Статья
Роль кишечной микробиоты в развитии сердечно-сосудистой патологии: фокус на метаболиты и маркеры повышенной кишечной проницаемости и воспаления кишечной стенки
В последние годы все больше исследований свидетельствуют о тесной взаимосвязи между составом и функцией микробиоты и здоровьем человека, в том числе с сердечно-сосудистыми заболеваниями (ССЗ). Повышенная проницаемость кишечника является одним из факторов, который может влиять на состояние микробиоты, а также привести к проникновению бактерий и их токсинов в кровоток, вызывая системное воспаление. Хроническое воспаление, в свою очередь, сопровождается повышенным уровнем цитокинов, которые могут вызвать повреждение эндотелия и привести к эндотелиальной дисфункции. Метаболиты некоторых бактерий могут снижать выработку молекул, регулирующих сосудистый тонус, таких как оксид азота, что может привести к вазоконстрикции и артериальной гипертензии. В обзоре уделяется внимание связи кальпротектина, зонулина, триметиламиноксида с риском возникновения ССЗ, а также освещаются возможные методы коррекции состава и функции микробиоты для профилактики ССЗ.
1. Российский статистический ежегодник. 2021: Росстат. Стат. сб. Под ред. П.В. Малкова. М., 2021. 692 с.
2. Vernon ST, Coffey S, Bhindi R, Soo Hoo SY, Nelson GI, Ward MR et al. Increasing proportion of ST elevation myocardial infarction patients with coronary atherosclerosis poorly explained by standard modifiable risk factors. Eur J Prev Cardiol. 2017;24(17):1824–1830. doi:10.1177/2047487317720287
3. Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290(7):898–904. doi:10.1001/jama.290.7.898
4. Hijová E. Benefits of biotics for cardiovascular diseases. Int J Mol Sci. 2023;24(7):6292. doi:10.3390/ijms24076292
5. D’Argenio V, Salvatore F. The role of the gut microbiome in the healthy adult status. Clin Chim Acta. 2015;451(PtA):97–102. doi:10.1016/j.cca.2015.01.003
6. Gulshan K. Crosstalk between cholesterol, ABC transporters, and PIP2 in inflammation and atherosclerosis. Adv Exp Med Biol. 2023;1422:353–377. doi:10.1007/978-3-031-21547-613
7. Sattar L, Memon RA, Ashfaq F, Hamdani SSQ, Rahim Vohra R, Ashraf J et al. Efficacy and safety of colchicine in prevention of secondary cardiovascular outcomes among patients with coronary vessel disease: a meta-analysis. Cureus. 2022;14(7): e26680. doi:10.7759/cureus.26680
8. Маслянский А.Л., Пенин И.Н., Чешуина М.Д., Тришина И.Н., Новикова А.Н., Колесова Е.П. и др. Общие закономерности продукции цитокинов и хемокинов у больных диффузными заболеваниями соединительной ткани, воспалительными артропатиями и атеросклерозом. Цитокины и воспаление. 2014;13(3):9–21
9. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59(12):1690–1697. doi:10.1002/art.24092
10. Liu Y, Kaplan MJ. Cardiovascular disease in systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2018;30(5):441– 448. doi:10.1097/BOR.0000000000000528
11. Sun HH, Tian F. Inflammatory bowel disease and cardiovascular disease incidence and mortality: a meta-analysis. Eur J Prev Cardiol. 2018;25(15):1623–1631. doi:10.1177/2047487318792952
12. Mistry P, Reitz CJ, Khatua TN, Rasouli M, Oliphant K, Young ME et al. Circadian influence on the microbiome improves heart failure outcomes. J Mol Cell Cardiol. 2020;149:54–72. doi:10.1016/j.yjmcc.2020.09.006
13. Mansuri NM, Mann NK, Rizwan S, Mohamed AE, Elshafey AE, Khadka A et al. Role of gut microbiome in cardiovascular events: a systematic review. Cureus. 2022;14(12):e32465. doi:10.7759/cureus.32465
14. Kumarapperuma H, Wang R, Little PJ, Kamato D. Mechanistic insight: linking cardiovascular complications of inflammatory bowel disease [published online ahead of print, 2023 Jan 24]. Trends Cardiovasc Med. 2023; S1050–1738(23)00004-X. doi:10.1016/j.tcm.2023.01.002
15. Kamperidis N, Kamperidis V, Zegkos T, Kostourou I, Nikolaidou O, Arebi N et al. Atherosclerosis and inflammatory bowel disease-shared pathogenesis and implications for treatment. Angiology. 2021;72(4):303–314. doi:10.1177/0003319720974552
16. Violi F, Cammisotto V, Bartimoccia S, Pignatelli P, Carnevale R, Nocella C. Gut derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease. Nat Rev Cardiol. 2023;20(1):24–37. doi:10.1038/s41569-022-00737-2
17. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411(6837):603–606. doi:10.1038/35079114
18. Galluzzo S, Patti G, Dicuonzo G, Di Sciascio G, Tonini G, Ferraro E et al. Association between NOD2/CARD15 polymorphisms and coronary artery disease: a case-control study. Hum Immunol. 2011;72(8):636–40. doi:10.1016/j.humimm.2011.04.005
19. Wu H, Liu P, Gong S, Liu X, Hill MA, Liu Z et al. Inflammatory bowel disease increases the levels of albuminuria and the risk of urolithiasis: a two-sample Mendelian randomization study. Eur J Med Res. 2023;28(1):167. doi:10.1186/s40001-023-01128-0
20. Di Tommaso N, Gasbarrini A, Ponziani FR. Intestinal barrier in human health and disease. Int J Environ Res Public Health. 2021;18(23):12836. doi:10.3390/ijerph182312836
21. Larabi A, Barnich N, Nguyen HTT. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy. 2020;16(1):38–51. doi:10.1080/15548627.2019.1635384
22. Sircana A, De Michieli F, Parente R, Framarin L, Leone N, Berrutti M et al. Gut microbiota, hypertension and chronic kidney disease: recent advances. Pharmacol Res. 2019;144:390–408. doi:10.1016/j.phrs.2018.01.013
23. Kim S, Goel R, Kumar A, Qi Y, Lobaton G, Hosaka K et al. Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. Clin Sci (Lond). 2018;132(6):701–718. doi:10.1042/CS20180087
24. Li C, Xiao P, Lin D, Zhong HJ, Zhang R, Zhao ZG et al. Risk factors for intestinal barrier impairment in patients with essential hypertension. Front Med (Lausanne). 2021;27(7):543698. doi:10.3389/fmed.2020.5436982019
25. Andersen K, Kesper MS, Marschner JA, Konrad L, Ryu M, Kumar S et al. Intestinal dysbiosis, barrier dysfunction, and bacterial translocation account for CKD-related systemic inflammation. J Am Soc Nephrol. 2017;28(1):76–83. doi:10.1681/ASN.2015111285
26. Kim S, Goel R, Kumar A, Qi Y, Lobaton G, Hosaka K et al. Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. Clin Sci Lond. 2018;132(6):701–718. doi:10.1042/CS20180087.17
27. Li C, Gao M, Zhang W, Chen C, Zhou F, Hu Z et al. Zonulin regulates intestinal permeability and facilitates enteric bacteria permeation in coronary artery disease. Sci Rep. 2016;29(6):29142. doi:10.1038/srep29142
28. Blöbaum L, Witkowski M, Wegner M, Lammel S, Schencke PA, Jakobs K et al. Intestinal barrier dysfunction and microbial translocation in patients with first-diagnosed atrial fibrillation. Biomedicines. 2023;11(1):176. doi:10.3390/biomedicines11010176
29. Khaleghi S, Ju JM, Lamba A, Murray JA. The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Therap Adv Gastroenterol. 2016;9(1):37–49. doi:10.1177/1756283X15616576
30. Kruzliak P, Novák J, Novák M, Fodor GJ. Role of calprotectin in cardiometabolic diseases. Cytokine Growth Factor Rev. 2014;25(1):67–75. doi:10.1016/j.cytogfr.2014.01.005
31. Jensen LJ, Kistorp C, Bjerre M, Raymond I, Flyvbjerg A. Plasma calprotectin levels reflect disease severity in patients with chronic heart failure. Eur J Prev Cardiol. 2012;19(5):999–1004. doi:10.1177/1741826711421078
32. Kunutsor SK, Flores-Guerrero JL, Kieneker LM, Nilsen T, Hidden C, Sundrehagen E et al. Plasma calprotectin and risk of cardiovascular disease: Findings from the PREVEND prospective cohort study. Atherosclerosis. 2018;275:205–213. doi:10.1016/j.atherosclerosis.2018.06.817
33. Løfblad L, Hov GG, Åsberg A, Videm V. Calprotectin and CRP as biomarkers of cardiovascular disease risk in patients with chronic kidney disease: a follow-up study at 5 and 10 years. Scand J Clin Lab Invest. 2023;83(4):258–263. doi:10.1080/00365513.2023.2211779
34. Sreejit G, Abdel Latif A, Murphy AJ, Nagareddy PR. Emerging roles of neutrophil-borne S100A8/A9 in cardiovascular inflammation. Pharmacol Res. 2020;161:105212. doi:10.1016/j.phrs.2020.105212
35. Bai B, Cheng M, Jiang L, Xu J, Chen H, Xu Y. High neutrophil to lymphocyte ratio and its gene signatures correlate with diastolic dysfunction in heart failure with preserved ejection fraction. Front Cardiovasc Med. 2021;8:614757. doi:10.3389/fcvm.2021.614757
36. Bai B, Xu Y, Chen H. Pathogenic roles of neutrophil-derived alarmins (S100A8/A9) in heart failure: from molecular mechanisms to therapeutic insights. Br J Pharmacol. 2023;180(5):573–588. doi:10.1111/bph.15998
37. Sanchez-Gimenez R, Ahmed-Khodja W, Molina Y, Peiró OM, Bonet G, Carrasquer A et al. Gut microbiota-derived metabolites and cardiovascular disease risk: a systematic review of prospective cohort studies. Nutrients. 2022;14(13):2654. doi:10.3390/nu14132654
38. Jing W, Huang S, Xiang P, Huang J, Yu H. Dietary precursors and cardiovascular disease: a Mendelian randomization study. Front Cardiovasc Med. 2023;10:1061119. doi:10.3389/fcvm.2023.1061119
39. Cho CE, Caudill MA. Trimethylamine-N-oxide: friend, foe, or simply caught in the cross-fire? Trends Endocrinol Metab. 2017;28(2):121–130. doi:10.1016/j.tem.2016.10.005
40. Sumida K, Kovesdy CP. The gut-kidney-heart axis in chronic kidney disease. Physiol Int. 2019;106(3):195–206. doi:10.1556/2060.106.2019.19
41. Xu KY, Xia GH, Lu JQ, Chen MX, Zhen X, Wang S et al. Impaired renal function and dysbiosis of gut microbiota contribute to increased trimethylamine-N-oxide in chronic kidney disease patients. Sci Rep. 2017;7(1):1445. doi:10.1038/s41598-017-01387-y
42. Zhao J, Ning X, Liu B, Dong R, Bai M, Sun S. Specific alterations in gut microbiota in patients with chronic kidney disease: an updated systematic review. Ren Fail. 2021;43(1):102–112. doi: 10.1080/0886022X.2020.1864404
43. Zhao J, Ning X, Liu B, Dong R, Bai M, Sun S. Gut microbiota-derived trimethylamine N-oxide is associated with the risk of all-cause and cardiovascular mortality in patients with chronic kidney disease: a systematic review and dose-response meta-analysis. Ann Med. 2023;55(1):2215542. doi:10.1080/07853890.2023.2215542
44. Zhang W, Miikeda A, Zuckerman J, Jia X, Charugundla S, Zhou Z et al. Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice. Sci Rep. 2021;11(1):518. doi:10.1038/s41598-020-80063-0
45. Canyelles M, Borràs C, Rotllan N, Tondo M, Escolà-Gil JC, Blanco-Vaca F. Gut microbiota-derived TMAO: a causal factor promoting atherosclerotic cardiovascular disease? Int J Mol Sci. 2023;24(3):1940. doi:10.3390/ijms24031940
46. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63. doi:10.1038/nature09922
47. Li XS, Obeid S, Klingenberg R, Gencer B, Mach F, Räber L 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):814–824. doi:10.1093/eurheartj/ehw582
48. Asgary S, Rastqar A, Keshvari M. Functional food and cardiovascular disease prevention and treatment: a review. J Am Coll Nutr. 2018;37(5):429–455. doi:10.1080/07315724.2017.1410867
49. Derkach A, Sampson J, Joseph J, Playdon MC, StolzenbergSolomon RZ. Effects of dietary sodium on metabolites: the dietary approaches to stop hypertension (DASH)—sodium feeding study. Am J Clin Nutr. 2017;106(4):1131–1141. doi:10.3945/ajcn.116.150136
50. Delgado-Lista J, Perez-Martinez P, Garcia-Rios A, Alcala-Diaz JF, Perez-Caballero AI, Gomez-Delgado F et al. CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (the CORDIOPREV study): Rationale, methods, and baseline characteristics: A clinical trial comparing the efficacy of a Mediterranean diet rich in olive oil versus a lowfat diet on cardiovascular disease in coronary patients. Am Heart J. 2016;177:42–50. doi:10.1016/j.ahj.2016.04.011
51. Jovanovski E, Nguyen M, Kurahashi Y, Komishon A, Li D, Hoang Vi Thanh H et al. Are all fibres created equal with respect to lipid lowering? Comparing the effect of viscous dietary fibre to non-viscous fibre from cereal sources: a systematic review and metaanalysis of randomised controlled trials. Br J Nutr. 2022;5:1–13. doi:10.1017/S0007114522002355
52. Reynolds AN, Akerman A, Kumar S, Diep Pham HT, Coffey S, Mann J. Dietary fibre in hypertension and cardiovascular disease management: systematic review and meta-analyses. BMC Med. 2022;20(1):139. doi:10.1186/s12916-022-02328-x
53. Markowiak P, Slizewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients. 2017;9(9):1021. doi:10.3390/nu9091021
54. Frei R, Akdis M, O’Mahony L. Prebiotics, probiotics, synbiotics, and the immune system. Curr Opin Gastroenterol. 2015;31(2):153–158. doi:10.1097/MOG.0000000000000151
55. Capuano E. The behavior of dietary fiber in the gastrointestinal tract determines its physiological effect. Crit Rev Food Sci Nutr.2017;57(16):3543–3564. doi:10.1080/10408398.2016.1180501
56. Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018;359(6380):1151–1156. doi:10.1126/science.aao5774
57. Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes. 2017;8(2):172–184. doi:10.1080/19490976.2017.1290756
58. Lordan C, Thapa D, Ross RP, Cotter PD. Potential for enriching next-generation health-promoting gut bacteria through prebiotics and other dietary components. Gut Microbes. 2020;11(1):1–20. doi:10.1080/19490976.2019.1613124
59. Medina-Vera I, Sanchez-Tapia M, Noriega-López L, Granados-Portillo O, Guevara-Cruz M, Flores-López A et al. A dietary intervention with functional foods reduces metabolic endotoxaemia and attenuates biochemical abnormalities by modifying faecal microbiota in people with type 2 diabetes. Diabetes Metab. 2019;45(2):122–131. doi:10.1016/j.diabet.2018.09.004
60. Javanshir N, Hosseini GNG, Sadeghi M, Esmaeili R, Satarikia F, Ahmadian G et al. Evaluation of the function of probiotics, emphasizing the role of their binding to the intestinal Epithelium in the stability and their effects on the immune system. Biol Proced Online. 2021;23(1):23. doi:10.1186/s12575-021-00160-w
61. Ahmadian F, Razmpoosh E, Ejtahed HS, Javadi M, Mirmiran P, Azizi F. Effects of probiotic supplementation on major cardiovascular-related parameters in patients with type 2 diabetes mellitus: a secondary-data analysis of a randomized doubleblind controlled trial. Diabetol Metab Syndr. 2022;14(1):52. doi:10.1186/s13098-022-00822-z
62. Dixon A, Robertson K, Yung A, Que M, Randall H, Wellalagodage D et al. Efficacy of probiotics in patients of cardiovascular disease risk: a systematic review and meta-analysis. Curr Hypertens Rep. 2020;22(9):74. doi:10.1007/s11906-020-01080-y
63. Khalesi S, Sun J, Buys N, Jayasinghe R. Effect of probiotics on blood pressure a systematic review and meta-analysis of randomized, controlled trials. Hypertension. 2014;64(4):897–903. doi:10.1161/Hypertensionaha.114.03469
64. Cicero AFG, Fogacci F, Bove M, Giovannini M, Borghi C. Impact of a short-term synbiotic supplementation on metabolic syndrome and systemic inflammation in elderly patients: a randomized placebo-controlled clinical trial. Eur J Nutr. 2021;60(2):655–663. doi:10.1007/s00394-020-02271-8
65. Żółkiewicz J, Marzec A, Ruszczyński M, Feleszko W. Postbiotics — a step beyond pre- and probiotics. Nutrients. 2020;12(8):2189. doi:10.3390/nu12082189
66. Hernández MAG, Canfora EE, Jocken JWE, Blaak EE. The short-chain fatty acid acetate in body weight control and insulin sensitivity. Nutrients. 2019;11(8):1943. doi:10.3390/nu11081943
67. Hamamah S, Gheorghita R, Lobiuc A, Sirbu IO, Covasa M. Fecal microbiota transplantation in non-communicable diseases: recent advances and protocols. Front Med. 2022;9:1060581. doi:10.3389/fmed.2022.1060581
68. Su L, Hong Z, Zhou T, Jian Y, Xu M, Zhang X et al. Health improvements of type 2 diabetic patients through diet and diet plus fecal microbiota transplantation. Sci Rep. 2022;12(1):1152. doi:10.1038/s41598-022-05127-9
69. Ng SC, Xu Z, Mak JWY, Yang K, Liu Q, Zuo T et al. Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial. Gut. 2022;71(4):716–723. doi:10.1136/gutjnl2020-323617
70. Qiu B, Liang J, Li C. Effects of fecal microbiota transplantation in metabolic syndrome: a meta-analysis of randomized controlled trials. PLoS One. 2023;18(7):e0288718. doi:10.1371/journal.pone.0288718
71. Hu D, Zhao J, Zhang H, Wang G, Gu Z. Fecal microbiota transplantation for weight and glycemic control of obesity as well as the associated metabolic diseases: meta-analysis and comprehensive assessment. Life (Basel). 2023;13(7):1488. doi:10.3390/life13071488
72. Toral M, Robles-Vera I, de la Visitacion N, Romero M, Yang T, Sanchez M et al. Critical role of the interaction gut microbiota — sympathetic nervous system in the regulation of blood pressure. Front Physiol. 2019;10:231. doi:10.3389/fphys.2019.00231.96
73. Kim TT, Parajuli N, Sung MM, Bairwa SC, Levasseur J, Soltys CM et al. Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice. Am J Physiol Endocrinol Metab. 2018;315(4): E511–E519. doi:10.1152/ajpendo.00471.2017.97