Molekulyarnaya Meditsina (Molecular medicine)Molekulyarnaya Meditsina (Molecular medicine)Молекулярная медицина1728-29182499-9490Russkiy Vrach Publishing House11357210.29296/24999490-2022-02-02ArticlesСтатьиReview ArticleIntestinal microbiota in the pathogenesis of chronic heart failureМикробиота кишечника в патогенезе хронической сердечной недостаточностиFadeevaMaria VadimovnaФадееваМария Вадимовна

graduate student Departament of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology

аспирант кафедры пропедевтики внутренних болезней, гастроэнтерологии и гепатологии

maria.fad@yandex.ruSkhirtladzeManana RevazovnaСхиртладзеМанана Ревазовна

Ph.D. Head of the Department of Cardiology of the Clinic for Propedeutics of Internal Diseases, Gastroenterology and Hepatology named after V.Kh. Vasilenko

кандидат медицинских наук, заведующая отделением кардиологии Клиники пропедевтики внутренних болезней, гастроэнтерологии и гепатологии им. В.Х. Василенко

maria.fad@yandex.ruZolnikovaOxana YuryevnaЗольниковаОксана Юрьевна

Doctor of Medical Sciences, Associate Prof., Departament of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology

доктор медицинских наук, доцент кафедры пропедевтики внутренних болезней, гастроэнтерологии и гепатологии

ks.med@mail.ruIvashkinVladimir TrofimovichИвашкинВладимир Трофимович

Doctor of Medical Sciences, RAS Academician, Prof., Departament Head, Departament of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology

доктор медицинских наук, профессор, академик РАН, заведующий кафедрой пропедевтики внутренних болезней, гастроэнтерологии и гепатологии

kont07@yandex.ruSechenov First Moscow State University (Sechenov University)ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» (Сеченовский Университет) Министерства здравоохранения Российской Федерации15022022202VOL 20, NO2 (2022)ТОМ 20, №2 (2022)111818112022Copyright ©; 2022, Russkiy Vrach Publishing HouseCopyright ©; 2022, ИД "Русский врач"2022Russkiy Vrach Publishing HouseИД "Русский врач"https://journals.eco-vector.com/1728-2918/article/view/113572

It is currently being discussed that the microbiota of the gastrointestinal tract and its metabolites affect the course of chronic heart failure (CHF). The purpose to summarize the available data on the role of the intestinal microbiota in the pathogenesis of CHF. Material and methods. A analysis of the main foreign and domestic sources on PubMed, MedLine, eLIBRARY databases over the last 20 years has been carried out. Results. In the course of the analysis of published works, the key links in the pathogenesis of CHF (imbalance of neurohumoral systems, inflammatory theory, metabolic disorders) and changes arising from disturbance of intestinal microbiota composition were compared. The results of studies where microbiota correction by prescribing antibiotics, probiotics and prebiotics resulted in positive effects on the course and prognosis in CHF are presented. Conclusion: Commonality in CHF pathogenesis (imbalance of neurohumoral systems, inflammatory theory and metabolic disorders) and changes in microbiota disturbances (including those mediated by microbial metabolites and inflammatory cytokines), the positive effects of pro- and prebiotics both on the microbial composition of the intestine and on course and prognosis in CHF, allow the consideration of microbiome as a marker and a possible target in CHF therapy. All of the above necessitates for further research in this area.

В настоящее время обсуждается, что микробиота желудочно-кишечного тракта и ее метаболиты влияют на течение хронической сердечной недостаточности (ХСН). Цель. Обобщить имеющиеся данные о роли микробиоты кишечника в патогенезе ХСН. Материал и методы. Проведен анализ основных зарубежных и отечественных источников по базам данных PubMed, MedLine, eLIBRARY за последние 20лет. Результаты. В ходе анализа опубликованных работ сопоставлены ключевые звенья патогенеза ХСН (дисбаланс нейрогуморальных систем, воспалительная теория, метаболические нарушения) и изменения, возникающие при нарушении состава микробиоты кишечника. Приведены результаты исследований положительных эффектов коррекции микробиоты, путем назначения антибиотиков, пробиотиков и пребиотиков на течение и прогноз при ХСН. Заключение. Общность в патогенезе ХСН (дисбаланс нейрогуморальных систем, воспалительная теория и метаболические нарушения) и изменений при нарушении микробиоты (в том числе, опосредованных микробными метаболитами и воспалительными цитокинами), положительные эффекты про- и пребиотиков как на микробный состав кишки, так и на течение и прогноз при ХСН, позволяют рассматривать микробиом как маркер и возможную мишень в терапии ХСН. Все выше названное диктует необходимость проведения дальнейших исследований в данной области.

intestinal microbiotachronic heart failureprobioticscytokinesмикробиота кишечникахроническая сердечная недостаточностьпробиотикицитокиныWang Z., Klipfell E., Bennett B.J., Koeth R., Levison B.S. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57-63. 290 https://doi.org/10.1038/nature09922.Luedde S.M., Winkler T, Heinsen F., Rühlemann M.S., Spehlmann M.E., Bajrovic A., Lieb W., Franke A., Ott S., Frey N. Heart failure is associated with depletion of core intestinal microbiota. ESC Heart Failure. 2017; 4: 282-90. https://doi.org/10.1002/ehf2.12155Kamo T., Akazawa H., Suda W. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLoS ONE. 2017; 12: 0174099. https://doi.org/10.1371/journal.pone.0174099.Katsimichas T., Ohtani T., Motooka D., Tsukamoto Y., Kioka H., Nakamoto K., Konishi S., Chimura M., Sengoku K., Miyawaki H., Sakaguchi T., Okumura R., Theofilis K., Iida T., Takeda K., Nakamura S., Sakata Y Non-Ischemic Heart Failure With Reduced Ejection Fraction Is Associated With Altered Intestinal Microbiota. Circ J. 2018; 82 (6): 1640-50. https://doi.org/10.1253/circj.CJ-17-1285.Kummen M., Mayerhofer C.C.K., Vestad B., Broch K., Awoyemi A., Storm-Larsen C., Ueland T., Yndestad A., Hov J.R., Trøseid M. Gut Microbiota Signature in Heart Failure Defined from Profiling of 2 Independent Cohorts. J. Am. Coll Cardiol. 2018; 71 (10): 1184-6. https://doi.org/10.10Wj.jacc.2017.12.057.Pasini E., Aquilani R., Testa C. Pathogenic gut flora in patients with chronic heart failure. J. JACC Heart Fail. 2016; 4: 220-7. https://doi.org/10.1016/jjchf.2015.10.009.Arpaia N., Campbell C., Fan X.l. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013; 504: 451-5. https://doi.org/10.1038/nature12726Kim O.Y., Monsel A., Bertrand M.S., Cavaillon J.M., Coriat P., Adib-Conquy M. Translocation of bacterial NOD2 agonist and its link with inflammation, Critical Care. 2009; 13 (4): 124. https://doi.org/10.1186/cc7980Niebauer J., Volk H., Kemp M. et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study Lancet. 1999; 353: 1838-42. https://doi.org/10.1016/S0140-6736(98)09286-1Sandek A., Bjarnason I., Volk H.D., Crane R., Meddings J.B., Niebauer J., Kalra P.R., Buhner S., Herrmann R., Springer J., Doehner W., Von Haehling S., Anker S.D., Rauchhaus M. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure.International Journal of Cardiology, 2010; 157 (1): 80-5. https://doi.org/10.1016/j.ijcard.2010.12.016Chen D., Assad-Kottner C., Orrego C., Torre-Amione G. Cytokines and acute heart failure. Crit Care Med. 2008; 36: 9-16. https://doi.org/10.1097/01.CCM.0000297160.48694.90Lauritano E.C., Valenza V, Sparano L., Scarpellini E., Gabrielli M., Cazzato A., Ferraro P.M., Gasbarrini A. Small intestinal bacterial overgrowth and intestinal permeability. Scand J. Gastroenterol. 2010; 45 (9): 1131-2. https://doi.org/10.3109/003655212010.485325Maslennikov R., Driga A., Ivashkin K., Ivashkin V. NT-proBNP as a biomarker for hyperdynamic circulation in decompensated cirrhosis. Gastroenterol Hepatol Bed Bench. 2018; 11 (4): 325-32. PMID: 30425812.Масленников Р.В., Татаркина М.А., Маевская М.В., Павлов Ч.С., Жаркова М.С., Ивашкин В.Т Влияние синдрома избыточного бактериального роста и системного воспаления на абдоминальную гемодинамику у больных циррозом печени. Российский журнал гастроэнтерологии, гепатологии колопроктологии. 2017; 27 (4): 52-61. https://doi.org/10.22416/1382-4376-2017-27-4-52-61Mollar A., Villanueva M.P., Nunez E., Carratal a.A., Mora F., Bayes-Genis A., Minguez M., Marrachelli V.G., Monleon D., Navarro D., Sanchis J., Nunez J. Hydrogen- and Methane-Based Breath Testing and Outcomes in Patients With Heart Failure. J. Card Fail. 2019; 25 (5): 319-27. https://doi.org/10.1016/j.cardfail.2018.10.004.Yokoyama T., Vaca L., Rossen R.D., Durante W., Hazarika P., Mann D.L. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J. Clin. Invest. 1993; 92: 2303-12. https://doi.org/10.1172/JCI116834.Sedej S., Schmidt A., Denegri M., Walther S., Matovina M., Arnstein G. et al. Subclinical abnormalities in sarcoplasmic reticulum Ca(2+) release promote eccentric myocardial remodeling and pump failure death in response to pressure overload. J. Am. Coll. Cardiol. 2014; 63: 1569-79. https://doi.org/10.1016/jjacc.2013.11.010Gurantz D., Cowling R.T., Varki N., Frikovsky E., Moore C.D., Greenberg B.H. IL-1beta and TNF-alpha upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart. J. Mol. Cell. Cardiol. 2005; 38: 505-15 https://doi.org/10.1016/j.yjmcc.2004.12.015.Spillmann F., Miteva K., Pieske B., Tschope C., Van Linthout S. High-density lipoproteins reduce endothelial-to-mesenchymal transition. Arterioscler Thromb Vasc Biol. 2015; 35: 1774-7. https://doi.org/10.1161/ATVBAHA.115.305887Chandrasekar B., Vemula K., Surabhi R.M., Li-Weber M., Owen-Schaub L.B., Jensen L.E. et al. Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J. Biol. Chem. 2004; 279: 20221-33. https://doi.org/10.1074/jbc.M313980200Yu Y., Wei S.G., Weiss R.M., Felder R.B. TNF-a receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats. Am. J. Physiol. Heart Circ Physiol. 2017; 313 (4): 744-56. DOI: 10.1152/ajpheart.00280.2017.Levin E.R., Gardner D.G., Samson W.K. Natriuretic peptides. N. Engl. J. Med. 1998; 339 (5): 321-8. https://doi.org/10.1056/NEJM199807303390507Schrier R.W., Abraham W.T. Hormones and hemodynamics in heart failure. N. Engl. J. Med. 1999; 341 (8): 577-85. https://doi.org/10.1056/NEJM199908193410806Mezzasoma L., Antognelli C., Talesa V.N. Atrial natriuretic peptide down-regulates LPS/ATP-mediated IL-1ß release by inhibiting NF-kB, NLRP3 inflammasome and caspase-1 activation in THP-1 cells. Immunol Res. 2016; 64 (1): 303-12. DOI: 10.1007/s12026-015-8751-0.Bozkurt B., Mann D.L., Deswal A. Biomarkers of inflammation in heart failure. Heart Failure Reviews. 2010; 15 (4): 331-41. https://doi.org/10.1007/s10741-009-9140-3Yin W.-H., Chen J.-W, Jen H.-L. Independent prognostic value of elevated high-sensitivity C-reactive protein in chronic heart failure. American Heart J. 2004; 147 (5): 931-8. https://doi.org/10.10Wj.ahj.2003.11.021Rauchhaus M., Doehner W., Francis D. P Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation. 2000; 102 (25): 3060-7. https://doi.org/10.1161/01.cir.102.25.3060Treacy E.P., Akerman B.R., Chow L.M., Youil R., Bibeau C., Lin J., Bruce A.G., Knight M., Danks D.M., Cashman J.R., Forrest S.M. Mutations of the flavincontaining monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Human molecular genetics. 1998; 7: 839-45. https://doi.org/10.1093/hmg/7.5.839Wang Z., Klipfell E., Bennett B.J., Koeth R., Levison B.S., Dugar B. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472 (7341): 57-63. https://doi.org/10.1038/nature09922Tang W.H., Wang Z., Levison B.S., Koeth R.A., Britt E.B., Fu X. et al.Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 2013; 368 (17): 1575-84. https://doi.org/10.1056/NEJMoa1109400Bennett B.J., de Aguiar Vallim T.Q., Wang Z., Shih D.M., Meng Y, Gregory J., Allayee H., Lee R., Graham M., Crooke R., Edwards P.A., Hazen S.L., Lusis A.J. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013; 17 (1): 49-60. https://doi.org/10.10Wj.cmet.2012.12.011.Chen M.L., Zhu X.H., Ran L., Lang H.D., Yi L., Mi M.T. Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway. J. Am. Heart Assoc. 2017; 6 (9): e006347. https://doi.org/doi:10.1161/JAHA.117.006347.Boini K.M., Hussain T., Li P.L., Koka S. Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction. Cell Physiol Biochem. 2017; 44 (1): 152-62. https://doi.org/10.1159/000484623.Tang W.H., Wang Z., Fan Y, Levison B., Hazen J.E., Donahue L.M., Wu Y, Hazen S.L. Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-oxide in Patients with Heart Failure: Refining the Gut Hypothesis. Am. Coll Cardiol. 2014; 64 (18): 1908-14. https://doi.org/10.1016/j.jacc.2014.02.617Organ C.L., Otsuka H., Bhushan S., Wang Z., Bradley J., Trivedi R., Polhemus D.J., Tang W.H., Wu Y, Hazen S.L., Lefer D.J. Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure. Circ Heart Fail. 2016; 9 (1): e002314. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002314.Huc T., Drapala A., Gawrys M., Konop M., Bielinska K., Zaorska E., Samborowska E., Wyczalkowska-Tomasik A., Pączek L., Dadlez M., Ufnal M. Chronic, low-dose TMAO treatment reduces diastolic dysfunction and heart fibrosis in hypertensive rats. Am. J. Physiol. Heart Circ Physiol. 2018; 315 (6): 1805-20. https://doi.org/10.1152/ajpheart.00536.2018Conraads V.M., Jorens P.G., De Clerck L.S., Van Saene H.K., Ieven M.M., Bosmans J.M., Schuerwegh A., Bridts C.H., Wuyts F., Stevens W.J., Anker S.D., Rauchhaus M., Vrints C.J. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur. J. of Heart Failure. 2004; 6 (4): 483-91. https://doi.org/10.10Wj.ejheart.2003.12.004Ting W.J., Kuo W.W., Hsieh D.J., Yeh Y.L., Day C.H., Chen Y.H., Chen R.J., Padma V.V., Chen Y.H., Huang C.Y Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-ß Suppression.Int J. Mol. Sci. 2015; 16 (10): 25881-96. https://doi.org/10.3390/ijms161025881.Ting W.J., Kuo W.W., Kuo C.H., Yeh Y.L., Shen C.Y, Chen Y.H., Ho T.J., Viswanadha V.P., Chen Y.H., Huang C.Y. Supplementary heat-killed Lactobacillus reuteri GMNL-263 a meliorates hyperlipidaemic and cardiac apoptosis in high-fat diet-fed hamsters to maintain cardiovascular function. Br. J. Nutr. 2015; 114 (5): 706-12. https://doi.org/10.1017/S0007114515002469.Gan X.T., Ettinger G., Huang C.X., Burton J.P., Haist J.V., Rajapurohitam V, Sidaway J.E., Martin G., Gloor G.B., Swann J.R., Reid G., Karmazyn M. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circ Heart Fail. 2014; 7 (3): 491-9. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000978.Lai C.H., Tsai C.C., Kuo W.W., Ho T.J., Day C.H., Pai Py, Chung L.C., Huang C.C., Wang H.F., Liao PH., Huang C.Y. Multi-Strain Probiotics Inhibit Cardiac Myopathies and Autophagy to Prevent Heart Injury in High-Fat Diet-Fed Rats.Int J. Med Sci. 2016; 13 (4): 277-85. https://doi.org/10.7150/ijms.14769.Annelise C. Costanza Samuel D. Moscavitch, Hugo C.C. Faria Neto, Evandro T Mesquita. Probiotic therapy with Saccharomyces boulardii for heart failure patients: A randomized, double-blind, placebocontrolled pilot trial.International J. of Cardiology 2015; 179: 348-50. https://doi.org/10.1016/j.ijcard.2014.11.034Makarewicz-Wujec M., Parol G., Parzonko A., Koztowska-Wojciechowska M. Supplementation with omega-3 acids after myocardial infarction and modification of inflammatory markers in light of the patients' diet: a preliminary study Kardiol Pol. 2017; 75: 674-81. https://doi.org/10.5603/KPa2017.0072.Singh R.K., Chang H.W., Yan D., Lee K.M., Ucmak D., Wong K., Abrouk M., Farahnik B., Nakamura M., Zhu T.H., Bhutani T., Liao W. Influence of diet on the gut microbiome and implications for human health. J. Transl Med. 2017; 15 (1): 73. https://doi.org/10.1186/s12967-017-1175-y