Кишечный метаболом, как отдельный маркер развития сердечно-сосудистых патологий

Сердечно-сосудистые заболевания (ССЗ) остаются одной из ведущих причин смертности в мире, особенно в развитых странах. В последние годы внимание исследователей привлекает роль кишечной микробиоты и её метаболитов в развитии и прогрессировании ССЗ. Кишечная микробиота производит различные метаболиты, такие как короткоцепочечные жирные кислоты (SCFA), триметиламин-N-оксид (ТМАО), вторичные желчные кислоты и производные триптофана, которые могут влиять на сердечно-сосудистую систему. ТМАО, образующийся из пищевых компонентов (холин, карнитин), связан с повышенным риском атеросклероза, воспаления и тромбоза. Высокие уровни ТМАО коррелируют с увеличением сердечно-сосудистых событий, таких как инфаркт миокарда и инсульт. SCFA, напротив, обладают противовоспалительными свойствами, улучшают эндотелиальную функцию и снижают риск ССЗ. Вторичные желчные кислоты и производные триптофана также играют важную роль в регуляции воспаления и сосудистой функции. Исследования показывают, что модуляция микробиоты через диету, пробиотики и пребиотики может стать перспективным подходом для профилактики и лечения сердечно-сосудистых заболеваний. Таким образом, изучение кишечного метаболома открывает новые возможности для выявления биомаркеров и разработки персонализированных стратегий лечения кардиометаболических заболеваний.

микробиота, микробиом, дисбактериоз, метаболиты, сердечно-сосудистые заболевания, триметиламин-N-оксид, желчные кислоты, индол, триптофан, атеросклероз, сердечная недостаточность, ХСН, ТМАО

1. Timmis A., Townsend N., Gale C.P. et al. European Society of Cardiology: Cardiovascular Disease Statistics 2019. European Heart Journal. 2020; (41):12-85. doi: 10.1093/eurheartj/ 17.ehz859.

2. Yang W., Cong Y. Gut microbiota-derived metabolites in the regulation of host immune re-sponses and immune-related inflammatory diseases. Cell Mol Immunol. 2021 Apr;18(4):866-877. doi: 10.1038/s41423-021-00661-4.

3. Singh A., Kishore P.S., Khan S. From Microbes to Myocardium: A Comprehensive Review of the Impact of the Gut-Brain Axis on Cardiovascular Disease. Cureus. 2024 Oct 5;16(10): e70877. doi: 10.7759/cureus.70877.

4. Martins D., Silva C., Ferreira A.C. et al. Unravelling the Gut Microbiome Role in Cardiovascu-lar Disease: A Systematic Review and a Meta-Analysis. Biomolecules. 2024 Jun 20;14(6):731. doi: 10.3390/biom14060731.

5. Wu W., Sun M., Chen F. et al.Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 2017 Jul;10(4):946-956. doi: 10.1038/mi.2016.114.

6. Jaén R.I., Val-Blasco A., Prieto P. et al. Innate Immune Receptors, Key Actors in Cardiovascu-lar Diseases. JACC Basic Transl Sci. 2020 Jul 27;5(7):735-749. doi: 10.1016/j.jacbts.2020.03.015.

7. Grylls A., Seidler K., Neil J. Link between microbiota and hypertension: Focus on LPS/TLR4 pathway in endothelial dysfunction and vascular inflammation, and therapeutic implication of probiotics. Biomed Pharmacother. 2021 May;137:111334. doi: 10.1016/j.biopha.2021.111334.

8. Bose S., Ramesh V., Locasale J.W. Acetate Metabolism in Physiology, Cancer, and Beyond. Trends Cell Biol. 2019 Sep;29(9):695-703. doi: 10.1016/j.tcb.2019.05.005.

9. Soldán M., Argalášová Ľ., Hadvinová L., Galileo B., Babjaková J. The Effect of Dietary Types on Gut Microbiota Composition and Development of Non-Communicable Diseases: A Narra-tive Review. Nutrients. 2024 Sep 17;16(18):3134. doi: 10.3390/nu16183134.

10. Khan Q.A., Asad M., Ali A.H. et al. Gut microbiota metabolites and risk of major adverse cardiovascular events and death: A systematic review and meta-analysis. Medicine (Balti-more). 2024 May 31;103(22): e37825. doi: 10.1097/MD.0000000000037825.

11. Ma G., Pan B., Chen Y. et al. Trimethylamine N-oxide in atherogenesis: impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci Rep. 2017 Mar 2;37(2): BSR20160244. doi: 10.1042/BSR20160244.

12. Ding L., Chang M., Guo Y., Zhang L. et al. Trimethylamine-N-oxide (TMAO)-induced ath-erosclerosis is associated with bile acid metabolism. Lipids Health Dis. 2018 Dec 19;17(1):286. doi: 10.1186/s12944-018-0939-6.

13. Tang W.H.W., Bäckhed F., Landmesser U., Hazen S.L.Intestinal Microbiota in Cardiovascu-lar Health and Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019 Apr 30;73(16):2089-2105. doi: 10.1016/j.jacc.2019.03.024.

14. Cheng X., Qiu X., Liu Y. 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 May;177:110-116. doi: 10.1016/j.thromres.2019.02.028.

15. Chou R.H., Chen C.Y., Chen I.C. et al. Trimethylamine N-Oxide, Circulating Endothelial Progenitor Cells, and Endothelial Function in Patients with Stable Angina. Sci. Rep. 2019;9:4249. doi: 10.1038/s41598-019-40638-y.

16. Querio G., Antoniotti S., Geddo F. et al. Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite.Int J Mol Sci. 2023 Mar 18;24(6):5806. doi: 10.3390/ijms24065806.

17. Witkowski M., Weeks T.L., Hazen S.L. Gut Microbiota and Cardiovascular Disease. Circ Res. 2020 Jul 31;127(4):553-570. doi: 10.1161/CIRCRESAHA.120.316242.

18. Li X., Sun Y., Zhang X., Wang J. Reductions in gut microbiota derived metabolite trimethyla-mine N oxide in the circulation may ameliorate myocardial infarction induced heart failure in rats, possibly by inhibiting interleukin 8 secretion. Mol Med Rep. 2019 Jul;20(1):779-786. doi: 10.3892/mmr.2019.10297.

19. Villar-Fincheira P., Sanhueza-Olivares F., Norambuena-Soto I. et al. Role of Interleukin-6 in Vascular Health and Disease. Front Mol Biosci. 2021 Mar 16;8:641734. doi: 10.3389/fmolb.2021.641734.

20. Dicks L.M.T. Cardiovascular Disease May Be Triggered by Gut Microbiota, Microbial Metab-olites, Gut Wall Reactions, and Inflammation.Int J Mol Sci. 2024 Oct 2;25(19):10634. doi: 10.3390/ijms251910634.

21. Dai Q., Zhang H., Liu Y. [Trimethylamine-N-oxide and cardiovascular events in chronic kid-ney disease]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2019 Nov 28;44(11):1294-1299. Chinese. doi: 10.11817/j.issn.1672-7347.2019.180406.

22. Zixin Y., Lulu C., Xiangchang Z. et al. TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review. Front Pharmacol. 2022 Aug 12;13:929262. doi: 10.3389/fphar.2022.929262.

23. Yu Y., Yin Y., Deng J. et al. Unveiling the causal effects of gut microbiome on trimethylamine N-oxide: evidence from Mendelian randomization. Front Microbiol. 2024 Oct 25;15:1465455. doi: 10.3389/fmicb.2024.1465455.

24. Zhang Y., Wang Y., Ke B., Du J. TMAO: how gut microbiota contributes to heart failure. Transl Res. 2021 Feb;228:109-125. doi: 10.1016/j.trsl.2020.08.007.

25. Polsinelli V.B., Marteau L., Shah S.J. The role of splanchnic congestion and the intestinal mi-croenvironment in the pathogenesis of advanced heart failure. Curr Opin Support Palliat Care. 2019 Mar;13(1):24-30. doi: 10.1097/SPC.0000000000000414.

26. Zuo K., Li J., Li K. et al. Disordered gut microbiota and alterations in metabolic patterns are associated with atrial fibrillation. Gigascience. 2019 Jun 1;8(6): giz058. doi: 10.1093/gigascience/giz058.

27. Wastyk H.C., Fragiadakis G.K., Perelman D. et al. Gut-microbiota-targeted diets modulate hu-man immune status. Cell. 2021 Aug 5;184(16):4137-4153.e14. doi: 10.1016/j.cell.2021.06.019.

28. Nenna A., Laudisio A., Taffon C. et al.Intestinal Microbiota and Derived Metabolites in Myo-cardial Fibrosis and Postoperative Atrial Fibrillation.Int J Mol Sci. 2024 May 30;25(11):6037. doi: 10.3390/ijms25116037.

29. Zuo K., Liu X., Wang P. et al. Metagenomic data-mining reveals enrichment of trimethyla-mine-N-oxide synthesis in gut microbiome in atrial fibrillation patients. BMC Genomics. 2020 Jul 30;21(1):526. doi: 10.1186/s12864-020-06944-w.

30. Ke C., Pan C.W., Zhang Y., Zhu X., Zhang Y. Metabolomics facilitates the discovery of meta-bolic biomarkers and pathways for ischemic stroke: a systematic review. Metabolomics. 2019 Nov 21;15(12):152. doi: 10.1007/s11306-019-1615-1.

31. Tobias D.K., Lawler P.R., Harada P.H. et al. Circulating Branched-Chain Amino Acids and Inci-dent Cardiovascular Disease in a Prospective Cohort of US Women. Circ Genom Precis Med. 2018 Apr;11(4): e002157. doi: 10.1161/CIRCGEN.118.002157.

32. Du X., Li Y., Wang Y. et al. Increased branched-chain amino acid levels are associated with long-term adverse cardiovascular events in patients with STEMI and acute heart failure. Life Sci. 2018 Sep 15;209:167-172. doi: 10.1016/j.lfs.2018.08.011.

33. Sanchez-Gimenez R., Ahmed-Khodja W., Molina Y. et al. Gut Microbiota-Derived Metabolites and Cardiovascular Disease Risk: A Systematic Review of Prospective Cohort Studies. Nutri-ents. 2022 Jun 27;14(13):2654. doi: 10.3390/nu14132654.

34. Guizoni D.M., Vettorazzi J.F., Carneiro E.M., Davel A.P. Modulation of endothelium-derived ni-tric oxide production and activity by taurine and taurine-conjugated bile acids. Nitric Oxide. 2020 Jan 1;94:48-53. doi: 10.1016/j.niox.2019.10.008.

35. Datta S., Pasham S., Inavolu S., Boini K.M. et al. Role of Gut Microbial Metabolites in Car-diovascular Diseases-Current Insights and the Road Ahead.Int J Mol Sci. 2024 Sep 23;25(18):10208. doi: 10.3390/ijms251810208.

36. Lau E.S., Paniagua S.M., Zarbafian S., Hoffman U., Long M.T. et al. Cardiovascular Bi-omarkers of Obesity and Overlap With Cardiometabolic Dysfunction. J Am Heart Assoc. 2021 Jul 20;10(14): e020215. doi: 10.1161/JAHA.120.020215.

37. Kaplan J., Kanwal A., Ahmed I., Lala V. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2024.

38. Fan P.C., Chang J.C., Lin C.N. et al. Serum indoxyl sulfate predicts adverse cardiovascular events in patients with chronic kidney disease. J Formos Med Assoc. 2019 Jul;118(7):1099-1106. doi: 10.1016/j.jfma.2019.03.005.

39. Zelante T., Iannitti R.G., Cunha C. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013 Aug 22;39(2):372-85. doi: 10.1016/j.immuni.2013.08.003.

40. Gawałko M., Linz D., Dobrev D. Gut-microbiota derived TMAO: A risk factor, a mediator or a bystander in the pathogenesis of atrial fibrillation? Int J Cardiol Heart Vasc. 2021 Jun 15;34:100818. doi: 10.1016/j.ijcha.2021.100818.

41. Bose S., Ramesh V., Locasale J.W. Acetate Metabolism in Physiology, Cancer, and Beyond. Trends Cell Biol. 2019 Sep;29(9):695-703. doi: 10.1016/j.tcb.2019.05.005.

42. Tang W.H.W., Li D.Y., Hazen S.L. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol. 2019 Mar;16(3):137-154. doi: 10.1038/s41569-018-0108-7.

43. Nogal A., Valdes A.M., Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes. 2021 Jan-Dec;13(1):1-24. doi: 10.1080/19490976.2021.1897212.

44. Cheng T.Y., Lee T.W., Li S.J., Lee T.I. et al. short-chain fatty acid butyrate against TMAO acti-vating endoplasmic-reticulum stress and PERK/IRE1-axis with reducing atrial arrhythmia. J Adv Res. 2024 Aug 5: S2090-1232(24)00332-1. doi: 10.1016/j.jare.2024.08.009.

45. Trehan S., Singh G., Bector G. et al. Gut Dysbiosis and Cardiovascular Health: A Comprehen-sive Review of Mechanisms and Therapeutic Potential. Cureus. 2024 Aug 16;16(8): e67010. doi: 10.7759/cureus.67010.

46. Stoeva M.K., Garcia-So J., Justice N. et al. Butyrate-producing human gut symbiont, Clostridi-um butyricum, and its role in health and disease. Gut Microbes. 2021 Jan-Dec;13(1):1-28. doi: 10.1080/19490976.2021.1907272.

47. Campos-Perez W., Martinez-Lopez E. Effects of short chain fatty acids on metabolic and in-flammatory processes in human health. Biochim Biophys Acta Mol Cell Biol Lipids. 2021 May;1866(5):158900. doi: 10.1016/j.bbalip.2021.158900.

48. Zhao L., Zhang F., Ding X., Wu G. et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018 Mar 9;359(6380):1151-1156. doi: 10.1126/science.aao5774.

49. Fusco W., Lorenzo M.B., Cintoni M. et al.Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Nutrients. 2023 May 6;15(9):2211. doi: 10.3390/nu15092211.

50. Niu H., Zhou M., Zogona D. et al. Akkermansia muciniphila: a potential candidate for amelio-rating metabolic diseases. Front Immunol. 2024 Mar 20;15:1370658. doi: 10.3389/fimmu.2024.1370658.

51. Markowiak-Kopeć P., Śliżewska K. The Effect of Probiotics on the Production of Short-Chain Fatty Acids by Human Intestinal Microbiome. Nutrients. 2020 Apr 16;12(4):1107. doi: 10.3390/nu12041107.

52. Wu Y., Xu H., Tu X., Gao Z. The Role of Short-Chain Fatty Acids of Gut Microbiota Origin in Hypertension. Front Microbiol. 2021 Sep 28;12:730809. doi: 10.3389/fmicb.2021.730809.

53. Ma H., Yang L., Liu Y. et al. Butyrate suppresses atherosclerotic inflammation by regulating macrophages and polarization via GPR43/HDAC-miRNAs axis in ApoE-/- mice. PLoS One. 2023 Mar 8;18(3): e0282685. doi: 10.1371/journal.pone.0282685.

54. Lenoir M., Martín R., Torres-Maravilla E. et al. Butyrate mediates anti-inflammatory effects of Faecalibacterium prausnitzii in intestinal epithelial cells through Dact3. Gut Microbes. 2020 Nov 9;12(1):1-16. doi: 10.1080/19490976.2020.1826748.

55. Canyelles M., Borràs C., Rotllan N. et al. Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease? Int J Mol Sci. 2023 Jan 18;24(3):1940. doi: 10.3390/ijms24031940.