Trimethylamine N-oxide Levels Research Articles

Donepezil ameliorates gut barrier disruption in doxorubicin-treated rats

An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.

Deciphering the causal relationship between plasma and cerebrospinal fluid metabolites and glioblastoma multiforme: a Mendelian Randomization study.

Glioblastoma Multiforme (GBM) is one of the most aggressive and fatal brain cancers. The study of metabolites could be crucial for understanding GBM's biology and reveal new treatment strategies. The GWAS data for GBM were sourced from the FinnGen database. A total of 1400 plasma metabolites were collected from the GWAS Catalog dataset. The cerebrospinal fluid (CSF) metabolites data were collected from subsets of participants in the WADRC and WRAP studies. We utilized the inverse variance weighting (IVW) method as the primary tool to explore the causal relationship between metabolites in plasma and CSF and glioblastoma, ensuring the exclusion of instances with horizontal pleiotropy. Additionally, four supplementary analytical methods were applied to reinforce our findings. Aberrant results were identified and omitted based on the outcomes of the leave-one-out sensitivity analysis. Conclusively, a reverse Mendelian Randomization analysis was also conducted to further substantiate our results. The study identified 69 plasma metabolites associated with GBM. Of these, 40 metabolites demonstrated a significant positive causal relationship with GBM, while 29 exhibited a significant negative causal association. Notably, Trimethylamine N-oxide (TMAO) levels in plasma, not CSF, were found to be a significant exposure factor for GBM (OR = 3.1627, 95% CI = (1.6347, 6.1189), P = 0.0006). The study did not find a reverse causal relationship between GBM and plasma TMAO levels. This research has identified 69 plasma metabolites potentially associated with the incidence of GBM, among which TMAO stands out as a promising candidate for an early detectable biomarker for GBM.

In-hospital trimethylamine N-oxide (TMAO) variation predicts major adverse cardiovascular events in myocardial infarction survivors

Abstract Funding Acknowledgements None. Background Trimethylamine N-oxide (TMAO), a gut microbiota result of the fermentation of animal foods rich in choline, L-carnitine and phosphatidylcholine (red meat, egg yolk, dairy food), is associated with alterations in lipid metabolism, increased foam cell formation, promotion of inflammation, oxidative stress, platelet aggregation and thrombosis. To date the data evaluating TMAO as a predictor of mortality and ischemic events in patients with acute myocardial infarction (AMI) based on one-time measurement of TMAO levels lead to conflicting results. TMAO levels are fluctuating and in addition to diet, genetic factors, general condition and some co-morbidities affect its circulating levels. Purpose Since, there is a need for better risk stratification of AMI patients before the hospital discharge for more personalised treatment, we evaluated in-hospital variation in TMAO levels and its impact on outcome. Methods Blood samples from 149 consecutive AMI patients were collected on admission and on discharge. The endpoint was a three-point major adverse cardiovascular events (MACE) composed as all-cause mortality, reinfarction and development of heart failure. Results The majority of AMI patients were male (77%), hospitalized for first coronary event, with mean age 64(11) years. Median circulating TMAO level was significantly higher on admission than on discharge, (7.81 [3.47 –19.98] vs 3.45 [2.3 – 4.78] μM, respectively, p<0.001). In order to evaluate the impact of TMAO variation during the hospital stay on outcome, we estimated TMAO cut-off value by continuous hazard ratio analysis; values above the 3.45 μM were associated with incident of MACE in a linear fashion (Fig. 1a). Subsequently, we stratified AMI patients in 2 groups: 1) LL/HL (low-low/high-low) that included 75 (50.3%) patients whose TMAO levels remained low or were high and decreased during hospitalization and 2) HH/LH (high-high/low-high) including 74 patients (49.7%) patients whose TMAO levels remained elevated or were initially low, but rose above the estimated threshold during hospitalisation (Fig. 1b). Thirty-two (21.5%) patients reached the combined endpoint during the median follow-up of 30 months. The Kaplan-Meier analysis demonstrated that patients from the HH/LH group had a higher likelihood of experiencing MACE (p=0.05) (Fig. 2a). The multivariate Cox analysis revealed that patients in the HH/LH group had over twice the risk of MACE compared to those in the LL/HL group. Furthermore, older age and worse left ventricular systolic function were identified as independent predictors of MACE during long-term follow-up (Fig. 2b). Conclusions AMI patients with permanently elevated or increasing levels of TMAO have a worse outcome. The novelty and the strength of our study is the fact that the direction of variation of TMAO during the index hospitalisation identifies patients at higher risk of MACE during 30 months follow-up.

The Gut Microbial Metabolite Trimethylamine N -oxide, Incident CKD, and Kidney Function Decline.

Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline. We included 10,564 participants from two community-based, prospective cohorts with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and Cystatin C were measured up to 4 times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline ≥ 30% from baseline and a resulting eGFR<60 ml/min/1.73 m2. Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels. During a median follow-up of 9.4 years (interquartile range: 9.1-11.6 years), 979 incident CKD events occurred. Higher TMAO levels associated with higher risk of incident CKD (2nd to 5th vs. 1st quintile HR[95%CI]= 1.65 [1.22-2.23], 1.68 [1.26-2.25], 2.28 [1.72-3.02], and 2.24[1.68-2.98], respectively) and greater annualized eGFR decline ( 2nd to 5th vs. 1st quintile annualized eGFR change= -0.21 [-0.32, -0.09], -0.17 [-0.29, -0.05], -0.35 [-0.47, -0.22], and -0.43[-0.56, -0.30], respectively) with monotonic dose-response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors including diabetes, per 10 mmHg of higher systolic blood pressure, per 10 years of older age, and Black race. In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.

Exploring the relationship between trimethylamine N-Oxide levels, kidney function, and diabetes

Exploring the relationship between trimethylamine N-Oxide levels, kidney function, and diabetes

Intra-hospital variation of gut microbiota product, trimethylamine N-oxide (TMAO), predicts future major adverse cardiovascular events after myocardial infarction

ObjectiveTrimethylamine N-oxide (TMAO) has been associated with atherosclerosis and poor outcome. We evaluated the prognostic impact of intra-hospital TMAO variation on patient outcome. Methods and ResultsBlood samples from 149 patients with acute myocardial infarction (AMI) were taken on admission and discharge. Plasma TMAO was determined by HPLC-MS. The endpoint was a composite three-point MACE (major adverse cardiovascular events), including all-cause mortality, re-infarction, or heart failure (HF) development. Median TMAO concentration on admission was significantly higher than on discharge (respectively, 7.81 [3.47–19.98] vs 3.45 [2.3–4.78] μM, p < 0.001). After estimating the 3.45 μM TMAO cut-off with the analysis of the continuous hazard ratio, we divided our cohort into two groups. The first group included 75 (50.3%) patients whose TMAO levels remained below or decreased under cut-off (low-low/high-low; LL/HL), while the second group included 74 (49.7%) patients whose TMAO levels remained high or increased above the cut-off during hospitalisation (high-high/low-high; HH/LH). During the median 30-month follow-up, 21.5% of patients experienced the composite endpoint. At Kaplan-Meier analysis, a trend of increasing MACE risk was observed in patients in the HH/LH group (p = 0.05). At multivariable Cox analysis, patients from the HH/LH group had more than two times higher risk of MACE during the follow-up than the LL/HL group (HR = 2.15 [95% CI, 1.03–4.5], p = 0.04). Other independent predictors of MACE were older age and worse left ventricular systolic function. ConclusionIn patients with AMI, permanently high or increasing TMAO levels during hospitalisation are associated with a higher risk of MACE during long-term follow-up.

Association of the trimethylamine N-oxide with cardiovascular risk and vascular alterations in middle-aged patients with risk factors for cardiovascular diseases.

Trimethylamine N-oxide (TMAO) is synthesized by the intestinal microbiota and is an independent predictor of cardiovascular disease (CVD). However, its underlying mechanisms remain unclear. We investigated TMAO levels across different CVD-risk patient groups, and evaluated associations between TMAO and vascular alterations (e.g., arterial stiffness, intima-media thickness (IMT), and the presence and grade of carotid artery plaques (CAPs)).Methods: We examined 95 patients (58.5 ± 7.3 years): 40 with clinical atherosclerotic cardiovascular disease (ASCVD), 40 with atherosclerosis risk factors (RF), and 15 controls. Arterial stiffness was measured by Carotid-Femoral Pulse Wave Velocity (C-F PWV). B-mode ultrasound was used to evaluate the presence and grade of CAPs and carotid IMT (CIMT). TMAO was measured by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and results were presented as the median (interquartile range).Results: TMAO levels were higher in patients with ASCVD (251.5 (164.5) µg/l) when compared to patients with RFs (194.0 (174) µg/l, p = 0.04) and controls (122.0 (77) µg/l, p < 0.001). A significant correlation was observed between TMAO and PWV (r = 0.31, p = 0.003), which was not confirmed after adjustment for RFs. TMAO levels were significantly correlated with plaque score (r = 0.46, p < 0.001) and plaque height (r = 0.41, p = 0.003), and were independent predictors for grade III plaques (odds ratio (OR) = 1.002, confidence interval (CI) 95%: 1.000047-1.003, p = 0.044).Conclusions: TMAO levels are increased with expanded CVD risk. Across different types of vascular damage, TMAO is associated with atherosclerotic changes.

The prediction value of combined serum levels of TMAO and TML for poor prognosis in patients with heart failure

Objective: To evaluate the predictive value of combined serum levels of trimethylamine N-oxide (TMAO) and trimethyllysine (TML) for poor prognosis in patients with heart failure. Methods: This single-center prospective cohort study included hospitalized patients with heart failure and complete baseline data from the Department of Cardiology at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from June 2017 to December 2020. Patients were categorized into four groups based on median serum levels of TMAO and TML after admission: TMAO low level TML low level group (TMAO<9.7 μmol/L, TML<0.73 μmol/L), TMAO low level TML high level group (TMAO<9.7 μmol/L, TML≥0.73 μmol/L), TMAO high level TML low level group (TMAO≥9.7 μmol/L, TML<0.73 μmol/L) and TMAO high level TML high level group (TMAO≥9.7 μmol/L, TML≥0.73 μmol/L). The primary endpoint was a composite endpoint of cardiovascular death and readmission for heart failure. Multiple factor Cox regression analysis was conducted to evaluate the correlation between serum TMAO and TML levels and poor prognosis in patients with heart failure. Results: A total of 471 patients with heart failure were included, with an mean age of (62.5±12.0) years and a median follow-up time of 1.61 (1.06, 2.90) years. Multivariate Cox regression analysis showed that after adjusting for age, gender, and traditional risk factors, the TMAO high level TML high level group had a higher incidence of primary endpoint events compared to the TMAO low level TML low level group (HR=1.71, 95%CI 1.05-2.77, P=0.03). Conclusion: Elevated serum levels of both TMAO and TML can effectively predict the occurrence of long-term adverse events in patients with heart failure.

Hif-1α expression targets the TMA/Fmo3/TMAO axis to participate in gallbladder cholesterol stone formation in individuals living in plateau regions

The incidence of gallbladder cholesterol stones (GCS) increases rapidly among people living in high-altitude hypoxic environments compared to those in normoxic areas. Upregulation of hepatic hypoxia inducible factor 1α (Hif-1α) plays a key role in the formation of GCS. High plasma trimethylamine-N-oxide (TMAO) levels are positively correlated with the occurrence of GCS. We hypothesized that HIF-1α may upregulate TMAO levels by promoting the transcription of flavin-containing monooxygenase 3 (Fmo3), which eventually leads to GCS formation. Our study shows that in women, high plasma total cholesterol and apolipoprotein B were positively correlated with cholecystolithiasis and hypoxia. Hif-1α binds to the Fmo3 promoter and promotes Fmo3 expression. Hypoxia and lithogenic diet induce the expression of Hif-1α, Fmo3, TMAO and cholesterol tube transporters in the livers of mice, disturb the proportion of bile and plasma components, and induce the formation of GCS. In cell experiments, silencing Hif-1α downregulates the expression of Fmo3, TMAO and cholesterol tube transporters. In a mouse model of hypoxic cholecystolithiasis, silencing Hif-1α downregulates the expression of related genes, restores the proportion of bile and plasma lipid components, and reduces the formation of GCS. Our study shows that Hif-1α binds to the promoter region of Fmo3 and promotes Fmo3 transcription. Thus, it mediates the transcriptional activation of the TMA/Fmo3/TMAO pathway, upregulates the expression of ATP-binding cassettes (Abc) g5 and g8, and participates in the regulation of the occurrence of GCS in the plateau region.

Gut-Derived Trimethylamine N-Oxide Promotes CCR2-Mediated Macrophage Infiltration in acute kidney injury.

Inflammation is crucial in the development of AKI and subsequent CKD following renal ischemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet, the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR. Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis, and macrophage dynamics. A choline-rich diet altered the gut microbiota and elevated TMAO levels, which exacerbated IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis, alleviated renal injury induced by IR. Our study provides valuable insights into the link between TMAO and IR-incited renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phase after IR.

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.

The impact of egg consumption on indices of gastrointestinal health: a systematic literature review

Eggs are highly digestible, nutrient-rich and are a valuable source of protein and choline, thereby promoting a range of health benefits. Several studies have found an association between protein intake and gastrointestinal microbial diversity(1), while bacterial fermentation of undigested protein in the large bowel can produce short-chain fatty acids, such as butyrate, positively influencing host metabolic health, gut integrity and immune function(2). On the other hand, dietary choline stimulates gastrointestinal bacterial production of trimethylamine and the prothrombotic compound trimethylamine-N-oxide (TMAO)(3). Despite these established links, limited studies have explored the effects of whole egg intake on indices of gastrointestinal health. This systematic literature review aimed to synthesise research that has investigated the impact of egg-supplemented diets or egg consumption on markers of gastrointestinal health including microbiome, function and symptoms. This review was conducted in accordance with PRISMA guidelines. Five databases (Ovid Medline, Embase, CINAHL Plus, SCOPUS, and PsychInfo), and reference lists of relevant papers, were searched from inception until April 2023. Studies were included if they examined the link between whole chicken egg consumption and gastrointestinal health in healthy adults (aged&gt;16). Indices of gastrointestinal health were defined as any outcomes related to gastrointestinal factors, including symptoms, microbiome, inflammation, colonic fermentation and TMAO. Reviews and case studies were excluded. All studies underwent risk of bias assessment. Overall, 548 studies were identified and 19 studies were included after screening. Eight of these were randomised controlled trials (RCTs), 8 cross-sectional and 3 prospective cohort studies. Participants ranged in number between 20-32,166 and in age between 18–84 years. Study periods varied between 3–14 weeks for RCTs and 6 months–12.5 years for prospective cohort studies. RCTs examined intakes between 1–4 eggs/day, with the majority examining 3 eggs/day (n = 6). The primary outcome across 15 articles was TMAO levels, with most reporting no significant associations (n = 13). Five studies examined inflammation with inconsistent findings ranging from no alterations (in TNF-α, IL-8, CRP), increases (in anti-inflammatory marker LTB5, TNF-α), and decreases (in IL-6, CRP). Lastly, 7 studies explored alterations in microbiome. Two RCTs and 2 cross-sectional trials reported no alterations in microbial diversity in response to eggs. Meanwhile, 2 cross-sectional and 1 prospective study linked specific bacteria to consistent egg intake. Eggs were associated with species that produce butyrate (E.rectale, F.prausnitzii, M.smithii, and R.bromii), and protect against metabolic syndrome (A.muciniphila). This systematic review found that egg consumption did not increase levels of the undesirable biomarker TMAO and were associated with butyrate-producing bacteria. Evidence regarding the effect of egg intake on inflammation was inconsistent. This review revealed the general lack of available research investigating whole eggs and gastrointestinal health. Future carefully designed RCTs are required to improve understanding of how eggs may influence the gastrointestinal microbiome and colonic fermentation.

Relevance of plasma lipoproteins and small metabolites in assessment of nutritional status among patients with severe injuries

BackgroundThis study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit (ICU) stay in patients with severe injuries. MethodsThis observational prospective exploratory study was conducted at two level-1 trauma centers in the Netherlands. Adult patients (aged ≥18 years) who were admitted to the ICU for more than 48 h between July 2018 and April 2022 owing to severe injuries (polytrauma, as defined by Injury Severity Scores of ≥16) caused by blunt trauma were eligible for inclusion. Overall, 51 patients were included; partial least squares discriminant analysis was used to analyze the relationship of 112 lipoprotein-related components and 23 small metabolites with the risk of malnutrition (modified Nutrition Risk in Critically Ill score). Malnutrition was diagnosed based on Subjective Global Assessment scores. The relationship of lipoprotein properties and small metabolite concentrations with malnutrition (during ICU admission) was evaluated using mixed effects logistic regression. ResultsLower (very) low-density lipoprotein ([V]LDL) (free) cholesterol and phospholipid levels, low particle number, and higher levels of LDL triglycerides were associated with a higher risk of malnutrition (variable importance in projection [VIP] value >1.5). Low levels of most (V)LDL and intermediate-density lipoprotein subfractions and high levels of high-density lipoprotein Apo-A1 were associated with the diagnosis of malnutrition (VIP value >1.5). Increased levels of dimethyl sulfone, trimethylamine N-oxide, creatinine, N, N-dimethylglycine, and pyruvic acid and decreased levels of creatine, methionine, and acetoacetic acid were also indicative of malnutrition (VIP value >1.5). Overall, 14 lipoproteins and 1 small metabolite were significantly associated with a high risk of malnutrition during ICU admission (P <0.05); however, the association did not persist after correcting the false discovery rate (P=0.35 for all). ConclusionIncreased triglyceride in several lipoprotein subfractions and decreased levels of other lipoprotein subfraction lipids and several small metabolites (involved in the homocysteine cycle, ketone body formation, and muscle metabolism) may be indicative of malnutrition risk. Following validation in larger cohorts, these indicators may guide institution of preventive nutritional measures in patients admitted to the ICU with severe injuries.

High-throughput metabolomics identifies new biomarkers for cervical cancer

BackgroundCervical cancer (CC) is a danger to women’s health, especially in many developing countries. Metabolomics can make the connection between genotypes and phenotypes. It provides a wide spectrum profile of biological processes under pathological or physiological conditions.MethodIn this study, we conducted plasma metabolomics of healthy volunteers and CC patients and integratively analyzed them with public CC tissue transcriptomics from Gene Expression Omnibus (GEO).ResultHere, we screened out a panel of 5 metabolites to precisely distinguish CC patients from healthy volunteers. Furthermore, we utilized multi-omics approaches to explore patients with stage I-IIA1 and IIA2-IV4 CC and comprehensively analyzed the dysregulation of genes and metabolites in CC progression. We identified that plasma levels of trimethylamine N-oxide (TMAO) were associated with tumor size and regarded as a risk factor for CC. Moreover, we demonstrated that TMAO could promote HeLa cell proliferation in vitro. In this study, we delineated metabolic profiling in healthy volunteers and CC patients and revealed that TMAO was a potential biomarker to discriminate between I-IIA1 and IIA2-IV patients to indicate CC deterioration.ConclusionOur study identified a diagnostic model consisting of five metabolites in plasma that can effectively distinguish CC from healthy volunteers. Furthermore, we proposed that TMAO was associated with CC progression and might serve as a potential non-invasive biomarker to predict CC substage.ImpactThese findings provided evidence of the important role of metabolic molecules in the progression of cervical cancer disease, as well as their ability as potential biomarkers.

Trimethylamine N-oxide impairs β-cell function and glucose tolerance

β-Cell dysfunction and β-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, β-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production improves β-cell GSIS, β-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.

STUDY OF DIETARY REMODELING OF THE INTESTINAL MICROBIOTA BY GRAPE POLYPHENOLS AT THE LEVEL OF TRIMETHYLAMINE N-OXIDE (TMAO) IN PATIENTS WITH ACUTE CORONARY SYNDROME WITH ELEVATION OF THE SEGMENT ST

The main cause of mortality and disability in the adult population of our planet is cardiovascular diseases caused by atherosclerosis. The relevance of research into new methods of treating atherosclerosis is only increasing. In addition to dyslipedemia, infections and inflammation, new predictors of atherogenesis are being sought, and one of them is the level of trimethylamine N-oxide (TMAO). Many large studies have shown that circulating TMAO levels correlate with the development of atherosclerosis. In turn, the formation of TMAO depends on the state of the intestinal microbiome. That is, the stages of development of atherosclerosis can be influenced by changes in the intestinal microbiome. Purpose: Based on domestic and foreign scientific publications, to determine the effect of dietary remodeling of the gut microbiota by grape polyphenols on trimethylamine N-oxide (TMAO) levels in patients with STsegment elevation acute coronary syndrome. Results and conclusions: It was revealed that in patients with STEMI, the use of the prebiotic Kainar with grape polyphenols changes the concentration of TMAO in the blood. It was confirmed that there were statistically significant differences in TMAO values in the control group and the group taking Kaynar after 3 months and after 12 months.

A Combined Measure of the Triglyceride Glucose Index and Trimethylamine N-Oxide in Risk Stratification of ST-Segment Elevation Myocardial Infarction Patients with High-Risk Plaque Features Defined by Optical Coherence Tomography: A Substudy of the OCTAMI Registry Study.

An elevated triglyceride-glucose (TyG) level is associated with increased risk of mortality in patients with CAD. Trimethylamine N-oxide (TMAO) has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is correlated with adverse outcomes. However, the incremental prognostic value of TMAO and TyG in the cohort of optical coherence tomography (OCT)-defined high-risk ST-segment elevation myocardial infarction (STEMI) patients is unknown. We studied 274 consecutive aged ≥18 years patients with evidence of STEMI and detected on pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019. There were 22 (22.68%), 27 (27.84%), 26 (26.80%), and 22 (22.68%) patients in groups A-D, respectively. The baseline characteristics according to the level of TMAO and TyG showed that patients with higher level in both indicators were more likely to have higher triglycerides (p < 0.001), fasting glucose (p < 0.001) and higher incidence of diabetes (p = 0.008). The group with TMAO > median and TyG ≤ median was associated with higher rates of MACEs significantly (p = 0.009) in fully adjusted analyses. During a median follow-up of 2.027 years, 20 (20.6%) patients experienced MACEs. To evaluate the diagnostic value of the TyG index combined with TMAO, the area under the receiver operating characteristic curve for predicting MACEs after full adjustment was 0.815 (95% confidence interval, 0.723-0.887; sensitivity, 85.00%; specificity, 72.73%; cut-off level, 0.577). Among the group of patients with TMAO > median and TyG ≤ median, there was a significantly higher incidence of MACEs (p=0.033). A similar tendency was found in the cohort with hyperlipidemia (p=0.016) and diabetes mellitus (p=0.036). This study demonstrated the usefulness of combined measures of the TyG index and TMAO in enhancing risk stratification in STEMI patients with OCT-defined high-risk plaque characteristics. This study was registered at ClinicalTrials.gov as NCT03593928.

The association of dietary nitrates/nitrites intake and the gut microbial metabolite trimethylamine N-oxide and kynurenine in adults: a population-based study.

Dietary nitrate and nitrite may affect the gut microbiota and its metabolites, such as trimethylamine N-oxide (TMAO) and kynurenine (KYN). However, this association and the exact mechanism are still unclear. Therefore, this study aimed to assess the association between dietary consumption of nitrite and nitrate on TMAO and KYN levels in adults. This cross-sectional study was employed on a subsample baseline phase of the Tehran University of Medical Sciences (TUMS) Employee's Cohort Study (TEC). A total of 250 adults aged 18 years or older were included in the current analysis. Data on the dietary intakes were collected using a validated dish-based food frequency questionnaire (FFQ), and dietary intakes of nitrite and nitrate were estimated using the FFQ with 144 items. Serum profiles and TMAO and KYN were measured using a standard protocol. The findings of this study demonstrate a significant association between the intake of animal sources of nitrate and nitrite and the likelihood of having elevated levels of TMAO and KYN. Specifically, after adjustment, individuals with the highest intake adherence to nitrates from animal sources exhibited increased odds of having the highest level of TMAO (≥51.02 pg/ml) (OR = 1.51, 95% CI = 0.59-3.88, P = 0.03) and KYN (≥417.41 pg/ml) (OR = 1.75, 95% CI = 0.73-4.17, P = 0.02). Additionally, subjects with the highest animal intake from nitrite sources have 1.73 and 1.45 times higher odds of having the highest levels of TMAO and KYN. These results emphasize the potential implications of animal-derived nitrate and nitrite consumption on the levels of TMAO and KYN. The present evidence indicates that a high level of nitrate and nitrite intake from animal sources can increase the odds of high levels of TMAO and KYN. Further studies suggest that we should better evaluate and understand this association.

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.

Modulating gut microbiota improves neurological function and depressive symptoms in rats with post-stroke depression

To evaluate the effect of modulating gut microbiota for improving brain injury in rats with post-stroke depression. Adult SD rats were randomized into normal control, middle cerebral artery occlusion (MCAO), post-stroke depression (PSD), PSD with fecal transplantation, PSD with antibiotics (rifaximin), PSD with probiotics (lactobacilli), and PSD with fluoxetine treatment groups (n=9). Neurological function scores of the rats were determined, and the changes in sugar water preference and immobility time in forced swimming test were observed; plasma levels of trimethylamine N-oxide (TMAO) and hydrogen sulfide (H2S) were detected with ELISA, Occludin, and the expressions of occludin, caudin-5 and IgG proteins Ⅰ the brain tissues were determined using Western blotting. Compared with those in the control group, the rats in MCAO and PSD groups had significantly increased neurological function scores, TMAO level, the ratio of TMAO/H2S, and immobility time in forced swimming test with a lowered level of H2S (P < 0.05). These changes were more obvious in PSD rats, which also exhibited a reduced sugar water preference with increased IgG protein and decreased occluding and caudin-5 expressions in the brain tissue (P < 0.05). TMAO/H2S ratio in PSD rats was positively correlated with neurological function score (R2=0.3235, P=0.0269) and immobility time in swimming (R2=0.6290, P=0.0004) and negatively with sugar water preference (R2=-0.4534, P=0.0059). Treatment with fecal transplantation, antibiotics, probiotics and fluoxetine all significantly reduced neurological function scores, immobility time in forced swimming, TMAO/H2S ratio, and IgG protein expression and increased sugar water preference and brain occludin and caudin-5 expressions of the PSD rats (P < 0.05). In PSD rats, TMAO/H2S ratio is correlated with neurological function score, immobility time in forced swimming and sugar water preference, and modulating intestinal flora can improve neurological function and depressive symptoms and improve the integrity of the blood-brain barrier.