Plasma TMAO Research Articles

Akkermansia muciniphila postbiotic administration mitigates choline-induced plasma Trimethylamine-N-Oxide production in mice

BackgroundTrimethylamine-N-Oxide (TMAO) is believed to be linked to increased likelihood of cardiovascular disease. While probiotics have shown limited effectiveness in reducing TMAO levels, the potential of postbiotics remains underexplored. This study aimed to evaluate the impact of Akkermansia muciniphila (A. muciniphila) postbiotic administration on choline-induced TMAO production in mice by modifying the gut microbiota.MethodsFemale C57BL/6J mice were divided into six groups, including a control group, high-choline diet group, live A. muciniphila probiotic group, pasteurized A. muciniphila postbiotic group, sodium butyrate group, and sodium propionate group. Various measurements and analyses were conducted, including TMAO and TMA levels in serum, urine, and cecal contents, as well as the expression of FXR and FMO3 in liver tissues. Additionally, metabolic parameters, body weight, serum lipid profile, hepatic protein expression (FMO3, FXR, CutC, and CutD), and gut microbiota composition were assessed.ResultsAdministration of A. muciniphila postbiotic significantly reduced choline-induced plasma TMAO levels in mice. Furthermore, improvements in serum lipid profiles and liver enzyme levels suggested potential enhancements in lipid metabolism and liver function. The study also observed modulation of specific proteins related to TMAO production and metabolism, including CutC and CutD.ConclusionThe findings highlight the potential of A. muciniphila postbiotics as a dietary strategy for mitigating cardiovascular disease risk by modulating the gut-TMAO axis. Postbiotics, particularly A. muciniphila, offer advantages over probiotics and warrant further investigation for their therapeutic applications in gastrointestinal and metabolic disorders.Graphical

Circulating trimethylamine N-oxide is correlated with high coronary artery atherosclerotic burden in individuals with newly diagnosed coronary heart disease

BackgroundTrimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota and has been reported to be correlated with cardiovascular diseases. Although TMAO is associated with the severity of coronary artery disease in subjects with coronary heart disease (CHD) history. However, the correlation between TMAO and the atherosclerotic burden in newly diagnosed cases of CHD is unknown.MethodsIn this hospital-based study, we enrolled 429 individuals newly diagnosed with CHD undergoing coronary angiography. Plasma TMAO was assessed before coronary angiography. SYNTAX score was computed during coronary angiography to estimate the coronary artery atherosclerotic burden. Both linear and logistic regression analyses were conducted to explore the correlation between plasma TMAO levels and SYNTAX score in newly diagnosed CHD population.ResultsThe TMAO in patients with SYNTAX ≥ 33 and subjects with SYNTAX < 23 were 6.10 (interquartile range [IQR]: 3.53 to 9.15) µmol/L and 4.90 [IQR: 3.25 to 7.68] µmol/L, respectively. Linear regression adjusting for traditional risk factors showed TMAO level was positively correlated with SYNTAX score (β = 0.179; p = 0.006) in CHD population. When TMAO was added to models with traditional risk factors, the predictive value improved significantly, with the receiver operating characteristic curve (AUC) increased from 0.7312 to 0.7502 (p = 0.003). Stratified analysis showed that the correlations did not hold true for subjects who were non-smoker or with histories of diabetes. None of the stratifying factors significantly altered the correlation (all p for interaction < 0.05).ConclusionsWe found a positive linear correlation between plasma TMAO and SYNTAX score among newly diagnosed CHD individuals in Chinese population.

Distinguishing benign and malignant thyroid nodules using plasma trimethylamine N-oxide, carnitine, choline and betaine

PurposeTrimethylamine N-oxide (TMAO), a gut microbiome–derived metabolite, and its precursors (carnitine, choline, betaine) have not been fully examined in relation to thyroid cancer (TC) risk. The aim of this study was to assess the value of TMAO and its precursors in diagnosis of benign and malignant thyroid nodules.MethodsIn this study, high-performance liquid chromatography-tandem mass spectrometry was utilized to measure the levels of plasma TMAO and its precursors (choline, carnitine, and betaine) in 215 TC patients, 63 benign thyroid nodules (BTN) patients and 148 healthy controls (HC). The distribution of levels of TMAO and its precursors among the three groups were compared by the Kruskal–Wallis test. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the sensitivity, specificity, and the predictive accuracy of single and combined biomarkers.ResultsIn comparison to HC, TC showed higher levels of TMAO and lower levels of its precursors (carnitine, choline, and betaine) (all P < 0.001). Plasma choline (P < 0.01) and betaine (P < 0.05) were declined in BTN than HC. The levels of carnitine (P < 0.001) and choline (P < 0.05) were significantly higher in BTN than that in TC group. Plasma TMAO showed lower levels in TC with lymph node metastasis (101.5 (73.1–144.5) ng/ml) than those without lymph node metastasis (131 (84.8–201) ng/ml, P < 0.05). Combinations of these four metabolites achieved good performance in the differential diagnosis, with the area under the ROC curve of 0.703, 0.741, 0.793 when discriminating between TC and BTN, BTN and HC, TC and HC, respectively.ConclusionPlasma TMAO, along with its precursors could serve as new biomarkers for the diagnosis of benign and malignant thyroid nodules.

P29-006-23 Developing and Evaluating the Construct Validity of a Diet Pattern Predictive of Plasma TMAO and Choline

P29-006-23 Developing and Evaluating the Construct Validity of a Diet Pattern Predictive of Plasma TMAO and Choline

Impact of dietary choline on lipid metabolism and atherosclerosis development in apoEKO mice deficient or overexpressing apolipoprotein A-I: Selected Abstract - XVI SITeCS Congress

TMAO, a metabolite of dietary choline, is considered a pro-atherogenic molecule for its ability to interfere with the reverse cholesterol transport, in which apolipoprotein A-I and HDL play a key role. In the present work it was evaluated how TMAO impacts on the development of atherosclerosis in mice with different levels of apoA-I/HDL. Mice deficient in both murine apoA-I and apoE (DKO) and DKO mice overexpressing human apoA-I (DKO/hA-I), characterized by extremely low or high plasma HDL levels respectively, were fed for 16 weeks two standard rodent diets, differing only in their choline content (0.09% or 1.2%). At the end of the dietary treatment, atherosclerosis development was quantified at the aortic sinus, targeted plasma metabolomics was performed, and gene expression was evaluated in liver, duodenum, jejunum and ileum. With both diets, DKO mice developed much larger plaques than DKO/hA-I mice. High-choline diet increased plasma TMAO levels in both genotypes. Interestingly, a worsening of plaque development by high choline diet occurred in DKO/hA-I mice only (0.057±0.048 mm2 vs 0.0988±0.064 mm2, p&lt;0.01). Plasma metabolomics indicated that choline supplementation, only in the presence of HDL, significantly increased the concentration of some ceramide species in addition to several markers of impaired kidney function. High-choline diet increased the hepatic gene expression of Fmo1 and Fmo2 in DKO/hA-I, whereas the expression of Scarb1 was lower in DKO/hA-I compared to DKO mice, regardless of the dietary treatment. Intestinal expression of genes involved in inflammatory response and in lipid metabolism was comparable between genotypes and was not modified by choline supplementation. In conclusion, high choline diet increased plasma TMAO concentration in both genotypes, but affected atherosclerosis development, plasma metabolome and hepatic gene expression only in high HDL mice. Intestinal gene expression was not affected neither by genotype nor by dietary choline content.

Choline and trimethylamine N-oxide impair metabolic activation of and platelet response to clopidogrel through activation of the NOX/ROS/Nrf2/CES1 pathway

BackgroundTrimethylamine N-oxide (TMAO), a gut microbe–generated metabolite, elicits thrombotic events by enhancing platelet reactivity; however, no studies have reported the effects of TMAO on the metabolism of and response to clopidogrel. ObjectivesTo determine whether choline and TMAO could significantly impair metabolic activation of and platelet response to clopidogrel in choline- or TMAO-fed mice and the mechanisms involved. MethodsMale mice were fed with vehicle control (Ctrl), TMAO, choline alone or in combination with 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 for 14 days and then treated with Ctrl or a single oral dose of clopidogrel. Plasma TMAO, protein levels of clopidogrel-metabolizing enzymes in the liver, plasma concentrations of clopidogrel and its metabolites, and adenosine diphosphate–induced platelet aggregation and activation were measured. In addition, HepG2 cells were treated with Ctrl or TMAO alone or in combination with N-acetyl-L-cysteine, ML385, or apocynin, and CES1, reactive oxygen species (ROS), and Nrf2 protein levels were measured, respectively. ResultsTMAO significantly increased Ces1 protein expression and activity and clopidogrel hydrolysis in the liver as well as intracellular ROS and CES1 levels and Nrf2 nucleus translocation in HepG2 cells but decreased the formation of clopidogrel active metabolite and impaired platelet response to clopidogrel. Furthermore, concomitant use of 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 effectively reversed choline- or TMAO-induced impairment of inhibition of platelet aggregation by clopidogrel in mice, respectively. ConclusionsCholine and TMAO impair the metabolic activation of and platelet response to clopidogrel through the activation of the NOX-dependent ROS/Nrf2/CES1 pathway, suggesting novel strategies for overcoming clopidogrel resistance from bench to bedside.

Higher circulating Trimethylamine N-oxide levels are associated with worse severity and prognosis in pulmonary hypertension: a cohort study

BackgroundTrimethylamine N-oxide (TMAO), the gut microbiota-dependent metabolite, is a potential biomarker in several cardiovascular diseases. However, no study has investigated its value in pulmonary hypertension (PH). Therefore, this study aimed to explore the association between plasma TMAO levels and prognosis in patients with PH.MethodsInpatients with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH), PAH associated with congenital heart disease (CHD-PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) at Fuwai Hospital were enrolled after excluding those with relative comorbidities. The endpoint was defined as a composite outcome including death, rehospitalisation due to heart failure, and at least 15% decreased 6-min walk distance from the baseline. Fasting blood samples were collected to measure plasma levels of TMAO and other clinical indicators. The associations between TMAO levels with disease severity and patients’ prognosis were investigated.ResultsIn total, 163 patients with PH were included, with a mean follow-up duration of 1.3 years. After adjusting for confounding factors, elevated TMAO levels were still associated with severe disease conditions. TMAO levels dynamically decreased in stable and improved patients after treatment [ΔTMAO = − 0.2 (− 1.6, 0.7) μmol/L, P = 0.006]. Moreover, high plasma TMAO levels predicted a poor prognosis in the PH cohort (P < 0.001), and the association remained significant after adjusting the confounders, including treatment, risk stratification, and PH subtypes.ConclusionElevated plasma TMAO levels were associated with severe disease conditions and poor prognosis in patients with PH, indicating its potential biomarker role in PH.

Residual Risk of Trimethylamine‐N‐Oxide and Choline for Stroke Recurrence in Patients With Intensive Secondary Therapy

Background Trimethylamine N-oxide (TMAO) contributes to cardiovascular disease through its prothrombotic, proatherothrombotic, and proinflammatory effects. We aimed to evaluate whether residual risk of recurrent stroke of TMAO and its precursor choline remain among patients who received dual-antiplatelet therapy and intensive lipid-lowering therapy and with a low inflammation level (high-sensitivity C-reactive protein <2 mg/L on admission). Methods and Results Patients with ischemic stroke or transient ischemic attack were enrolled from the CNSR-III (Third China National Stroke Registry) in China. Plasma TMAO and choline concentrations at baseline were measured in 9793 participants using liquid chromatography-mass spectrometry. The primary outcome was a new stroke within 1 year. Multivariable-adjusted hazard ratios were calculated using Cox regression models to investigate the associations of TMAO and choline with stroke recurrence. Among all patients, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke (adjusted hazard ratios, 1.28 [95% CI, 1.12-1.45]; and 1.50 [95% CI, 1.32-1.71], respectively). Moreover, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke among patients who received dual-antiplatelet therapy (1.65 [95% CI, 1.28-2.13]; and 1.70 [95% CI, 1.32-2.19], respectively), intensive lipid-lowering therapy (1.49 [95% CI, 1.15-1.94]; and 1.49 [95% CI, 1.15-1.92], respectively), with high-sensitivity C-reactive protein <2 mg/L (1.39 [95% CI, 1.14-1.69]; and 1.88 [95% CI, 1.53-2.30], respectively), and concurrently received dual-antiplatelet therapy, intensive lipid-lowering therapy and with high-sensitivity C-reactive protein <2 mg/L (3.57 [95% CI, 1.73-7.38]; and 2.19 [95% CI, 1.16-4.16], respectively). Conclusions TMAO and choline were risk factors for recurrent stroke independent of dual-antiplatelet therapy, intensive lipid-lowering therapy at discharge, and low inflammation on admission.

Long-term prognostic value of trimethylamine N-oxide in community-based adults and patients with coronary heart disease

Abstract Background Trimethylamine N-oxide (TMAO) is an amine oxide generated by gut microbial metabolism. Emerging evidence suggests pro-atherosclerotic and pro-inflammatory properties of TMAO; however, the clinical utility of circulating TMAO in risk stratification is uncertain. Purpose We prospectively assessed relationships of plasma TMAO with long-term risk of all-cause, cardiovascular (CV) and non-CV mortality in community-dwelling adults and patients with coronary heart disease. Methods By Cox modelling, risk-associations were examined in the Hordaland Health Study (HUSK; 6393 community-based adults) and the Western Norway Coronary Angiography Cohort (WECAC; 4132 patients with suspected chronic coronary syndrome). Results Median follow-up time was 11.0 and 10.3 years in HUSK and WECAC, respectively. Following adjustments for established CV risk factors in HUSK, the HRs (95% CIs) comparing the 4th vs. 1st TMAO-quartile were 1.11 (0.88–1.40), 0.97 (0.65–1.46) and 1.17 (0.88–1.54) for all-cause, CV and non-CV mortality, respectively. Corresponding risk estimates in WECAC were 1.07 (0.86–1.32), 1.16 (0.83–1.62) and 1.02 (0.77–1.34). Similar results were observed in patients with angiographically significant coronary artery disease and patients with reduced left ventricular ejection fraction. Conclusion Plasma TMAO was not predictive of long-term all-cause, CV or non-CV mortality in patients with or without established coronary heart disease. This large-scale study does not support a role of TMAO for patient risk stratification in primary or secondary prevention. Funding Acknowledgement Type of funding sources: None.

TMAO Response to a High-Fat High-Sugar Meal Challenge in Generally Healthy United States Adults

ObjectivesTrimethylamine n-oxide (TMAO) is linked to the gut microbiome's metabolism of choline, carnitine, and betaine and is associated with adverse cardiovascular health. In a secondary analysis, we assessed the plasma TMAO response to a high-fat high-sugar meal challenge devoid of choline, carnitine, or betaine in metabolically healthy male (n = 48) and female (n = 49) participants residing near Davis, California, USA.MethodsThe standardized meal challenge was a 3000-gram shake containing 60% kilocalories from fat (shortening and palm oil), 25% kilocalories from carbohydrate (granulated white sugar), and 15% kilocalories from protein (pasteurized egg white). The shake contained limited amounts of direct TMAO-precursors including 2.9 mg of choline and 0.76 mg of betaine. Blood samples were collected at fasting and 0.5, 3, and 6 hours after consuming the meal challenge. TMAO was measured by liquid chromatography-high resolution mass spectrometry using the MxP Quant 500 kit (Biocrates, Innsbruck, Austria). Differences in TMAO concentration by time were assessed by ANOVA and values are means ± standard deviation.ResultsTMAO response demonstrated a post-prandial rise in concentration that peaked at 3 hours and returned to fasting levels by 6 hours. Mean TMAO levels at fasting, 0.5, 3, and 6 hours were 5.27 ± 3.43 μM, 6.09 ± 6.01 μM, 6.87 ± 8.11 μM, 4.76 ± 4.00 μM, respectively. Significant differences were observed between fasting and 3 hours (P = 0.039), and 3 and 6 hours (P = 0.011).ConclusionsPlasma TMAO concentration was affected by a high-fat high-sugar meal challenge despite providing limited amounts of direct TMAO-precursors. The circadian rhythm of the gut microbiome or the host, or the gut microbiome's utilization of phosphatidylcholine from biological sources may contribute to these results. Understanding the regulation of TMAO and its relationship to meals is critical to identifying its role in the etiology of diabetes and cardiovascular disease.Funding SourcesThis work was funded in part by the USDA-Agricultural Research Service (2032–51,530-025–00D) and the National Institute of Health (RO1HL148110).

Diet, Fecal Microbiome, and Trimethylamine N-Oxide in a Cohort of Metabolically Healthy United States Adults.

TMAO is elevated in individuals with cardiometabolic diseases, but it is unknown whether the metabolite is a biomarker of concern in healthy individuals. We conducted a cross-sectional study in metabolically healthy adults aged 18–66 years with BMI 18–44 kg/m2 and assessed the relationship between TMAO and diet, the fecal microbiome, and cardiometabolic risk factors. TMAO was measured in fasted plasma samples by liquid chromatography mass spectrometry. The fecal microbiome was assessed by 16S ribosomal RNA sequencing and recent food intake was captured by multiple ASA24 dietary recalls. Endothelial function was assessed via EndoPAT. Descriptive statistics were computed by fasting plasma TMAO tertiles and evaluated by ANOVA and Tukey’s post-hoc test. Multiple linear regression was used to assess the relationship between plasma TMAO and dietary food intake and metabolic health parameters. TMAO concentrations were not associated with average intake of animal protein foods, fruits, vegetables, dairy, or grains. TMAO was related to the fecal microbiome and the genera Butyribrio, Roseburia, Coprobaciullus, and Catenibacterium were enriched in individuals in the lowest versus the highest TMAO tertile. TMAO was positively associated with α-diversity and compositional differences were identified between groups. TMAO was not associated with classic cardiovascular risk factors in the healthy cohort. Similarly, endothelial function was not related to fasting TMAO, whereas the inflammatory marker TNF-α was significantly associated. Fasting plasma TMAO may not be a metabolite of concern in generally healthy adults unmedicated for chronic disease. Prospective studies in healthy individuals are necessary.

Coronary atherosclerotic burden and trimethylamine N-oxide in non-ST-segment myocardial infarction patients: SZ-NSTEMI cohort

Abstract Funding Acknowledgements Type of funding sources: None. Background Trimethylamine N-oxide (TMAO) is reported to accelerate atherosclerosis and adverse cardiac outcomes. Relationship between coronary atherosclerotic burden and TMAO has linked in stable coronary artery disease and ST-segment elevation myocardial infarction, but not in non-ST-segment elevation myocardial infarction (NSTEMI). Objective We examined an association of TMAO with coronary atherosclerosis burden in NSTEMI. Methods In this prospective cohort, two groups including NSTEMI (n = 73) and age-sex matched Healthy (n = 35) individuals were enrolled between 2019 and 2020. The number of diseased coronary vessels and clinical risk scores including SYNTAX and GENSINI were used to stratify coronary atherosclerotic burden. Fasting plasma TMAO was measured by isotope dilution high-performance liquid chromatography. Results The median plasma TMAO levels (0.59 mM; [interquartile range [IQR]: 0.43-0.78) versus (0.42 mM; IQR: 0.33-0.64) were significantly higher in NSTEMI group versus Healthy group, respectively (P = 0.006). Among the patients with NSTEMI group, the plasma TMAO levels were significantly higher in the multivessel disease (MVD) versus single vessel disease (P = 0.002), and intermediate-high risk (score³23) versus low risk (score &amp;lt; 23) of SYNTAX (P = 0.003) and GENSINI (P = 0.005). TMAO levels remained independently associated with MVD (odds ratio [OR]: 5.94, P = 0.005), and intermediate-high risk SYNTAX (OR: 3.61, P = 0.013) and GENSINI scores (OR: 4.60, P = 0.008) following traditional risk factors adjustment. Area under receiver operating characteristic curves (AUC) for TMAO also predicted MVD (AUC: 0.73, 95% confidence interval [Cl]: 0.60-0.86, P = 0.002), and intermediate-high SYNTAX score (AUC: 0.70, 95%Cl: 0.58-0.82, P = 0.003) and GENSINI score (AUC: 0.70, 95%Cl: 0.57-0.83, P = 0.005). Conclusions TMAO levels are independently associated with high coronary atherosclerotic burden in NSTEMI. Abstract Figure. Abstract

Fasting Blood Glucose but not TMAO is Associated with In-Stent Restenosis in Patients with Acute Coronary Syndrome

Background: The purpose of our study was to assess whether the occurrence of ISR might be associated with plasma TMAO levels in patients with ACS after DES implantation. Methods: This was a single center retrospective case-control study, in which 64 symptomatic patients with repeated coronary angiography after PCI and 15 patients with ISR were included in the ISR group, and 49 patients without ISR were included in the non-ISR group. High-performance liquid chromatography with tandem mass spectrometry was used to measure plasma TMAO levels. Results: No significant differences were observed in plasma TMAO between the ISR and non-ISR groups. Plasma TMAO levels showed no significant correlation with ISR, but were significantly positively correlated with diabetes mellitus, serum HbA1c levels and serum creatinine levels; moreover, they were significantly negatively correlated with female sex. ISR was significantly positively correlated with diabetes mellitus, fasting blood glucose levels, the neutrophil to lymphocyte ratio and syntax score; in addition, it was significantly negatively correlated with platelets. Logistic regression analysis indicated that fasting blood glucose was the only independent predictor of ISR. Conclusion: Plasma TMAO may not be associated with ISR and plaque burden in patients with ACS after DES implantation, whereas FBG may predict the development of ISR in these patients.

Increased plasma trimethylamine-N-oxide levels are associated with mild cognitive impairment in high cardiovascular risk elderly population

Trimethylamine-N-oxide (TMAO) has been shown to be associated with cardiovascular (CV) disease and cognitive impairment. The association between early stages of cognitive impairment and TMAO in a high CV risk population has not been previously investigated. This study aimed to investigate the association between the plasma TMAO level and cognitive function in a population with a high risk of CV disease. Participants at a high risk of CV were included. The cognition was evaluated using the Montreal Cognitive Assessment. A score lower than 25 out of 30 was used to indicate mild cognitive impairment (MCI). Blood samples of all participants (n = 233) were collected to measure the plasma levels of TMAO and other metabolic parameters, including fasting blood sugar and lipid profiles. Logistic regression was used to evaluate the association between MCI and high plasma TMAO levels, adjusted for confounding factors. Of 233 patients, the mean age of patients in this study was 64 years old (SD 8.4). The median TMAO level was 4.31 μM (IQR 3.95). The high TMAO level was an independent risk factor of MCI (aOR 2.36, 95% CI 1.02 to 5.47; p 0.046), when adjusted for age, gender, health care service scheme, smoking history, metabolic syndrome, and history of established CV events. The high TMAO level was associated with MCI, after adjustment for potential confounding factors. These findings demonstrate that plasma TMAO levels can serve for target prediction as an independent risk factor for MCI in this population.

Fecal Microbiome Composition Does Not Predict Diet-Induced TMAO Production in Healthy Adults.

BackgroundTrimethylamine‐N‐oxide (TMAO) is a small molecule derived from the metabolism of dietary nutrients by gut microbes and contributes to cardiovascular disease. Plasma TMAO increases following consumption of red meat. This metabolic change is thought to be partly because of the expansion of gut microbes able to use nutrients abundant in red meat.Methods and ResultsWe used data from a randomized crossover study to estimate the degree to which TMAO can be estimated from fecal microbial composition. Healthy participants received a series of 3 diets that differed in protein source (red meat, white meat, and non‐meat), and fecal, plasma, and urine samples were collected following 4 weeks of exposure to each diet. TMAO was quantitated in plasma and urine, while shotgun metagenomic sequencing was performed on fecal DNA. While the cai gene cluster was weakly correlated with plasma TMAO (rho=0.17, P=0.0007), elastic net models of TMAO were not improved by abundances of bacterial genes known to contribute to TMAO synthesis. A global analysis of all taxonomic groups, genes, and gene families found no meaningful predictors of TMAO. We postulated that abundances of known genes related to TMAO production do not predict bacterial metabolism, and we measured choline‐ and carnitine‐trimethylamine lyase activity during fecal culture. Trimethylamine lyase genes were only weakly correlated with the activity of the enzymes they encode.ConclusionsFecal microbiome composition does not predict systemic TMAO because, in this case, gene copy number does not predict bacterial metabolic activity.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01427855.

Paradox of trimethylamine-N-oxide, the impact of malnutrition on microbiota-derived metabolites and septic patients

BackgroundTrimethylamine N-oxide (TMAO) is a microbiota-derived metabolite, which is linked to vascular inflammation and atherosclerosis in cardiovascular (CV) diseases. But its effect in infectious diseases remains unclear. We conducted a single-center prospective study to investigate association of TMAO with in-hospital mortality in septic patients admitted to an intensive care unit (ICU).MethodsTotally 95 septic, mechanically ventilated patients were enrolled. Blood samples were obtained within 24 h after ICU admission, and plasma TMAO concentrations were determined. Septic patients were grouped into tertiles according to TMAO concentration. The primary outcome was in-hospital death, which further classified as CV and non-CV death. Besides, we also compared the TMAO concentrations of septic patients with 129 non-septic patients who were admitted for elective coronary angiography (CAG).ResultsSeptic patients had significantly lower plasma TMAO levels than did subjects admitted for CAG (1.0 vs. 3.0 μmol/L, p < 0.001). Septic patients in the lowest TMAO tertile (< 0.4 μmol/L) had poorer nutrition status and were given longer antibiotic courses before ICU admission. Circulating TMAO levels correlated positively with daily energy intake, the albumin and prealbumin concentration. Compared with those in the highest TMAO tertile, septic patients in the lowest TMAO tertile were at greater risk of non-CV death (hazard ratio 2.51, 95% confidence interval 1.21–5.24, p = 0.014). However, TMAO concentration was no longer an independent predictor for non-CV death after adjustment for disease severity and nutritional status.ConclusionPlasma TMAO concentration was inversely associated with non-CV death among extremely ill septic patients, which could be characterized as TMAO paradox. For septic patients, the impact of malnutrition reflected by circulating TMAO levels was greater than its pro-inflammatory nature.

Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults.

BackgroundTrimethylamine N‐oxide (TMAO) is a gut microbiota‐dependent metabolite of dietary choline, L‐carnitine, and phosphatidylcholine‐rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community‐based populations and the potential mediating or modifying role of renal function are not established.Methods and ResultsWe investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community‐based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography–tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time‐varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow‐up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02–1.42; P‐trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR‐adjusted HR, 1.07; 95% CI, 0.90–1.27), as well as modified by eGFR (P‐interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m2: HR, 1.56 [95% CI, 1.13–2.14]; P‐trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m2: HR, 1.03 [95% CI, 0.85–1.25]; P‐trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01–1.56]; P‐trend=0.009), without significant modification by eGFR.ConclusionsIn this large community‐based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

The Association of Plasma Trimethylamine N-Oxide With All-Cause and Cardiovascular Mortality: The Multi-Ethnic Study of Atherosclerosis

Abstract Objectives Trimethylamine N-oxide (TMAO) is a gut-microbiota generated metabolite of dietary phosphatidylcholine, choline, and carnitine. TMAO has been suggested to play a role in the pathogenesis of multiple diseases. Yet, studies of TMAO and mortality were conducted in convenience samples of patients with prevalent diseases and lacked socioeconomic and lifestyle data, raising the likelihood of selection bias and residual confounding. To address these research gaps, we investigated the associations of plasma TMAO levels with all-cause and cardiovascular disease (CVD) mortality in a prospective multi-ethnic community-based cohort. Methods The study included 6776 participants from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline using mass spectrometry. Adjudicated CVD deaths included death due to coronary heart disease, stroke, other atherosclerotic diseases, or other CVDs. Multivariable Cox proportional hazards models assessed associations with adjustment for baseline sociodemographic, lifestyle, diet, and traditional CVD risk factors (BMI, blood pressure, lipids, diabetes, CRP, medications). We also assessed pre-specified interactions by age, sex, race/ethnicity, low vs. high adherence to Alternate Healthy Eating index, and renal function measured by creatinine-based estimated glomerular filtration rate (eGFR). Results During median follow-up of 15.9 years, 1548 participants died, 362 from CVD. Higher TMAO levels were associated with higher risk of both all-cause mortality (HR = 1.09, 95%CI: 1.04 - 1.13, per inter-quintile range increase, 7.5 µM/L) and CVD mortality (HR = 1.10, 95%CI: 1.02 - 1.19). Interaction by renal function was observed for all-cause mortality (P-interaction &amp;lt; 0.005), with a positive association between TMAO and risk in those with impaired renal function (eGFR &amp;lt; 60) [HR = 1.15, 95%CI: 1.09 -1.21], but not normal or mildly reduced renal function (eGFR ≥ 60) [HR = 1.02, 95%CI: 0.95 - 1.08]. No other significant interactions were observed. Conclusions In this multi-ethnic community-based cohort of US adults, higher plasma TMAO levels were associated with a higher risk of all-cause and CVD mortality. The mechanisms of interaction by renal function need to be further studied, especially given that TMAO is renally cleared. Funding Sources NIH

Trimethylaminuria and Vascular Complications

Background: Trimethylaminuria (Fish-Odour Syndrome) is a rare metabolic disorder characterized by an unpleasant odour in body secretions similar to rotting fish. The disorder is most commonly caused from mutations affecting the Flavin containing monooxygenase 3 (FMO3) gene, the vital enzyme for the metabolism of trimethylamine. Although uncommon, it is important to be conscious of this condition, which can be devastating psychosocially even with reliable diagnostic tests. We present here an individual with this syndrome who, in addition to the psychosocial difficulties, presented physical complications that we relate to the disease’s physiopathology. Case: R.M.F., 56 years old, lawyer, self-diagnosed at 25 after identifying himself with a disease description in a local newspaper. He describes fish odour symptoms from infancy and his mother used to demand excessive hygiene habits. He has always suffered from social disturbances. At 44, a physician’s investigation detected FMO3 mutation. The patient is not obese, has never smoked and denies any comorbidity, except erectile dysfunction for 10 years. He presented 4 years ago extensive acute venous thrombosis in the right lower limb femoral veins, lateral and medial gastrocnemius, solar and fibular popliteal veins. Laboratory investigation excluded other causes and negative antibodies. Besides, ENMG confirmed last year peripheral motor sensitive polyneuropathy, axonal pattern, distal both lower extremities. The patient failed treatment with modifications in diet and hygiene, but achieved symptomatic improvement after metronidazole. Genetic analysis showed a new homozygotic variant in the FMO3 gene, with substitution of adenine for cytosine and exchange of Threonine for proline at position 307 of the FMO3 protein with protein dysfunction computably predicted. Comments: Considering the deep venous thrombosis and symmetrical peripheral neuropathy developed by the patient, we searched for a possible association with TMAU but we did not find previous reports. However, Weifei Zhu et al. (Circulation, 135(17), 1671–73,2017) have shown TMAO generated by gut microbes contributing to platelet hyper reactivity and causing a prothrombotic phenotype in vivo. Plasma TMAO levels could predict incident thrombosis risk. Also, direct TMAO exposure enhanced platelet activation from multiple agonists stimulus. Although the “chemical sensor” for TMAO within platelets remains unknown, these findings could increase our understanding of the relationship between TMAO and CVD risk. Although the disorder might not appear to be a significant health problem, its social and psychological burden can be devastating, since the few treatments available provide modest benefits. In addition, it may be associated with other complications, including CVD, to which we would like to draw attention with this report

Trimethylamine N-Oxide, a Gut Microbiota-Dependent Metabolite, is Associated with Frailty in Older Adults with Cardiovascular Disease.

ObjectiveOur study aimed to explore the association between trimethylamine N-oxide and frailty in older adults with cardiovascular disease.Patients and MethodsThis cross-sectional study analyzed a total of 451 people aged 65 years or older who underwent comprehensive geriatric assessments. Frailty status was determined using a frailty index constructed with 48 variables according to the cumulative deficits model. Physical frailty and cognitive frailty were also assessed in detail. Fasting plasma TMAO was measured by mass spectrometry.ResultsThe proportion of frail subjects was 29.9% (135/451). Plasma TMAO levels were significantly higher in frail patients than in nonfrail individuals (4.04 [2.84–7.01] vs 3.21 [2.13–5.03] µM; p<0.001). Elevated plasma TMAO levels were independently associated with the likelihood of frailty (OR 2.12, 95% CI 1.01–4.38, p=0.046). Dose–response analysis revealed a linear association between the TMAO concentration and the OR for frailty. A 2-unit increase in TMAO was independently correlated with physical frailty (OR 1.23, 95% CI 1.08–1.41, p for trend 0.002) and cognitive frailty (OR 1.21, 95% CI 1.01–1.45, p for trend 0.04).ConclusionElevated circulating TMAO levels are independently associated with frailty among older adults with cardiovascular disease.