Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.
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ABSTRACT:
SUBMITTER: Andrikopoulos P
PROVIDER: S-EPMC10511707 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.
Andrikopoulos Petros P Aron-Wisnewsky Judith J Chakaroun Rima R Myridakis Antonis A Forslund Sofia K SK Nielsen Trine T Adriouch Solia S Holmes Bridget B Chilloux Julien J Vieira-Silva Sara S Falony Gwen G Salem Joe-Elie JE Andreelli Fabrizio F Belda Eugeni E Kieswich Julius J Chechi Kanta K Puig-Castellvi Francesc F Chevalier Mickael M Le Chatelier Emmanuelle E Olanipekun Michael T MT Hoyles Lesley L Alves Renato R Helft Gerard G Isnard Richard R Køber Lars L Coelho Luis Pedro LP Rouault Christine C Gauguier Dominique D Gøtze Jens Peter JP Prifti Edi E Froguel Philippe P Zucker Jean-Daniel JD Bäckhed Fredrik F Vestergaard Henrik H Hansen Torben T Oppert Jean-Michel JM Blüher Matthias M Nielsen Jens J Raes Jeroen J Bork Peer P Yaqoob Muhammad M MM Stumvoll Michael M Pedersen Oluf O Ehrlich S Dusko SD Clément Karine K Dumas Marc-Emmanuel ME
Nature communications 20230920 1
The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composi ...[more]
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Project description:IntroductionPrevious studies have reported a potential association between trimethylamine N-oxide (TMAO) and Parkinson's disease (PD). The objective of this study was to examine the potential relationship between the levels of circulating TMAO and its precursors and the risk of PD using a two-sample Mendelian randomization (MR) approach.Material and methodsWe aggregated data from three genome-wide association studies (International Parkinson's Disease Genomics Consortium, Parkinson's Research: The Organized Genetics Initiative and GenePD, and FinnGen) to extract single-nucleotide polymorphisms (SNPs) associated with circulating concentrations of TMAO, choline, carnitine, and betaine. These SNPs were employed as instrumental variables in a random-effects model to evaluate the causal relationship between circulating concentrations of TMAO and its precursors and the risk of Parkinson's disease, by estimating odds ratios with accompanying 95% confidence intervals. The primary analysis employed the inverse variance-weighted (IVW) method, which was complemented with MR-Egger regression analysis.ResultsThe analysis using the IVW method, which aggregated data from the three databases, did not show any causal relationship between circulating concentrations of TMAO and its precursors, and the risk of PD (p > 0.05). This finding was further confirmed by the results of the MR-Egger analysis. A sensitivity analysis demonstrated that the results were not influenced by any biases, and a heterogeneity test indicated no significant variation among the SNPs.ConclusionsThis study did not identify any conclusive evidence of a causal association between the circulating concentrations of TMAO or its precursors and the risk of PD. Further investigation is warranted to determine whether such an association indeed exists.
| S-EPMC11831356 | biostudies-literature
Project description:Trimethylamine N-oxide (TMAO) is a diet and gut microbiota-derived metabolite that has been linked to cardiovascular disease risk in human studies and animal models. TMAO levels show wide inter and intra individual variability in humans that can likely be accounted for by multiple factors including diet, the gut microbiota, levels of the TMAO generating liver enzyme Flavin-containing monooxygenase 3 (FMO3) and kidney function. We recently found that dioxin-like (DL) environmental pollutants increased FMO3 expression to elevate circulating diet-derived TMAO in mice, suggesting that exposure to this class of pollutants might also contribute to inter-individual variability in circulating TMAO levels in humans. To begin to explore this possibility we examined the relationship between body burden of DL pollutants (reported by serum lipid concentrations) and serum TMAO levels (n = 340) in the Anniston, AL cohort, which was highly exposed to polychlorinated biphenyls (PCBs). TMAO concentrations in archived serum samples from the Anniston Community Health Survey (ACHS-II) were measured, and associations of TMAO with 28 indices of pollutant body burden, including total dioxins toxic equivalent (TEQ), were quantified. Twenty-three (22 after adjustment for multiple comparisons) of the 28 indices were significantly positively associated with TMAO. Although the design of ACHS-II does not enable quantitative assessment of the contributions of previously known determinants of TMAO variability to this relationship, limited multivariate modeling revealed that total dioxins TEQ was significantly associated with TMAO among females (except at high BMIs) but not among males. Our results from this cross-sectional study indicate that exposure to DL pollutants may contribute to elevated serum TMAO levels. Prospective longitudinal studies will be required to assess the joint relationship between DL pollutant exposures, other determinants of TMAO, and health outcomes.
| S-EPMC5811317 | biostudies-literature
Project description:BackgroundWhile several risk factors for knee osteoarthritis (KOA) have been recognized, the pathogenesis of KOA and the causal relationship between modifiable risk factors and KOA in genetic epidemiology remain unclear. This study aimed to determine the causal relationship between KOA and its risk factors.MethodsData were obtained from published Genome-Wide Association study (GWAS) databases. A two-sample Mendelian randomization (MR) analysis was performed with genetic variants associated with risk factors as instrumental variables and KOA as outcome. First, inverse variance weighting was used as the main MR analysis method, and then a series of sensitivity analyses were conducted to comprehensively evaluate the causal relationship between them.ResultsUnivariate forward MR analysis revealed that genetically predicted hypothyroidism, hyperthyroidism/thyrotoxicosis, educational level, income level, metabolic syndrome (MS), essential hypertension, height, hot drink temperature, diet (abstaining from sugar-sweetened or wheat products), and psychological and psychiatric disorders (stress, depression, and anxiety) were causally associated with KOA. Reverse MR exhibits a causal association between KOA and educational attainment. Multivariate MR analysis adjusted for the inclusion of potential mediators, such as body mass index (BMI), smoking, alcohol consumption, and sex, exhibited some variation in causal effects. However, hyperthyroidism/thyrotoxicosis had a significant causal effect on KOA, and there was good evidence that height, hypothyroidism, educational level, psychological and psychiatric disorders (stress, depression, and anxiety), and abstaining from wheat products had an independent causal relationship. The mediating effect of BMI as a mediator was also identified.ConclusionThis study used MR to validate the causal relationship between KOA and its risk factors, providing new insights for preventing and treating KOA in clinical practice and for developing public health policies.
| S-EPMC11402680 | biostudies-literature
Project description:Trimethylamine N-oxide (TMAO) is a metabolite originated from bacterial metabolism of choline-rich foods. Evidence suggests an association between TMAO and atherosclerosis, but the relationship between TMAO and endothelial progenitor cells (EPCs) remains unclear. This study aimed to identify the relationship between TMAO concentrations, circulating EPCs, and endothelial function in patients with stable angina. Eighty-one stable angina subjects who underwent coronary angiography were enrolled. The circulating EPCs and flow-mediated vasodilation (FMD) were measured to evaluate endothelial function. Plasma TMAO and inflammatory markers, such as hsCRP and IL-1β, were determined. Furthermore, the effect of TMAO on EPCs was assessed in vitro. Patients with lower FMD had significantly decreased circulating EPCs, elevated TMAO, hsCRP, and IL-1β concentrations. Plasma TMAO levels were negatively correlated with circulating EPC numbers and the FMD, and positively correlated with hsCRP, IL-1β concentrations. In in vitro studies, incubation of TMAO in cultured EPCs promoted cellular inflammation, elevated oxidative stress, and suppressed EPC functions. Enhanced plasma TMAO levels were associated with reduced circulating EPCs numbers, endothelial dysfunction, and more adverse cardiovascular events. These findings provided evidence of TMAO's toxicity on EPCs, and delivered new insight into the mechanism of TMAO-mediated atherosclerosis, which could be derived from TMAO-downregulated EPC functions.
| S-EPMC6414518 | biostudies-literature
Project description:BackgroundTrimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described.ObjectivesThe objective of this study was to identify dietary predictors of plasma TMAO concentrations.MethodsTMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations.ResultsIn models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P < 0.001). There was no association between red meat intake and TMAO concentrations. The unhealthful plant-based diet index (uPDI) was inversely associated (β = -0.013; 95% CI: -0.021, -0.005; P = 0.001) and healthy dietary scores were positively correlated with TMAO concentration.ConclusionsTMAO concentration was significantly associated with fish intake, but not with red meat consumption. uPDI, an unhealthy dietary pattern, was inversely related to TMAO concentration. As such, this study suggests that in free-living populations, higher circulating concentrations of TMAO cannot simply be interpreted as a marker of unhealthy food intake or an unhealthy dietary pattern.
| S-EPMC7727477 | biostudies-literature
Project description:For a long time, the decline in lung function has been regarded as a potential factor associated with the risk of osteoporosis (OP). Although several observational studies have investigated the relationship between lung function and OP, their conclusions have been inconsistent. Given that Mendelian randomization (MR) studies can help reduce the interference of confounding factors on outcomes, we adopted this approach to explore the causal relationship between lung function and OP at the genetic level. To investigate the potential causality between lung function (FVC, FEV1, FEV1/FVC, PEF) and OP, we conducted a MR analysis employing three approaches: inverse variance weighted (IVW), MR-Egger, and weighted median. We used Cochran's Q test to detect potential heterogeneity, MR-Egger regression to evaluate directional pleiotropy, and the MR-PRESSO method to evaluate horizontal pleiotropy. In addition, we used MR-PRESSO and MR radial methods to exclude SNPs exhibiting pleiotropic outliers. Upon identification of potential outliers, we removed them and subsequently ran MR analysis again to assess the reliability of our findings. The MR analysis suggested that there was no causal effect of lung function (FVC, PEF, FEV1/FVC, FEV1) on OP, which is consistent with the. results after excluding potential outliers using MR-PRESSO and MR radial. methods. Sensitivity analysis confirmed the reliability and consistency of these. results. The study concluded that there is no causal link between lung function and OP. The association found in observational studies might be attributable to shared risk factors.
| S-EPMC11487126 | biostudies-literature
Project description:Elevated circulating trimethylamine N-oxide (TMAO) concentrations have been observed in patients with chronic kidney disease (CKD). We aimed to systematically estimate and quantify the association between TMAO concentrations and kidney function. The PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science databases were systematically searched from 1995 to 1 June, 2020, for clinical studies on circulating TMAO concentrations and kidney function indicators. We used R software to conduct meta-analyses of the extracted data. A cumulative meta-analysis was applied to test whether health status affected the pooled effect value. Meta-regression and subgroup analyses were performed to identify possible sources of heterogeneity. Ultimately, we included a total of 32 eligible clinical studies involving 42,062 participants. In meta-analyses of continuous-outcome variables, advanced CKD was associated with a 67.9 μmol/L (95% CI: 52.7, 83.2; P < 0.01) increase in TMAO concentration, and subjects with high concentrations of TMAO had a 12.9 mL/(min·1.73 m2) (95% CI: -16.6, -9.14; P < 0.01) decrease in glomerular filtration rate (GFR). In meta-analyses of the correlations, TMAO was strongly inversely correlated with GFR [Fisher's z-transformed correlation coefficient (ZCOR): -0.45; 95% CI: -0.58, -0.32; P < 0.01] and positively associated with the urine albumin-to-creatinine ratio (UACR; ZCOR: 0.26; 95% CI: 0.08, 0.43; P < 0.01), serum creatinine (sCr; ZCOR: 0.43; 95% CI: 0.28, 0.58; P < 0.01), urine albumin excretion rate (UAER; ZCOR: 0.06; 95% CI: 0.04, 0.09; P < 0.01), blood urea (ZCOR: 0.50; 95% CI: 0.29, 0.72; P < 0.01), blood uric acid (ZCOR: 0.32; 95% CI: 0.25, 0.38; P < 0.01), and serum cystatin C (CysC; ZCOR: 0.47, 95% CI: 0.44, 0.51; P < 0.01). This is the first systematic review and meta-analysis to reveal a negative association between circulating TMAO concentrations and kidney function.
| S-EPMC8321840 | biostudies-literature
Project description:PurposeSome species of fish and seafood are high in trimethylamine N-oxide (TMAO), which accumulates in muscle where it protects against pressure and cold. Trimethylamine (TMA), the metabolic precursor to TMAO, is formed in fish during bacterial spoilage. Fish intake is promoted for its potential cardioprotective effects. However, numerous studies show TMAO has pro-atherothrombotic properties. Here, we determined the effects of fish or seafood consumption on circulating TMAO levels in participants with normal renal function.MethodsTMAO and omega-3 fatty acid content were quantified across multiple different fish or seafood species by mass spectrometry. Healthy volunteers (n = 50) were recruited for three studies. Participants in the first study consented to 5 consecutive weekly blood draws and provided dietary recall for the 24 h preceding each draw. In the second study, TMAO levels were determined following defined low and high TMAO diets. Finally, participants consumed test meals containing shrimp, tuna, fish sticks, salmon or cod. TMAO levels were quantified by mass spectrometry in blood collected before and after dietary challenge.ResultsTMAO + TMA content varied widely across fish and seafood species. Consumption of fish sticks, cod, and to a lesser extent salmon led to significant increases in circulating TMAO levels. Within 1 day, circulating TMAO concentrations in all participants returned to baseline levels.ConclusionsWe conclude that some fish and seafood contain high levels of TMAO, and may induce a transient elevation in TMAO levels in some individuals. Selection of low TMAO content fish is prudent for subjects with elevated TMAO, cardiovascular disease or impaired renal function.
| S-EPMC9283263 | biostudies-literature
Project description:Circulating triglyceride (TG) and leukocytes, the main components of the vascular system, may impact each other and co-fuel atherosclerosis. While the causal relationship between plasma TG levels and leukocyte counts remains unclear. Bidirectional Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationship between TG levels and the counts of leukocytes and their subtypes. A cross-lagged panel model (CLPM) using longitudinal healthy screening data (13,389 adults with a follow-up of 4 years) was fitted to examine the temporal relationship between them. Genetically predicted plasma TG levels were positively associated with total leukocyte counts (TLC) [β(se) = 0.195(0.01)], lymphocyte counts (LC) [β(se) = 0.196(0.019)], and neutrophil counts (NC) [β(se) = 0.086(0.01)], which remained significant after adjusting for several confounders. Inversely, the genetically predicted TLC [β(se) = 0.033(0.008)], LC [β(se) = 0.053(0.008)], and NC [β(se) = 0.034(0.008)] were positively associated with plasma TG levels. However, when all three of them were put into the MR model adjusted for each other, only LC was significantly associated with TG levels. There was no association between genetically predicted TG levels and monocyte counts (MC), basophil counts, and eosinophil counts. The results of CLPM showed that the temporal effect of elevated TLC, MC, LC, and NC on plasma TG levels was stronger than the inverse effect. Our findings suggest causal associations of plasma TG levels with TLC, LC, and NC. In turn, LC was positively associated with plasma TG levels. Additionally, elevated circulating LC may precede high plasma TG levels.
| S-EPMC11564958 | biostudies-literature
Project description:β-Cell dysfunction, manifested as impaired glucose-stimulated insulin secretion (GSIS), and β-cell loss, which presents as dedifferentiation, inhibited transcriptional identity and death, are the hallmarks of type 2 diabetes. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has been shown to play a role in cardiovascular disease. Here, we found that plasma TMAO levels are elevated in both diabetic mice and human subjects and that TMAO at a similar concentration to that found in diabetes could directly decrease β-cell GSIS in both MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels through choline diet feeding impairs GSIS, the β-cell proportion, and glucose tolerance. TMAO inhibits calcium transients through NLRP3 inflammasome-related inflammatory 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 through either genetic knockdown or antisense oligomers of Fmo3, the TMAO-producing enzyme, improves β-cell GSIS, the β-cell proportion, and glucose tolerance in both db/db and choline diet-fed mice. These observations elucidate a novel role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be a new approach for the treatment of type 2 diabetes.
2024-02-23 | GSE243083 | GEO