Serum Trimethylamine N-oxide Levels Research Articles

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.

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.

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.

Empagliflozin Mitigates TMAO-Induced NLRP3 Inflammation and Alters Transporter Expression in Renal Proximal Tubular Cells

The gut-microbe-derived metabolite, trimethylamine N-oxide (TMAO), not only exhibits elevated levels but also serves as a predictor of higher mortality in patients with chronic kidney disease (CKD). In additional to CKD, elevated TMAO levels were also observed in organic anion transporter 3 (OAT 3) knockout mice and in the presence of trimethoprim, an antibiotic known for inhibiting multiple transporters on renal proximal tubule (PT) cells. These findings suggest that plasma TMAO level is a marker for diminished transporter function in PT cells. Moreover, the pro-inflammatory effects of TMAO on PT cells is relatively underexplored. Besides reno-protective effect, a recent study has shown that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin attenuates hyperuricemia by enhancing efflux transporter function. Therefore, we propose that empagliflozin can ameliorate TMAO-induced inflammation in PT cells by regulating the expression of membrane transporters. Western blotting results revealed that empagliflozin mitigated TMAO-induced NLRP3 inflammatory cytokines IL-1β, and IL-18. Additionally, empagliflozin reduced the elevated serum levels of TMAO in a CKD mouse model resulting from 5/6 nephrectomy (5/6Nx). Immuno-fluorescent staining demonstrated that TMAO decreased the expression of the basolateral transporter organic anion transporter 1 (OAT1) but increased the expression of apical membrane transporters ATP-binding cassette super-family G member 2 (ABCG2) on the PT cells of 5/6Nx mice. Our in vitro study indicated that TMAO reduced the expression of basolateral membrane transporters OAT1 and OAT3. But empagliflozin significantly increased the expression of OAT3 and ABCG2 in TMAO-treated HK-2 cells. In summary, TMAO induced NLRP3 inflammation in PT cells, while empagliflozin ameliorated the inflammation. Empagliflozin also lowered TMAO levels and influenced transporter expressions in a CKD mouse model. In conclusion, we have shown that empagliflozin mitigate TMAO-induced NLRP3 inflammation. Beyond inhibiting SGLT2, empagliflozin possesses additional effect on the expression of membrane transporters in PT, particularly in CKD mice. This research was funded by Chang Gung Medical Foundation CMRPG8K0011 and CMRPG8M0311. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

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.

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.

Serum levels of trimethylamine N-oxide and kynurenine novel biomarkers are associated with adult metabolic syndrome and its components: a case-control study from the TEC cohort.

Epidemiologic research suggests that gut microbiota alteration (dysbiosis) may play a role in the pathogenesis of metabolic syndrome (MetS). Dysbiosis can influence Trimethylamine N-oxide (TMAO) a gut microbiota-derived metabolite, as well as kynurenine pathways (KP), which are known as a new marker for an early predictor of chronic diseases. Hence, the current study aimed to investigate the association between KYN and TMAO with MetS and its components. This case-control study was conducted on 250 adults aged 18 years or over of Tehran University of Medical Sciences (TUMS) Employee's Cohort study (TEC) in the baseline phase. 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 FFQ with 144 items. MetS was defined according to the NCEP ATP criteria. Serum profiles TMAO and KYN were measured by standard protocol. The mean level of TMAO and KYN in subjects with MetS was 51.49 pg/mL and 417.56 nmol/l. High levels of TMAO (≥30.39 pg/mL) with MetS were directly correlated, after adjusting for confounding factors, the odds of MetS in individuals 2.37 times increased (OR: 2.37, 95% CI: 1.31-4.28, P-value = 0.004), also, high levels of KYN (≥297.18 nmol/L) increased odds of Mets+ 1.48 times, which is statistically significant (OR: 1.48, 95% CI: 0.83-2.63, P-value = 0.04). High levels of TMAO compared with the reference group increased the odds of hypertriglyceridemia and low HDL in crude and adjusted models (P < 0.05). Additionally, there was a statistically significant high level of KYN increased odds of abdominal obesity (P < 0.05). Our study revealed a positive association between serum TMAO and KYN levels and MetS and some of its components. For underlying mechanisms and possible clinical implications of the differences. Prospective studies in healthy individuals are necessary.

CHRONIC HIGH-FAT DIET CONSUMPTION ACCELERATES OSTEOBLAST DYSFUNCTION AND OSTEOPOROSIS BY GUT MICROBIAL METABOLITE TRIMETHYLAMINE-N-OXIDE

Obesity is correlated with the development of osteoporotic diseases. Gut microbiota-derived metabolite trimethylamine-n-oxide (TMAO) accelerates obesity-mediated tissue deterioration. This study was aimed to investigate what role TMAO may play in osteoporosis development during obesity.Mice were fed with high-fat diet (HFD; 60 kcal% fat) or chow diet (CD; 10 kcal% fat) or 0.2% TMAO in drinking water for 6 months. Body adiposis and bone microstructure were investigated using μCT imaging. Gut microbiome and serum metabolome were characterized using 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry. Osteogenic differentiation of bone-marrow mesenchymal cells was quantified using RT-PCR and von Kossa staining. Cellular senescence was evaluated by key senescence markers p16, p21, p53, and senescence association β-galactosidase staining.HFD-fed mice developed hyperglycemia, body adiposis and osteoporosis signs, including low bone mineral density, sparse trabecular microarchitecture, and decreased biomechanical strength. HFD consumption induced gut microbiota dysbiosis, which revealed a high Firmicutes/Bacteroidetes ratio and decreased α-diversity and abundances of beneficial microorganisms Akkermansiaceae, Lactobacillaceae, and Bifidobacteriaceae. Serum metabolome uncovered increased serum L-carnitine and TMAO levels in HFD-fed mice. Of note, transplantation of fecal microbiota from CD-fed mice compromised HFD consumption-induced TMAO overproduction and attenuated loss in bone mass, trabecular microstructure, and bone formation rate. TMAO treatment inhibited trabecular and cortical bone mass and biomechanical characteristics; and repressed osteogenic differentiation capacity of bone-marrow mesenchymal cells. Mechanistically, TMAO accelerated mitochondrial dysfunction and senescence program, interrupted mineralized matrix production in osteoblasts.Gut microbial metabolite TMAO induced osteoblast dysfunction, accelerating the development of obesity-induced skeletal deterioration. This study, for the first time, conveys a productive insight into the catabolic role of gut microflora metabolite TMAO in regulating osteoblast activity and bone tissue integrity during obesity.

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

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

Serum Trimethylamine N-Oxide, Choline, Betaine, and Carnitine levels among Coronary Artery Disease patients

Background and aimRecent studies have linked Trimethylamine N-oxide (TMAO) to cardiovascular diseases; our study aimed to analyze the association between coronary artery disease (CAD) and TMAO. MethodsPubMed, Scopus, Embase, and Web of Science were searched using terms; such as “CAD” and “TMAO”. Only observational controlled studies were included. RevMan software version 5.4 was used for the analysis. ResultsA significant association was found between the CAD group and increased serum TMAO levels compared with the control group (MD = 1.16, 95% CI = 0.54 to 1.78, p-value =0.0003). This association remained significant among acute coronary syndrome (ACS) patients (MD=0.98, 95% CI =0.73 to 1.23, p-value <0.00001) and was also detected among young and old CAD patients (MD = 0.35, 95% CI = 0.06 to 0.64, p-value = 0.02 and MD = 1.36, 95% CI = 0.71 to 2.01, p-value <0.0001, respectively). On further analysis of intestinal metabolites, we detected an insignificant association between choline, betaine, carnitine, and CAD. According to our sensitivity analysis, TMAO is an acceptable discriminatory marker for CAD (0.721, SE was 0.0816, 95% CI 0.561 to 0.881). ConclusionTMAO is an acceptable discriminatory marker for CAD, with significantly higher levels among these patients regardless of their age. Other metabolites didn't show such an association. The role of serum level TMAO in the early diagnosis of CAD should be further explored.

Investigation of serum trimethylamine-N-oxide levels in missed abortion: A prospective study.

The aim of our study was to investigate the relationship between missed abortion and serum trimethylamine N-oxide (TMAO) levels. A total of 129 patients with 56 missed abortions and 73 healthy pregnancies were included in our study. Patients who had more than one pregnancy loss, had systemic disease (hypertension, diabetes, rheumatologic disease, hematologic disease, and so forth) and did not accept to participate in the study were excluded. Pregnant women who did not have a fetal heartbeat in the first 20th week of pregnancy were considered as missed abortion. Demographic characteristics of the patients were recorded. The serum TMAO levels of these patients were compared with the serum TMAO levels of healthy pregnant women with the same gestational week between the two groups. The median (IQR) serum level of TMAO was significantly higher in woman with missed abortus compared to the healthy controls (201.5 [IQR, 129.75-345] vs 150 [IQR, 86.9-273], U = 1534, P = 0.015, rrb = 0.25 [95% CI: 0.05-0.43]). We observed a positive and significant relationship between serum TMAO levels and age of the patients (Spearman's rho = 0.272 [95% CI: 0.01-0.50], P = 0.043). However, no significant relationship was found between serum TMAO levels and BMI (Spearman's rho = 0.093 [95% CI: -0.18 to 0.35], P = 0.496). In our study, we found that the serum TMAO level was higher in patients with missed abortion compared to healthy pregnancies. Serum TMAO levels measured at early gestational weeks can provide information about the course of pregnancy.

Higher serum trimethylamine N-oxide (TMAO) levels are associated with increased visceral fat in hemodialysis patients.

Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has emerged as a new potentially important cause of increased atherosclerosis and cardiovascular risk in chronic kidney disease (CKD) patients. However, the possible causes whereby TMAO potentiates atherosclerosis development remain poorly defined. The strong association between gut microbiota and obesity suggested that the TMAO pathway may be linked to the pathogenesis of obesity. A total of 184 hemodialysis (HD) patients and 38 healthy controls were enrolled in the study from March 2019 to May 2019. We evaluated visceral fat area (VFA) by anthropometric measurement and measured serum TMAO concentrations using liquid chromatography/differential ion mobility spectrometry tandem mass spectrometry. We also examined the relationship between TMAO levels and visceral fat accumulation. TMAO level was markedly higher in HD patients than in control subjects (5.80 (3.96, 9.46) vs. 0.18 (0.11, 0.32) µg/mL, p<0.01), and its level in diabetic HD patients was significantly higher than in nondiabetic patients (6.93 (4.67, 11.40) vs. 5.25 (3.78, 8.02) µg/mL, p<0.01). A significant positive correlation was found between serum TMAO level and VFA in these patients (r=0.282, p=0.005). Multiple regression analysis showed that Ln(TMAO) was independently associated with Ln(VFA) in HD patients (p=0.008). Our results showed that there was a significant positive correlation between serum TMAO levels and visceral fat in HD patients, which suggested that TMAO may predict cardiovascular risk through increased visceral fat.

Serum trimethylamine N-oxide levels among coronary artery disease and acute coronary syndrome patients: a systematic review and meta-analysis

Background and Aim: Recent studies have linked trimethylamine N-oxide (TMAO) to cardiovascular diseases; our study aimed to analyze the association between coronary artery disease (CAD), acute coronary syndrome (ACS), and TMAO. Methods: PubMed, Scopus, Embase, and Web of Science were searched using terms such as ʻCADʼ and ʻTMAOʼ. Only observational controlled studies were included. RevMan software version 5.4 was used for the analysis. Results: A significant association was found between the CAD group and increased serum TMAO levels compared with the control group (MD=1.16, 95% CI=0.54–1.78, P=0.0003). This association remained significant among acute coronary syndrome patients (MD=0.98, 95% CI=0.73–1.23, P&lt;0.00001) and was also detected among young and old CAD patients (MD=0.35, 95% CI=0.06–0.64, P=0.02 and MD=1.36, 95% CI=0.71–2.01, P&lt;0.0001, respectively). On further analysis of intestinal metabolites, the authors detected an insignificant association between choline, betaine, carnitine, and CAD. According to our sensitivity analysis, TMAO is an acceptable diagnostic marker for CAD (0.721, SE was 0.0816, 95% CI: 0.561–0.881). Conclusion: TMAO is an acceptable diagnostic marker for CAD, with significantly higher levels among these patients regardless of their age. Other metabolites did not show such an association. The role of serum level TMAO in the early diagnosis of CAD should be further explored.

Abstract 13681: Association of Serum Trimethylamine N-oxide Levels With Cardiovascular Disease and All-Cause Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies

Background: Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite of red meat, has emerged as a potential biomarker for CVD and all-cause mortality. It is also found in preformed amounts in fish. However, the association between serum TMAO levels and CVD outcomes remain unclear. Aim: To conduct a systematic review and dose-response meta-analysis evaluating the association between serum TMAO and CVD and all-cause mortality in prospective cohort studies. Methods: A comprehensive literature search was conducted in MEDLINE, EMBASE, and Cochrane Library up to and including March 6, 2023. A manual search through references found in reviews and meta-analyses was also conducted. Studies reporting hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs) for the association between serum TMAO levels and CVD or all-cause mortality in adults ≥ 18 years with follow-up of ≥ 1 year were included. Random-effects models were utilized for pooled risk estimates and assess the dose-response. GRADE was used to evaluate certainty of evidence. Results: 2459 papers, 44 prospective cohort studies were included involving 84771 participants included in final analysis (fig.1). Pooled analyses revealed a significant positive association between elevated serum TMAO levels and the risk of total CVD (RR 1.29 [1.16-1.44]), CVD mortality (RR 1.51 [1.23-1.87]) and all-cause mortality (RR 1.30 [1.21,1.39]). Non-significant associations were found for MI, stroke, total CHD, MI mortality and CHD mortality. All outcomes were of low to very low certainty.Dose response analysis revealed a significant linear association with all-cause mortality (RR 1.01 [95% CI 1.01, 1.02] per 2μM/L) up to a threshold of 6μM/L and total CVD (RR 1.04 [1.02-1.06]). Conclusion: This study provides evidence supporting the positive association of serum TMAO levels with increased risk of total CVD, CVD mortality and all-cause mortality. A recent review found 13/15 studies demonstrated a strong positive correlation between TMAO and fish intake, complicating the hypotheses relating TMAO in red meat and CVD risk. Thus, further assessments of diet components are needed to explore the clinical implications of the associations found in our study.

Serum Trimethylamine N-Oxide Level Is Positively Associated with Aortic Stiffness Measured by Carotid-Femoral Pulse Wave Velocity in Patients Undergoing Maintenance Hemodialysis.

Trimethylamine N-oxide (TMAO) is a biomarker that is effective in predicting major adverse cardiovascular (CV) events. Age-related vascular problems are significantly affected by aortic stiffness (AS), which is independently linked to CV morbidity and mortality. This study aimed to determine the association between serum TMAO levels and carotid-femoral pulse wave velocity (cfPWV) in patients receiving hemodialysis (HD) therapy. In total, 115 patients with HD were enrolled in this study. The AS group included patients whose cfPWV was >10 m/s. Using high-performance liquid chromatography and mass spectrometry, the levels of serum TMAO were measured. The AS group included 42 (36.5%) patients, and compared with the non-AS group, the rates of diabetes, hypertension, older age, systolic blood pressure, serum glucose, and TMAO levels were high. In the multivariate logistic regression analysis, serum TMAO and age were independently linked with AS after correcting for the factors significantly associated with AS. Following multivariate stepwise linear regression analysis, serum TMAO in these individuals was found to be strongly correlated with cfPWV values (p < 0.001). In patients on chronic HD, serum TMAO level is an independent measure of AS and strongly correlated with cfPWV.

Serum trimethylamine N-oxide and lipopolysaccharide binding protein levels among children diagnosed with autism spectrum disorder.

In the literature, there have been several studies available investigating the relationship between autism spectrum disorder and intestinal permeability. In this study, it is aimed to examine the relationship between the levels of trimethylamine N-oxide (TMAO), which is a parameter associated with intestinal permeability, and lipopolysaccharide binding protein (LBP), which is a marker associated with bacterial translocation from the intestine, in patients with autism spectrum disorder (ASD) and healthy controls. Fifty-three children with ASD as the patient group and 30 healthy children as the control group have been included in the study. The diagnostic evaluation has been made according to DSM-5 criteria. According to the obtained results, there has been no significant difference between groups in terms of serum TMAO and LBP levels. Considering the existence of various studies that found different results on ASD and intestinal permeability, it is thought that the studies conducted in this field that did not find statistically different results will also make a contribution to the literature.

Alterations in trimethylamine-N-oxide in response to Empagliflozin therapy: a secondary analysis of the EMMY trial

IntroductionThe relationship between sodium glucose co-transporter 2 inhibitors (SGLT2i) and trimethylamine N-oxide (TMAO) following acute myocardial infarction (AMI) is not yet explored.MethodsIn this secondary analysis of the EMMY trial (ClinicalTrials.gov registration: NCT03087773), changes in serum TMAO levels were investigated in response to 26-week Empagliflozin treatment following an AMI compared to the standard post-MI treatment. Additionally, the association of TMAO changes with clinical risk factors and cardiorenal biomarkers was assessed.ResultsThe mean age of patients (N = 367) was 57 ± 9 years, 82% were males, and 14% had type 2 diabetes. In the Empagliflozin group, the median TMAO value was 2.62 µmol/L (IQR: 1.81) at baseline, 3.74 µmol/L (2.81) at 6 weeks, and 4.20 µmol/L (3.14) at 26 weeks. In the placebo group, the median TMAO value was 2.90 µmol/L (2.17) at baseline, 3.23 µmol/L (1.90) at 6 weeks, and 3.35 µmol/L (2.50) at 26 weeks. The serum TMAO levels increased significantly from baseline to week 6 (coefficient: 0.233; 95% confidence interval 0.149–0.317, p < 0.001) and week 26 (0.320, 0.236–0.405, p < 0.001). The average increase in TMAO levels over time (pinteraction = 0.007) was significantly higher in the Empagliflozin compared to the Placebo group. Age was positively associated with TMAO, whereas eGFR and LVEF were negatively associated with TMAO.ConclusionsOur results are contrary to existing experimental studies that showed the positive impact of SGLT2i on TMAO precursors and cardiovascular events. Therefore, we recommend further research investigating the impact of SGLT2i therapy on acute and long-term changes in TMAO in cardiovascular cohorts.