in cardiovascular disease (CVD) pathogenesis, mechanistically via metaorganismal pathways. The trimethylamine N-oxide (TMAO) metaorganismal pathway is the most deeply investigated one, which comprises trimethylamine precursors, such as choline, trimethylamine lyase, trimethylamine, host liver FMO3, TMAO, and downstream effectors involving unfolded protein response (UPR), NF-κB and NLRP3 inflammasome. Accumulating data from clinical investigations of CVD patient cohorts and rodent models have supported the critical role of this metaorganismal pathway in the pathogenesis of CVD. We summarize an array of significant animal studies especially for arthrosclerosis with an emphasis on downstream molecular effectors of this metaorganismal pathway. We highlight clinical investigations of the prognostic value of plasma TMAO levels in predicting prospective risk for future major adverse cardiac events (MACE) indicated by composite end points of myocardial infarction (MI), stroke, heart failure (HF), other ischemic cardiovascular events, or death. Further, we discuss the latest advances of preclinical models targeting the gut microbiota trimethylamine lyase of the TMAO metaorganismal pathway for CVD intervention, as well as the catalog of gut microbiota TMA lyase genes and microbes in the human gut as the prerequisite for potential clinical intervention. In-depth characterization of TMAO metaorganismal pathway holds great promise for CVD clinical metagenomics, diagnostics and therapeutics. 10.21037/jlpm.2020.01.01
    Two Gut Microbiota-Derived Toxins Are Closely Associated with Cardiovascular Diseases: A Review. Yamashita Tomoya,Yoshida Naofumi,Emoto Takuo,Saito Yoshihiro,Hirata Ken-Ichi Toxins Cardiovascular diseases (CVDs) have become a major health problem because of the associated high morbidity and mortality rates observed in affected patients. Gut microbiota has recently been implicated as a novel endocrine organ that plays critical roles in the regulation of cardiometabolic and renal functions of the host via the production of bioactive metabolites. This review investigated the evidence from several clinical and experimental studies that indicated an association between the gut microbiota-derived toxins and CVDs. We mainly focused on the pro-inflammatory gut microbiota-derived toxins, namely lipopolysaccharides, derived from Gram-negative bacteria, and trimethylamine N-oxide and described the present status of research in association with these toxins, including our previous research findings. Several clinical studies aimed at exploring the effectiveness of reducing the levels of these toxins to inhibit cardiovascular events are currently under investigation or in the planning stages. We believe that some of the methods discussed in this review to eliminate or reduce the levels of such toxins in the body could be clinically applied to prevent CVDs in the near future. 10.3390/toxins13050297
    The Role of Microbiota in Cardiovascular Risk: Focus on Trimethylamine Oxide. Al-Rubaye Hussein,Perfetti Giulia,Kaski Juan-Carlos Current problems in cardiology The extensive collection of bacteria cohabiting within the host collaborates with human functions and metabolisms in both health and disease. The fine equilibrium of commensals is tightly controlled and an imbalance ("dysbiosis") in the gut microbiota can play different roles in human disease. The development of new genome sequencing techniques has allowed a better understanding of the role of human gut microbiota. This led to the identification of numerous metabolites produced in the gut, which have been suggested to play a role in human disease. Among these, trimethylamine oxide (TMAO) appears to be of particular importance as a risk factor and potentially as a causative agent of various pathologies, most remarkably cardiovascular and disease and other associated conditions. Mechanistic links are yet to be established, however, increased levels of TMAO have been shown to augment the risk of developing renal failure, metabolic syndrome, diabetes mellitus, heart failure, hypertension, atherosclerosis, and dyslipidemia ultimately leading to increased risk of serious cardiovascular events. This article reviews the potential impact of TMAO in human cardiovascular disease. 10.1016/j.cpcardiol.2018.06.005
    In Vitro Anti-inflammatory Effects of the Phenylbutyric Acid Metabolite Phenylacetyl Glutamine. Hazekawa Mai,Ono Kazuhiko,Nishinakagawa Takuya,Kawakubo-Yasukochi Tomoyo,Nakashima Manabu Biological & pharmaceutical bulletin Sodium 4-phenylbutyrate (PBA), which exerts a wide range of anti-inflammatory effects, is rapidly cleared from the body (approximately 98%) by urinary excretion by 24 h after oral treatment in humans. PBA was almost entirely excreted to urine as phenylacetyl glutamine (PAGln). However, no data describe the potential anti-inflammatory effects of PAGln. The purpose of this study was to evaluate the anti-inflammatory effects of PAGln on mouse spleen cells and peritoneal cavity cells, and explore the potential mechanism underlying this effect. PAGln was added to mouse spleen cell cultures stimulated by concanavalin A, or mouse peritoneal cavity cell cultures stimulated by lipopolysaccharide. After 72 h of culture, levels of inflammatory cytokines in culture supernatants were measured using a sandwich enzyme-linked immunosorbent assay system, and levels of inflammatory proteins were assessed by Western blotting. PAGln significantly inhibited inflammatory cytokine (interferon-γ, interleukin-6, and tumor necrosis factor-α) production, decrease of cell number in the spleen cell, and suppressed the expression of inflammatory proteins (nuclear factor κB, and inducible nitric oxide synthase). These results suggest that PAGln possesses anti-inflammatory activity via inhibition of T cell activation and Toll-like receptor 4 signaling. This study of the anti-inflammatory mechanism of PAGln provides useful information about its potential for therapeutic applications. 10.1248/bpb.b17-00799
    Phenylacetylglutamine is associated with the degree of coronary atherosclerotic severity assessed by coronary computed tomographic angiography in patients with suspected coronary artery disease. Liu Yang,Liu Shaoyan,Zhao Zhizhuang,Song Xiang,Qu Haixian,Liu Hongbin Atherosclerosis BACKGROUND AND AIMS:Phenylacetylglutamine (PAG), a gut microbiota metabolite, has recently been found to be associated with major adverse cardiovascular events. In this study, we analyzed the relationship between plasma PAG and coronary atherosclerotic severity assessed by coronary computed tomographic angiography (CCTA). METHODS:We enrolled consecutive patients with suspected coronary artery disease (CAD) who underwent CCTA. Plasma PAG was measured by mass spectrometry. Coronary atherosclerotic severity was evaluated based on plaque burden and plaque vulnerability. Plaque burden was quantified as percent atheroma volume (PAV), CCTA-derived SYNTAX score (CT-SYNTAX) and CAD reporting and data system score (CAD-RADS). Plaque vulnerability was evaluated by the presence of adverse characteristics. RESULTS:A total of 686 patients were enrolled. The patients were divided into two groups based on median plasma PAG (3.25 μM). A correlation was found between plasma PAG and PAV (r = 0.499, p < 0.01). Patients with obstructive CAD (CAD-RADS>3) and high coronary lesion complexity (CT-SYNTAX≥23) had higher plasma PAG (2.04 vs. 3.8 μM and 2.85 vs. 4.49 μM, respectively; p < 0.01 for all). After adjustment for confounding factors, plasma PAG remained associated with PAV (β: 0.98, p < 0.01), and patients in the higher PAG group had higher risks of obstructive CAD (odds ratio [OR]: 1.88, p < 0.01) and high coronary lesion complexity (OR: 1.47; p < 0.01). In addition, a high plasma PAG level (≥3.25 μM) was not an independent predictor of the presence of high-risk plaques. CONCLUSIONS:There was an independent association between plasma PAG levels and the coronary atherosclerotic burden among patients with suspected CAD. 10.1016/j.atherosclerosis.2021.08.029
    Gut Microbiota and Cardiovascular Disease. Witkowski Marco,Weeks Taylor L,Hazen Stanley L Circulation research Fecal microbial community changes are associated with numerous disease states, including cardiovascular disease (CVD). However, such data are merely associative. A causal contribution for gut microbiota in CVD has been further supported by a multitude of more direct experimental evidence. Indeed, gut microbiota transplantation studies, specific gut microbiota-dependent pathways, and downstream metabolites have all been shown to influence host metabolism and CVD, sometimes through specific identified host receptors. Multiple metaorganismal pathways (involving both microbe and host) both impact CVD in animal models and show striking clinical associations in human studies. For example, trimethylamine N-oxide and, more recently, phenylacetylglutamine are gut microbiota-dependent metabolites whose blood levels are associated with incident CVD risks in large-scale clinical studies. Importantly, a causal link to CVD for these and other specific gut microbial metabolites/pathways has been shown through numerous mechanistic animal model studies. Phenylacetylglutamine, for example, was recently shown to promote adverse cardiovascular phenotypes in the host via interaction with multiple ARs (adrenergic receptors)-a class of key receptors that regulate cardiovascular homeostasis. In this review, we summarize recent advances of microbiome research in CVD and related cardiometabolic phenotypes that have helped to move the field forward from associative to causative results. We focus on microbiota and metaorganismal compounds/pathways, with specific attention paid to short-chain fatty acids, secondary bile acids, trimethylamine N-oxide, and phenylacetylglutamine. We also discuss novel therapeutic strategies for directly targeting the gut microbiome to improve cardiovascular outcomes. 10.1161/CIRCRESAHA.120.316242
    The gut microbiota-related metabolite phenylacetylglutamine associates with increased risk of incident coronary artery disease. Ottosson Filip,Brunkwall Louise,Smith Einar,Orho-Melander Marju,Nilsson Peter M,Fernandez Céline,Melander Olle Journal of hypertension OBJECTIVE:The gut microbiota is increasingly being implicated in cardiovascular health. Metabolites produced by bacteria have been suggested to be mediators in the bacterial action on cardiovascular health. We aimed to identify gut microbiota-related plasma metabolites and test whether these metabolites associate with future risk of coronary artery disease (CAD). METHODS:Nontargeted metabolomics was performed using liquid chromatography-mass spectrometry in order to measure 1446 metabolite features in the Malmö Offspring Study (MOS) (N = 776). The gut microbiota was characterized using 16S rRNA sequencing. Gut bacteria-related metabolites were measured in two independent prospective cohorts, the Malmö Diet and Cancer - Cardiovascular Cohort (MDC-CC) (N = 3361) and the Malmö Preventive Project (MPP) (N = 880), in order to investigate the associations between gut bacteria-related metabolites and risk of CAD. RESULTS:In MOS, 33 metabolite features were significantly (P < 4.8e-7) correlated with at least one operational taxonomic unit. Phenylacetylglutamine (PAG) was associated with an increased risk of future CAD, using inverse variance weighted meta-analysis of age and sex-adjusted logistic regression models in MDC-CC and MPP. PAG remained significantly associated with CAD (OR = 1.17, 95% CI = 1.06-1.29, P = 1.9e-3) after adjustments for cardiovascular risk factors. CONCLUSION:The levels of 33 plasma metabolites were correlated with the gut microbiota. Out of these, PAG was associated with an increased risk of future CAD independently of other cardiovascular risk factors. Our results highlight a link between the gut microbiota and CAD risk and should encourage further studies testing if modification of PAG levels inhibits development of CAD. 10.1097/HJH.0000000000002569
    Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia. Andrade Fernando,Cano Ainara,Unceta Suarez María,Arza Arantza,Vinuesa Ana,Ceberio Leticia,López-Oslé Nuria,de Frutos Gorka,López-Oceja Raquel,Aznal Elena,González-Lamuño Domingo,de Las Heras Javier Journal of clinical medicine Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, could be used as a non-invasive biomarker. In this cross-sectional study, a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method was used for urinary PAG quantification in 35 participants with hyperphenylalaninemia (HPA) and 33 age- and sex-matched healthy controls. We have found that (a) PKU patients present higher urine PAG levels than healthy control subjects, and that (b) there is a significant correlation between urine PAG and circulating Phe levels in patients with HPA. In addition, we show a significant strong correlation between Phe levels from venous blood samples and from capillary finger-prick dried blood spot (DBS) samples collected at the same time in patients with HPA. Further research in order to assess the potential role of urine PAG as a non-invasive biomarker in PKU is warranted. 10.3390/jcm10163674
    Intestinal barrier dysfunction as a therapeutic target for cardiovascular disease. Lewis Caitlin V,Taylor W Robert American journal of physiology. Heart and circulatory physiology The gut microbiome and intestinal dysfunction have emerged as potential contributors to the development of cardiovascular disease (CVD). Alterations in gut microbiome are well documented in hypertension, atherosclerosis, and heart failure and have been investigated as a therapeutic target. However, a perhaps underappreciated but related role for intestinal barrier function has become evident. Increased intestinal permeability is observed in patients and mouse models of CVD. This increased intestinal permeability can enhance systemic inflammation, alter gut immune function, and has been demonstrated as predictive of adverse cardiovascular outcomes. The goal of this review is to examine the evidence supporting a role for intestinal barrier function in cardiovascular disease and its prospect as a novel therapeutic target. We outline key studies that have investigated intestinal permeability in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction. We highlight the central mechanisms involved in the breakdown of barrier function and look at emerging evidence for restored barrier function as a contributor to promising treatment strategies such as short chain fatty acid, probiotic, and renin angiotensin system-targeted therapeutics. Recent studies of more selective targeting of the intestinal barrier to improve disease outcomes are also examined. We suggest that although current data supporting a contribution of intestinal permeability to CVD pathogenesis are largely associative, it appears to be a promising avenue for further investigation. Additional studies of the mechanisms of barrier restoration in CVD and testing of intestinal barrier-targeted compounds will be required to confirm their potential as a new class of CVD therapeutic. 10.1152/ajpheart.00612.2020
    Ginkgolide B treatment regulated intestinal flora to improve high-fat diet induced atherosclerosis in ApoE mice. Lv Zhiyang,Shan Xin,Tu Qingbo,Wang Jie,Chen Jing,Yang Yuwei Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Intestinal flora plays a major role in cardiovascular diseases, like atherosclerosis (AS). Ginkgolide B (GB), a natural substance extracted from Ginkgo biloba L., is recently acknowledged as a potential therapeutic drug of AS. However, the underlying mechanism of GB is not fully clear. Thus, we evaluated whether the antiatherosclerotic effect of GB was related to alterations in gut microbial structure and if so, whether specific bacterial taxa contributed to the beneficial effects of GB. We constructed a high fat diet (HFD)-induced ApoE mice model to explore the antiatherosclerotic effects of GB. The effects of GB on lipid metabolism, hypoglycemia, inflammation and gut barrier integrity were also investigated. Then HFD inventories and high throughput sequencing of the V3-V4 region of the bacterial 16S ribosomal RNA gene were used to characterize how GB modulated gut microbiome composition. We found that HFD-induced dyslipidemia, inflammation, increased atherosclerotic plaque and gut barrier dysfunction were reduced by GB treatment. Moreover, GB treatment obviously inhibited the mRNA level and protein expression of FMO3, and then decreased the concentrations of TMA and TMAO, which was related to changes of gut microbiota in HFD-fed mice. Modulation of gut microbiota, specifically the increased abundance of Bacteroides and decreased abundance of Helicobacter, might contribute to the antiatherosclerotic effects of GB. Our findings first support the therapeutic value of GB on gut microbiota manipulation in treating AS, which still need to further study. 10.1016/j.biopha.2020.111100
    Gut microbiota metabolites as integral mediators in cardiovascular diseases (Review). Zhu Ying,Shui Xiaorong,Liang Zheng,Huang Zufeng,Qi Yi,He Yuan,Chen Can,Luo Hui,Lei Wei International journal of molecular medicine Cardiovascular diseases (CVDs), such as atherosclerosis, hypertension, myocardial infarction and diabetic heart disease, are associated with high morbidity and mortality rates worldwide, and may also induce multiple organ failure in their later stages, greatly reducing the long‑term survival of the patients. There are several causes of CVDs, but after nearly a decade of investigation, researchers have found that CVDs are usually accompanied by an imbalance of gut microbiota and a decreased abundance of flora. More importantly, the metabolites produced by intestinal flora, such as trimethylamine and trimethylamine N‑oxide, bile acids, short‑chain fatty acids and aromatic amino acids, exert different effects on the occurrence and development of CVDs, as observed in the relevant pathways in the cells, which may either promote or protect against CVD occurrence. It is known that changes in the intestinal flora following antibiotic administration, diet supplementation with probiotics, or exercise, can interfere with the composition of the intestinal flora and may represent an effective approach to preventing or treating CVDs. The focus of this review was the analysis of gut microbiota metabolites to elucidate their effects on CVDs and to identify the most cost‑effective and beneficial methods for treating CVDs with minimal side effects. 10.3892/ijmm.2020.4674
    Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension. Yan Xuefang,Jin Jiajia,Su Xinhuan,Yin Xianlun,Gao Jing,Wang Xiaowei,Zhang Shucui,Bu Peili,Wang Mansen,Zhang Yun,Wang Zhe,Zhang Qunye Circulation research RATIONALE:High-salt diet is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt-induced hypertension (hSIH). However, the detailed roles of intestinal flora in hSIH pathogenesis have not yet been fully elucidated. OBJECTIVE:To reveal the roles and mechanisms of intestinal flora in hSIH development. METHODS AND RESULTS:The abovementioned issues were investigated using various techniques including 16S rRNA gene sequencing, untargeted metabolomics, selective bacterial culture, and fecal microbiota transplantation. We found that high-salt diet induced hypertension in Wistar rats. The fecal microbiota of healthy rats could dramatically lower blood pressure (BP) of hypertensive rats, whereas the fecal microbiota of hSIH rats had opposite effects. The composition, metabolism, and interrelationship of intestinal flora in hSIH rats were considerably reshaped, including the increased corticosterone level and reduced and arachidonic acid levels, which tightly correlated with BP. The serum corticosterone level was also significantly increased in rats with hSIH. Furthermore, the above abnormalities were confirmed in patients with hypertension. The intestinal could inhibit the production of intestinal-derived corticosterone induced by high-salt diet through its metabolite arachidonic acid. CONCLUSIONS:hSIH could be transferred by fecal microbiota transplantation, indicating the pivotal roles of intestinal flora in hSIH development. High-salt diet reduced the levels of and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation. This study revealed a novel mechanism different from inflammation/immunity by which intestinal flora regulated BP, namely intestinal flora could modulate BP by affecting steroid hormone levels. These findings enriched the understanding of the function of intestinal flora and its effects on hypertension. 10.1161/CIRCRESAHA.119.316394
    Gut microbiome and cardiovascular disease. Zhao Yongzhong,Wang Zeneng Current opinion in cardiology PURPOSE OF REVIEW:This review aims to highlight the association between gut microbiome and cardiovascular disease (CVD) with emphasis on the possible molecular mechanisms by which how gut microbiome contributes to CVD. RECENT FINDINGS:Increasingly, the roles of gut microbiome in cardiovascular health and disease have gained much attention. Most of the investigations focus on how the gut dysbiosis contributes to CVD risk factors and which gut microbial-derived metabolites mediate such effects. SUMMARY:In this review, we discuss the molecular mechanisms of gut microbiome contributing to CVD, which include gut microbes translocalization to aortic artery because of gut barrier defect to initiate inflammation and microbial-derived metabolites inducing inflammation-signaling pathway and renal insufficiency. Specifically, we categorize beneficial and deleterious microbial-derived metabolites in cardiovascular health. We also summarize recent findings in the gut microbiome modulation of drug efficacy in treatment of CVD and the microbiome mechanisms by which how physical exercise ameliorates cardiovascular health. Gut microbiome has become an essential component of cardiovascular research and a crucial consideration factor in cardiovascular health and disease. 10.1097/HCO.0000000000000720
    Interaction between gut microbiome and cardiovascular disease. Peng Jieting,Xiao Xun,Hu Min,Zhang Xiangyu Life sciences Traditional cardiovascular risk factors do not underlie all incidence of cardiovascular disease. In recent years, accumulating evidence has demonstrated that gut microbiota and its metabolites also play a pivotal role in the onset and development of cardiovascular disease, including atherosclerosis, hypertension, heart failure, atrial fibrillation and myocardial fibrosis. Trillions of bacteria indwell the gastrointestinal tract and metabolize nutrients into trimethylamine-N-oxide, short-chain fatty acids and so on. Targeting these microorganisms and relevant metabolic pathways has beneficial effects in cardiovascular disease. This review will summarize the role of gut microbiota and its metabolites, mainly trimethylamine-N-oxide, in the pathogenesis of cardiovascular diseases, and discuss the possible mechanisms that drive cardiovascular diseases and highlight potential therapies in this field. 10.1016/j.lfs.2018.10.063
    Polyphenolic Compounds and Gut Microbiome in Cardiovascular Diseases. McGrail Lindsay,Garelnabi Mahdi Current pharmaceutical biotechnology The onset of Cardiovascular Disease (CVD) is known to be associated with multiple risk factors related to exogenous exposures on predisposed genetic makeup. Diet and lifestyle have a cascade effect on microbiota biodiversity, thus impacting inflammation and heart health. Atherosclerosis is a type of CVD where chronic inflammation contributes to plaque buildup in the arteries resulting in narrowed blood vessels, which obstruct blood flow. Polyphenolic compounds, including flavonoids, most commonly consumed in the form of plants, have been identified to have various mechanisms of action to reduce the inflammatory response in the body. Flavonoids provide a variety of nutraceutical functions including antioxidant, antimicrobial, anti-inflammatory, antiangiogenic, antitumor, and improved pharmacokinetic properties. Therefore, the medicinal use of polyphenolic compounds as an intervention for the inflammatory response, especially relating to the gut microbiome, may significantly reduce the risk of atherosclerotic plaque development and disease onset. This review addresses the role of polyphenolic compounds and gut microbiome in cardiovascular disease. Research studies conducted in cells and animals were reviewed. These studies clearly illustrate that dietary polyphenolic compounds influence resident gut microbiota thus they are associated with the prevention of atherosclerosis progression. Further research in this field is warranted to identify potential gut microbiome mediated therapeutic approaches for CVD. 10.2174/1389201020666191111150239
    The role of intestinal microbiota in cardiovascular disease. Jin Mengchao,Qian Zhiyuan,Yin Jiayu,Xu Weiting,Zhou Xiang Journal of cellular and molecular medicine Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N-oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora. 10.1111/jcmm.14195
    Understanding connections and roles of gut microbiome in cardiovascular diseases. Rajendiran Ethendhar,Ramadass Balamurugan,Ramprasath Vanu Canadian journal of microbiology The gut microbiome encompasses trillions of residing microbes, mainly bacteria, which play a crucial role in maintaining the physiological and metabolic health of the host. The gut microbiome has been associated with several diseases, including cardiovascular disease (CVD). A growing body of evidence suggests that an altered gut environment and gut-microbiome-derived metabolites are associated with CVD events. The gut microbiome communicates with host physiology through different mechanisms, including trimethylamine -oxide generation, primary and secondary bile acid metabolism pathways, and short-chain fatty acids production. The main focus of this review is to understand the association of the gut microbiome with CVD and its implications on the interactions between the gut microbiome and the host. Manipulation of the gut microbiome through specific dietary intervention is a simple approach to identifying novel targets for therapy or better dietary recommendations, and new preventive measures for screening biomarkers to reduce CVD risk in humans. 10.1139/cjm-2020-0043