Serum Trimethylamine N-oxide Research Articles

Trimethylamine N-Oxide (TMAO) and TNF-α Levels in Periodontal Disease Associated With Smoking.

Trimethylamine N-oxide (TMAO) is a compound involved in the pathogenesis of various systemic inflammatory diseases, including cardiovascular conditions. The aim of this study was to determine differences in saliva and serum levels of TMAO between periodontitis and healthy patients according to smoking status. The study included four systemically healthy groups: periodontally healthy non-smokers (NS-Control; n = 25), non-smokers with Stage-III-Grade-B periodontitis (NS-Periodontitis; n = 25), periodontally healthy smokers (S-Control; n = 25), and smokers with Stage-III Grade-C periodontitis (S-Periodontitis; n = 25). Periodontal parameters were recorded. TMAO levels were determined in saliva and serum samples using liquid chromatography-mass spectrometry (LC-MS/MS). TNF-α levels were measured by the ELISA method. Salivary TNF-α and TMAO levels were significantly elevated in the smoking periodontitis group compared to other groups (p < 0.001 and p = 0.003, respectively). Serum TMAO levels were also significantly higher in the smoking periodontitis group compared to non-smoking controls and non-smoking periodontitis. TMAO/SFR ratios were notably higher in the smoking periodontitis group compared to other groups, and a strong positive correlation was observed between salivary TMAO and TNF-α levels (r = 0.892, p < 0.001). The data suggested that TMAO and TNF-α are associated with inflammatory mechanisms of periodontitis in cases where periodontitis coexists with smoking. NCT06580431.

Effects of Dietary Fiber Supplementation on Modulating Uremic Toxins and Inflammation in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Emerging evidence supports the beneficial effects of dietary fiber supplementation in alleviating gut dysbiosis, which leads to a reduction in uremic toxins and inflammatory markers in chronic kidney disease (CKD) patients. However, current evidence-based renal nutrition guidelines do not provide recommendations regarding dietary fiber intake. We performed a systematic review and meta-analysis to investigate and highlight the effects of dietary fiber supplementation on modulating uremic toxins and inflammatory markers in individuals with CKD, with or without dialysis. The eligible randomized controlled trials (RCTs) were identified from PubMed, Scopus, and Cochrane Central Register of Controlled trials until 27 November 2024. The results were synthesized using a random-effects model and presented as standardized mean differences (SMDs) with a 95% confidence interval (CI). A total of 21 studies with 700 patients were included. When compared with the control group, dietary fiber supplementation ranging from 6 to 50 g/day, for typically more than 4 weeks, could significantly reduce the levels of serum uremic toxins, including p-cresyl sulfate, indoxyl sulfate, and blood urea nitrogen (SMD −0.22, −0.34, −0.25, respectively, with p-values &lt; 0.05), as well as biomarkers of inflammation, including interleukin-6 and tumor necrosis factor alpha (SMD −0.44, −0.34, respectively, with p-values &lt; 0.05). These beneficial effects were consistent across different types of fibers and CKD status (with or without dialysis). However, no significant reduction in serum trimethylamine N-oxide, uric acid, and high-sensitivity C-reactive protein levels was observed with dietary fiber intervention. This study would pave the way for prioritizing dietary quality, particularly a fiber-rich diet, beyond the traditional focus on the quantities of protein, energy, and electrolyte restrictions among individuals with CKD.

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].

Pre-procedural TMAO as a predictor for recurrence of atrial fibrillation after catheter ablation

BackgroundNumerous studies have demonstrated the significance of trimethylamine-N-oxide (TMAO) in the progression of atrial fibrillation (AF). However, the association between TMAO and AF recurrence (RAF) post-catheter ablation is not yet fully understood. This study aims to elucidate the predictive capability of pre-procedural TMAO levels in determining RAF following catheter ablation (CA).MethodsThis study was conducted as a prospective, single-center observational study. Between June 2021 and June 2022, 152 patients from the Department of Cardiology at The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University were enrolled. Baseline characteristics and serum TMAO levels were assessed for all participants. Patients with AF who underwent CA were monitored for recurrences of AF using electrocardiography (ECG) or 24-hour Holter monitoring during the follow-up period.ResultsThe study found that serum TMAO levels were significantly higher in persistent AF (PeAF) patients compared to those in sinus rhythm (SR) and paroxysmal AF (PaAF) patients (3.96 ± 1.69 vs. 1.81 ± 0.59, 3.02 ± 1.50 µM, P < 0.001 and P < 0.01, respectively). After a one-year follow-up, 29 (21.2%) AF patients experienced recurrence after CA. Multivariate Cox proportional hazards regression analysis revealed that pre-procedural serum TMAO was an independent predictor of recurrent AF (HR = 1.78, 95% CI = 1.43–2.21, P < 0.001). The receiver operating characteristic (ROC) curve analysis identified a cut-off value of 4.3µM for serum TMAO levels in predicting recurrent AF (area under the curve: 0.835, P < 0.001). The Kaplan-Meier plot demonstrated that patients with TMAO levels greater than 4.3µM had a significantly higher rate of recurrent AF (HR = 13.53, 95% CI = 6.19–29.56, P < 0.001).ConclusionPatients with AF exhibited elevated levels of circulating TMAO compared to patients with SR. The findings suggest a potential role of TMAO in the development of AF, with pre-procedural serum TMAO levels serving as a reliable predictor of recurrence of AF CA.

Study on the Mechanism of Bifidobacterium animalis subsp. lactis F1-3-2 Regulating Bile Acid Metabolism Through TMA-TMAO Pathway to Improve Atherosclerosis.

Atherosclerosis is a major cause of cardiovascular disease (CVD). The trimethylamine (TMA)-trimethylamine N-oxide (TMAO) pathway is a key crossover pathway highly associated with diet, gut microbiome, and atherosclerosis. The Bifidobacterium animalis subsp. lactis F1-3-2 (Bif. animalis F1-3-2, No. CCTCCM2020832) was screened through in vitro and in vivo experiments in the early stage of this study with excellent lipid-lowering and anti-inflammatory function. By building an atherosclerosis model and focusing on TMAO, the specific mechanism of Bif. animalis F1-3-2 to improve atherosclerosis was explored. The study found that Bif. animalis F1-3-2 effectively improved the accumulation of aortic plaque in atherosclerotic mice. The strain improved lipid metabolism in serum and liver. It decreased the serum TMA and TMAO, regulated bile acid composition, participated in the farnesoid X receptor (FXR) pathway to improve lipid metabolism, and further reduced the aortic macrophage foam cell accumulation. In addition, the strain could improve the structure of the intestinal microbiome and reduce the proportion of Firmicutes and Bacteroidetes. The abundance of Turicibacter, Clostridium sensu stricto_1, and Romboutsia was reduced at the genus level. The differential microbiota is highly correlated with bile acid metabolism, which is speculated to be involved in ameliorating atherosclerotic lipid metabolism disorders.

The Association Between Serum Trimethylamine N-Oxide and Arterial Stiffness in Chronic Peritoneal Dialysis Patients: A Cross-Sectional Study.

Trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, participates in the atherogenesis and vascular stiffening that is closely linked with cardiovascular (CV) complications and related deaths in individuals with kidney failure undergoing peritoneal dialysis (PD) therapy. In these patients, arterial stiffness (AS) is also an indicator of adverse CV outcomes. This study assessed the correlation between serum TMAO concentration quantified with high-performance liquid chromatography and mass spectrometry and central AS measured by carotid-femoral pulse wave velocity (cfPWV) in patients with chronic PD. Of the 160 participants included, 23.8% had a cfPWV of ≥10 m/s, which fulfilled the AS criteria. Multivariable logistic regression analysis revealed that TMAO, age, and waist circumference were positively associated with AS. Multivariable stepwise linear regression showed that underlying diabetes, advanced age, waist circumference, systolic blood pressure, and logarithmic-transformed TMAO were independently correlated with cfPWV. The area under the receiver operating characteristic curve for TMAO in differentiating AS from non-AS was 0.737. In conclusion, serum TMAO level was significantly independently correlated with central AS among participants undergoing PD for end-stage kidney failure.

Correlation of Triethylamine N-oxide (TMAO), LPS, and TNF-Alpha Levels With Clinical Features of the Disease in Patients With and Without Septic Shock Infected With COVID-19 Virus

BackgroundInflammation is a response of the immune system to protect the body against various diseases or injuries. Serum trimethylamine N-oxide (TMAO) levels may vary depending on age, gender, habits, comorbidities, and microbiota. AimsIn this study, we investigated whether TMAO levels have diagnostic significance and their potential as a marker in the early diagnosis of the disease. Another aim of the research was to identify changes in TMAO levels as a reflection of the deterioration in the microflora, and IL-6, IL-10, IL-1β, TNF-alpha, and LPS levels in patient groups. Then, we recognized relationships between these parameters in patients infected with COVID-19 without septic shock and with COVID-19 who were without transmission of COVID-19 in septic shock. Study DesignA total of 160 patients were investigated, including 40 patients infected with COVID-19 without septic contact, 40 patients with COVID-19 positive septic shock, 40 patients with COVID-19 negative septic shock, and 40 healthy individuals as the control group. ResultsTNF-α and IL-1β levels were significantly lower (P < 0.001) and IL-6 and IL-10 levels were significantly higher (P < 0.001) in patient groups than in control groups. IL-1β showed a significant decrease, especially in the groups infected with COVID-19. Although IL-6, increased even more in the groups infected with COVID-19. ConclusionsLPS level was remarkably high in the sepsis group infected with COVID-19 compared to the other groups. TMAO level was significantly higher (P < 0.001) in the sepsis group. Therefore, TMAO is a potential biomarker in sepsis and septic shock.

Palmitoleic Acid Inhibits Hepatotoxic Effects by Reducing Trimethylamine-N-Oxide (TMAO) Formation in High L-Carnitine-Treated Mice.

This study investigated the effects of palmitoleic acid (POA) consumption on liver function, intestinal microbiota, and trimethylamine-N-oxide (TMAO) levels in the serum of mice treated with 3% L-carnitine drinking water. The purpose was to highlight the impact of POA on liver injury associated with high L-carnitine intake. A correlation analysis was carried out. The physiological and biochemical results showed that the administration of POA could alleviate liver injury induced by high L-carnitine ingestion, as reflected by a reduction in liver function indices (ALT, AST, AKP, and TBA activities) and modulation of antioxidant enzyme activities (SOD, GSH-Px, MDA, and RAHFR). The study also monitored the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Additionally, to assess the impact of POA on intestinal microbiota, we conducted a 16S rRNA high-throughput sequencing analysis. The findings indicated that POA administration resulted in lower levels of TMAO in treated mice. Furthermore, POA could regulate the composition of intestinal microbiota in L-carnitine mice, particularly affecting Bacteroides vulgatus, Parabacteroides distasonis, Alistipes shahii, Lachnospiraceae NK4A136 group, and Parasutterella secunda, which were closely related to liver injury. In summary, POA could repair liver damage caused by high intake of L-carnitine by regulating the distribution of intestinal flora and subsequently decreasing serum TMAO levels.

Small Molecule Inhibitor of Gut Microbial Choline Trimethylamine Lyase Reduces Serum Trimethylamine N-oxide and Slows the Loss of Kidney Function in a Rat Model of CKD

Small Molecule Inhibitor of Gut Microbial Choline Trimethylamine Lyase Reduces Serum Trimethylamine N-oxide and Slows the Loss of Kidney Function in a Rat Model of CKD

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.

Treatment with Gac Fruit Extract and Probiotics Reduces Serum Trimethylamine N-Oxide in Chronic Kidney Disease Rats.

Chronic kidney disease (CKD) affects more than 850 million people worldwide, contributing to morbidity and mortality, particularly through cardiovascular disease (CVD). The altered composition in CKD patients leads to increased production and absorption of uremic toxins such as trimethylamine (TMA) and its oxidized form, trimethylamine N-oxide (TMAO), which are associated with cardiovascular risks. This study investigated the potential of supplementary interventions with high-carotenoid-content gac fruit extract and probiotics to mitigate serum TMAO by modulating the gut microbiota. We conducted an animal study involving 48 male Wistar rats, divided into six groups: the control, CKD control, and four treatment groups receiving gac fruit extract, carotenoid extract, or combinations with Ligilactobacillus salivarius and Lactobacillus crispatus and Lactobacillus casei as a standard probiotic. CKD was induced in rats using cisplatin and they were supplemented with choline to enhance TMA production. The measures included serum creatinine, TMAO levels, gut microbiota composition, and the expression of fecal TMA lyase and intestinal zonula occluden-1 (ZO-1). CKD rats showed increased TMA production and elevated serum levels of TMAO. Treatment with gac fruit extract and selective probiotics significantly altered the composition of the gut microbiota by decreasing Actinobacteriota abundance and increasing the abundance of Bacteroides. This combination effectively promoted ZO-1 expression, reduced fecal TMA lyase, and subsequently lowered serum TMAO levels, demonstrating the therapeutic potential of these interventions. Our results highlight the benefits of gac fruit extract combined with probiotics for the effective reduction in serum TMAO levels in rats with CKD, supporting the further exploration of dietary and microbial interventions to improve outcomes in patients with CKD.

Association of Serum Trimethylamine-N-Oxide Concentration from Childhood to Early Adulthood with Age and Sex.

Primary prevention is the cornerstone of cardiometabolic health. In the randomized, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP), dietary counseling intervention was given to children from infancy to 20 years of age and a follow-up was completed at age 26 years. We investigated the associations of age, sex, gut microbiome, and dietary intervention with the gut metabolite and the cardiac biomarker trimethylamine-N-oxide (TMAO). Overall, 592 healthy participants (females 46%) from STRIP were investigated. Compared to the control group, the intervention group had received dietary counseling between ages 7 months and 20 years focused on low intakes of saturated fat and cholesterol and the promotion of fruit, vegetable, and whole-grain consumption. TMAO serum concentrations were measured by a liquid chromatography-tandem mass spectrometry method at ages 11, 13, 15, 17, 19, and 26 years. Microbiome composition was assessed using 16S rRNA gene sequencing at 26 years of age. TMAO concentrations increased from age 11 to 26 years in both sexes. At all measurement time points, males showed significantly higher serum TMAO concentrations compared to females, but concentrations were similar between the intervention and control groups. A direct association between TMAO concentrations and reported fiber intake was found in females. Gut microbiome analysis did not reveal associations with TMAO. TMAO concentration increased from childhood to early adulthood but was not affected by the given dietary intervention. In females, TMAO concentrations could be directly associated with higher fiber intake suggesting sex-specific differences in TMAO metabolism.

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.

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.

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.

Red meat intake, faecal microbiome, serum trimethylamine N-oxide and hepatic steatosis among Chinese adults.

Emerging evidence suggests a detrimental impact of high red meat intake on hepatic steatosis. We investigated the potential interplay between red meat intake and gut microbiome on circulating levels of trimethylamine N-oxide (TMAO) and hepatic steatosis risk. This cross-sectional study was conducted in a representative sample of 754 community-dwelling adults in Huoshan, China. Diet was collected using 4 quarterly 3 consecutive 24-h dietary (12-day) recalls. We profiled faecal microbiome using 16S ribosomal RNA sequencing and quantified serum TMAO and its precursors using LC-tandem MS (n = 333). We detected hepatic steatosis by FibroScan. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression. TMAO levels but not its precursors were positively associated with the likelihood of hepatic steatosis (aOR per 1-SD increment 1.86, 95% CI 1.04-3.32). We identified 14 bacterial genera whose abundance was associated with TMAO concentration (pFDR < .05) belonging to the phyla Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria families. Per 10 g/day increase in red meat intake was positively associated with TMAO levels among participants who had higher red meat intake (>70 g/day) and higher TMAO-predicting microbial scores (TMS, β = .045, p = .034), but not among others (pinteraction = .030). TMS significantly modified the positive association between red meat and steatosis (pinteraction = .032), with a stronger association being observed among participants with higher TMS (aOR 1.30, 95% CI 1.07-1.57). The bacterial genera that predicted TMAO levels may jointly modify the association between red meat intake and TMAO levels and the subsequent risk of hepatic steatosis.

Randomized clinical trial evaluating the efficacy of synbiotic supplementation on serum endotoxin and trimethylamine N-oxide levels in patients with dyslipidaemia.

Elevated serum endotoxin and trimethylamine N-oxide (TMAO) are associated with metabolic disorders including dyslipidaemia and insulin resistance. This study aimed to evaluate the impact of a 12-week treatment with a synbiotic supplement on serum endotoxin and TMAO levels in patients diagnosed with dyslipidaemia. A total of 56 patients who met the study inclusion criteria were recruited in this randomized, double-blind clinical trial. Participants were randomly assigned into intervention and control groups and received either synbiotic or placebo sachets twice a day for 12 weeks. The sociodemographic data, food intake, physical activity, and anthropometric indices of participants were assessed before and after intervention. Serum endotoxin, TMAO, and fasting blood glucose (FBG) levels were measured at the baseline and end of the study. No significant difference in the baseline characteristics of participants in the 2 groups was observed. After the 12 weeks of intervention, the mean of serum endotoxin (p < 0.0001), TMAO (p < 0.0001), and FBG (p < 0.0001) was decreased in patients who received synbiotic supplements while no significant change was observed in the control group. Moreover, a significant positive correlation between changes in endotoxin (r = 0.41, p = 0.041) and TMAO (r = 0.40, p = 0.047) with FBG changes was observed. A significant reduction in serum endotoxin and TMAO levels, as well as improvements in FBG, following 12 weeks of supplementation with synbiotics, may offer a potential approach for improving metabolic status in patients with dyslipidaemia.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10[95% CI] =1.90 [CI, 1.24-2.92; p=.003] and 1.26 [1.17-1.36; p<.0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI]=0.77 [0.76-0.79; p<.001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho=0.10; p=.0003). Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Association of serum trimethylamine N-oxide levels and bone mineral density in type 2 diabetes mellitus.

The relationship between trimethylamine N-oxide (TMAO) and bone mineral density (BMD) in type 2 diabetes mellitus (T2DM) is unclear. We explore the relationship between TMAO levels and BMD in T2DM. This is a cross-sectional study. 254 T2DM patients were enrolled and divided into three groups by TMAO tertiles, and the clinical data were collected. BMD was determined by dual-energy X-ray absorptiometry (DXA) and serum TMAO levels was determined by stable isotope dilution high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Patients in the highest tertile of TMAO levels (TMAO > 6.72 μmol/L) showed relatively low BMD and a higher number of fracture history, osteoporosis (OP) than those in the lower tertiles. Spearman correlation analysis showed that serum TMAO was negatively correlated with BMD of whole body (WB), lumbar spine (LS) and femoral neck (FN), while TMAO was positive correlated with osteoporotic fracture (p < 0.05). Logistic regression models showed that TMAO was an independent influencing factor of fracture history after adjusting for confounders in TMAO > 6.72 μmol/L group. There is a significant linear correlation between TMAO levels and BMD in T2DM patients. Especially in TMAO > 6.72 μmol/L group, TMAO was negatively correlated with WB, LS, and FN BMD, and was positive correlated with osteoporotic fracture in T2DM patients. The findings suggest that elevated TMAO levels are associated with OP and osteoporotic fracture in T2DM patients.

Association Between Trimethylamine N-oxide and Adverse Kidney Outcomes and Overall Mortality in Type 2 Diabetes Mellitus.

Type 2 diabetes (T2D) is the major contributor to chronic kidney disease and end-stage kidney disease (ESKD). The influence of trimethylamine N-oxide (TMAO) on kidney outcomes in T2D remains unclear. To examine the association between fasting serum TMAO levels and adverse kidney outcomes in patients with T2D. Between October 2016 and June 2020, patients with T2D were recruited and monitored every 3 months until December 2021. Serum TMAO levels were assessed using liquid chromatography-mass spectrometry. The primary kidney outcomes were doubling of serum creatinine levels or progression to ESKD necessitating dialysis; the secondary kidney outcome was a rapid 30% decline in estimated glomerular filtration rate within 2 years. All-cause mortality was also evaluated. Among the 440 enrolled patients with T2D, those in the highest serum TMAO tertile (≥0.88 μM) were older, had a longer diabetes duration, elevated blood urea nitrogen, and lower estimated glomerular filtration rate. Over a median follow-up period of 4 years, 26 patients (5.9%) had a doubling of serum creatinine level or progression to ESKD. After propensity score weighting, the patients in the highest serum TMAO tertile had a 6.45-fold increase in the risk of doubling of serum creatinine levels or progression to ESKD and 5.86-fold elevated risk of rapid decline in kidney function compared with those in the lowest tertile. Additionally, the stepwise increase in serum TMAO was associated with all-cause mortality. Patients with T2D with elevated circulating TMAO levels are at higher risk of doubling serum creatinine, progressing to ESKD, and mortality. TMAO is a potential biomarker for kidney function progression and mortality in patients with T2D.