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Trimethylamine N-Oxide in Relation to Cardiometabolic Health-Cause or Effect?

ABSTRACT: Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO. Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous studies questioned the role of TMAO in these diseases. Several animal studies reported neutral or even beneficial effects of TMAO or its precursors in cardiovascular disease model systems, supporting the clinically proven beneficial effects of its precursor, L-carnitine, or a sea-food rich diet (naturally containing TMAO) on cardiometabolic health. In this review, we summarize recent preclinical and epidemiological evidence on the effects of TMAO, in order to shed some light on the role of TMAO in cardiometabolic diseases, particularly as related to the microbiome.

SUBMITTER: Papandreou C

PROVIDER: S-EPMC7284902 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Trimethylamine N-Oxide in Relation to Cardiometabolic Health-Cause or Effect?

Papandreou Christopher C Moré Margret M Bellamine Aouatef A

Nutrients 20200507 5

Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO. Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous s ...[more]

PMID: 32392758

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Project description:BackgroundTrimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities.ObjectivesTo examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia.MethodsIncluded were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant.ResultsAfter adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses.ConclusionsIn an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.

Project description:ObjectivePrevious studies have demonstrated that trimethylamine N-oxide (TMAO) and its precursors, including choline, betaine, and carnitine, are closely associated with blood pressure (BP) changes. Nevertheless, with the limitation of reverse causality and confounder in observational studies, such a relationship remains unclear. We aimed to assess the causal relationship of TMAO and its precursors with BP by the Mendelian Randomization (MR) approach.MethodIn this study, two-sample MR was used to reveal the causal effect of TMAO and its precursors on BP. Pooled data of TMAO and its precursors was from genome-wide association studies (GWAS) which includes summary data of human metabolome in 2,076 European participants from Framingham Heart Study. Summary-level data for BP was extracted from the International Consortium of Blood Pressure-Genome Wide Association Studies. Inverse variance weighted (IVW), MR Egger regression, Maximum likelihood, Weighted median, and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used in this MR analysis.ResultsA total of 160 independent SNP loci were associated with TMAO and three precursors, including 58 associated with TMAO, 29 associated with choline, 44 associated with betaine, and 29 associated with carnitine, were selected. MR results suggested that a 1 unit increase in TMAO should be associated with a 1SD increase in systolic BP mmHg (beta: 0.039, SE, 0.072, p = 0.020). Additionally, our findings also indicated that a 1 unit increase in carnitine should be associated with a 1SD increase in systolic BP mmHg (beta: 0.055, SE: 0.075, p = 0.039). This result was also confirmed by sensitivity analysis methods such as Maximum likelihood, MR-PRESSO, and Weighted median. No effects of betaine or choline on systolic or diastolic BP were observed in the present study.ConclusionOur study provides evidence of a causal relationship of TMAO and its precursors with BP, suggesting that mediating the generation of TMAO would be beneficial for lowering BP.

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Trimethylamine N-Oxide in Relation to Cardiometabolic Health-Cause or Effect?

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Trimethylamine N-Oxide in Relation to Cardiometabolic Health-Cause or Effect?

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