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Gut microbiota – a new companion on the path of cardiovascular diseases progression: surprising roles of long-time neighbors

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The last decade is marked by the significant reinterpretation of the gut microbiota contribution to chronic disease progression. The researchers’ careful attention is focused on improving the understanding of the metabolic pathways of two dietary compounds – choline and L-carnitine, which stand at the origins of trimethylamine N-oxide (TMAO) formation. This small molecule of great expectations has gained an impressive appreciation due to its ability to promote atherogenesis, and thus increasing the risk of major adverse cardiovascular events and affecting patients’ prognosis. This paper aims to discuss updated concept of microbiota-dependent cardiometabolic consequences of consumption of food rich in quaternary amines as well as to touch upon the currently existing interventions in TMAO production, their limitations and future scientific directions.

About the Authors

O. M. Drapkina
State Research Centre for Preventive Medicine. Petroverigsky per. 10, Moscow, 101990 Russia
Russian Federation

A. N. Kaburova
I.M. Sechenov First Moscow State Medical University. Trubetskaya ul. 8-2, Moscow, 119991, Russia
Russian Federation


1. Cambien F, Tiret L. Genetics of cardiovascular diseases: from single mutations to the whole genome. Circulation 2007; 116(15): 1714-24.

2. Zubareva MY, Rozhkova TA, Gorbunova NB, et al. Residual (remaining) risk in patients with very high risk with atherogenic dyslipidemia, are on statin therapy. A prospective study "CRYSTAL". Part 1: The purpose, tasks, design and initial properties included patients. Ateroskleroz i dislipidemii 2013; 1 (10): 26-34. In Russian (Зубарева М.Ю., Рожкова Т. А., Горнякова Н. Б., и др. Резидуальный (остаточный) риск у нездоровых очень высочайшего риска с атерогенными дислипидемиями, находящихся на терапии статинами. Проспективное исследование «КРИСТАЛЛ». Часть 1: Цель, задачки, дизайн и начальные свойства включенных пациентов. Атеросклероз и дислипидемии 2013;1(10):26-34).

3. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21):2195-207.

4. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTeRHeART study): case-control study. Lancet 2004;364(9438): 937-52.

5. Turnbaugh PJ, Ley RE, Hamady M et al. The human microbiome project. Nature 2007; 449(7164): 804-10.

6. Patel SS, Malakouti M, Cortez MD, et al. Is the gut microbiome the next target for atherosclerosis? JSM Clin Case Rep 2014; 2(5):1055.

7. Vinje S, Stroes E, Nieuwdorp M, et al. The gut microbiome as novel cardio-metabolic target: the time has come! Eur Heart J 2014;35(14):883-7.

8. Brown JM, Hazen SL. Meta-organismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 2014; 25(1):48-53.

9. Backhead F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004;101(44):15718-23.

10. Velagapudi VR, Hezaveh R, Reigstad CS, et al. The gut microbiota modulates host energy and lipid metabolism in mice. J Lipid Res 2010;51(5):1101-12.

11. Delzenne NM, Cani PD. Gut microbiota and the pathogenesis of insulin resistance. Curr Diab Rep 2011;11(3):154-9.

12. Aron-Wisnewsky J, Gaborit B, Dutour A, et al. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect 2013;19(4):338-48.

13. Griffin JL, Scott J, Nicholson JK. The influence of pharmacogenetics on fatty liver disease in the Wistar and Kyoto rats: A combined transcriptomic and metabolomic study. J Proteome Res 2007;6(1):54-61.

14. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499(7456):97-101.

15. Sjögren K, Engdahl C, Henning P, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res. 2012;27(6):1357-67.

16. Shah SH, Kraus WE, Newgard CB. Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function. Circulation 2012;126(9):1110-20.

17. Tremaroli V, Bachhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489 (7415):242-9.

18. Lozupone CA, Stombaugh JI, Gordon JI et al. Diversity, Stability and resilience of the human gut microbiota. Nature 2012; 489 (7415): 220-30

19. Tilg H. Obesity, metabolic syndrome, and microbiota: multiple interactions. J Clin Gastroecterol 2010; 44 (Suppl. 1): 16-8.

20. Faith JJ, Guruge JL, Charbonneau M, et al. The long-term stability of the human microbiota. Science 2013; 341(6141): 1237439.

21. Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature 2014;509(7500):357-60.

22. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. MetaHIT Consortium. Nature 2010;464(7285):59-65.

23. Kostyukevich OI. Influence of intestinal microflora on human health. From Pathogenesis to modern methods of correction of dysbiosis. Rossiyskiy meditsinskiy zhurnal 2011; 5: 304-8. In Russian (Костюкевич О.И. Влияние кишечной микрофлоры на здоровье человека. От патогенеза к современным методам коррекции дисбиоза. Российский медицинский журнал 2011; 5:304-8).

24. Kushnir IE. Intestinal microbiota and human health. Modern approaches to intestinal dysbiosis correction. Zdorov'e Ukrainy 2015; 1: 41-3. In Russian (Кушнир И.Э. Микробиота кишечника и здоровье человека. Современные подходы к коррекции дисбиоза кишечника. Здоровье Украины 2015;1:41-3).

25. Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 2014;124(10):4204-11.

26. Micha R, Wallace SR, Mozaffarian D. Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis. Circulation 2010; 121(21):2271-83.

27. Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472: 57-63.

28. Bennett BJ, De Aguiar Vallim TQ, Wang Z et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metabolism 2013; 17(1):49-60.

29. Tang WH, Wang Z, Levison BS et al. Intestinal Microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368:1575-84.

30. Prospective Studies collaboration, Lewington S, Whitlock G, et al. Blood cholesterol and vascular mortality by age, sex and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007; 370(9602): 1829-39.

31. Tang WH, Wang Z, Fan Y, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite, trimethylamine-N-oxide, in parents with heart failure: refining the gut hypothesis. О Am Coll Cardiol 2013; 64(18):1908-14.

32. Bell JD, Lee JA, Lee HA et al. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide. Biochim Biophys Acta 1991; 1096(2):101-7.

33. Rhee EP, Clish CB, Ghorbani A, et al. A combines epidemiologic and metabolomics approach improves CKD prediction. О Am Soc Nephrol 2013;24(8):1330-38.

34. Gao X, Liu X, Xu J, et al. Dietary trimethylamine-N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J Biosci Bioeng 2014:118(4):476-81.

35. Ierardi E, Sorrentino C, Principi M, et al. Intestinal microbial metabolism of phosphatidylchline: a novel insight in the cardiovascular risk scenario. Hepatobiliary Surg Nutr 2015;4(4):289-92.

36. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19(5):576-85.

37. Wang D, Xia M, Yan X, et al. Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circ Res 2012; 111(8):967-81.

38. Ueland PM. Choline and betaine in health and disease. J Inherit Metab Dis 2011;34(1):3-15.

39. Dumas ME, Barton RH, Toye A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci USA 2006;103(33):12511-6.

40. Bain MA, Faull R, Milne RW, et al. Oral L-carnitine: metabolite formation and hemodialysis. Curr Drug Metab 2006;7(7):811-6.

41. Marcovina SM, Sirtori C, Peracino A, et al. Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine. Transl Res 2013;161(2):73-84.

42. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and mortality: results from 2 prospective cohort studies. Arch Intern Med 2012; 172(7):555-63.

43. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505(7484):559-63.

44. Lekawanvijit S, Kumfu S, Wang BH, et al. The uremic toxin absorbent AST-120 abogates cardiorenal injury following myocardial infarction. PLoS One 2013;8(12):e83687.

45. Ito S, Higuchi Y, Yagi Y, et al. Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease. J Leukoc Biol 2013;93(6):837-45.

46. Backhed F, Manchester JK, Semenkovich CF, et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007; 104(3):979-84.

47. Тurnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027-31.

48. Gregory JC, Buffa JA, Org E, et al. Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation. J Biol Chem 2015;290(9):5647-60.

49. Serino M, Blasco-Baque V, Nicolas S, et al. Far from the eyes, close to the heart: dysbiosis of gut microbiota and cardiovascular consequences. Curr Cardiol Rep 2014; 16(11):540.

50. Messenger J, Clark S, Massick S, et al. A review of trimethylaminuria: (fish odor syndrome). О Clin Aesthet Dermatol 2013;6(11):45-8.

51. Hartiala J, Bennett BJ, Tang WH, 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 2014;34(6):1307-13.

For citation:

Drapkina O.M., Kaburova A.N. Gut microbiota – a new companion on the path of cardiovascular diseases progression: surprising roles of long-time neighbors. Rational Pharmacotherapy in Cardiology. 2016;12(1):66-71. (In Russ.)

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