Kardiyovasküler Hastalıklarda Bağırsak Mikrobiyota Metaboliti Trimetilamin N-oksit (TMAO) : Önleme ve Tedavi İçin Yeni Bir Molekül mü?

Öz

Dünya çapında ölümlerin en önde gelen nedeni olan kardiyovasküler hastalıkların önlenmesi ve prognozunun kontrolünde bağırsak mikrobiyota türevli moleküllerin katkısının bulunması ile bağırsak ve kardiyovasküler sistem arasındaki bağlantıya olan ilgi önemli ölçüde artmıştır. Güncel çalışmalar bağırsak mikrobiyomu ve metabolitlerinin ateroskleroz, hipertansiyon, kalp yetmezliği, atrial fibrilasyon ve miyokard fibrozu gibi kardiyovasküler hastalıkların başlangıcında ve ilerlemesinde önemli rol oynadığını göstermektedir. Diyetin içeriği bağırsak mikrobiyotasını değiştiren önemli bir faktördür. Hayvansal kaynaklarda bulunan kolin ve L-karnitinin bağırsak mikroorganizmaları tarafından metabolize edilmesiyle trimetilamin (TMA) oluşmaktadır. Üretilen TMA?nın çoğunluğu pasif olarak portal dolaşıma geçmekte ve hepatik flavine bağımlı monooksigenazlar (FMO?lar) tarafından trimetilamin-N-oksit (TMAO)?e okside edilmektedir. Kırmızı et, süt ürünleri, yumurta, balık ve kümes hayvanlarında bol miktarda bulunan fosfotidilkolin, L-karnitin ve betain TMA kaynağı olan bileşiklerdir. Trimetilamin veya öncüllerini içeren besinler kan ve idrar TMAO düzeylerini artırmaktadır. Son zamanlarda birçok çalışmada TMAO düzeylerinin yüksek olması kardiyovasküler hastalık riski ile ilişkilendirilmektedir. Kardiyovasküler hastalıklar ve TMAO arasındaki bağlantının anlaşılması; TMAO?nun bir biyomarker olup olmadığının belirlenmesi ve TMAO?yu etkileyen diyet bileşenlerinin varlığının tespit edilmesi yeni tedavi yaklaşımlarına odaklanılması açısından önemlidir. Böylece, bu derleme kırmızı et ve diğer hayvansal ürünlerde bulunan kolin ve L-karnitinin bir metaboliti olan TMAO?nun kardiyovasküler hastalıklar üzerine etkisini içeren mekanizmalar ile ilgili literatürün derlenmesi amacıyla yazılmıştır.

Anahtar Kelimeler

• Diyet
• Beslenme
• Mikrobiyota
• TMAO
• Ateroskleroz

Gut Microbiota-Dependent Metabolite Trimethylamine N-oxide (TMAO), in Cardiovascular Diseases: A New Molecule for Prevention and Treatment?

Abstract

ABSTRACT There has been an increasing interest in the relationship between the gut and the cardiovascular system, since the contribution of intestinal microbiota-derived molecules in the prevention and control of the prognosis of cardiovascular diseases, the leading cause of mortality worldwide, was determined. Current studies have demonstrated that intestinal microbiome and its metabolites play a significant role in the development and progression of cardiovascular diseases such as atherosclerosis, hypertension, heart failure, atrial fibrillation and myocardial fibrosis. The content of the diet is an important factor that changes the gut microbiota. Trimethylamine (TMA) is produced by the intestinal microorganisms which metabolize choline and L-carnitine found in animal sources. The majority of the TMA produced passively passes into the portal circulation and is oxidized to trimethylamine-N-oxide (TMAO) by the hepatic flavin-dependent monooxygenases (FMOs). Phosphatidylcholine, L-carnitine and betaine which are abundant in red meat, dairy products, eggs, fish and poultry are the sources of TMA. Foods containing trimethylamine or its precursors increase TMAO levels in blood and urine. In many studies conducted recently, high levels of TMAO have been associated with the risk of cardiovascular diseases. Understanding the relationship between cardiovascular diseases and TMAO, determining whether TMAO is a biomarker and determining the presence of dietary components affecting TMAO are of importance in focusing on new treatment approaches. Thus, this review was performed to compile the literature on the mechanisms involving the effect of TMAO, a metabolite of choline and L-carnitine found in red meat and other animal products, on cardiovascular diseases.

Keywords

• Diet
• Nutrition
• Microbiota
• TMAO
• Atherosclerosis

References

1. 1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388(10053):1459–544.
2. 2. Benjamin EJ, Virani SS, et al. Heart Disease and Stroke Statistics-2018 Update. Circulation 2018;137:e67–e492.
3. 3. World Health Organization. Cardiovascular diseases (CVDs). World Health Organization. (https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds))
4. 4. Türkiye İstatistik Kurumu, Ölüm Nedeni İstatistikleri, 2018, 2019. (http://www.tuik.gov.tr/PreHaberBultenleri.do?id=30626).
5. 5. World Health Organization. Global Status Report on Noncommunicable Diseases. Geneva, WHO, 2014.
6. 6. Cardiology ES of. European Society of Cardiology annual report 2018. European Society of Cardiology, 2018. (https://www.escardio.org/static_file/Escardio/About the ESC/Annual-Reports/ESC-Annual-Report-2018.pdf)
7. 7. Ulusal Hastalık Yükü ve Maliyet Etkililik Projesi Hastalık Yükü Final Rapor. Ankara, Başkent Üniversitesi, 2004.
8. 8. McGuire S. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Washington, DC: US Departments of Agriculture and Health and Human Services, 2015. Advances in Nutrition 2016;7(1):202–4.

9. 9. Ou Y, Zhang C, Yao M, Wang L. Gut Flora: Novel Therapeutic Target of Chinese Medicine for the Treatment of Cardiovascular Diseases. Evidence-Based Complementary and Alternative Medicine 2019;2019.
10. 10. Ahmadmehrabi S, Tang WHW. Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol 2017;32(6):761–6.
11. 11. Lippi G, Danese E, Mattiuzzi C, Favaloro E. The Intriguing Link between the Intestinal Microbiota and Cardiovascular Disease. Semin Thromb Hemost 2017;43(06):609–13.
12. 12. Emoto T, Yamashita T, et al.Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease. J Atheroscler Thromb 2016;23(8):908–21.
13. 13. Li X, Geng J, et al.Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome. Frontiers in Physiology 2019;10:866.
14. 14. Yang W, Zhang S, et al. Gut microbe-derived metabolite trimethylamine N-oxide accelerates fibroblast-myofibroblast differentiation and induces cardiac fibrosis. J Mol Cell Cardiol 2019;134:119–30.
15. 15. Gentile CL, Weir TL. The gut microbiota at the intersection of diet and human health. Science 2018;362(6416):776–80.
16. 16. Janeiro M, Ramírez M, et al. Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target. Nutrients 2018;10(10):1398. 17. Wilson A, McLean C, Kim RB. Trimethylamine-N-oxide. Curr Opin Lipidol 2016;27(2):148–54.
17. 18. Al-Rubaye H, Perfetti G, Kaski J-C. The Role of Microbiota in Cardiovascular Risk: Focus on Trimethylamine Oxide. Curr Probl Cardiol 2019;44(6):182–96.
18. 19. Tang WHW, Wang Z, et al. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. N Engl J Med 2013;368(17):1575–84.
19. 20. Koeth RA, Wang Z,et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19(5):576–85. 21. Qi J, You T, Li J, Pan T, Xiang L, Han Y, Zhu L. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. Journal of Cellular and Molecular Medicine 2018;22(1):185–94.
20. 22. Tang WHW, Wang Z, Fan Y, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014;64(18):1908–14.
21. 23. Geng J, Yang C,et al. Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway. Biomed Pharmacother 2018;97:941–7.
22. 24. Peng J, Xiao X, Hu M, Zhang X. Interaction between gut microbiome and cardiovascular disease. Life Sci 2018;214:153–7.
23. 25. Kanitsoraphan C, Rattanawong P, Charoensri S, Senthong V. Trimethylamine N-Oxide and Risk of Cardiovascular Disease and Mortality. Current Nutrition Reports 2018;7(4):207–13.
24. 26. Wang Z, Zhao Y. Gut microbiota derived metabolites in cardiovascular health and disease. Protein & Cell 2018;9(5):416–31. 27. Nowiński A, Ufnal M. Trimethylamine N -oxide: A harmful, protective or diagnostic marker in lifestyle diseases? Nutrition 2018;46:7–12.
25. 28. Moludi J, Maleki V, et al. Metabolic endotoxemia and cardiovascular disease: A systematic review about potential roles of prebiotics and probiotics. Clinical and Experimental Pharmacology and Physiology 2020;47(6), 927-939.
26. 29. Tomlinson JAP, Wheeler DC. The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease. Kidney Int 2017;92(4):809–15.
27. 30. Li DY, Tang WHW. Gut Microbiota and Atherosclerosis. Current Atherosclerosis Reports 2017;19(10):39.
28. 31. Chhibber-Goel J, Gaur A,et al. The complex metabolism of trimethylamine in humans: endogenous and exogenous sources. Expert Reviews in Molecular Medicine 2016;18.
29. 32. Fennema D, Phillips IR, Shephard EA. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Drug Metab Dispos 2016;44(11):1839–50.
30. 33. Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel) 2016;8(11):326.
31. 34. Subramaniam S, Fletcher C. Trimethylamine N-oxide: breathe new life. Br J Pharmacol 2018;175(8):1344–53.
32. 35. Canyelles M, Tondo M, et al. Trimethylamine N-Oxide: A Link among Diet, Gut Microbiota, Gene Regulation of Liver and Intestine Cholesterol Homeostasis and HDL Function. International Journal of Molecular Sciences 2018;19(10):3228.
33. 36. Solanki A, Bhatt LK, Johnston TP. Evolving targets for the treatment of atherosclerosis. Pharmacol Ther 2018;187:1–12.
34. 37. Ufnal M, Zadlo A, Ostaszewski R. TMAO: A small molecule of great expectations. Nutrition 2015;31(11–12):1317–23.
35. 38. Zeisel SH, Warrier M. Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease. Annu Rev Nutr 2017;37(1):157–81.
36. 39. Aron-Wisnewsky J, Clément K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol 2016;12(3):169–81.
37. 40. Mente A, Chalcraft K, et al. The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada. Can J Cardiol 2015;31(9):1189–94.
38. 41. Senthong V, Wang Z, et al. Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease. Journal of the American Heart Association 2016;5(10).
39. 42. Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies. Journal of the American Heart Association 2017;6(7).
40. 43. Meyer K, Shea J. Dietary Choline and Betaine and Risk of CVD: A Systematic Review and Meta-Analysis of Prospective Studies. Nutrients 2017;9(7):711.
41. 44. Collins HL, Drazul-Schrader D, et al. L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP. Atherosclerosis 2016;244:29–37. 45. Jonsson AL, Caesar R, et al. Impact of gut microbiota and diet on the development of atherosclerosis in ApoE−/− mice. Arterioscler Thromb Vasc Biol 2018;38(10):2318–2326.
42. 46. Aldana-Hernández P, Leonard K-A, et al. Dietary Choline or Trimethylamine N-oxide Supplementation Does Not Influence Atherosclerosis Development in Ldlr−/− and Apoe−/− Male Mice. J Nutr 2019;150(2):249–55.
43. 47. Randrianarisoa E, Lehn-Stefan A, et al. Relationship of Serum Trimethylamine N-Oxide (TMAO) Levels with early Atherosclerosis in Humans. Scientific Reports 2016;6:26745.
44. 48. Miller CA, Corbin KD, et al. Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr 2014;100(3):778–86.
45. 49. Zhao Y, Yang N, et al. The Effect of Different l-Carnitine Administration Routes on the Development of Atherosclerosis in ApoE Knockout Mice. Molecular Nutrition & Food Research 2018;62(5).
46. 50. Wang Z, Klipfell E, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57–63.
47. 51. Ding L, Chang M,et al. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids in Health and Disease 2018;17(1).
48. 52. Chung RWS, Wang Z, et al. Effect of long-term dietary sphingomyelin supplementation on atherosclerosis in mice. PLoS One 2017;12(12):e0189523.
49. 53. Zhu W, Gregory JC, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 2016;165(1):111–24.
50. 54. Cheng X, Qiu X, et al. Trimethylamine N-oxide promotes tissue factor expression and activity in vascular endothelial cells: A new link between trimethylamine N-oxide and atherosclerotic thrombosis. Thromb Res 2019;177:110–6.
51. 55. Zhu W, Wang Z, Tang WHW, Hazen SL. Gut Microbe-Generated Trimethylamine N-Oxide From Dietary Choline Is Prothrombotic in Subjects. Circulation 2017;135(17):1671–3.
52. 56. Tang WHW, Hazen SL. Microbiome, trimethylamine N-oxide, and cardiometabolic disease. Translational Research 2017;179:108–15.
53. 57. Trøseid M, Ueland T, et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 2015;277(6):717–26.
54. 58. Zhou X, Jin M, et al. Trimethylamine N-oxide and cardiovascular outcomes in patients with chronic heart failure after myocardial infarction. ESC Heart Failure 2020.
55. 59. Suzuki T, Heaney LM, et al. Trimethylamine N-oxide and prognosis in acute heart failure. Heart 2016;102(11):841–8.
56. 60. Lever M, George PM, et al. Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study. PLoS One 2014;9(12):e114969.
57. 61. Organ CL, Otsuka H, et al. Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure. Circulation Heart Failure 2016;9(1):e002314.
58. 62. Chen K, Zheng X, et al. Gut Microbiota-Dependent Metabolite Trimethylamine N-Oxide Contributes to Cardiac Dysfunction in Western Diet-Induced Obese Mice. Frontiers in Physiology 2017;8:139.
59. 63. Li Z, Wu Z, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Invest 2019;99(3):346–57.
60. 64. Senthong V, Wang Z, et al. Intestinal Microbiota‐Generated Metabolite Trimethylamine‐ N‐ Oxide and 5‐Year Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of Intestinal Microbiota in a COURAGE‐Like Patient Cohort. Journal of the American Heart Association 2016;5(6).
61. 65. Zheng Y, Li Y, et al. Dietary phosphatidylcholine and risk of all-cause and cardiovascular-specific mortality among US women and men. Am J Clin Nutr 2016;104(1):173–80. 66. Zhu Y, Li Q, Jiang H. Gut microbiota in atherosclerosis: focus on trimethylamine N-oxide. Apmis 2020; 128(5):353-366.
62. 67. Liu T-X, Niu H-T, Zhang S-Y. Intestinal Microbiota Metabolism and Atherosclerosis. Chin Med J (Engl) 2015;128(20):2805–11.
63. 68. Borrel G, McCann A, et al. Genomics and metagenomics of trimethylamine-utilizing Archaea in the human gut microbiome. The ISME Journal 2017;11(9):2059–74.
64. 69. Gaci N, Borrel G, et al. Archaea and the human gut: New beginning of an old story. World Journal of Gastroenterology 2014;20(43):16062–78.
65. 70. Chen M, Yi L, et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. MBio 2016;7(2):e02210-15 . 71. Yu D, Shu X, et al. Urinary Levels of Trimethylamine‐N‐Oxide and Incident Coronary Heart Disease: A Prospective Investigation Among Urban Chinese Adults. Journal of the American Heart Association 2019;8(1):e010606.
66. 72. Krüger R, Merz B, et al. Associations of current diet with plasma and urine TMAO in the KarMeN study: direct and indirect contributions. Molecular Nutrition & Food Research 2017;61(11):1700363.
67. 73. Yazdekhasti N, Brandsch C, et al. Fish protein increases circulating levels of trimethylamine- N -oxide and accelerates aortic lesion formation in apoE null mice. Molecular Nutrition & Food Research 2016;60(2):358–68.
68. 74. Li T, Chen Y, Gua C, Li X. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress. Frontiers in Physiology 2017;8:350.
69. 75. Tenore GC, Caruso D, et al. Lactofermented Annurca Apple Puree as a Functional Food Indicated for the Control of Plasma Lipid and Oxidative Amine Levels: Results from a Randomised Clinical Trial. Nutrients 2019;11(1).
70. 76. Yu H, Yu Z, et al. Gut microbiota signatures and lipids metabolism profiles by exposure to polyene phosphatidylcholine. Biofactors 2019;45(3):439–49.
71. 77. Park JE, Miller M,et al. Differential effect of short-term popular diets on TMAO and other cardio-metabolic risk markers. Nutrition, Metabolism & Cardiovascular Diseases 2019;29(5):513–7.
72. 78. Pignanelli M, Just C, et al. Mediterranean Diet Score: Associations with Metabolic Products of the Intestinal Microbiome, Carotid Plaque Burden, and Renal Function. Nutrients 2018;10(6).
73. 79. Shi Y, Hu J, et al. Berberine treatment reduces atherosclerosis by mediating gut microbiota in apoE-/- mice. Biomed Pharmacother 2018;107:1556–63.
74. 80. Fatkhullina AR, Peshkova IO, et al. An Interleukin-23-Interleukin-22 Axis Regulates Intestinal Microbial Homeostasis to Protect from Diet-Induced Atherosclerosis. Immunity 2018;49(5):943–957.e9.
75. 81. Olek RA, Samulak JJ, et al. Increased Trimethylamine N-Oxide Is Not Associated with Oxidative Stress Markers in Healthy Aged Women. Oxidative Medicine and Cellular Longevity 2019;2019.
76. 82. Rohrmann S, Linseisen J, 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 2016;146(2):283–9.
77. 83. Mödinger Y, Schön C, Wilhelm M, Hals PA. Plasma Kinetics of Choline and Choline Metabolites After A Single Dose of SuperbaBoostTM Krill Oil or Choline Bitartrate in Healthy Volunteers. Nutrients 2019;11(10).
78. 84. Zia Y, Al Rajabi A, et al. Hepatic Expression of PEMT, but Not Dietary Choline Supplementation, Reverses the Protection against Atherosclerosis in Pemt -/- /Ldlr -/- Mice. J Nutr 2018;148(10):1513–20.
79. 85. Roberts AB, Gu X, et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 2018;24(9):1407–17.
80. 86. Gong D, Zhang L, et al. Gut Microbial Metabolite Trimethylamine N-Oxide Is Related to Thrombus Formation in Atrial Fibrillation Patients. Am J Med Sci 2019;358(6):422–8.
81. 87. Reiner MF, Müller D, et al. Gut microbiota-dependent trimethylamine-N-oxide (TMAO) shows a U-shaped association with mortality but not with recurrent venous thromboembolism. Thromb Res 2019;174:40–7.
82. 88. Subramaniam S, Boukhlouf S, Fletcher C. A bacterial metabolite, trimethylamine N-oxide, disrupts the hemostasis balance in human primary endothelial cells but no coagulopathy in mice. Blood Coagul Fibrinolysis 2019;30(7):324–30.
83. 89. Hayashi T, Yamashita T, et al. Gut microbiome and plasma microbiome-related metabolites in patients with decompensated and compensated heart failure. Circulation Journal 2019;83(1):182–92.
84. 90. Wang G, Kong B, et al. 3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice. Journal of Nutritional Biochemistry 2020;78:108341. 91. Zhang H, Meng J, Yu H. Trimethylamine N-oxide Supplementation Abolishes the Cardioprotective Effects of Voluntary Exercise in Mice Fed a Western Diet. Frontiers in Physiology 2017;8:944.
85. 92. Li XS, Obeid S, et al. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J 2017;38(11):ehw582.
86. 93. Schiattarella GG, Sannino A, et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: A systematic review and dose-response meta-analysis. Eur Heart J 2017;38(39):2948–56.