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It has been suggested that trimethylamine oxide (TMAO), a liver oxygenation product of gut bacteria-produced trimethylamine (TMA), is a marker of cardiovascular risk. However, mechanisms of the increase and biological effects of TMAO are obscure. Furthermore, the potential role of TMAO precursor, that is TMA, has not been investigated. We evaluated the effect of age, a cardiovascular risk factor, on plasma levels of TMA and TMAO, gut bacteria composition, gut-to-blood penetration of TMA, histological and hemodynamic parameters in 3-month-old and 18-month-old, male, Sprague-Dawley and Wistar-Kyoto rats. Cytotoxicity of TMA and TMAO was studied in human vascular smooth muscle cells. Older rats showed significantly different gut bacteria composition, a significantly higher gut-to-blood TMA penetration, and morphological and hemodynamic alterations in intestines. In vitro, TMA at concentration of 500 µmol/L (2-fold higher than in portal blood) decreased human vascular smooth muscle cells viability. In contrast, TMAO at 1,000-fold higher concentration than physiological one had no effect on human vascular smooth muscle cells viability. In conclusion, older rats show higher plasma level of TMA due to a "leaky gut". TMA but not TMAO affects human vascular smooth muscle cells viability. We propose that TMA but not TMAO may be a marker and mediator of cardiovascular risk., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Trimethylamine-N-oxide (TMAO) has been suggested as a marker and mediator of cardiovascular diseases. However, data are contradictory, and the mechanisms are obscure. Strikingly, the role of the TMAO precursor trimethylamine (TMA) has not drawn attention in cardiovascular studies even though toxic effects of TMA were proposed several decades ago. We assessed plasma TMA and TMAO levels in healthy humans (HH) and cardiovascular patients qualified for aortic valve replacement (CP). The cytotoxicity of TMA and TMAO in rat cardiomyocytes was evaluated using an MTT test. The effects of TMA and TMAO on albumin and lactate dehydrogenase (LDH) were assessed using fluorescence correlation spectroscopy. In comparison to HH, CP had a two-fold higher plasma TMA ( p < 0.001) and a trend towards higher plasma TMAO ( p = 0.07). In CP plasma, TMA was inversely correlated with an estimated glomerular filtration rate (eGFR, p = 0.002). TMA but not TMAO reduced cardiomyocytes viability. Incubation with TMA but not TMAO resulted in the degradation of the protein structure of LDH and albumin. In conclusion, CP show increased plasma TMA, which is inversely correlated with eGFR. TMA but not TMAO exerts negative effects on cardiomyocytes, likely due to its disturbing effect on proteins. Therefore, TMA but not TMAO may be a toxin and a marker of cardiovascular risk.

Introduction: Increased plasma level of trimethylamine N-oxide (TMAO), a bacterial metabolite of choline, is associated with an increased cardiovascular risk. Indoxyl sulfate, a bacterial metabolite of tryptophan, is thought to be associated with higher mortality in cardiorenal syndrome. We hypothesized that enalapril, a well-established drug reducing cardiovascular mortality, may affect the plasma level of gut bacteria-derived metabolites and gut bacteria composition., Materials and Methods: 14-16-week-old Wistar rats were maintained either on water (controls) or water solution of enalapril for two weeks (5.3 or 12.6 mg/kg b.w.). Blood plasma and urine were analyzed for the concentration of TMAO and indoxyl sulfate using liquid chromatography coupled with triple-quadrupole mass spectrometry. Gut bacteria composition was analyzed with 16S rRNA gene sequence analysis., Results: Rats treated with enalapril showed a significantly lower plasma TMAO level and a trend towards higher 24 h urine excretion of TMA and TMAO. Plasma indoxyl level was similar between the groups. There was no significant difference between the groups in gut bacteria composition., Conclusions: Enalapril decreases rat plasma TMAO, but does not affect the plasma level of indoxyl sulfate and gut bacteria composition. The enalapril-induced decrease in plasma TMAO level may be of therapeutic and diagnostic importance.

Diet has been considered a general health determinant for many years. Recent research shows a connection between gut microbiota composition that is shaped by our diet and lifestyle diseases. Several studies point to a positive correlation between elevated plasma trimethylamine N-oxide (TMAO), a gut bacteria metabolite, and an increased risk for cardiovascular diseases, diabetes, and cancer. Therefore, it has been suggested that TMAO is a link between the diet, gut microbiota, and illness. Emerging experimental and clinical evidence shows that TMAO may be involved in the etiology of hypertension, atherosclerosis, coronary artery disease, diabetes, and renal failure. On the contrary, a number of studies have shown protective functions of TMAO, such as stabilization of proteins and protection of cells from osmotic and hydrostatic stresses. Finally, it is possible that TMAO is neither a causative nor a protecting factor, but may be merely a marker of disrupted homeostasis. Blood TMAO level depends on numerous factors including diet, gut microbiota composition and activity, permeability of the gut-blood barrier, activity of liver enzymes, and the rate of methylamines excretion. Therefore, the usefulness of TMAO as a specific biomarker in lifestyle diseases seems questionable. Here, we review research showing both physiological and pathophysiological actions of TMAO, as well as limitations of using TMAO as a biomarker., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent studies suggest that blood-borne metabolites of gut microbiota, such as trimethylamine N-oxide (TMAO) are involved in the aetiology of cardiovascular diseases and may serve as markers of cardiovascular risk. To enter the bloodstream the microbiota-derived molecules need to pass the gut-blood barrier (GBB). The GBB plays an important role in maintaining organism homeostasis. It is a complex multi-layer system which determines the absorption of nutrients, water and many other substances. The integrity and permeability of the GBB may be impaired in numerous diseases including gastrointestinal, metabolic and cardiovascular diseases. Here, we propose that the evaluation of the GBB permeability may have a significant diagnostic potential in cardiovascular and metabolic diseases. Second, we suggest that the GBB permeability is a variable that confounds diagnostic value of new gut microbiota-derived biomarkers such as TMAO. Therefore, cardiovascular risk assessment requires the evaluation of both TMAO and the GBB permeability., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Trimethylamine N-oxide (TMAO) is a small organic compound whose concentration in blood increases after ingesting dietary l-carnitine and phosphatidylcholine. Recent clinical studies show a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events defined as death, myocardial infarction, or stroke. Several experimental studies suggest a possible contribution of TMAO to the etiology of cardiovascular diseases by affecting lipid and hormonal homeostasis. On the other hand, TMAO-rich seafood, which is an important source of protein and vitamins in the Mediterranean diet, has been considered beneficial for the circulatory system. Although in humans TMAO is known mainly as a waste product of choline metabolism, a number of studies suggest an involvement of TMAO in important biological functions in numerous organisms, ranging from bacteria to mammals. For example, cells use TMAO to maintain cell volume under conditions of osmotic and hydrostatic pressure stresses. In this article, we reviewed well-established chemical and biological properties of TMAO and dietary sources of TMAO, as well as looked at the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and other diseases, such as kidney failure, diabetes, and cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Accumulating evidence points to a pivotal role of the brain in the regulation of the circulatory system and energy balance. It has also been found that common civilization diseases such as depression, obesity, hypertension, myocardial infarction or heart failure are accompanied by an increase in concentration of inflammatory mediators in the blood, cerebrospinal fluid and various tissues. Recent studies have revealed that inflammatory mediators that are synthesized peripherally or in the brain may affect the nervous regulation of animal body systems. For example, it has been found that non-specific pro-inflammatory stimuli as well as treatment with several cytokines may cause depressive behavior, disturbances in energy balance and alterations in the circulatory system. On the other hand, knockout of genes for pro-inflammatory cytokines or administration of anti-inflammatory mediators may normalize the pathological changes. In the present manuscript we will review studies that imply the common neuroinflammatory pathogenesis of cardiovascular diseases, depression and energy balance disorders.

In the eighties of the twentieth century nitric oxide (NO) was identified as the endothelium-derived relaxing factor. This discovery has triggered an interest in gaseous transmitters and their role in the regulation of the circulatory system. Recently, it has become evident that hydrogen sulfide (H2S) and carbon monoxide are also involved in physiological and pathological processes in the cardiovascular system. Nitrates that have been used for over a century and nebivolol, a third-generation b-blocker with vasodilating properties by increasing bioavailability of NO, provide convincing arguments that the compounds acting via NO pathway will remain an important class of cardiovascular drugs. A rapidly growing number of publications on functions of H2S in the circulatory system suggests that the gaseous transmitter may become a promising target for new treatment strategies in cardiovascular diseases. This review is focused on the role of gaseous transmitters in the regulation of the cardiovascular system and their pharmacotherapeutic potential.

Introduction: Increased plasma trimethylamine oxide (TMAO) is observed in cardiovascular and metabolic diseases, originating from the gut microbiota product, trimethylamine (TMA), via flavin-containing monooxygenases (FMOs)-dependent oxidation. Numerous studies have investigated the association between plasma TMAO and various pathologies, yet limited knowledge exists regarding tissue concentrations of TMAO, TMAO precursors, and interspecies variability. Methods: Chromatography coupled with mass spectrometry was employed to evaluate tissue concentrations of TMAO and its precursors in adult male mice, rats, and guinea pigs. FMO mRNA and protein levels were assessed through PCR and Western blot, respectively. Results: Plasma TMAO levels were similar among the studied species. However, significant differences in tissue concentrations of TMAO were observed between mice, rats, and guinea pigs. The rat renal medulla exhibited the highest TMAO concentration, while the lowest was found in the mouse liver. Mice demonstrated significantly higher plasma TMA concentrations compared to rats and guinea pigs, with the highest TMA concentration found in the mouse renal medulla and the lowest in the rat lungs. FMO5 exhibited the highest expression in mouse liver, while FMO3 was highly expressed in rats. Guinea pigs displayed low expression of FMOs in this tissue. Conclusion: Despite similar plasma TMAO levels, mice, rats, and guinea pigs exhibited significant differences in tissue concentrations of TMA, TMAO, and FMO expression. These interspecies variations should be considered in the design and interpretation of experimental studies. Furthermore, these findings may suggest a diverse importance of the TMAO pathway in the physiology of the evaluated species. [ABSTRACT FROM AUTHOR]

Purpose: Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Damage to the endothelium is the earliest event in atherothrombosis, including AMI. Nitric oxide (NO), an endothelium-derived compound, protects the vasculature from damage. This study evaluated whether an association exists between plasma concentration of endogenous NO-related pathway metabolites linked to AMI and major adverse cardiovascular events (MACE) after AMI. Methods: We compared plasma concentrations of NO-related pathway metabolites in patients after AMI (n=60) and healthy controls (n=27) and investigated the prognostic value of these metabolites for post-AMI MACE development over a median of 3.5-years. In search of biomarkers, we compared plasma concentrations of dimethylarginines (ADMA, SDMA), citrulline, arginine and ornithine using ultra performance liquid chromatograph coupled with a mass spectrometer. Results: Patients after AMI had higher concentrations of dimethylarginines, compared to controls (p=0.0068, p< 0.0001, respectively). Conversely, the concentration of citrulline was lower in the AMI group (p=0.0006). The concentration of SDMA was higher in patients who developed MACE than in those who did not (p=0.015). SDMA was the only independent predictor of MACE in multivariate analysis (p=0.023). There was an intermediate, negative correlation between plasma SDMA level and platelet reactivity (r=− 0.33, p=0.02). Conclusion: Plasma concentration of dimethylarginines differs between patients with AMI and healthy volunteers. The study's novel finding is that SDMA is an independent predictor of MACE during a 3.5 year follow-up period after AMI. [ABSTRACT FROM AUTHOR]

Recent research demonstrates a reciprocal relationship between gut microbiota-derived metabolites and the host in controlling the energy homeostasis in mammals. On the one hand, to thrive, gut bacteria exploit nutrients digested by the host. On the other hand, the host utilizes numerous products of gut bacteria metabolism as a substrate for ATP production in the colon. Finally, bacterial metabolites seep from the gut into the bloodstream and interfere with the host's cellular bioenergetics machinery. Notably, there is an association between alterations in microbiota composition and the development of metabolic diseases and their cardiovascular complications. Some metabolites, like short-chain fatty acids and trimethylamine, are considered markers of cardiometabolic health. Others, like hydrogen sulfide and nitrite, demonstrate antihypertensive properties. Scientific databases were searched for pre-clinical and clinical studies to summarize current knowledge on the role of gut microbiota metabolites in the regulation of mammalian bioenergetics and discuss their potential involvement in the development of cardiometabolic disorders. Overall, the available data demonstrates that gut bacteria products affect physiological and pathological processes controlling energy and vascular homeostasis. Thus, the modulation of microbiota-derived metabolites may represent a new approach for treating obesity, hypertension and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that gut bacteria play a role in homeostasis of the circulatory system in mammals. First, gut bacteria may affect the nervous control of the circulatory system via the sensory fibres of the enteric nervous system. Second, gut bacteria-derived metabolites may cross the gut-blood barrier and target blood vessels, the heart and other organs involved in the regulation of the circulatory system. A number of studies have shown that hydrogen sulfide (H2S) is an important biological mediator in the circulatory system. Thus far, research has focused on the effects of H2S enzymatically produced by cardiovascular tissues. However, some recent evidence indicates that H2S released in the colon may also contribute to the control of arterial blood pressure. Incidentally, sulfate-reducing bacteria are ubiquitous in mammalian colon, and H2S is just one among a number of molecules produced by the gut flora. Other gut bacteria-derived compounds that may affect the circulatory system include methane, nitric oxide, carbon monoxide, trimethylamine or indole. In this paper, we review studies that imply a role of gut microbiota and their metabolites, such as H2S, in circulatory system homeostasis. [ABSTRACT FROM AUTHOR]

Accumulating evidence points to a pivotal role of the brain in the regulation of the circulatory system and energy balance. It has also been found that common civilization diseases such as depression, obesity, hypertension, myocardial infarction or heart failure are accompanied by an increase in concentration of inflammatory mediators in the blood, cerebrospinal fluid and various tissues. Recent studies have revealed that inflammatory mediators that are synthesized peripherally or in the brain may affect the nervous regulation of animal body systems. For example, it has been found that non-specific pro-inflammatory stimuli as well as treatment with several cytokines may cause depressive behavior, disturbances in energy balance and alterations in the circulatory system. On the other hand, knockout of genes for pro-inflammatory cytokines or administration of anti-inflammatory mediators may normalize the pathological changes. In the present manuscript we will review studies that imply the common neuroinflammatory pathogenesis of cardiovascular diseases, depression and energy balance disorders. [ABSTRACT FROM AUTHOR]