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      Association of Urinary and Plasma Levels of Trimethylamine N-Oxide (TMAO) with Foods

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          Abstract

          Introduction: Trimethylamine N-oxide (TMAO) may play a key mediator role in the relationship between the diet, gut microbiota and cardiovascular diseases, particularly in people with kidney failure. The aim of this review is to evaluate which foods have a greater influence on blood or urinary trimethylamine N-oxide (TMAO) levels. Methods: 391 language articles were screened, and 27 were analysed and summarized for this review, using the keywords “TMAO” AND “egg” OR “meat” OR “fish” OR “dairy” OR “vegetables” OR “fruit” OR “food” in December 2020. Results: A strong correlation between TMAO and fish consumption, mainly saltwater fish and shellfish, but not freshwater fish, has been demonstrated. Associations of the consumption of eggs, dairy and meat with TMAO are less clear and may depend on other factors such as microbiota or cooking methods. Plant-based foods do not seem to influence TMAO but have been less investigated. Discussion: Consumption of saltwater fish, dark meat fish and shellfish seems to be associated with an increase in urine or plasma TMAO values. Further studies are needed to understand the relationship between increased risk of cardiovascular disease and plasma levels of TMAO due to fish consumption. Interventions coupled with long-term dietary patterns targeting the gut microbiota seem promising.

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          Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

          Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
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            Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

            Intestinal microbiota metabolism of choline/phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). Herein we demonstrate that intestinal microbiota metabolism of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis. Omnivorous subjects are shown to produce significantly more TMAO than vegans/vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. Specific bacterial taxa in human feces are shown to associate with both plasma TMAO and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predict increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (MI, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice significantly altered cecal microbial composition, markedly enhanced synthesis of TMA/TMAO, and increased atherosclerosis, but not following suppression of intestinal microbiota. Dietary supplementation of TMAO, or either carnitine or choline in mice with intact intestinal microbiota, significantly reduced reverse cholesterol transport in vivo. Intestinal microbiota may thus participate in the well-established link between increased red meat consumption and CVD risk.
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              Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

              Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans. We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography. Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups. The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.).
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                23 April 2021
                May 2021
                : 13
                : 5
                : 1426
                Affiliations
                [1 ]Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, 00166 Rome, Italy; giovanni.aulisa@ 123456uniroma5.it (G.A.); daniele.mar16@ 123456yahoo.com (D.M.); massimiliano.caprio@ 123456uniroma5.it (M.C.)
                [2 ]Department of Systems Medicine, University of Rome “Tor Vergata”, 00173 Rome, Italy; federicm@ 123456uniroma2.it
                [3 ]Independent Researcher, via Venezuela 66, 98121 Messina, Italy; gianlucarizzo@ 123456email.it
                [4 ]Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; mariagrazia.tarsitano@ 123456uniroma1.it
                [5 ]Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Tor Vergata, via Montpellier 1, 00133 Rome, Italy; laura.di.renzo@ 123456uniroma2.it (L.D.R.); delorenzo@ 123456uniroma2.it (A.D.L.)
                [6 ]Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy
                Author notes
                Author information
                https://orcid.org/0000-0001-7509-5487
                https://orcid.org/0000-0002-6039-3083
                https://orcid.org/0000-0002-5540-0621
                https://orcid.org/0000-0001-8875-6723
                https://orcid.org/0000-0001-6524-4493
                Article
                nutrients-13-01426
                10.3390/nu13051426
                8145508
                33922680
                0c344bf2-7405-4c70-8c5b-29f27a6a9547
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 27 March 2021
                : 22 April 2021
                Categories
                Review

                Nutrition & Dietetics
                tmao,trimethylamine n-oxide,foods,fish,meat,eggs,dairy,microbiota
                Nutrition & Dietetics
                tmao, trimethylamine n-oxide, foods, fish, meat, eggs, dairy, microbiota

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