Trimethylamine N-oxide In Patients Research Articles

#1801 Gut dysbiosis contributes to TMAO accumulation in CKD

Abstract Background and Aims Chronic kidney disease (CKD) patients face a substantial morbidity risk, especially related to cardiovascular complications. The imbalance of circulating metabolites influences inter-organ crosstalk and disease pathophysiology. In this regard, metabolites of microbial origin have gained increasing attention. Trimethylamine N-oxide (TMAO) originates from microbial Trimethylamine (TMA) metabolism and is found at high concentrations in the blood of CKD patients. A high TMAO concentration is known to be an independent risk factor for cardiovascular disease. This study aims to investigate the extent to which high concentrations of TMAO in the blood are due to increased bacterial production or are mainly a consequence of impaired renal clearance. Methods We used existing biomaterials and clinical data of a pediatric CKD cohort, consisting of patients enrolled at CKD stage G3-5, including G5 patients treated with hemodialysis (HD), as well as patients after kidney transplantation (KT) and individuals with normal kidney function. We analyzed TMAO in plasma and urine samples using LC-MS/MS and developed a novel gene targeting assay (GTA) that quantifies the abundance of the bacterial target genes (CutC, CntA) encoding for the key enzymes of microbial TMA synthesis in each fecal sample. Results Plasma TMAO levels were stage-dependently elevated in CKD, with HD patients showing the highest levels (75 ± 46 µmol/l). While urinary TMAO levels were lower in the CKD groups, TMAO/creatinine ratios and fractional excretion were not significantly different in CKD compared to controls. Fecal microbial gene abundance of both CutC and CntA genes was elevated across CKD stages and correlated with both plasma TMAO levels and eGFR. Although KT patients exhibited an eGFR range comparable to controls, they still showed higher plasma TMAO levels and elevated TMAO-associated gene abundances. In a regression analysis, this gene abundance was associated with plasma TMAO independent of eGFR in a model adjusted for age, sex, and BMI. Using a likelihood ratio test, we showed that adding fecal microbial gene abundance to the model provided a significantly better fit compared to only eGFR, age, sex, and BMI. Conclusion Our data indicate that the production of TMA by intestinal bacteria contributes significantly to the accumulation of TMAO in patients with CKD and after kidney transplantation. This finding opens the possibility for new potential interventions in the management of patients with CKD.

Enhanced chronic inflammation and increased branched chain amino acids in adrenal disorders: a cross-sectional study.

Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality. We aimed to determine the impact of adrenal disorders on the inflammation marker GlycA, total branched-chain amino acids (BCAA), ketone bodies and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine. We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFA), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGL), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n=802). Referent subjects included participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) study (n=5241). GlycA, BCAA, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus and statin therapy. In age-and sex-adjusted comparison to referent subjects, increased GlycA was noted in all patient categories, increased BCAA in NFA, MACS, CS, PA and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of subjects with diabetes and cardiovascular disease. Patients with functioning and non-functioning adrenal masses demonstrated increased GlycA and BCAA, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.

Trimethylamine N-oxide predicts cardiovascular events in coronary artery disease patients with diabetes mellitus: a prospective cohort study.

Gut microbiota has significant impact on the cardio-metabolism and inflammation, and is implicated in the pathogenesis and progression of atherosclerosis. However, the long-term prospective association between trimethylamine N-oxide (TMAO) level and major adverse clinical events (MACEs) in patients with coronary artery disease (CAD) with or without diabetes mellitus (DM) habitus remains to be investigated. This prospective, single-center cohort study enrolled 2090 hospitalized CAD patients confirmed by angiography at Beijing Hospital from 2017-2020. TMAO levels were performed using liquid chromatography-tandem mass spectrometry. The composite outcome of MACEs was identified by clinic visits or interviews annually. Multivariate Cox regression analysis, Kaplan-Meier analysis, and restricted cubic splines were mainly used to explore the relationship between TMAO levels and MACEs based on diabetes mellitus (DM) habitus. During the median follow-up period of 54 (41, 68) months, 266 (12.7%) developed MACEs. Higher TMAO levels, using the tertile cut-off value of 318.28 ng/mL, were significantly found to be positive dose-independent for developing MACEs, especially in patients with DM (HR 1.744, 95%CI 1.084-2.808, p = 0.022). Higher levels of TMAO are significantly associated with long-term MACEs among CAD patients with DM. The combination of TMAO in patients with CAD and DM is beneficial for risk stratification and prognosis.

The gut microbe-derived metabolite trimethylamine N-oxide in patients with systemic lupus erythematosus

Background/Aim: Both human and animal studies suggest that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) is strongly associated with several autoimmune diseases including systemic lupus erythematosus (SLE) and correlates to disease severity. The study aimed to investigate the diagnostic and prognostic validity of TMAO as a potential biomarker in patients with SLE, particularly focusing on lupus nephritis patients and its relation to disease activity. Methods: A total of 90 patients were included and assigned into either: group I (SLE without nephritis (NN)), group II (lupus nephritis (LN)) and group III (healthy controls). Serum TMAO levels were compared between the study groups and correlated to the clinical, laboratory and histopathological criteria. Results: Unpredictably, TMAO levels were significantly higher in healthy controls compared to the total SLE population (p = 0.003), to LN and NN groups individually (p = 0.01). TMAO levels did not significantly vary be-tween (NN) and (LN) patients and only correlated to anti-dsDNA titres (p = 0.02) and red blood cells count (p = 0.02) among LN patients. Conclusion: Contrary to previous studies, TMAO levels were found to be higher in healthy controls. A possible confounding effect of the dietary pat-tern and ingested drugs on the gut microbiome limits the utility of TMAO as a potential marker in different diseases.

The Gut Microbial Metabolite Trimethylamine N-Oxide is Linked to Specific Complications of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare immune-mediated connective tissue disease characterized by fibrosis of the skin and internal organs, whose pathogenesis is not fully understood. Recent studies have revealed dysbiosis in patients with systemic sclerosis and have indicated the possible role of the microbiota and its metabolites in the pathogenesis of the disease. Trimethylamine N-oxide (TMAO) is a compound produced by dysbiotic microbiota observed at higher concentrations in several autoimmune diseases. To determine concentrations of the bacteria-derived metabolite TMAO in patients with systemic sclerosis and to assess possible correlation between TMAO and a specific manifestation of the disease. The study included 63 patients with SSc and 47 matched control subjects. The concentration of TMAO was measured with high-performance liquid chromatography. Plasma TMAO level was significantly increased in patients with SSc (283.0 [188.5-367.5] ng/mL versus 205.5 [101.0-318.0] ng/mL; p < 0.01). An increased concentration of TMAO was observed in patients with concomitant interstitial lung disease (ILD) (302.0 ng/mL [212.0-385.5] ng/mL versus 204.0 [135.5-292.0] ng/mL; p < 0.01) and esophageal dysmotility (289.75 [213.75-387.5] ng/mL versus 209.5 ng/mL [141.5-315.0] ng/mL; p < 0.05) compared to patients without these complications. Furthermore, TMAO concentration exhibited significant correlation with markers of heart involvement (left ventricle ejection fraction, NT-proBNP), marker of ILD severity and Scleroderma Clinical Trials Consortium Damage Index. The concentration of TMAO, gut microbiota-associated metabolite, is increased in systemic sclerosis, particularly in patients with advanced organ involvement. This is the first study evaluating plasma TMAO in systemic sclerosis. Bacterial metabolites may be a link between dysbiosis and organ involvement in the course of the disease. Modulation of gut bacterial-derived metabolites may represent a new therapeutic approach in the management of systemic sclerosis.

Prognostic value of gut microbiota-derived trimethylamine N-oxide in patients with ischemic stroke: A meta-analysis

Objective: This study aimed to evaluate the relationship between the intestinal microbial metabolite trimethylamine N-oxide (TMAO) level in the plasma and the outcomes of patients with ischemic stroke (IS). Methods: The PubMed, Web of Science, Cochrane Library, and Embase databases were systematically searched until July 1, 2022 to identify clinical studies on TMAO levels and prognosis of IS. The identified studies were then screened according to the inclusion and exclusion criteria, and a meta-analysis on the final included studies was performed using the Stata (version 17.0) software to investigate the effects of TMAO level on the prognosis of IS. Results: Four studies involving 1,026 participants from 2019 to 2022 were considered. The results indicated an association between high circulating TMAO concentration and poor functional outcomes (rate ratio [RR]: 2.76; 95% confidence interval [CI]:1.33,5.72; P = 0.006; I2 = 72.7%; P-heterogeneity = 0.012; random-effects model), mortality (RR: 5.37; 95%CI: 2.63,10.97; P &lt; 0.001; I2 = 0.0%; P-heterogeneity = 0.704; fixed-effects model), and recursive ischemic events (RR: 2.71; 95%CI: 1.68,4.36; P &lt; 0.001; I2 = 0.0%; P heterogeneity = 0.779; fixed-effects model) 3 months after IS. Conclusions: Elevated TMAO level may be an adverse prognostic indicator in patients with IS.

Trimethylamine N-oxide (TMAO) in patients with subarachnoid hemorrhage: a prospective observational study

BackgroundIt is suspected that microbiome-derived trimethylamine N-oxide (TMAO) may enhance platelet responsiveness and accordingly be thrombophilic. The purpose of this prospective observational study is to evaluate TMAO in patients with subarachnoid hemorrhage (SAH) and compare it with a control group. A secondary aim was to investigate TMAO in the cerebrospinal fluid (CSF) from SAH patients. This should provide a better understanding of the role of TMAO in the pathogenesis of SAH and its thrombotic complications.MethodsThe study included patients with diagnosed spontaneous SAH recruited after initial treatment on admission and patients with nerve, nerve root, or plexus disorders serving as controls. Blood samples were gathered from all patients at recruitment. Additionally, sampling of SAH patients in the intensive care unit continued daily for 14 days. The CSF was collected out of existing external ventricular drains whenever possible.ResultsThirty-four patients diagnosed with SAH, and 108 control patients participated in this study. Plasma TMAO levels at baseline were significantly lower in the SAH group (1.7 μmol/L) compared to the control group (2.9 μmol/L). TMAO was detectable in the CSF (0.4 μmol/L) and significantly lower than in plasma samples of the SAH group at baseline. Plasma and CSF TMAO levels correlated positively. The TMAO levels did not differ significantly during the observation period of 15 days.ConclusionsAlthough we assumed that patients with higher TMAO levels were at higher risk for SAH a priori, plasma TMAO levels were lower in patients with SAH compared with control subjects with nerve, nerve root, or plexus disorders on admission to the hospital. A characteristic pattern of plasma TMAO levels in patients with SAH was not found.

Trimethylamine N-Oxide Levels in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Non-alcoholic fatty liver disease (NAFLD) represents an entity with an increasing prevalence which is characterized by significant hepatic and extrahepatic complications. Its pathophysiology is multifactorial, with gut dysbiosis being considered a major determinant. In this systematic review and meta-analysis, we tried to evaluate the association between the major gut microbial metabolite trimethylamine N-oxide (TMAO) and NAFLD. We performed a literature search for studies that determined circulating TMAO in patients with and without NAFLD. The database search identified 136 studies, and upon application of the exclusion criteria, 7 studies with 7583 individuals (NAFLD 2923, control 4660) were ultimately included in the meta-analysis. Compared to the control group, NAFLD patients had significantly higher circulating TMAO (SMD: 0.66, 95% CI -0.12 to 1.21, p = 0.02, I2: 94%). The results remained unaffected after the exclusion of one influential study. The subgroup analysis revealed significantly higher TMAO in individuals with histologically proven NAFLD and in studies measuring TMAO with high-performance liquid chromatography. No differences were observed according to the study design or study region. However, funnel plot asymmetry was observed, indicating publication bias. In conclusion, patients with NAFLD had increased levels of TMAO, a hazardous gut microbial metabolite, suggesting its important role in the gut-liver interaction.

TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review.

The gut microbiota and its metabolites have become a hotspot of recent research. Trimethylamine N-oxide (TMAO) metabolized by the gut microbiota is closely related to many diseases such as cardiovascular disease, chronic kidney disease, type 2 diabetes, etc. Chronic kidney disease (CKD) is an important contributor to morbidity and mortality from non-communicable diseases. Recently, increasing focus has been put on the role of TMAO in the development and progress of chronic kidney disease. The level of TMAO in patients with chronic kidney disease is significantly increased, and a high level of TMAO deteriorates chronic kidney disease. This article describes the relationship between TMAO and chronic kidney disease and the research progress of drugs targeted TMAO, providing a reference for the development of anti-chronic kidney disease drugs targeted TMAO.

Berberine treats atherosclerosis via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway in gut microbiota

Trimethylamine-N-oxide (TMAO) derived from the gut microbiota is an atherogenic metabolite. This study investigates whether or not berberine (BBR) could reduce TMAO production in the gut microbiota and treat atherosclerosis. Effects of BBR on TMAO production in the gut microbiota, as well as on plaque development in atherosclerosis were investigated in the culture of animal intestinal bacterial, HFD-fed animals and atherosclerotic patients, respectively. We found that oral BBR in animals lowers TMAO biosynthesis in intestine through interacting with the enzyme/co-enzyme of choline-trimethylamine lyase (CutC) and flavin-containing monooxygenase (FMO) in the gut microbiota. This action was performed by BBR’s metabolite dihydroberberine (a reductive BBR by nitroreductase in the gut microbiota), via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway. Oral BBR decreased TMAO production in animal intestine, lowered blood TMAO and interrupted plaque formation in blood vessels in the HFD-fed hamsters. Moreover, 21 patients with atherosclerosis exhibited the average decrease of plaque score by 3.2% after oral BBR (0.5 g, bid) for 4 months (*P < 0.05, n = 21); whereas the plaque score in patients treated with rosuvastatin plus aspirin, or clopidogrel sulfate or ticagrelor (4 months, n = 12) increased by 1.9%. TMA and TMAO in patients decreased by 38 and 29% in faeces (*P < 0.05; *P < 0.05), and 37 and 35% in plasma (***P < 0.001; *P < 0.05), after 4 months on BBR. BBR might treat atherosclerotic plaque at least partially through decreasing TMAO in a mode of action similar to that of vitamins.

Relation of Statin Use to Gut Microbial Trimethylamine N-Oxide and Cardiovascular Risk

Accumulating evidence suggests that statins can influence the microbiota. We investigated the effects of statin therapy on circulating levels of atherogenic gut microbial metabolite, trimethylamine N-oxide (TMAO), and subsequent clinical outcomes. We examined the effects of statin use on plasma TMAO in patients who are statin-naive with dyslipidemia previously enrolled in 2 intervention studies, International Medical Innovations (n=79) and Advances in Atorvastatin Research Group (n=27) in a post hoc analysis. A propensity score matching model stratified by statin use was used to validate the associations between statin use, plasma TMAO, and major adverse cardiovascular events across 4,007 patients who underwent elective coronary angiography. In the International Medical Innovations cohort, at 4weeks, statin use was associated with decreased plasma TMAO (p=0.03) and a return to baseline after statin discontinuation. In both intervention cohorts, patients with higher baseline TMAO (predefined cutoff 6.18μM) showed significant reductions in TMAO (all p &lt;0.05). Propensity score matching on statin use (1,196 patient-pairs) revealed lower plasma TMAO (p=0.002) with statin use. An adjusted cox regression model including statin use, TMAO, and cholesterol showed preserved association of statin use and TMAO but not cholesterol with major adverse cardiovascular events (p=0.005, p &lt;0.001, p=0.24, respectively). A likelihood ratio test showed improved model fit (p &lt;0.001) with the addition of TMAO. In conclusion, our findings demonstrate that statin therapy significantly decreases plasma TMAO levels, suggesting the potential contribution of a statin-mediated reduction of TMAO production in cardiovascular benefits in addition to improved lipid profile and attenuated inflammation.

Serum Trimethylamine N-oxide and the Diversity of the Intestinal Microbial Flora in Type 2 Diabetes Complicated by Diabetic Kidney Disease.

Trimethylamine N-oxide (TMAO) serves as a metabolite of intestinal bacteria as well as a urotoxin influencing the prognosis of chronic kidney disease (CKD), which has become a research hotspot in the field of kidney disease. This study preliminarily explored the alternations of the microbial flora and serum TMAO in patients with type 2 diabetes mellitus (T2DM) complicated with diabetic kidney disease (DKD). Seventeen T2DM patients at the Affiliated Hospital of Zunyi Medical University between September 2018 and February 2019 were included. Among these patients, 8 patients had T2DM complicated with DKD. Eight healthy volunteers constituted the control group. Fresh stool was collected for Illumina sequencing. Based on the sequencing outcomes, the flora diversity and species differences were analyzed. Serum TMAO, cystatin C, urinary albumin/urine creatinine ratios (ACRs), and routine biochemical outcomes were also compared. The DKD group exhibited a significantly higher TMAO level than the remaining groups. The high-TMAO group had a significantly increased ACR level compared with the low-TMAO group. TMAO positively correlated with the ACR. Compared with the control group, the DKD group exhibited a decreased flora diversity. At the genus level, both the T2DM group and the DKD group showed decreased numbers of Alloprevotella and Megasphaera compared with the control group. The difference in Megasphaera between the DKD group and the control group was significant. The alternation of the intestinal microbial flora may participate in the development of DKD, and TMAO and chronic inflammation might be important factors for DKD development.

Plaque instability in acute coronary syndromes: a possible pathogenic role of gut microbial communities

Abstract Background The imbalance between protective and harmful bacteria in the microbial communities leads to a non-physiological condition, known as “dysbiosis”. In the last decade, several studies have suggested that gut microbiota can contribute to the development and progression of various disease including cardiovascular disease through metabolism-mediated pathways. The production and the release of bacterial metabolites, including Trimethylamine N-oxide (TMAO), can affect host health acting to distant organs. Purpose The aim of the present study was to explore the gut microbiota and the levels of TMAO in patients with stable angina (SA) and acute coronary syndrome (ACS) with or without elevation of the ST segment, respectively STEMI and NSTEMI, and in control subjects. Methods Feces were obtained from ACS (n=31) and SA (n=23) patients and controls (n=24). Genomic DNA was isolated using the QIamp DNA Stool Mini Kit. Samples were subjected to 16S rRNA gene V3–V4 region sequencing by an Illumina MiSeq TM platform. A combination of software packages QIIME and VSEARCH was used to generate a biological observation matrix (BIOM) at different taxonomic levels (from phylum to genus). The BIOM was analysed using the Web-based program MicrobiomeAnalyst. β-diversity between groups was obtained by weighted UniFrac distance metric analysis. Serum TMAO levels were measured with a UPLC-MS/MS mass spectrometry in SA and ACS patients. Results β-diversity analysis showed a different bacterial composition in SA and ACS patients and controls ([PERMANOVA] F-value: 1.9706; R-squared: 0.050567; p-value &amp;lt;0.018) (Figure 1A). In particular, analysis between the three groups revealed a significant enrichment of Streptococcus genus in ACS patients (Kruskas Wallis test; p=0.0085) (Figure 1B). Controls and ACS revealed a similar gut microbial composition ([PERMANOVA] F-value: 0.7591; R-squared: 0.014388; p-value &amp;lt;0.61) (Figure 2A); in contrast, controls and SA showed separate clusters according to relative differences in taxonomic composition ([PERMANOVA] F-value: 3.0498; R-squared: 0.064821 p-value &amp;lt;0.006) (Figure 2B). Finally, β-diversity analysis in SA and ACS revealed different microbial communities in the two groups [PERMANOVA] F-value: 2.5103; R-squared: 0.046051; p-value &amp;lt;0.025) (Figure 2C) that could partially explain the severity progression of cardiovascular disease. Serum TMAO levels were higher in STEMI (n=14) as compared to SA and to NSTEMI (n=16) (respectively p=0.016 and p=0.028) (Figure 3). Conclusion These results, taken together, suggest that gut microbiota and its derived metabolites might play an essential role in the progression of atherosclerosis and in coronary plaque instability. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Linea D1 Università Cattolica del Sacro Cuore

The correlation between plasma trimethylamine N-oxide level and heart failure classification in northern Chinese patients.

Trimethylamine N-oxide (TMAO) has been identified as a new biomarker of cardiovascular disease. Our aim was to evaluate the plasma levels of TMAO in patients with or without heart failure (HF), and to indicate the correlation between plasma TMAO level and HF classification in northern Chinese patients. A total of 112 control participants and 184 HF patients participated in this study. Plasma levels of TMAO and N-terminal probrain natriuretic peptide (NT-proBNP) in all participants were examined and analyzed. The plasma TMAO levels were remarkably higher in HF patients than that in control participants (7.0±0.6 vs. 1.5±0.1 μmol/L; P<0.01). In addition, the plasma TMAO levels of significantly increased from NYHA II to NYHA IV group (3.5±0.9, 6.0±0.8 and 8.1±1.0 μmol/L, respectively). The receiver operating characteristic analysis (ROC) showed that area under the curve (AUC) of TMAO was 0.881 (P<0.01). Furthermore, the AUC value for TMAO was 0.857 (95% CI: 0.674-1.000; P<0.01), 0.845 (95% CI: 0.778-0.911; P<0.01) and 0.914 (95% CI: 0.872-0.956; P<0.01) in NYHA II, NYHA III and NYHA IV groups, respectively. Univariate and multivariate logistic regression analysis indicated that TMAO was an independent risk factor for HF in patients. The level of TMAO was positively correlated with NT-proBNP. However, the diagnostic ability of TMAO was lower than that of NT-proBNP. TMAO was an independent predictor of HF, moreover, the TMAO levels were highly associated with HF classification in northern Chinese patients.

Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease.

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)—produced in the liver by colonic microorganisms—cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)—a gut microbe-dependent metabolite of dietary L-carnitine and choline—is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD.

Trimethylamine N-oxide and cardiovascular outcomes in patients with chronic heart failure after myocardial infarction.

AimAccumulating evidence has demonstrated that intestinal microbiota‐dependent trimethylamine N‐oxide (TMAO) is involved in the pathogenesis of various cardiovascular diseases. The present study was designed to investigate the prognostic value of TMAO in patients with chronic heart failure (CHF) after myocardial infarction (MI).Methods and resultsWe included 1208 CHF patients after MI in a prospective cohort study and determined the association between plasma TMAO and cardiovascular outcomes using Cox regression analysis. Patients with elevated TMAO levels were more likely to be older and have histories of atrial fibrillation and diabetes. Cox regression analysis indicated that TMAO was a significant predictor of major adverse cardiac events (MACE) (hazard ratio = 2.31, 95% confidence interval 1.42–3.59, P < 0.01) following adjustment for conventional risk factors. Integrated discrimination and net reclassification improvements for MACE were markedly improved by addition of TMAO to the model of traditional risk factors. The Kaplan–Meier survival analysis showed that MACE risk increased with the elevation in TMAO levels and this positive correlation became more significant when TMAO levels were higher than the median. TMAO was also found to be an independent predictor of all‐cause mortality (hazard ratio = 2.15, 95% confidence interval 1.37–3.24, P < 0.01) after adjusting for traditional risk factors.ConclusionsOur study suggests that TMAO is a valuable prognostic indicator of MACE in patients with CHF after MI.

Effect of Oat β-Glucan Supplementation on Chronic Kidney Disease: A Feasibility Study

Dietary supplementation with grains containing high β-glucan fiber has been shown to attenuate the progression of chronic kidney disease (CKD) and vascular calcification in animal models. The aim of this study was to investigate the feasibility of consuming an oat β-glucan supplement and to assess its effects on certain uremic toxins and markers of mineral metabolism in patients with CKD. This is a 20-week, nonrandomized, single-center, pretest-posttest study. Twenty-eight subjects with CKD stages 3-4 were enrolled. The mean age was 67.6±8.9years, and the mean estimated glomerular filtration rate was 35±14mL/min/1.73m2. Subjects received a dietary supplement containing 3g of oat β-glucan per day for 12weeks. The 4-week period before the start of the intervention was used as a baseline comparison for each subject. The primary outcome was pre-post supplement changes in plasma levels of two uremic toxins: trimethylamine N-oxide (TMAO) and asymmetric dimethylarginine. Secondary outcomes were pre-post supplement changes in serum calcium, phosphorus, and Klotho levels. Repeated-measures analysis of variance was used to test the differences in outcomes over the three-month-long intervention. Serum levels of TMAO decreased by a median of -17% (interquartile range: -46%, 7%) at the end of the intervention. A nonstatistically significant change was observed for asymmetric dimethylarginine (median -0.6% [-12%, 20%]) and serum Klotho (median -3% [-8%, 7%]). There were no changes in serum levels of calcium and phosphorus. One month after discontinuation of β-glucan therapy, TMAO levels increased by a median of 16% (-12%, 36%) but remained slightly below the pretreatment levels. Eight subjects experienced side effects and discontinued the treatment. A diet supplemented with β-glucan is safe and potentially efficacious in lowering serum concentrations of TMAO in patients with CKD. Larger trials with longer follow-up times are needed to determine whether such reductions translate into clinical benefits.

Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke.

Objective: Accumulating evidence suggests that Trimethylamine-N-oxide (TMAO), a gut microbial metabolite, is implicated in the pathogenesis of many cardiovascular diseases. The aim of the present study was to investigate the serum levels of TMAO in Chinese patients with ischemic stroke.Method: In the present study, 255 consecutive patients with first-ever acute ischemic stroke and 255 age and gender-matched healthy volunteers were included for testing serum TMAO. Stroke severity was determined by the NIH Stroke Scale (NIHSS). The stroke severity was dichotomized as minor (NIHSS ≤ 5) and moderate-to-high clinical severity (NIHSS > 6).Results: The serum levels of TMAO in stroke ranged from 0.5 to 18.3 μM, with a median value of 5.8 (interquartile range (IQR), 3.3–10.0) μM, which was higher than in those controls (3.9; IQR, 2.6–6.1 μM). The median level of TMAO in those patients was significantly lower than in those moderate-to-high stroke patients (4.1 μM [IQR, 2.8–6.2] vs. 9.1 μM [5.1–11.0]; P<0.001). In univariate and multivariable models, the unadjusted risk of moderate-to-high stroke was increased by 31% (odds ratio (OR) = 1.31 [95% confidence interval (CI): 1.21–1.42], P<0.001) and 22% (OR = 1.22; 95% CI = 1.08–1.32; P<0.001), when TMAO was increased each by 1 μM. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value of serum level of TMAO as an indicator for screening of moderate-to-high stroke was estimated to be 6.6 μM, which yielded a sensitivity of 69.3 % and a specificity of 79.0%, with the area under the curve at 0.750 (95% CI, 0.687–0.812).Conclusions: Higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit in Chinese patients.

Gut microbe-generated metabolite trimethylamine N-oxide and the risk of diabetes: A systematic review and dose-response meta-analysis.

Elevated circulating concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) were found in patients with type 2 diabetes mellitus (T2DM). However, whether a high level of TMAO is related to the risk of diabetes has not been studied. We aimed to synthesize the evidence on the relation between TMAO levels and the risk of diabetes mellitus (DM) and to investigate the association further in a dose-response meta-analysis. PubMed, Web of Science, and Scopus databases were searched for studies from inception to June 2018. A total of 12 clinical studies were included in this study, and 15314 enrolled subjects were included. A meta-analysis of two-class variables and continuous variables were used to obtain pooled effects. Dose-response meta-analysis was used to investigate the dose-response relationship between TMAO concentrations and the risk of DM. Meta-regression and subgroup analyses were applied to identify the source of heterogeneity in this study. High levels of circulating TMAO were associated with an increased risk of DM (odds ratio [OR]=1.89) using the two-class meta-analysis. Plasma levels of TMAO in patients with diabetes were higher than in subjects without diabetes (standardized mean difference [SMD]: 0.36) using a meta-analysis of continuous variables. The OR for DM prevalence increased by 54% per 5μmolL-1 increment of plasma TMAO (OR=1.54) according to the dose-response meta-analysis. This is the first systematic review and meta-analysis to demonstrate a positive dose-dependent association between circulating TMAO levels and increased diabetes risk.

Trimethylamine N-oxide and prognosis in acute heart failure

ObjectiveAcute heart failure (AHF) is associated with high mortality and morbidity. Trimethylamine N-oxide (TMAO), a gut-derived metabolite, has reported association with mortality risk in chronic HF but this association in...