Higher Trimethylamine N-oxide Levels Research Articles

Prognostic Value of Serum TMAO Measurement in Patients with STEMI: A Systematic Literature Review.

Gut microbiota-derived metabolite Trimethylamine-N-oxide (TMAO) is increasingly recognized as a potential novel prognostic biomarker for cardiovascular disease. Our research work aimed to investigate the potential utility of TMAO measurement in patients with STelevation Myocardial Infarction (STEMI). We performed a systematic literature search in PubMed from inception to the 1st of February 2024 to identify all studies examining the association between plasma TMAO levels and disease complexity or clinical outcomes in STEMI patients. A total of eight prospective cohort studies were included, encompassing a total of 2,378 STEMI patients. Three of the studies provided only in-hospital evidence (i.e., increased odds for more severe coronary artery disease, plaque rupture, and plaque healing in patients with increased TMAO levels). Four studies examined the long-term prognostic value of TMAO after 10-12 months of follow-up post-STEMI (i.e., increased risk of adverse cardiovascular events in patients with increased TMAO levels), while one study provided data for both in-hospital and mid-term prognosis, indicating that 4-months after STEMI patients with greater TMAO elevation had larger infarct size. Higher TMAO levels were associated with a greater prevalence of high-risk coronary plaque characteristics and worse in-hospital and follow-up outcomes in STEMI patients. Further study is needed on whether modulating the diet-dependent TMAO levels could improve clinical outcomes in these patients. [(OSF): https://doi.org/10.17605/OSF.IO/WNG8V].

Plasma trimethylamine-n-oxide associates with reduced hippocampal volume and cognitive impairment in atrial fibrillation

Abstract Background/Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in modern society and affected patients appear particularly vulnerable to cognitive dysfunction. Yet, the pathomechanism of this association other than thromboembolism (TE) is not fully understood. We have shown earlier an association of cognitive dysfunction with the gut microbiome derivate trimethylamine-N-oxide (TMAO), which predominantly results from the consumption of red meat. We therefore hypothesized that TMAO may affect hippocampal volume (HV) as a brain structure relevant for cognition. Purpose To demonstrate the structure-function correlation of high TMAO levels with reduced cognitive function and lower HV in a large cohort of patients with atrial fibrillation. Methods We included 1’736 patients with confirmed AF from the Swiss-AF-cohort with both, available blood samples for TMAO measurement and with brain magnetic resonance imaging (bMRI) for the determination of HV at baseline. TMAO levels were measured by liquid chromatography-mass spectrometry (LC-MS). bMRI were obtained by 1.5 or 3 Tesla scanners. HV was assessed by the FreeSurfer software (v 7.4.0) subregion segmentation module and normalized by using Sequence Adaptive Multimodal SEGmentation (SAMSEG) to determine the segmentation based intracranial volume. Patients were divided into TMAO quartiles (Q1: 0.6-3.8, Q2: 3.8-5.5, Q3: 5.5-8.5, Q4: 8.5-164.3μmol/l). Their TMAO levels were compared with their HV (unit = mm3) in linear mixed effect models adjusted for multiple covariates (model 1: age, sex, total intracranial volume (ICV), education level; model 2 = model 1 + smoking status, body mass index (BMI), alcohol consumption, physical activity; model 3 = model 2 + hypertension, coronary artery disease, previous stroke, geriatric depression scale). We assessed both unilateral HV (right = RHV, left = LHV) and bilateral HV standardized by the individual total ICV. Results Overall mean age was 72.5 years (+/-8.4 SD), 27.2% were female. Most of the patients were well educated (39.4% advanced, 48.8% middle education) and 44% never smoked. After multivariable adjustments, patients in the highest TMAO quartile showed a significant reduction of bilateral HV volume of 93.4mm3 (95% CI -179.0 to -7.8, p = 0.03). The RHV appeared more affected and was significantly reduced by 48.2mm3 (CI -93.4, -3.0, p=0.04), whereas LHV was decreased by 44.2mm3 (-89.4, 1.0, p=0.06) in the highest TMAO quartile. Conclusion(s) TMAO negatively associates with bilateral HV in patients with AF. Our results suggest a structure-function-correlation between high TMAO levels and cognitive dysfunction. The findings may be relevant for the high TMAO-exposed patients and advocates for the importance of (possible dietary) prevention in AF.

Trimethylamine N-oxide promotes PERK-mediated endothelial-mesenchymal transition and apoptosis thereby aggravates atherosclerosis

The endothelial-mesenchymal transition (EndMT) is involved in the development of atherosclerosis (AS) and is a key process in vascular endothelial injury. Oxidative stress, inflammation, and apoptosis are common causes of EndMT, and EndMT progression can further accelerate the development of AS. The metabolite trimethylamine N-oxide (TMAO) is produced by the gut microbiome and is implicated in the development of several diseases, including diabetes and chronic kidney disease. However, the impact of TMAO on transforming growth factor β1(TGF-β1)-induced EndMT remains unclear. We hypothesize that TMAO exacerbates plaque formation and cardiac function impairment by promoting EndMT. Herein, we showed that high serum TMAO levels caused plaque formation, cardiac function damage and haemodynamic changes in ApoE−/− mice. In vitro, TMAO upregulated mesenchymal markers and downregulated endothelial markers in HAECs. Furthermore, TMAO increased the migratory capacity of EndMT cells. Mechanistically, we found that PERK downregulation could alleviate TMAO-induced oxidative stress, EndMT, plaque formation and cardiac function damage. Further study showed that activated transcription factor 3 (ATF3), the downstream molecule of protein kinase RNA-like endoplasmic reticulum kinase (PERK), could bind with TGF-β1/2 and affect EndMT. Overall, TMAO promotes EndMT, possibly through the PERK-eIF2α-ATF4-CHOP or the PERk-eIF2α-ATF3-TGF-β signalling pathways.

Inulin does not affect trimethylamine N-oxide formation in mice with a high-fat diet combined with choline and L-carnitine.

Emerging evidence suggests that gut bacteria-derived trimethylamine N-oxide (TMAO) elevates the risk of cardiovascular disease, and dietary fiber holds the potential to attenuate TMAO formation. However, the effectiveness of dietary fiber, such as inulin, in inhibiting TMAO formation remains controversial. Therefore, this study investigated the effect of inulin supplementation on TMAO formation in mice with high TMAO levels induced by a high-fat diet (HFD) combined with choline and L-carnitine. Results showed that HFD treatment significantly elevated blood TMAO concentrations and increased the abundances of TMAO formation-associated gut bacteria, as well as the abundances of functional genes responsible for TMA formation. While the supplementation of choline and L-carnitine greatly enhanced blood trimethylamine (TMA) and TMAO levels, inulin supplementation did not significantly affect TMAO levels and had limited impact on TMA-associated gut bacteria, except for Desulfitobacterium hafniense.

Potential Trimethylamine (TMA)-Producing Bacteria in patients with chronic kidney disease undergoing hemodialysis.

Trimethylamine (TMA), produced by gut microbiota, is the precursor of trimethylamine-N-oxide (TMAO), a uremic toxin that accumulates in patients with chronic kidney disease (CKD). Elevated TMAO plasma levels are associated with cardiovascular complications and CKD progression. To evaluate the association between gut microbiota composition and TMAO plasma levels in CKD patients undergoing hemodialysis (HD). This is a cross-sectional study with 25 patients evaluated (60% female, 53 (18) years, body mass index (BMI) 25.8 (6.75)Kg/m2). They were divided into two groups according to their TMAO plasma levels: normal (≤ 7.4μM) and high (> 7.4μM). Uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS), and indol acetic acid (IAA) were measured with RP-HPLC, and TMAO plasma levels were quantified using LC-MS/MS. Fecal DNA was extracted with a commercial kit, PCR amplified the V4 region of the 16S rRNA gene, and short-read sequencing was performed on the Illumina platform. Dietary intake, anthropometric measurements, and inflammation markers were also evaluated. Nrf2, NF-κB, IL-1β, and NLRP3 mRNA expressions were measured from peripheral blood mononuclear cells (PBMC) using quantitative real-time polymerase chain reaction (qPCR). There were significant positive correlations between TMAO and plasma levels of pCS, NLPR3 inflammasome mRNA expression, serum phosphorus levels, and negative correlations with dietary lipid intake. The group with TMAO > 7.4μM showed an increase in the microbiome abundance of Saccharibacteria (genus incertae sedis), Colidextribacter, Dorea, and Staphylococci genera, and a decrease in abundance in the genera Lachnospira, Lactobacilli, and Victivallis. TMAO plasma level was positively correlated with the abundance of bacteria of the genera Colidextribacter and Helicobacter and was negatively correlated with Sphingomanos, Lachnospira, Streptomyces, and Bacillus genera. Saccharibacteria (genus incertae sedis), Colidextribacter, Dorea, and Staphylococci genera showed higher abundance in patients with high TMAO levels. In addition, we observed that elevated plasma TMAO levels are associated with inflammation markers, dietary lipid intake, and serum phosphorus levels in patients undergoing HD.

Dynamic Changes in Gut Microbiota-Derived Metabolite Trimethylamine-N-Oxide and Risk of Type 2 Diabetes Mellitus: Potential for Dietary Changes in Diabetes Prevention.

A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.

Effect of three oral pathogens on the TMA-TMAO metabolic pathway.

Trimethylamine-N-oxide (TMAO) is produced by hepatic flavin-containing monooxygenase 3 (FMO3) from trimethylamine (TMA). High TMAO level is a biomarker of cardiovascular diseases and metabolic disorders, and it also affects periodontitis through interactions with the gastrointestinal microbiome. While recent findings indicate that periodontitis may alter systemic TMAO levels, the specific mechanisms linking these changes and particular oral pathogens require further clarification. In this study, we established a C57BL/6J male mouse model by orally administering Porphyromonas gingivalis (P. gingivalis, Pg), Fusobacterium nucleatum (F. nucleatum, Fn), Streptococcus mutans (S. mutans, Sm) and PBS was used as a control. We conducted LC-MS/MS analysis to quantify the concentrations of TMAO and its precursors in the plasma and cecal contents of mice. The diversity and composition of the gut microbiome were analyzed using 16S rRNA sequencing. TMAO-related lipid metabolism and enzymes in the intestines and liver were assessed by qPCR and ELISA methods. We further explored the effect of Pg on FMO3 expression and lipid molecules in HepG2 cells by stimulating the cells with Pg-LPS in vitro. The three oral pathogenic bacteria were orally administered to the mice for 5 weeks. The Pg group showed a marked increase in plasma TMAO, betaine, and creatinine levels, whereas no significant differences were observed in the gut TMAO level among the four groups. Further analysis showed similar diversity and composition in the gut microbiomes of both the Pg and Fn groups, which were different from the Sm and control groups. The profiles of TMA-TMAO pathway-related genera and gut enzymes were not significantly different among all groups. The Pg group showed significantly higher liver FMO3 levels and elevated lipid factors (IL-6, TG, TC, and NEFA) in contrast to the other groups. In vitro experiments confirmed that stimulation of HepG2 cells with Pg-LPS upregulated the expression of FMO3 and increased the lipid factors TC, TG, and IL-6. This study conclusively demonstrates that Pg, compared to Fn and Sm, plays a critical role in elevating plasma TMAO levels and significantly influences the TMA-TMAO pathway, primarily by modulating the expression of hepatic FMO3 and directly impacting hepatic lipid metabolism.

Trimethylamine-N-Oxide and Related Metabolites: Assessing Cardiovascular Risk in the Dallas Heart Study

ObjectiveTo evaluate the association between trimethylamine N-oxide (TMAO) and related metabolites with adverse cardiovascular events in a multiethnic urban primary prevention population. MethodsWe performed a case-control study of 361 participants of the Dallas Heart Study, including 88 participants with an incident atherosclerotic cardiovascular disease (ASCVD) event and 273 controls matched for age, sex, and body mass index without an ASCVD event during 12 years of follow-up (January 1, 2000, through December 31, 2015). Plasma levels of TMAO, choline, carnitine, betaine, and butyrobetaine were measured by mass spectrometry. The differential odds for incident ASCVD by metabolite levels between cases and controls were compared by a conditional logistic regression model adjusted for cardiovascular risk factors. ResultsParticipants with incident ASCVD had higher levels of TMAO and related metabolites compared with those without ASCVD (P<.05 for all). Those with plasma TMAO concentrations in quartile 4 had a more than 2-fold higher odds of ASCVD compared with those in quartile 1 (odds ratio, 2.77 [95% CI, 1.05 to 7.7; P=.04] for hard ASCVD and 2.41 [95% CI, 1.049 to 5.709; P=.04]). Similar trends were seen with the related metabolites choline, betaine, carnitine, and butyrobetaine. ConclusionOur results suggest that TMAO and related metabolites are independently associated with ASCVD events. Although further studies are needed, measurement of TMAO and related metabolites may have a role in ASCVD risk stratification for primary prevention.

Gut microbial metabolite trimethylamine N-oxide induces aortic dissection

Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 μM vs. 1.85, IQR: 1.40 to 3.35 μM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or β-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management.

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 association between the gut microbiota metabolite trimethylamine N-oxide and heart failure.

This systematic review explores the relationship between the gut microbiota metabolite trimethylamine N-oxide (TMAO) and heart failure (HF), given the significant impact of TMAO on cardiovascular health. A systematic search and meta-analysis of peer-reviewed studies published from 2013 to 2024 were conducted, focusing on adult patients with heart failure and healthy controls. The review found that elevated levels of TMAO are associated with atherosclerosis, endothelial dysfunction, and increased cardiovascular disease risk, all of which can exacerbate heart failure. The analysis also highlights that high TMAO levels are linked to reduced left ventricular ejection fraction (LVEF) and glomerular filtration rate (GFR), further supporting TMAO's role as a biomarker in heart failure assessment. The findings suggest that interventions targeting gut microbiota to reduce TMAO could potentially benefit patients with heart failure, although further research is needed to evaluate the effectiveness of such approaches.

The significance of dynamic monitoring plasma TMAO level in pulmonary arterial hypertension - a cohort study.

Gut microbiota assumes an essential role in the development and progression of pulmonary arterial hypertension (PAH). Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite, is correlated with the prognosis of patients with PAH. However, the correlation between changes in TMAO (ΔTMAO) and the prognosis of PAH remains elusive. To investigate the association between ΔTMAO and prognosis of PAH, and explore whether dynamic assessment of TMAO level was superior to measurement at a single time point in predicting prognosis. Single-center cohort study. Consecutive patients diagnosed with PAH and had at least two TMAO measurements taken from May 2019 to June 2020 were eligible. The outcome events of this study were defined as adverse clinical events. A total of 117 patients with PAH who had two TMAO measurements and follow-up were included in this study. Patients with ΔTMAO ⩾1.082 μmol/L had over four times increased risk of adverse clinical events than their counterparts after adjusting for confounders [hazard ratio (HR) 4.050, 95% confidence interval (CI): 1.468-11.174; p = 0.007]. Patients with constant high TMAO levels at both time points had the highest risk of adverse clinical events compared with patients with constant low TMAO levels (HR 3.717, 95% CI: 1.627-8.492; p = 0.002). ΔTMAO was also associated with changes in parameters reflecting PAH severity (p < 0.05). Changes in TMAO were independently correlated with prognosis in patients with PAH, irrespective of baseline level of TMAO. ΔTMAO also correlated with alteration in disease severity. Repeated assessment of TMAO level contributes to better identification of patients with increased risk of adverse clinical events.

Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway.

Recently, trimethylamine N-oxide (TMAO) has been considered a risk factor for cardiovascular disease and has a proatherogenic effect. Many studies have found that TMAO is involved in plaque oxidative stress and lipid metabolism, but the specific mechanism is still unclear. In our study, meta-analysis and bioinformatic analysis were firstly conducted in the database, and found that the effect of high plasma TMAO levels on promoting atherosclerotic plaque may be related to the expression of key antioxidant genes nuclear factor erytheroid-derived-2-like 2 (NFE2L2/Nrf2) decreased. Next, we assessed the role of Nrf2-mediated signaling pathway in TMAO-treated foam cells. Our results showed that TMAO can inhibit the expression of Nrf2 and its downstream antioxidant response element such as heme oxygenase-1 (HO-1) and glutathione peroxidase4 (GPX4), resulting in increased production of reactive oxygen species and decreased activity of superoxide dismutase, promoting oxidative stress. And TMAO can also promote lipid accumulation in foam cells by inhibiting cholesterol efflux protein expression. In addition, upregulation of Nrf2 expression partially rescues TMAO-induced oxidative stress and reduces ATP-binding cassette A1 (ABCA1)-mediated lipid accumulation. Therefore, TMAO promotes oxidative stress and lipid accumulation in macrophage foam cells through the Nrf2/ABCA1 pathway, which may provide a potential mechanism for the proatherogenic effect of TMAO.

Gut microbiota and metabolomics profiles in patients with chronic stable angina and acute coronary syndrome.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The gut microbiota and its associated metabolites may be involved in the development and progression of CVD, although the mechanisms and impact on clinical outcomes are not fully understood. This study investigated the gut microbiome profile and associated metabolites in patients with chronic stable angina (CSA) and acute coronary syndrome (ACS) compared with healthy controls. Bacterial alpha diversity in stool from patients with ACS or CSA was comparable to healthy controls at both baseline and follow-up visits. Differential abundance analysis identified operational taxonomic units (OTUs) assigned to commensal taxa differentiating patients with ACS from healthy controls at both baseline and follow-up. Patients with CSA and ACS had significantly higher levels of trimethylamine N-oxide compared with healthy controls (CSA: 0.032 ± 0.023 mmol/L, P < 0.01 vs. healthy, and ACS: 0.032 ± 0.023 mmol/L, P = 0.02 vs. healthy, respectively). Patients with ACS had reduced levels of propionate and butyrate (119 ± 4 vs. 139 ± 5.1 µM, P = 0.001, and 14 ± 4.3 vs. 23.5 ± 8.1 µM, P < 0.001, respectively), as well as elevated serum sCD14 (2245 ± 75.1 vs. 1834 ± 45.8 ng/mL, P < 0.0001) and sCD163 levels (457.3 ± 31.8 vs. 326.8 ± 20.7 ng/mL, P = 0.001), compared with healthy controls at baseline. Furthermore, a modified small molecule metabolomic and lipidomic signature was observed in patients with CSA and ACS compared with healthy controls. These findings provide evidence of a link between gut microbiome composition and gut bacterial metabolites with CVD. Future time course studies in patients to observe temporal changes and subsequent associations with gut microbiome composition are required to provide insight into how these are affected by transient changes following an acute coronary event.NEW & NOTEWORTHY The study found discriminative microorganisms differentiating patients with acute coronary syndrome (ACS) from healthy controls. In addition, reduced levels of certain bacterial metabolites and elevated sCD14 and sCD163 were observed in patients with ACS compared with healthy controls. Furthermore, modified small molecule metabolomic and lipidomic signatures were found in both patient groups. Although it is not known whether these differences in profiles are associated with disease development and/or progression, the findings provide exciting options for potential new disease-related mechanism(s) and associated therapeutic target(s).

The Association of Circulating L-Carnitine, γ-Butyrobetaine and Trimethylamine N-Oxide Levels with Gastric Cancer.

Our study aimed to evaluate the association between gastric cancer (GC) and higher concentrations of the metabolites L-carnitine, γ-butyrobetaine (GBB) and gut microbiota-mediated trimethylamine N-oxide (TMAO) in the circulation. There is evidence suggesting that higher levels of TMAO and its precursors in blood can be indicative of either a higher risk of malignancy or indeed its presence; however, GC has not been studied in this regard until now. Our study included 83 controls without high-risk stomach lesions and 105 GC cases. Blood serum L-carnitine, GBB and TMAO levels were measured by ultra-high-performance liquid chromatography-mass spectrometry (UPLC/MS/MS). Although there were no significant differences between female control and GC groups, we found a significant difference in circulating levels of metabolites between the male control group and the male GC group, with median levels of L-carnitine reaching 30.22 (25.78-37.57) nmol/mL vs. 37.38 (32.73-42.61) nmol/mL (p < 0.001), GBB-0.79 (0.73-0.97) nmol/mL vs. 0.97 (0.78-1.16) nmol/mL (p < 0.05) and TMAO-2.49 (2.00-2.97) nmol/mL vs. 3.12 (2.08-5.83) nmol/mL (p < 0.05). Thus, our study demonstrated the association between higher blood levels of L-carnitine, GBB, TMAO and GC in males, but not in females. Furthermore, correlations of any two investigated metabolites were stronger in the GC groups of both genders in comparison to the control groups. Our findings reveal the potential role of L-carnitine, GBB and TMAO in GC and suggest metabolic differences between genders. In addition, the logistic regression analysis revealed that the only significant factor in terms of predicting whether the patient belonged to the control or to the GC group was the blood level of L-carnitine in males only. Hence, carnitine might be important as a biomarker or a risk factor for GC, especially in males.

The role of gut-dependent molecule trimethylamine N-oxide as a novel target for the treatment of chronic kidney disease.

Trimethylamine N-oxide (TMAO) is an intestinal uremic toxin molecule mainly excreted by the kidney. Therefore, the plasma TMAO concentration is significantly increased in chronic kidney disease (CKD) patients, and plasma TMAO can be cleared by dialysis. Furthermore, TMAO damage the kidney mainly through three mechanisms: oxidative stress, inflammation and endoplasmic reticulum stress. Clinical experiments have indicated that higher TMAO levels are strongly related to the elevated incidence and mortality of cardiovascular (CV) events in CKD patients. Moreover, experimental data have shown that high levels of TMAO directly aggravate atherosclerosis, thrombosis and enhance myocardial contractility, resulting in myocardial ischemia and stroke. Specially, there are currently four potential ways to reduce blood TMAO concentration or block the effect of TMAO, including reducing the intake of trimethylamine (TMA) precursors in the diet, regulating the intestinal flora to reduce TMA production, interrupting the role of flavin-dependent monooxygenase isoforms (FMOs) to reduce the generation of TMAO, and blocking the TMAO receptor protein kinase R-like endoplasmic reticulum kinase (PERK). We hope that more clinical studies and clinicians will focus on clinical treatment to reduce the concentration of TMAO and alleviate renal damage.

Association between plasma trimethylamine-N-oxide and cognitive impairment in patients with transient ischemic attack

ABSTRACT Background There is increasing evidence for the association of trimethylamine-N-oxide (TMAO) with cognitive impairment after minor stroke or transient ischemic attack (TIA). However, how TMAO affects cognitive function in TIA patients has seldom been studied. Methods A total of 310 TIA participants were retrospectively collected from our stroke register between January 2020 and July 2021. Plasma TMAO was measured by liquid chromatography‒mass spectrometry at baseline. Cognitive performance was assessed by neuropsychological evaluation at 3 months after TIA onset. Results A total of 310 patients were included (mean age, 74 years; male, 160 [51.6%]; mean ABCD2 score, 2.6). TMAO was positively associated with cognitive impairment after TIA (aOR, 1.423; 95% CI, 1.125–2.561). The highest quartile of TMAO was related to an almost 2-fold increased risk of cognitive decline compared to the lowest quartile. Furthermore, executive and memory function were more susceptible to impairment after TIA in groups with higher levels of TMAO. Mediation analysis revealed that the overall mediated effect was−0.347 (p < 0.001), and the intermediary effect of CRP was−0.108. Conclusion Plasma TMAO at baseline was independently associated with cognitive impairment at the 3-month follow-up after TIA. In addition, the inflammatory marker CRP may serve as an important mediator in this relationship. Our study may provide some insights into anti-inflammatory therapy to improve the cognitive trajectory of TIA patients with high TMAO levels.

Cardiovascular disease risk prediction in scleroderma.

Cardiovascular disease risk prediction in scleroderma is important. In this study of scleroderma patients, the aim was to investigate the relationship between cardiac myosin-binding protein-C, sensitive troponin T, and trimethylamine N-oxide and cardiovascular disease risk with the Systematic COronary Risk Evaluation 2 model of the European Society of Cardiology. Systematic COronary Risk Evaluation 2 risk groups of 38 healthy controls and 52 women with scleroderma were evaluated. Cardiac myosin-binding protein-C, sensitive troponin T, and trimethylamine N-oxide levels were analyzed with commercial ELISA kits. In scleroderma patients, cardiac myosin-binding protein-C and trimethylamine N-oxide levels were higher than healthy controls but sensitive troponin T was not (p<0.001, p<0.001, and p=0.274, respectively). Out of 52 patients, 36 (69.2%) were at low risk, and the other 16 (30.8%) patients were at high-moderate risk with the Systematic COronary Risk Evaluation 2 model. At the optimal cutoff values, trimethylamine N-oxide could discriminate high-moderate risk with sensitivity 76%, specificity 86% and cardiac myosin-binding protein-C with sensitivity 75%, specificity 83%. Patients with high trimethylamine N-oxide levels (≥10.28 ng/mL) could predict high-moderate- Systematic COronary Risk Evaluation 2 risk 15 times higher than those with low trimethylamine N-oxide (<10.28 ng/mL) levels (odds ratio [OR]: 15.00, 95%CI 3.585-62.765, p<0.001). Similarly, high cardiac myosin-binding protein-C (≥8.29 ng/mL) levels could predict significantly higher Systematic COronary Risk Evaluation 2 risk than low cardiac myosin-binding protein-C (<8.29 ng/mL) levels (OR: 11.00, 95%CI 2.786-43.430). Noninvasive cardiovascular disease risk prediction indicators in scleroderma, cardiac myosin-binding protein-C, and trimethylamine N-oxide could be recommended to distinguish between high-moderate risk and low risk with the Systematic COronary Risk Evaluation 2 model.

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 Are Associated with Severe Aortic Stenosis and Predict Long-Term Adverse Outcome.

Objective: Trimethylamine N-oxide (TMAO), a pathological microbial metabolite, is demonstrated to be related to cardiovascular diseases. This study was (1) to investigate the association between TMAO and aortic stenosis and (2) to determine the prognostic value of TMAO for predicting mortality after transcatheter aortic valve replacement (TAVR). Methods: 299 consecutive patients (77 (72−81) years, 58.2% male, Society of Thoracic Surgeons (STS) score 5.8 (4.9−9.3)) with severe aortic stenosis and 711 patients (59 (52−66) years, 51.9% male) without aortic stenosis were included in this retrospective study. A total of 126 pairs of patients were assembled by Propensity Score Matching. The primary outcome was all-cause mortality using survival analyses stratified by TMAO quartiles. Results: Patients with severe aortic stenosis had higher TMAO levels (3.18 (1.77−6.91) μmol/L vs. 1.78 (1.14−2.68) μmol/L, p < 0.001), and TMAO remained significantly higher after adjusting for baseline characteristics. Higher TMAO level was associated with higher 2-year all-cause mortality (19.2% vs. 9.5%, log-rank p = 0.028) and higher late cumulative mortality (34.2% vs. 19.1%, log-rank p = 0.004). In Cox regression multivariate analysis, higher TMAO level remained an independent predictor (hazard ratio 1.788; 95% CI 1.064−3.005, p = 0.028) of all-cause mortality after adjusting for STS score, N-terminal pro b-type natriuretic peptide, and maximum velocity. Conclusions: The TMAO level was higher in aortic stenosis patients. Elevated TMAO was associated with poor adverse outcome after TAVR.