ДИСБАЛАНС КИШЕЧНОЙ МИКРОБИОТЫ КАК ФАКТОР РИСКА КАРДИОМЕТАБОЛИЧЕСКИХ ЗАБОЛЕВАНИЙ

В обзоре подчеркивается роль кишечной микрофлоры в развитии атеросклероза, ишемической болезни сердца, избыточного веса /ожирения и сахарного диабета. Хорошо известно, что потребление продуктов, богатых насыщенными жирами и холестерином (мяса, яичного желтка и молочных продуктов с высоким содержанием жира), связано с повышенным риском сердечно-сосудистых заболеваний. Новые исследования показывают, что атерогенные свойства этих продуктов также обусловлены высоким содержанием L-карнитина и его структурного аналога холина, которые после поступления в организм метаболизируются кишечными бактериями до триметиламина (TMA), а затем преобразуются в печени до триметиламин-N-оксида (ТМАО), обладающего прямым атерогенным действием. Оказалось, что повышенный уровень ТМАО увеличивает риск развития инфаркта миокарда, инсульта, сердечной недостаточности и смерти, в том числе от общих причин. В центре мирового внимания также находится вопрос о роли дисбаланса кишечной микробиоты в развитии инсулинорезистентности, эндотелиальной дисфункции, нарастании адгезивных свойств макрофагов, появлении дислипидемии, повышении артериального давления, увеличении веса. Внимание врачей акцентируется на том, что для предотвращения кардиометаболических заболеваний, помимо реализации уже хорошо известных и общепринятых профилактических мероприятий, крайне важно поддержание нормального баланса микробиоты кишечника.

1. Avdeeva M.V., Samojlova I.G., Shheglov D.S. Pathogenetics aspects of relationship mouth infectious diseases with development and progression atherosclerosis and possibility for their integrated prevention. Zhurnal infektologii. 2012; 4 (3): 30–34. (in Russian).

2. Pan A., Sun Q., Bernstein A.M. et al. Red meat consumption and mortality: results from 2 prospective cohort studies. Arch. Intern. Med. 2012; 172: 555–63.

3. Howitt M.R., Garrett W.S. Gut microbiota and cardiovascular disease connectivity. Nat. Med. 2012; 18 (8): 1188–89.

4. Brown J.M., Hazen Brown S.L. Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr. Opin. Lipidol. 2014; 25 (1): 48–53.

5. Löster H. Carnitin and cardiovascular diseases. Bochum.: Ponte Press Verlags-GmbH., 2003.

6. Wang Z., Klipfell E., Bennett B.J. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57–63.

7. Loscalzo J. Gut microbiota, the genome, and diet in atherogenesis. N. Engl. J. Med. 2013; 368: 1647–1649.

8. Tang W.H.W., Wang Z., Levison B.S. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 2013; 368: 1575–84.

9. Ley R.E., Hamady M., Lozupone C. et al. Evolution of mammals and their gut microbes. Science. 2008; 320: 1647–51.

10. Scott K.P., Gratz S.W., Sheridan P.O. et al. The influence of diet on the gut microbiota. Pharmacol. Res. 2012; 69 (1): 52–60.

11. Kuka J., Liepinsh E., Makrecka-Kuka M. et al. Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci. 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/25301199.

12. Koeth R.A., Wang Z., Levison B.S. et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 2013; 19: 576–85.

13. Clarke S.F., Murphy E.F., O’Sullivan O. et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014; 63 (12): 1913−20.

14. Cannon J.A., McMurray J.V. Gut feelings about heart failure. J. Am. Coll. Cardiol. 2014; 64: 1915–16.

15. Bennett B.J., de Aguiar Vallim T.Q., Wang Z. et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell. Metab. 2013; 17: 49–60.

16. Suzuki H., Kurihara Y., Takeya M. et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature. 1997; 386: 292–296.

17. Kunjathoor V.V., Febbraio M., Podrez E.A. et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 2002; 277 (51): 49982–88.

18. Febbraio M., Podrez E.A., Smith J.D. et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 2000; 105: 1049–56.

19. Trauner M., Fickert P., Tilg H. Bile acids as modulators of gut microbiota linking dietary habits and inflammatory bowel disease: a potentially dangerous liaison. Gastroenterology. 2013; 144 (4): 844–46.

20. Pluznick J.L., Protzko R.J., Gevorgyan H. et al. Olfactory receptor esponding to gut microbiota derived signals plays a role in renin secretion and blood pressure regulation. Natl. Acad. Sci. USA. 2013; 110 (11): 4410–15.

21. Chen D., Yang Z., Chen X. et al. The effect of Lactobacillus rhamnosus hsryfm 1301 on the intestinal microbiota of a hyperlipidemic rat model. BMC Complement Altern. Med. 2014; 14: 386.

22. Scheepers L.E., Penders J., Mbakwa C.A. et al. The intestinal

23. microbiota composition and weight development in children: the koala birth cohort study. Int. J. Obes. (Lond). 2014; 11: doi: 10.1038/ijo.2014.178.

24. Woting A., Pfeiffer N., Loh G. et al. Clostridium ramosum promotes high-fat diet-induced obesity in gnotobiotic mouse models. MBio. 2014; 5: 14.

25. Lazebnik L.B., Konev Ju.V. New understanding of the role of the microbiota in the pathogenesis of the metabolic syndrome. Consilium medicum. 2014; 8: 77–82. (in Russian).

26. Cani P.D., Delzenne N.M. The gut microbiome as therapeutic target. Pharmacol. Ther. 2011; 130: 202–12.

27. Vrieze A., Nood E.V., Holleman F. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012; 143: 913–16.

28. Everard A., Cani P.D. Diabetes, obesity and gut microbiota. Best. Pract. Res. Clin. Gastroenterol. 2013; 27: 73–83.

29. Kimura I., Ozawa K., Inoue D. et al. The gut microbiota suppresses insulin-mediated fat accumulation via the shortchain fatty acid receptor GPR43. Nat. Commun. 2013; 4: 1829.

30. Zhao L., Shen J. Whole-body systems approaches for gut microbiota-targeted, preventive healthcare. J. Biotechnol. 2010; 149: 183–190.

31. Tilg H., Moschen A.R. Microbiota and Diabetes: An Evolving Relationship. Gut. 2014; 63 (9): 1513-21.

32. Xiao S., Zhao L. Gut microbiota-based translational biomarkers to prevent metabolic syndrome via nutritional modulation. FEMS Microbiology Ecology. 2014; 87 (2): 303–14.

33. Muccioli G.G., Naslain D., Bäckhed F. et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 2010; 6: 392.

34. Sivapalaratnam S., Farrugia R., Nieuwdorp M. et al. Identification of candidate genes linking systemic inflammation to atherosclerosis; results of a human in vivo LPS infusion study. BMC Med. Genomic. 2011; 4: 64.

35. Mafra D., Lobo J.C., Barros A.F. et al. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol. 2014; 9 (3): 399–410.

36. Meijers B.K., Claes K., Bammens B. et al. Р-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin. J. Am. Soc. Nephrol. 2010; 5: 1182–89.

37. Yamamoto H., Tsuruoka S., Ioka T. et al. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int. 2006; 69: 1780–85.

38. Xu H., Barnes G.T., Yang Q.et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 2003; 112: 1821–30.

39. Cai D., Yuan M., Frantz D.F. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 2005; 11: 183–190.

40. Hara T., Kimura I., Inoue D.et al. Free fatty acid receptors and their role in regulation of energy metabolism. Rev. Physiol. Biochem. Pharmacol. 2013; 164: 77–116.

41. Cani P.D., Delzenne N.M. The role of the gut microbiota in energy metabolism and metabolic disease. Curr. Pharm. Des. 2009; 15: 1546–58.

42. Cani P.D., Delzenne N.M. Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota. Curr. Opin. Pharmacol. 2009; 9: 737–43.

43. Kovatcheva-Datchary P., Arora Nutrition T., Nutrition, the gut microbiome and the metabolic syndrome. Best Pract. Res. Clin. Gastroenterol. 2013; 27: 59–72.