Plasma Trimethylamine N-Oxide
Introduction
Section titled “Introduction”Plasma trimethylamine N-oxide (TMAO) is a metabolite that has garnered significant attention due to its emerging role as a potential risk factor for various chronic diseases. Understanding its origins, biological pathways, and clinical implications is crucial for public health and personalized medicine.
Background and Biological Basis
Section titled “Background and Biological Basis”TMAO is a small organic molecule primarily synthesized in the liver from trimethylamine (TMA).[1]TMA itself is a product of microbial metabolism in the gut, where specific gut bacteria break down TMA-containing dietary compounds such as choline, betaine, lecithin, and L-carnitine.[1] These dietary precursors are commonly found in foods like red meat, seafood, dairy, and eggs.[2]After TMA is produced by the gut microbiota, it is absorbed into the bloodstream and transported to the liver, where host enzymes, primarily flavin-containing monooxygenases (FMOs), convert it into TMAO.[3]The levels of circulating TMAO in the body are influenced by a complex interplay of dietary intake, the composition and activity of the gut microbiome, and host genetics.[4] While animal studies have demonstrated both genetic and environmental regulation of TMAO levels, human studies have shown a moderate genetic influence, with an estimated heritability of 27%.[1] One notable genetic determinant identified in humans is a cluster of rare missense mutations in the FMO3 gene, which is associated with trimethylaminuria, commonly known as ‘fish odor syndrome’.[5]Beyond genetic variations, epigenetic factors like DNA methylation may also play a role in TMAO homeostasis, as dietary substrates like betaine can impact methylation processes.[1] Plasma concentrations of TMAO are often preferred for analysis over urine concentrations, as they are considered more stable and less prone to acute dietary fluctuations.[6]
Clinical Relevance
Section titled “Clinical Relevance”Elevated plasma TMAO levels have been identified as a significant factor in the pathogenesis of several chronic diseases. It has emerged as a possible causal risk factor for cardiovascular disease (CVD).[7]Studies have linked plasma L-carnitine, a dietary precursor, to both prevalent and incident CVD in a TMAO-dependent manner.[2]Furthermore, high plasma TMAO has been associated with an increased cardiovascular risk, even in individuals generally considered to be in low-risk subgroups.[1]Beyond CVD, TMAO levels have also been linked to adverse clinical outcomes in conditions such as heart failure and chronic kidney disease, underscoring its broad importance in chronic disease pathogenesis.[1]However, some research indicates that TMAO may not be directly associated with other plasma markers of cardiovascular disease, such as lipids or inflammatory cytokines.[1]
Social Importance
Section titled “Social Importance”The growing understanding of plasma TMAO’s role in health and disease carries substantial social importance. Given its strong links to diet and the gut microbiome, TMAO research provides valuable insights that could inform public health strategies aimed at preventing widespread conditions like cardiovascular disease. Dietary interventions, probiotic therapies, or even pharmacologic approaches targeting the gut microbiome or liver enzymes could potentially modulate TMAO levels, offering new avenues for disease prevention and management. This highlights the intricate connection between lifestyle, environmental factors, and genetic predispositions in shaping individual health outcomes, moving towards more personalized approaches to medicine.
Limitations
Section titled “Limitations”Understanding the limitations of research on plasma trimethylamine N-oxide (TMAO) is crucial for interpreting findings and guiding future investigations. Several factors related to study design, population characteristics, and the complexity of TMAO metabolism influence the generalizability and completeness of current knowledge.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The investigation into the genetic and epigenetic determinants of plasma TMAO, while novel, faced several methodological and statistical constraints. The genome-wide association study (GWAS) included 626 participants, and the epigenome-wide association study (EWAS) included 847 participants.[1]These sample sizes, while substantial for some genetic studies, may limit the power to detect subtle or rare genetic variants with small effect sizes, especially when accounting for multiple testing correction across millions of variants. This is evidenced by the finding of only one genome-wide significant single nucleotide polymorphism (SNP) and no significant epigenetic associations, despite a moderate heritability estimate of 27% for TMAO.[1] Furthermore, the top GWAS hits were predominantly rare variants (minor allele frequency <0.05).[1] which inherently present challenges for replication in independent cohorts, as demonstrated by the unavailability of rs114755225 and its proxies in other TMAO studies.[1] The Illumina HumanMethylation450 array used for epigenome-wide analysis also covers a limited portion of the genome, with a bias towards coding and promoter regions, potentially obscuring other relevant epigenetic signals.[1]
Population Specificity and Phenotype Characterization
Section titled “Population Specificity and Phenotype Characterization”The generalizability of findings is constrained by the specific characteristics of the study population. The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study exclusively recruited families of European descent.[1] which limits the direct applicability of the results to other ancestral groups where genetic architecture and environmental exposures may differ significantly. Additionally, the study population was described as metabolically healthy.[1] which might not fully capture the genetic or epigenetic influences on TMAO levels in individuals with existing metabolic diseases, where TMAO is often implicated. While plasma TMAO measurements are considered reliable due to reduced variation from acute dietary intake compared to urine.[1] the choice of CD4+ T-cells for epigenetic profiling, while justifiable for inflammatory processes, is a limitation for understanding TMAO metabolism.[1] TMAO is primarily synthesized in the liver.[1] and the absence of liver tissue samples or other more metabolically proximal tissues means that the epigenetic correlates captured in CD4+ T-cells may not fully reflect the primary sites of TMAO synthesis and regulation.[1]
Unaccounted Environmental Factors and Knowledge Gaps
Section titled “Unaccounted Environmental Factors and Knowledge Gaps”Despite the estimated heritability of TMAO, the research highlighted a significant gap in understanding its determinants, particularly concerning environmental interactions. The study noted that dietary variation among GOLDN participants was limited, with few vegetarians, which restricted the power to explore the modifying effects of habitual diet on TMAO levels.[1]This is critical because TMAO synthesis is profoundly influenced by gut microbiota from dietary precursors.[1]The composition of the gut microbiota, which is itself influenced by diet, likely plays a substantial role in circulating TMAO levels and could confound observed relationships, yet metagenomic data were not incorporated into the analysis.[1]The fact that the study did not replicate known associations between circulating TMAO and other cardiovascular risk factors or the consumption of animal products, as observed in other studies.[1]further underscores the complexity of environmental factors and cohort-specific dietary patterns that may influence TMAO levels. The large proportion of unexplained heritability, coupled with the strong influence of the gut microbiota, suggests that environmental factors and gene-environment interactions are critical missing pieces in fully elucidating the biological pathways governing plasma TMAO.
Variants
Section titled “Variants”Genetic variations play a role in influencing circulating levels of trimethylamine N-oxide (TMAO), an atherogenic metabolite linked to cardiovascular disease. Studies have estimated TMAO heritability at approximately 27%, suggesting a moderate genetic influence on its levels.[8] Among the variants associated with plasma TMAO, rs114755225 , located in an intergenic region on chromosome 4, stands out as a genome-wide significant hit.[8] While the context identifies rs114755225 as intergenic, it is linked to TENM3-AS1, an antisense RNA that may regulate the expression of the TENM3 gene, involved in nervous system development. This intergenic variant, along with others like rs143831173 , rs114858855 , and rs58180025 near the FIG4 gene, are among the top genetic associations identified, many of which are rare variants.[8]Such intergenic variants can affect gene regulation, influencing the expression of nearby genes or acting as independent regulatory elements, thereby impacting metabolic pathways that contribute to TMAO production from dietary precursors like choline and L-carnitine.
Other variants, such as rs114145653 in PHACTR4, rs75116832 in UBE2G1, and rs143482172 in MOB3B, are also associated with plasma TMAO levels.[8] The PHACTR4 gene encodes a protein involved in regulating cell shape, motility, and actin cytoskeleton dynamics, processes critical for various cellular functions, including vascular health. Variations here could indirectly affect endothelial function or metabolic regulation, impacting TMAO’s pro-atherogenic effects. UBE2G1 is a ubiquitin-conjugating enzyme, a key component of the ubiquitin-proteasome system responsible for protein degradation and quality control within cells. Alterations in UBE2G1 activity due to rs75116832 could influence cellular stress responses or the metabolism of proteins involved in TMAO synthesis or clearance. Similarly, MOB3B plays a role in cell signaling and proliferation, and its variants like rs143482172 might modulate cellular processes that are intertwined with metabolic health and TMAO regulation.
Variants affecting membrane transport and lipid metabolism pathways also show associations with TMAO. The rs75363923 variant, located in an intergenic region between SLC35F1 and CEP85L, is associated with TMAO.[8] SLC35F1 is a solute carrier family member, suggesting a role in transporting specific molecules across cell membranes, which could include TMAO precursors or even TMAO itself. Changes in its function could alter the availability of these compounds for metabolic processing. CEP85L is involved in centrosome organization, a process not directly linked to TMAO but potentially influencing overall cellular health and metabolic efficiency. Additionally, rs146839869 in the ENPP4 gene is associated with TMAO.[8] ENPP4encodes an ectonucleotide pyrophosphatase/phosphodiesterase, an enzyme involved in nucleotide and phospholipid metabolism. Dysregulation of these pathways could impact the availability of TMAO-related phospholipids or influence broader metabolic states relevant to cardiovascular risk.
Finally, genetic variations in EYA3 and RHOBTB2 are also linked to TMAO. The EYA3 gene, associated with rs148553452 , is involved in transcriptional regulation and developmental processes, and has been implicated in circadian rhythm functioning.[8] Given that circadian rhythms have shown relationships with urinary TMAO concentrations, variants in EYA3 could indirectly influence TMAO homeostasis by affecting these biological clocks.[8] The rs6557607 variant is found within the RHOBTB2 gene, which encodes a Rho GTPase-activating protein involved in critical cellular processes like signaling, cytoskeletal organization, and protein degradation. Variations in RHOBTB2could affect cellular responses to metabolic stress or inflammation, thereby contributing to individual differences in TMAO levels and associated cardiovascular risk.
Key Variants
Section titled “Key Variants”Nature and Biogenesis of Trimethylamine-N-oxide
Section titled “Nature and Biogenesis of Trimethylamine-N-oxide”Trimethylamine-N-oxide (TMAO) is precisely defined as an atherogenic metabolite species, recognized as a possible causal risk factor for cardiovascular disease (CVD).[1]Its synthesis occurs in the liver, where it is formed from trimethylamine (TMA). TMA, in turn, is a product released by the gut microbiota through the metabolism of various dietary phospholipid components, including choline, betaine, lecithin, and L-carnitine.[1]This intricate metabolic pathway highlights the crucial interplay between diet, gut microbiome, and host metabolism in regulating circulating TMAO levels. The term “circulating trimethylamine-N-oxide” specifically refers to the levels of this metabolite found within the plasma.[1]The clinical and scientific significance of TMAO stems from its established associations with several chronic diseases. Elevated plasma TMAO has been linked to increased cardiovascular risk, even in subgroups considered low-risk, and its importance is further underscored by associations with clinical outcomes in heart failure and chronic kidney disease.[1] Related concepts include the FMO3 gene, which, when mutated, can lead to trimethylaminuria, also known as “fish odor syndrome,” demonstrating a genetic component to TMAO metabolism.[1]
Analytical Methods and Operational Definitions
Section titled “Analytical Methods and Operational Definitions”The precise of plasma trimethylamine-N-oxide levels is critical for research and potential clinical application. A common approach involves proton nuclear magnetic resonance (NMR) spectroscopy, utilizing instruments such as the Vantera® NMR Clinical Analyzer.[1]For accurate quantification, plasma samples are typically diluted with a citrate/phosphate buffer to adjust the pH to 5.3, a step essential for separating the TMAO signal from overlapping signals, particularly that of betaine.[1] Following dilution, the specimen is preheated to 47°C, and spectra are acquired using a Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, involving signal averaging over 48 transients, with a total acquisition time of approximately 5.5 minutes per sample.[1] Operational definitions for TMAO quantification involve processing the acquired data: free induction decay (FID) signals are multiplied by an exponential window function, Fourier transformed, and then automatically phased and baseline corrected.[1] The TMAO methyl signal, typically observed at approximately 3.30 ppm, is quantified using proprietary non-negative linear least squares analysis, modeling the line shape as a mix of Gaussian and Lorentzian peak shapes.[1] The resulting signal amplitudes are transformed into μmol/L concentrations using a conversion factor, ensuring consistency and comparability across studies. This NMR-derived quantification method has demonstrated high correlation (r² = 0.98) with results obtained from liquid chromatography/mass spectrometry (LC/MS) assays, indicating its reliability.[1]
Clinical Classification and Risk Assessment
Section titled “Clinical Classification and Risk Assessment”Trimethylamine-N-oxide is classified fundamentally as a pro-atherogenic metabolite species and has emerged as a potential new risk factor for cardiovascular disease.[1]While no standardized diagnostic criteria or specific disease classifications are based solely on TMAO levels, its role as a biomarker is increasingly recognized. Research criteria often employ a dimensional approach to categorize TMAO levels within a population, typically by dividing individuals into quartiles.[1] For instance, in studies, median TMAO values across these quartiles can range from 6.08 μM to 42.31 μM, allowing for analysis of associations between varying levels and health outcomes.[1]The association of elevated plasma TMAO with increased cardiovascular risk highlights its potential utility in risk assessment, even in individuals without overt disease.[1]While specific clinical thresholds or cut-off values for diagnosing a TMAO-related condition are not universally established, the consistent observation of higher TMAO levels correlating with adverse cardiovascular events supports its consideration as a significant metabolic marker. Furthermore, studies investigating the heritability of TMAO levels explore the influence of genetic and environmental factors, acknowledging that while robust genetic associations observed in animal models have not always been replicated in humans, rare genetic variants, particularly in theFMO3 gene, are known to impact TMAO metabolism.[1]
The Gut Microbiota-Liver Axis in TMAO Production
Section titled “The Gut Microbiota-Liver Axis in TMAO Production”Plasma trimethylamine N-oxide (TMAO) is an atherogenic metabolite whose production involves a complex interplay between dietary intake, gut microbiota, and hepatic metabolism. This process begins with the consumption of TMA-containing dietary phospholipid components such as choline, betaine, lecithin, and L-carnitine.[1] Foods rich in these precursors include red meat, seafood, and dairy products.[2]The gut microbiota metabolizes these dietary compounds, releasing trimethylamine (TMA) as a byproduct.[1]Once produced in the gut, TMA is absorbed into the bloodstream and transported to the liver.[1]In the liver, TMA undergoes an enzymatic conversion to TMAO, completing the gut microbiota-liver axis pathway.[1]This metabolic pathway is crucial for understanding the systemic levels of TMAO and how they are influenced by both diet and the composition of an individual’s gut metagenome.[1]
Molecular Pathways and Key Enzymes in TMAO Metabolism
Section titled “Molecular Pathways and Key Enzymes in TMAO Metabolism”The hepatic conversion of trimethylamine (TMA) to TMAO is primarily catalyzed by the enzyme Flavin-containing monooxygenase 3 (FMO3).[1]This enzyme plays a central role in the detoxification of various xenobiotics and endogenous compounds by adding an oxygen atom to nitrogen, sulfur, or phosphorus-containing substrates. The efficiency ofFMO3 activity directly influences the circulating levels of TMAO, thus impacting overall TMAO homeostasis.[1] Beyond its role as a TMAO precursor, betaine also participates in other crucial metabolic pathways, notably as a methyl donor.[1]Betaine can serve as an alternative methyl source, facilitating the conversion of homocysteine to methionine. This process is integral to the one-carbon metabolism cycle, which can influence DNA methylation patterns and subsequent gene expression, thereby creating a potential link between TMAO precursors and broader epigenetic regulation.[1]
TMAO’s Role in Pathophysiological Processes
Section titled “TMAO’s Role in Pathophysiological Processes”Circulating TMAO has emerged as a significant biomarker and potential causal risk factor in various pathophysiological processes, particularly cardiovascular disease (CVD).[1]Elevated plasma TMAO levels are associated with increased cardiovascular risk, including both prevalent and incident CVD.[1]It is recognized as a proatherogenic metabolite, contributing to the development and progression of atherosclerosis.[9]Beyond its strong association with CVD, TMAO levels have also been linked to adverse clinical outcomes in other chronic conditions. Studies indicate associations with heart failure and chronic kidney disease, where the gut microbiota-dependent TMAO pathway contributes to renal insufficiency and increased mortality risk.[1]Despite these critical links, research indicates that TMAO levels are not consistently associated with other traditional plasma markers of cardiovascular disease, such as lipids or inflammatory cytokines.[1]
Genetic and Epigenetic Influences on Circulating TMAO Levels
Section titled “Genetic and Epigenetic Influences on Circulating TMAO Levels”The regulation of circulating TMAO levels involves both genetic and environmental factors, though their exact interplay in humans is still being elucidated.[1] Human studies have estimated the heritability of plasma TMAO at approximately 27%, suggesting a moderate genetic influence.[1] Genome-wide association studies (GWAS) in humans have identified some genetic variants, including a significant hit in an intergenic region on chromosome 4, that may contribute to TMAO level variation.[1] However, common genetic variations have not consistently shown strong associations with plasma TMAO in large-scale human cohorts, with some studies suggesting the importance of rarer genetic variants.[1] The most well-established genetic determinant of TMAO in humans involves rare missense mutations in the FMO3 gene, which are linked to trimethylaminuria, commonly known as “fish odor syndrome”.[1]Epigenetic mechanisms, particularly DNA methylation, have been hypothesized to play a role in TMAO homeostasis, as they integrate both genetic predispositions and environmental inputs like diet.[1]For instance, betaine, a dietary precursor of TMA, is also a methyl source, potentially influencing DNA methylation and gene expression patterns.[1]While some studies have reported inverse associations between plasma TMAO and methylation capacity, epigenome-wide association studies evaluating DNA methylation in CD4+ T-cells have not yet yielded statistically significant associations with circulating TMAO levels, suggesting that the optimal tissue for detecting such links or the specific epigenetic loci involved may require further investigation.[1]
Dietary Precursors and Gut Microbiota Metabolism
Section titled “Dietary Precursors and Gut Microbiota Metabolism”Plasma trimethylamine N-oxide (TMAO) levels are intricately linked to dietary intake and the metabolic activities of the gut microbiota. Key dietary precursors, including choline, betaine, lecithin, and L-carnitine, are consumed through foods such as red meat, seafood, eggs, and dairy products . This suggests its utility in identifying a broader population at risk for conditions such as atherosclerosis, myocardial infarction, coronary bypass surgery, or coronary angioplasty.[1]Furthermore, TMAO contributes to the development of renal insufficiency and increased mortality risk in chronic kidney disease patients, highlighting its relevance in assessing kidney health and related complications.[1]While TMAO is a pro-atherogenic metabolite, it is important to note that in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, TMAO levels were not found to be associated with other traditional plasma markers of cardiovascular disease, such as lipids or inflammatory cytokines.[1]This independence suggests that TMAO may represent a distinct pathway in disease pathogenesis, offering complementary information to existing risk stratification tools. Its synthesis is dependent on gut microbiota processing of dietary components like choline, betaine, lecithin, and L-carnitine, which are commonly found in red meat and seafood.[1] Understanding these dietary associations can inform risk assessment, especially in populations with specific dietary patterns.
Prognostic Indicator for Disease Progression and Outcomes
Section titled “Prognostic Indicator for Disease Progression and Outcomes”The of plasma TMAO holds prognostic value, offering insights into the likely course of disease progression and long-term patient outcomes. Studies have linked elevated TMAO levels to adverse clinical outcomes in patients with heart failure and chronic kidney disease, underscoring its role in chronic disease pathogenesis.[1]Specifically, in chronic kidney disease, TMAO not only contributes to the initial development of renal insufficiency but also independently predicts mortality risk.[1]This prognostic capability means that TMAO levels could serve as an indicator for identifying individuals at higher risk for severe complications or accelerated disease progression, enabling more proactive clinical management.
The association between plasma L-carnitine, a nutrient prevalent in red meat and seafood, and both prevalent and incident CVD has been observed to be TMAO-dependent.[1]This highlights TMAO as a critical mediator in the link between specific dietary exposures and cardiovascular outcomes. Clinically, monitoring TMAO levels could therefore offer a window into the long-term implications of dietary habits on disease trajectory, potentially informing interventions aimed at slowing disease progression or improving patient prognosis.
Guiding Personalized Interventions and Monitoring
Section titled “Guiding Personalized Interventions and Monitoring”Plasma TMAO offers a pathway towards personalized medicine approaches and tailored prevention strategies, particularly concerning dietary modifications. Given that TMAO is a gut microbiota-dependent metabolite derived from dietary precursors like choline and L-carnitine, its levels can be influenced by diet, offering a modifiable target for intervention.[1]Identifying individuals with elevated TMAO levels could prompt personalized dietary counseling, focusing on reducing intake of TMAO-precursors from sources such as red meat, dairy, and eggs, to mitigate cardiovascular and renal risks.[10], [11]Beyond diet, TMAO could guide monitoring strategies in patients with existing conditions like heart failure or chronic kidney disease, allowing clinicians to track the effectiveness of lifestyle interventions or other treatments aimed at reducing TMAO levels. While genetic factors play a moderate role in circulating TMAO levels, with heritability estimated at 27%.[1]the strong environmental and dietary influences suggest that personalized dietary and lifestyle interventions could be particularly impactful. The only well-established genetic determinant related to TMAO in humans involves rare mutations in theFMO3 gene, linked to trimethylaminuria, or ‘fish odor syndrome’, which represents a distinct clinical entity.[5]
Frequently Asked Questions About Plasma Trimethylamine N Oxide
Section titled “Frequently Asked Questions About Plasma Trimethylamine N Oxide”These questions address the most important and specific aspects of plasma trimethylamine n oxide based on current genetic research.
1. Why do my friends eat eggs daily but I worry about my heart?
Section titled “1. Why do my friends eat eggs daily but I worry about my heart?”Your worry might be valid due to how your body processes certain foods. Eggs contain choline, which gut bacteria convert to TMA. Your liver then transforms this into TMAO, a metabolite linked to heart disease risk. Individual differences in gut bacteria and your own genetics can affect how much TMAO your body produces, even with the same diet.
2. Could my family’s heart issues be linked to how I process food?
Section titled “2. Could my family’s heart issues be linked to how I process food?”Yes, there’s a good chance. Your genetics play a moderate role in your TMAO levels, with an estimated heritability of 27%. This means if heart disease runs in your family, partly due to how food like red meat or eggs is metabolized into TMAO, you might also have a predisposition. Factors like your gut bacteria and specific liver enzymes also contribute to these family patterns.
3. Can taking probiotics help lower my heart disease risk?
Section titled “3. Can taking probiotics help lower my heart disease risk?”Potentially, yes. TMAO is largely produced when gut bacteria break down certain dietary compounds. By influencing the composition and activity of your gut microbiome through probiotic therapies, you might be able to modulate the initial production of TMA, and subsequently, your TMAO levels. This could be a new avenue for reducing cardiovascular risk.
4. Is there a blood test to see my unique heart risk from diet?
Section titled “4. Is there a blood test to see my unique heart risk from diet?”Yes, a plasma TMAO is gaining attention for this. Elevated plasma TMAO levels have been identified as a significant factor in cardiovascular disease, even independent of traditional risk markers like lipids. This test can give you insight into how your diet, gut bacteria, and genetics interact to influence your specific heart health risk.
5. Does my TMAO level matter even if my cholesterol is fine?
Section titled “5. Does my TMAO level matter even if my cholesterol is fine?”Yes, it absolutely can. Research suggests that high plasma TMAO is associated with increased cardiovascular risk, even in individuals with otherwise low-risk profiles and normal cholesterol levels. TMAO appears to be a separate, possible causal risk factor for heart disease, not necessarily directly linked to lipids or inflammatory markers.
6. Why do some people seem to handle red meat better than me?
Section titled “6. Why do some people seem to handle red meat better than me?”This difference likely comes down to a complex interplay of your gut microbiome and your own genetics. Red meat is a source of L-carnitine, which gut bacteria convert into TMA. Your specific gut bacteria, along with the activity of your liver enzymes, primarily flavin-containing monooxygenases (FMOs), determine how efficiently TMA is converted to TMAO, and how much circulates in your body.
7. Does my ethnic background change my risk from certain foods?
Section titled “7. Does my ethnic background change my risk from certain foods?”It’s possible, yes. Studies on TMAO have primarily focused on populations of European descent, and genetic architecture can differ significantly across ancestral groups. While we know genetics influence TMAO levels, more research is needed to fully understand how ethnic background might specifically impact your susceptibility to elevated TMAO from certain foods.
8. Can what I eat actually change how my body uses genes?
Section titled “8. Can what I eat actually change how my body uses genes?”Yes, it can. Beyond directly influencing TMAO levels, dietary components like betaine can impact epigenetic factors such as DNA methylation. These epigenetic changes can, in turn, play a role in how your body regulates TMAO homeostasis and overall health, showing a fascinating connection between your diet and gene activity.
9. I heard about ‘fish odor syndrome’ – is that related to my heart?
Section titled “9. I heard about ‘fish odor syndrome’ – is that related to my heart?”Yes, there’s a connection through the same metabolic pathway. ‘Fish odor syndrome,’ or trimethylaminuria, is caused by rare mutations in the FMO3gene, which is crucial for converting TMA to TMAO in the liver. While primarily known for the odor, this gene is also central to TMAO production, which is linked to cardiovascular risk.
10. What can I do to lower my heart risk from daily eating?
Section titled “10. What can I do to lower my heart risk from daily eating?”You have several promising avenues. Since TMAO is influenced by diet and gut microbes, you could consider dietary changes, such as reducing intake of TMA-containing foods like red meat and eggs. Additionally, exploring probiotic therapies to modify your gut microbiome, or even future pharmacologic approaches targeting liver enzymes, could help modulate your TMAO levels and reduce heart risk.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Aslibekyan S et al. “Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).”J Nutr Intermed Metab, vol. 6, 2017, pp. 1-8.
[2] Koeth RA et al. “Intestinal microbiota metabolism of L-carnitine in diet links red meat consumption to atherosclerosis.”Nat Med, vol. 19, no. 5, 2013, pp. 576–85.
[3] Loscalzo, J. “Lipid metabolism by gut microbes and atherosclerosis.”Circ Res, 2011.
[4] Bennett BJ et al. “Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation.”Cell Metab, vol. 17, no. 1, 2013, pp. 49–60.
[5] Teresa E et al. “A spectrum of molecular variation in a cohort of Italian families with trimethylaminuria: identification of three novel mutations of the FM03 gene.” Mol Genet Metab, vol. 88, no. 2, 2006, pp. 192–5.
[6] Walsh, M. C., et al. “Effect of acute dietary standardization on the urinary, plasma, and salivary metabolomic profiles of healthy humans.” Am J Clin Nutr, vol. 84, no. 3, 2006, pp. 531–9.
[7] Mayr, Manuel. “Recent highlights of metabolomics in cardiovascular research.”Circ Cardiovasc Genet, vol. 4, no. 4, 2011, pp. 463–4.
[8] Aslibekyan S, et al. “Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).”J Nutr Intermed Metab. 2018 June 01; Author manuscript; available in PMC 2018 June 01. PMID: 28439531.
[9] Hartiala J et al. “Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine.”Arterioscler Thromb Vasc Biol, vol. 34, no. 6, 2014, pp. 1307–13.
[10] Rohrmann S et al. “Plasma Concentrations of Trimethylamine-N-oxide Are Directly Associated with Dairy Food Consumption and Low-Grade Inflammation in a German Adult Population.” J Nutr, vol. 146, no. 2, 2016, pp. 283–9.
[11] Zhang AQ et al. “Dietary precursors of trimethylamine in man: a pilot study.” Food Chem Toxicol, vol. 37, no. 5, 1999, pp. 515–20.