TMAO: een risicofactor voor hart- en vaatziekten? Ach welnee!

TMAO wordt in onze lever gemaakt uit trimethylamine (TMA). TMA ontstaat uit de activiteit van specifieke bacteriën in onze dikke darm. De belangrijkste voedingsstoffen die ze daarvoor gebruiken zijn (fosfatidyl)choline, carnitine (in vlees, vis, ei), betaïne (in bieten, spinazie en garnalen) en ergothioneïne (in paddenstoelen). TMAO-zelf zit echter ook in vis. Viseters scoren zelfs de hoogste TMAO-gehaltes! Hoe dieper in de zee een vis leeft, hoe meer TMAO in zijn cellen.

TMAO functioneert in een vis als ‘osmoliet’: een stof die de druk in een cel gelijk houdt aan de druk van buiten. Een collectieve eigenschap van osmolieten is dat ze tot de minst giftige stoffen behoren die we kennen. TMA is wel giftig. Daarom zet onze lever TMA uit de darm om naar het veilige TMAO. In vissen die al even liggen, zetten bacteriën de aanwezige TMAO om in het ‘naar vis ruikende’ TMA. Bij mensen met het genetisch-overerfbare en zeer zeldzame ‘visgeursyndroom’ wordt TMA niet omgezet in TMAO. Dat heeft verstrekkende sociale- en psychologische gevolgen, maar het veroorzaakt geen lichamelijke gezondheidsproblemen. Wat vormt dan wel de ongunstige relatie tussen TMAO en bovengenoemde ziektes?

Verhoogde TMAO-gehaltes in het bloed gaan vaak samen met een slechte nierfunctie en die is ook gerelateerd aan diverse van de bovengenoemde ziektes. Ook gaat een verhoogd TMAO-gehalte vaak vergezeld met een verstoorde samenstelling van het darm-microbioom. TMAO stijgt bovendien met de leeftijd en dat correleert met meer TMA-producerende bacteriën in de darm. Er is dan vaak sprake van ‘dysbiose’: een afname van ‘goede’ bacteriën en/of een toename van ‘schadelijke’ bacteriën. Dysbiose wordt reeds lange tijd in verband gebracht met een scala aan ziektes, waaronder hart- en vaatziekten, kanker, luchtwegaandoeningen, diabetes, inflammatoire darmziekten, hersenaandoeningen, chronische nierziekten en leverziekten.

TMAO is een marker voor lage graadontsteking in de darm

Een plantaardig voedingspatroon leidt tot minder TMAO in het bloed, minder opportunistische bacteriën, meer gunstige korteketenvetzuren uit vezels, minder ontsteking in het lichaam en een betere barrièrefunctie van de darm. Fytochemicaliën uit planten, zoals resveratrol, curcumine en berberine, kunnen via hun invloed op de samenstelling van het darm-microbioom in hoge mate de productie van TMA voorkomen. Dat is vooral belangrijk voor ouderen, omdat het immuunsysteem met de leeftijd slechter werkt en de darm-microbiota een samenstelling aanneemt die ontsteking bevordert.  

De worsteling van de wetenschap met TMAO als een vermeende risicofactor op hart- en vaatziekten nadert zijn einde. Een risicofactor duidt op een oorzaak en een risicomarker op een associatie. TMA-productie in onze darmen ontpopt zich als een marker voor lage graad ontstekingen in de darm. TMAO duidt op een ontstekingsbevorderend microbioom vanwege een voeding met teveel dierlijk materiaal ten opzichte van plantaardig materiaal. Via een grote omweg zijn we dus te weten gekomen wat we al wisten: eet gevarieerd, met mate en in balans.

Is er sprake van een verhoogd TMAO-gehalte in het bloed en komt het niet door een slechte nierfunctie of het eten van vis? Grijp deze kanarie in de kolenmijn dan aan om de leefstijl te verbeteren. Geneesmiddelen die de TMA-productie remmen zijn niet nodig: ze liggen voor je neus als je de supermarkt binnenloopt.

TMAO and disease

1.           Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011 Apr 7;472(7341):57-63. doi: 10.1038/nature09922. PMID: 21475195; PMCID: PMC3086762.

https://pubmed.ncbi.nlm.nih.gov/21475195

2.           Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.1056/NEJMoa1109400. PMID: 23614584; PMCID: PMC3701945.

https://pubmed.ncbi.nlm.nih.gov/23614584

3.           Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 May;19(5):576-85. doi: 10.1038/nm.3145. Epub 2013 Apr 7. PMID: 23563705; PMCID: PMC3650111.

https://pubmed.ncbi.nlm.nih.gov/23563705

4.           Wang Z, Levison BS, Hazen JE, Donahue L, Li XM, Hazen SL. Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal Biochem. 2014 Jun 15;455:35-40. doi: 10.1016/j.ab.2014.03.016. Epub 2014 Apr 1. PMID: 24704102; PMCID: PMC4167037.

https://pubmed.ncbi.nlm.nih.gov/24704102

4a.         Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016 Nov 8;8(11):326. doi: 10.3390/toxins8110326. PMID: 27834801; PMCID: PMC5127123.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5127123

5.           Marques FZ, Mackay CR, Kaye DM. Beyond gut feelings: how the gut microbiota regulates blood pressure. Nat Rev Cardiol. 2018 Jan;15(1):20-32. doi: 10.1038/nrcardio.2017.120. Epub 2017 Aug 24. PMID: 28836619.

https://pubmed.ncbi.nlm.nih.gov/28836619

6.           Svingen GFT, Zuo H, Ueland PM, Seifert R, Løland KH, Pedersen ER, Schuster PM, Karlsson T, Tell GS, Schartum-Hansen H, Olset H, Svenningsson M, Strand E, Nilsen DW, Nordrehaug JE, Dhar I, Nygård O. Increased plasma trimethylamine-N-oxide is associated with incident atrial fibrillation. Int J Cardiol. 2018 Sep 15;267:100-106. doi: 10.1016/j.ijcard.2018.04.128. PMID: 29957250.

https://pubmed.ncbi.nlm.nih.gov/29957250

7.           Farhangi MA, Vajdi M, Asghari-Jafarabadi M. Gut microbiota-associated metabolite trimethylamine N-Oxide and the risk of stroke: a systematic review and dose-response meta-analysis. Nutr J. 2020 Jul 30;19(1):76. doi: 10.1186/s12937-020-00592-2. PMID: 32731904; PMCID: PMC7393891.

https://pubmed.ncbi.nlm.nih.gov/32731904

8.           Papandreou C, Moré M, Bellamine A. Trimethylamine N-Oxide in Relation to Cardiometabolic Health-Cause or Effect? Nutrients. 2020 May 7;12(5):1330. doi: 10.3390/nu12051330. PMID: 32392758; PMCID: PMC7284902.

https://pubmed.ncbi.nlm.nih.gov/32392758

9.           Gupta N, Buffa JA, Roberts AB, Sangwan N, Skye SM, Li L, Ho KJ, Varga J, DiDonato JA, Tang WHW, Hazen SL. Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease. Arterioscler Thromb Vasc Biol. 2020 May;40(5):1239-1255. doi: 10.1161/ATVBAHA.120.314139. Epub 2020 Mar 26. PMID: 32212854; PMCID: PMC7203662.

https://pubmed.ncbi.nlm.nih.gov/32212854

10.         Rath S, Rox K, Kleine Bardenhorst S, Schminke U, Dörr M, Mayerle J, Frost F, Lerch MM, Karch A, Brönstrup M, Pieper DH, Vital M. Higher Trimethylamine-N-Oxide Plasma Levels with Increasing Age Are Mediated by Diet and Trimethylamine-Forming Bacteria. mSystems. 2021 Oct 26;6(5):e0094521. doi: 10.1128/mSystems.00945-21. Epub 2021 Sep 14. PMID: 34519520; PMCID: PMC8547441.

https://pubmed.ncbi.nlm.nih.gov/34519520

11.         Li X, Hong J, Wang Y, Pei M, Wang L, Gong Z. Trimethylamine-N-Oxide Pathway: A Potential Target for the Treatment of MAFLD. Front Mol Biosci. 2021 Oct 1;8:733507. doi: 10.3389/fmolb.2021.733507. PMID: 34660695; PMCID: PMC8517136.

https://pubmed.ncbi.nlm.nih.gov/34660695

12.         Brunt VE, Casso AG, Gioscia-Ryan RA, Sapinsley ZJ, Ziemba BP, Clayton ZS, Bazzoni AE, VanDongen NS, Richey JJ, Hutton DA, Zigler MC, Neilson AP, Davy KP, Seals DR. Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans. Hypertension. 2021 Aug;78(2):499-511. doi: 10.1161/HYPERTENSIONAHA.120.16895. Epub 2021 May 10. PMID: 33966451; PMCID: PMC8266738.

https://pubmed.ncbi.nlm.nih.gov/33966451

13.         Pierce GL, Roy SJ, Gimblet CJ. The Gut-Arterial Stiffness Axis: Is TMAO a Novel Target to Prevent Age-Related Aortic Stiffening? Hypertension. 2021 Aug;78(2):512-515. doi: 10.1161/HYPERTENSIONAHA.121.17487. Epub 2021 Jul 7. PMID: 34232682; PMCID: PMC8274311.

https://pubmed.ncbi.nlm.nih.gov/34232682

14.         Ilyas A, Wijayasinghe YS, Khan I, El Samaloty NM, Adnan M, Dar TA, Poddar NK, Singh LR, Sharma H, Khan S. Implications of trimethylamine N-oxide (TMAO) and Betaine in Human Health: Beyond Being Osmoprotective Compounds. Front Mol Biosci. 2022 Aug 26;9:964624. doi: 10.3389/fmolb.2022.964624. PMID: 36310589; PMCID: PMC9601739.

https://pubmed.ncbi.nlm.nih.gov/36310589

15.         Zheng Y, He JQ. Pathogenic Mechanisms of Trimethylamine N-Oxide-induced Atherosclerosis and Cardiomyopathy. Curr Vasc Pharmacol. 2022;20(1):29-36. doi: 10.2174/1570161119666210812152802. PMID: 34387163; PMCID: PMC9680907.

https://pubmed.ncbi.nlm.nih.gov/34387163

15a.       Caradonna E, Abate F, Schiano E, Paparella F, Ferrara F, Vanoli E, Difruscolo R, Goffredo VM, Amato B, Setacci C, Setacci F, Novellino E. Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health. Metabolites. 2025 Mar 24;15(4):220. doi: 10.3390/metabo15040220. PMID: 40278349; PMCID: PMC12029716.

https://pubmed.ncbi.nlm.nih.gov/40278349

16.         Zeisel SH, Warrier M. Trimethylamine N-Oxide, the Microbiome, and Heart and Kidney Disease. Annu Rev Nutr. 2017 Aug 21;37:157-181. doi: 10.1146/annurev-nutr-071816-064732. Epub 2017 Jul 17. PMID: 28715991.

https://pubmed.ncbi.nlm.nih.gov/28715991

17.         Landfald B, Valeur J, Berstad A, Raa J. Microbial trimethylamine-N-oxide as a disease marker: something fishy? Microb Ecol Health Dis. 2017 May 19;28(1):1327309. doi: 10.1080/16512235.2017.1327309. PMID: 28588431; PMCID: PMC5444358.

https://pubmed.ncbi.nlm.nih.gov/28588431

TMA and TMAO

18.         Cho CE, Caudill MA. Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? Trends Endocrinol Metab. 2017 Feb;28(2):121-130. doi: 10.1016/j.tem.2016.10.005. Epub 2016 Nov 5. PMID: 27825547.

https://pubmed.ncbi.nlm.nih.gov/27825547

19.         Liu Y, Dai M. Trimethylamine N-Oxide Generated by the Gut Microbiota Is Associated with Vascular Inflammation: New Insights into Atherosclerosis. Mediators Inflamm. 2020 Feb 17;2020:4634172. doi: 10.1155/2020/4634172. PMID: 32148438; PMCID: PMC7048942.

https://pubmed.ncbi.nlm.nih.gov/32148438

20.         Zhou Y, Zhang Y, Jin S, Lv J, Li M, Feng N. The gut microbiota derived metabolite trimethylamine N-oxide: Its important role in cancer and other diseases. Biomed Pharmacother. 2024 Aug;177:117031. doi: 10.1016/j.biopha.2024.117031. Epub 2024 Jun 25. PMID: 38925016.

https://pubmed.ncbi.nlm.nih.gov/38925016

Microbiota metabolites

21.         Holmes E, Li JV, Marchesi JR, Nicholson JK. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab. 2012 Nov 7;16(5):559-64. doi: 10.1016/j.cmet.2012.10.007. PMID: 23140640.

https://pubmed.ncbi.nlm.nih.gov/23140640

22.         Kashtanova DA, Popenko AS, Tkacheva ON, Tyakht AB, Alexeev DG, Boytsov SA. Association between the gut microbiota and diet: Fetal life, early childhood, and further life. Nutrition. 2016 Jun;32(6):620-7. doi: 10.1016/j.nut.2015.12.037. Epub 2015 Dec 31. PMID: 26946974.

https://pubmed.ncbi.nlm.nih.gov/26946974

23.         Ahmadmehrabi S, Tang WHW. Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol. 2017 Nov;32(6):761-766. doi: 10.1097/HCO.0000000000000445. PMID: 29023288; PMCID: PMC5746314.

https://pubmed.ncbi.nlm.nih.gov/29023288

24.         Zuo K, Yin X, Li K, Zhang J, Wang P, Jiao J, Liu Z, Liu X, Liu J, Li J, Yang X. Different Types of Atrial Fibrillation Share Patterns of Gut Microbiota Dysbiosis. mSphere. 2020 Mar 18;5(2):e00071-20. doi: 10.1128/mSphere.00071-20. PMID: 32188747; PMCID: PMC7082137.

https://pubmed.ncbi.nlm.nih.gov/32188747

25.         Gui DD, Luo W, Yan BJ, Ren Z, Tang ZH, Liu LS, Zhang JF, Jiang ZS. Effects of gut microbiota on atherosclerosis through hydrogen sulfide. Eur J Pharmacol. 2021 Apr 5;896:173916. doi: 10.1016/j.ejphar.2021.173916. Epub 2021 Jan 30. PMID: 33529724.

https://pubmed.ncbi.nlm.nih.gov/33529724

26.         Gawałko M, Agbaedeng TA, Saljic A, Müller DN, Wilck N, Schnabel R, Penders J, Rienstra M, van Gelder I, Jespersen T, Schotten U, Crijns HJGM, Kalman JM, Sanders P, Nattel S, Dobrev D, Linz D. Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications. Cardiovasc Res. 2022 Aug 24;118(11):2415-2427. doi: 10.1093/cvr/cvab292. PMID: 34550344; PMCID: PMC9400433.

https://pubmed.ncbi.nlm.nih.gov/34550344

27.         Ma YY, Li X, Yu JT, Wang YJ. Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside. Transl Neurodegener. 2024 Feb 27;13(1):12. doi: 10.1186/s40035-024-00404-1. PMID: 38414054; PMCID: PMC10898075.

https://pubmed.ncbi.nlm.nih.gov/38414054

TMAO as osmolyte

28.         Burg MB, Ferraris JD. Intracellular organic osmolytes: function and regulation. J Biol Chem. 2008 Mar 21;283(12):7309-13. doi: 10.1074/jbc.R700042200. Epub 2008 Feb 6. PMID: 18256030; PMCID: PMC2276334.

https://pubmed.ncbi.nlm.nih.gov/18256030

29.         Khan SH, Ahmad N, Ahmad F, Kumar R. Naturally occurring organic osmolytes: from cell physiology to disease prevention. IUBMB Life. 2010 Dec;62(12):891-5. doi: 10.1002/iub.406. PMID: 21190292.

https://pubmed.ncbi.nlm.nih.gov/21190292

30.         Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, Schröder A, Rakova N, Jantsch J, Dikalova AE, Dikalov SI, Harrison DG, Müller DN, Nishiyama A, Rauh M, Harris RC, Luft FC, Wassermann DH, Sands JM, Titze J. High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest. 2017 May 1;127(5):1944-1959. doi: 10.1172/JCI88532. Epub 2017 Apr 17. PMID: 28414295; PMCID: PMC5409074.

https://pubmed.ncbi.nlm.nih.gov/28414295

31.         Gil RB, Ortiz A, Sanchez-Niño MD, Markoska K, Schepers E, Vanholder R, Glorieux G, Schmitt-Kopplin P, Heinzmann SS. Increased urinary osmolyte excretion indicates chronic kidney disease severity and progression rate. Nephrol Dial Transplant. 2018 Dec 1;33(12):2156-2164. doi: 10.1093/ndt/gfy020. PMID: 29554320.

https://pubmed.ncbi.nlm.nih.gov/29554320

32.         Yancey PH, Gerringer ME, Drazen JC, Rowden AA, Jamieson A. Marine fish may be biochemically constrained from inhabiting the deepest ocean depths. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4461-5. doi: 10.1073/pnas.1322003111. Epub 2014 Mar 3. PMID: 24591588; PMCID: PMC3970477.

https://pubmed.ncbi.nlm.nih.gov/24591588

TMAO is beneficial

33.         Gawrys-Kopczynska M, Konop M, Maksymiuk K, Kraszewska K, Derzsi L, Sozanski K, Holyst R, Pilz M, Samborowska E, Dobrowolski L, Jaworska K, Mogilnicka I, Ufnal M. TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats. Elife. 2020 Jun 8;9:e57028. doi: 10.7554/eLife.57028. PMID: 32510330; PMCID: PMC7334024.

https://pubmed.ncbi.nlm.nih.gov/32510330

Choline and betaine in common foods

33a.       Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003 May;133(5):1302-7. doi: 10.1093/jn/133.5.1302. Erratum in: J Nutr. 2003 Sep;133(9):2918. PMID: 12730414.

https://pubmed.ncbi.nlm.nih.gov/12730414

TMA is toxic

34.         Ufnal M. Trimethylamine, a Toxic Precursor of Trimethylamine Oxide, Lost in Medical Databases. J Nutr. 2020 Feb 1;150(2):419. doi: 10.1093/jn/nxz265. PMID: 32030429.

https://pubmed.ncbi.nlm.nih.gov/32030429

35.         Maksymiuk KM, Szudzik M, Gawryś-Kopczyńska M, Onyszkiewicz M, Samborowska E, Mogilnicka I, Ufnal M. Trimethylamine, a gut bacteria metabolite and air pollutant, increases blood pressure and markers of kidney damage including proteinuria and KIM-1 in rats. J Transl Med. 2022 Oct 15;20(1):470. doi: 10.1186/s12967-022-03687-y. PMID: 36243862; PMCID: PMC9571686.

https://pubmed.ncbi.nlm.nih.gov/36243862

Fish odor disease (trimethylaminuria)

36.         Schmidt AC, Leroux JC. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today. 2020 Sep;25(9):1710-1717. doi: 10.1016/j.drudis.2020.06.026. Epub 2020 Jun 29. PMID: 32615074.

https://pubmed.ncbi.nlm.nih.gov/32615074

37.         Hoyles L, Jiménez-Pranteda ML, Chilloux J, Brial F, Myridakis A, Aranias T, Magnan C, Gibson GR, Sanderson JD, Nicholson JK, Gauguier D, McCartney AL, Dumas ME. Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota. Microbiome. 2018 Apr 20;6(1):73. doi: 10.1186/s40168-018-0461-0. PMID: 29678198; PMCID: PMC5909246.

https://pubmed.ncbi.nlm.nih.gov/29678198

TMAO and kidney disease

38.         Bain MA, Faull R, Fornasini G, Milne RW, Evans AM. Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis. Nephrol Dial Transplant. 2006 May;21(5):1300-4. doi: 10.1093/ndt/gfk056. Epub 2006 Jan 9. PMID: 16401621.

https://pubmed.ncbi.nlm.nih.gov/16401621

39.         Pelletier CC, Croyal M, Ene L, Aguesse A, Billon-Crossouard S, Krempf M, Lemoine S, Guebre-Egziabher F, Juillard L, Soulage CO. Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate. Toxins (Basel). 2019 Nov 1;11(11):635. doi: 10.3390/toxins11110635. PMID: 31683880; PMCID: PMC6891811.

https://pubmed.ncbi.nlm.nih.gov/31683880

TMAO, immune system and gut microbiome with age, dysbiosis

40.         Rath S, Rox K, Kleine Bardenhorst S, Schminke U, Dörr M, Mayerle J, Frost F, Lerch MM, Karch A, Brönstrup M, Pieper DH, Vital M. Higher Trimethylamine-N-Oxide Plasma Levels with Increasing Age Are Mediated by Diet and Trimethylamine-Forming Bacteria. mSystems. 2021 Oct 26;6(5):e0094521. doi: 10.1128/mSystems.00945-21. Epub 2021 Sep 14. PMID: 34519520; PMCID: PMC8547441.

https://pubmed.ncbi.nlm.nih.gov/34519520

40a.       El Hage R, Al-Arawe N, Hinterseher I. The Role of the Gut Microbiome and Trimethylamine Oxide in Atherosclerosis and Age-Related Disease. Int J Mol Sci. 2023 Jan 25;24(3):2399. doi: 10.3390/ijms24032399. PMID: 36768722; PMCID: PMC9917289.    

https://pubmed.ncbi.nlm.nih.gov/36768722

41.         Wang X, Chen L, Teng Y, Xie W, Huang L, Wu J, Wang H, Xie S. Effect of three oral pathogens on the TMA-TMAO metabolic pathway. Front Cell Infect Microbiol. 2024 May 21;14:1413787. doi: 10.3389/fcimb.2024.1413787. PMID: 38836053; PMCID: PMC11148326.

https://pubmed.ncbi.nlm.nih.gov/38836053

42.         Fan H, Liu X, Ren Z, Fei X, Luo J, Yang X, Xue Y, Zhang F, Liang B. Gut microbiota and cardiac arrhythmia. Front Cell Infect Microbiol. 2023 Apr 25;13:1147687. doi: 10.3389/fcimb.2023.1147687. PMID: 37180433; PMCID: PMC10167053.

https://pubmed.ncbi.nlm.nih.gov/37180433

43.         Dou L, Peng Y, Zhang B, Yang H, Zheng K. Immune Remodeling during Aging and the Clinical Significance of Immunonutrition in Healthy Aging. Aging Dis. 2024 Aug 1;15(4):1588-1601. doi: 10.14336/AD.2023.0923. PMID: 37815906; PMCID: PMC11272210.

https://pubmed.ncbi.nlm.nih.gov/37815906

44.         Safarchi A, Al-Qadami G, Tran CD, Conlon M. Understanding dysbiosis and resilience in the human gut microbiome: biomarkers, interventions, and challenges. Front Microbiol. 2025 Mar 4;16:1559521. doi: 10.3389/fmicb.2025.1559521. PMID: 40104586; PMCID: PMC11913848.

https://pubmed.ncbi.nlm.nih.gov/40104586

45.         Cheraghi M, Nazari A, Souri F. Gut microbiota and cardiac arrhythmogenesis: Unveiling the gut-heart axis. Pathol Res Pract. 2025 Sep;273:156125. doi: 10.1016/j.prp.2025.156125. Epub 2025 Jul 15. PMID: 40675025.

https://pubmed.ncbi.nlm.nih.gov/40675025

46.         Fan Y, Ying J, Ma H, Cui H. Microbiota-related metabolites fueling the understanding of ischemic heart disease. Imeta. 2023 Feb 26;2(2):e94. doi: 10.1002/imt2.94. PMID: 38868424; PMCID: PMC10989774.

https://pubmed.ncbi.nlm.nih.gov/38868424

Plants-food diet, microbiota, TMA-producing bacteria

47.         Wu WK, Chen CC, Liu PY, Panyod S, Liao BY, Chen PC, Kao HL, Kuo HC, Kuo CH, Chiu THT, Chen RA, Chuang HL, Huang YT, Zou HB, Hsu CC, Chang TY, Lin CL, Ho CT, Yu HT, Sheen LY, Wu MS. Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Gut. 2019 Aug;68(8):1439-1449. doi: 10.1136/gutjnl-2018-317155. Epub 2018 Oct 30. PMID: 30377191; PMCID: PMC6691853.

https://pubmed.ncbi.nlm.nih.gov/30377191

48.         Beam A, Clinger E, Hao L. Effect of Diet and Dietary Components on the Composition of the Gut Microbiota. Nutrients. 2021 Aug 15;13(8):2795. doi: 10.3390/nu13082795. PMID: 34444955; PMCID: PMC8398149.

https://pubmed.ncbi.nlm.nih.gov/34444955

49.         Yang S, Li X, Yang F, Zhao R, Pan X, Liang J, Tian L, Li X, Liu L, Xing Y, Wu M. Gut Microbiota-Dependent Marker TMAO in Promoting Cardiovascular Disease: Inflammation Mechanism, Clinical Prognostic, and Potential as a Therapeutic Target. Front Pharmacol. 2019 Nov 19;10:1360. doi: 10.3389/fphar.2019.01360. PMID: 31803054; PMCID: PMC6877687.

https://pubmed.ncbi.nlm.nih.gov/31803054

50.         Iglesias-Carres L, Hughes MD, Steele CN, Ponder MA, Davy KP, Neilson AP. Use of dietary phytochemicals for inhibition of trimethylamine N-oxide formation. J Nutr Biochem. 2021 May;91:108600. doi: 10.1016/j.jnutbio.2021.108600. Epub 2021 Feb 9. PMID: 33577949.

https://pubmed.ncbi.nlm.nih.gov/33577949

51.         Lombardo M, Aulisa G, Marcon D, Rizzo G. The Influence of Animal- or Plant-Based Diets on Blood and Urine Trimethylamine-N-Oxide (TMAO) Levels in Humans. Curr Nutr Rep. 2022 Mar;11(1):56-68. doi: 10.1007/s13668-021-00387-9. Epub 2022 Jan 6. PMID: 34990005.

https://pubmed.ncbi.nlm.nih.gov/34990005

51a.       Wan ZW, Zheng LJ, Huang YF, Xie JW, Li JL, Chen YR. Effects of prebiotics and phytochemicals on serum trimethylamine N-oxide reduction and gut microbiota: a systematic review and meta-analysis. J Transl Med. 2025 Jul 9;23(1):759. doi: 10.1186/s12967-025-06806-7. PMID: 40634923; PMCID: PMC12239411.

https://pubmed.ncbi.nlm.nih.gov/40634923

52.         Ke Y, Li D, Zhao M, Liu C, Liu J, Zeng A, Shi X, Cheng S, Pan B, Zheng L, Hong H. Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress. Free Radic Biol Med. 2018 Feb 20;116:88-100. doi: 10.1016/j.freeradbiomed.2018.01.007. Epub 2018 Jan 8. Erratum in: Free Radic Biol Med. 2018 Dec;129:608-610. doi: 10.1016/j.freeradbiomed.2018.06.007. PMID: 29325896.

https://pubmed.ncbi.nlm.nih.gov/29325896

53.         Brunt VE, Casso AG, Gioscia-Ryan RA, Sapinsley ZJ, Ziemba BP, Clayton ZS, Bazzoni AE, VanDongen NS, Richey JJ, Hutton DA, Zigler MC, Neilson AP, Davy KP, Seals DR. Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans. Hypertension. 2021 Aug;78(2):499-511. doi: 10.1161/HYPERTENSIONAHA.120.16895. Epub 2021 May 10. PMID: 33966451; PMCID: PMC8266738.

https://pubmed.ncbi.nlm.nih.gov/33966451

54.         Simbirtseva KY, O’Toole PW. Healthy and Unhealthy Aging and the Human Microbiome. Annu Rev Med. 2025 Jan;76(1):115-127. doi: 10.1146/annurev-med-042423-042542. Epub 2025 Jan 16. PMID: 39531852.

https://pubmed.ncbi.nlm.nih.gov/39531852

55.         Krueger ES, Lloyd TS, Tessem JS. The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad. Nutrients. 2021 Aug 21;13(8):2873. doi: 10.3390/nu13082873. PMID: 34445033; PMCID: PMC8400152.

https://pubmed.ncbi.nlm.nih.gov/34445033

56.         Evans M, Dai L, Avesani CM, Kublickiene K, Stenvinkel P. The dietary source of trimethylamine N-oxide and clinical outcomes: an unexpected liaison. Clin Kidney J. 2023 Apr 21;16(11):1804-1812. doi: 10.1093/ckj/sfad095. PMID: 37915930; PMCID: PMC10616480.

https://pubmed.ncbi.nlm.nih.gov/37915930

57.         Macpherson ME, Hov JR, Ueland T, Dahl TB, Kummen M, Otterdal K, Holm K, Berge RK, Mollnes TE, Trøseid M, Halvorsen B, Aukrust P, Fevang B, Jørgensen SF. Gut Microbiota-Dependent Trimethylamine N-Oxide Associates With Inflammation in Common Variable Immunodeficiency. Front Immunol. 2020 Sep 16;11:574500. doi: 10.3389/fimmu.2020.574500. PMID: 33042155; PMCID: PMC7525000.

https://pubmed.ncbi.nlm.nih.gov/33042155

58.         Schmidt AC, Leroux JC. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today. 2020 Sep;25(9):1710-1717. doi: 10.1016/j.drudis.2020.06.026. Epub 2020 Jun 29. PMID: 32615074.

https://pubmed.ncbi.nlm.nih.gov/32615074

Beeld: Pexels