EFFECT BY INTESTINAL MICROBIOM ON THE PROGRESSION OF VIRAL HEPATITIS

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Abstract

According to the modern concepts an intestinal microbiome has a significant effect on the functioning of the whole body including the immune system, digestive tract and liver in particular. This review displays current understanding of the intestinal microbiome impacting on the progression of chronic viral hepatitis caused by HCV- and HBV-infection, as well as changes in bowel microbiocenosis features depending on the duration of chronic process in the liver. It is indicated that chronic hepatitis to cirrhosis progression is accompanied by Bifidobacterium and strains of lactic acid (Lactobacillus, Pediococcus, Leuconostoc, Weissella) number decreasing and overgrowth of opportunistic species such as Enterococcaceae, Veillonellaceae, Enterobactericeae, Candida spp., Clostridia spp. This phenomena caused by PAMPs entry into the bloodstream including various types of toxins playing a role in liver immune inflammation processes progression. Thus patients with HBV and HCV infection are increased the number of CD4+, CD25+ in the blood and liver significantly, FOXP3+ Treg cell providing an immunosuppressive effect, and the function of specific CD8 lymphocytes is reduced and insufficient leveling virus significantly. Microbial imbalance has a negative effect on the biosynthesis of bile acids and sterolbiom functioning of our body as a result of changes in the balance between Bacteroides/Firmicutes, overgrowth of pathogenic and opportunistic Enterobacteriaceae, Veillonellaceae, Alcaligeneaceae and Porphyromonadaceae, Clostridium cluster XIVa, Helicobacter spp. and Clostridium difficile. These toxins formation and various carcinogenic metabolites from these strains leads to the inflammation development in the intestines and as a consequence to the progression of the inflammatory process in the liver. In turn, the reduction in the bacteria number producing short-chain fatty acid contributes to intestinal colonization by pathogenic representatives Gracilicutes (Salmonella, Shigella, enterohaemorrhagic E. coli) and Firmicutes (Clostridia), the toxins having a direct toxic effect on the liver. It is examined a little-studied question about a possible cofactor effect of enteric viruses (rotavirus, adenovirus, poliovirus type 1, Coxsackie virus, ECHO) and bacteria (Shigella, Salmonella, diarrheagenic E. coli, C. jejuni) on the progression of chronic hepatitis. In view of the above, it is necessary to study in further detailed the influence of the intestinal microbiome on the progression of chronic hepatitis HBV/HCV etiology in order to develop a comprehensive approach to treatment and reduce the risk of adverse outcomes in patients.

About the authors

N. N. Polishchuk

Zaporozhye State Medical University, Zaporozhye, Ukraine

Author for correspondence.
Email: natalya-polishchuck@ya.ru

PhD (Medicine), Senior Lecturer, Department of Microbiology, Virology and Immunology, Head of Bacteriological Research Laboratory

Ukraine

A. M. Kamyshny

Zaporozhye State Medical University, Zaporozhye, Ukraine

Email: natalya-polishchuck@ya.ru

PhD, MD (Medicine), Professor, Head of Department of Microbiology, Virology and Immunology, Head of Molecular Genetics Laboratory

Ukraine

References

  1. Ардатская М.Д. Масляная кислота и инулин в клинической практике. Теоретические аспекты и возможности применения. М.: Форте принт, 2014. 64 с. [Ardatskaya M.D. Maslyanaya kislota i inulin v klinicheskoi praktike. Teoreticheskie aspekty i vozmozhnosti primeneniya [Butyric acid and inulin in clinical practice. Theoretical aspects and applications]. Moscow: Forte print, 2014. 64 p.]
  2. Гураль А.Л., Мариевский В.Ф., Сергеева Т.А., Шагинян В.Р. Современное состояние проблемы эпидемиологии гепатита С в Украине // Мир вирусных гепатитов. 2009. № 2. C. 27–28. [Gural A.L., Marievsky D.F., Sergeeva T.A., Shaginyan V.R. The present condition of problem of the epidemiology of hepatitis C in Ukraine. Mir virusnykh gepatitov = World of Viral Hepatitis, 2009, no. 2, pp. 27–28. (In Russ.)]
  3. Домашенко О.М., Біломеря Т.А., Дараган Г.М., Філіппова Т.І., Ткаченко І.М. Про захворюваність на парентеральні гепатити в Донецькій області в 2014 році // Актуальна нефрологія. 2014. № 3 (4). С 31–34. [Domashenko O.M., Bilomerya T.A., Daragan H.M., Filippova T.I., Tkachenko I.M. About parenteral hepatitis incidence in the Donetsk region in 2014. Aktual’na nefrologіya = Actual Nephrology, 2014, vol. 3, no. 4, pp. 31–34.]
  4. Ершова И.Б. Особенности кишечного микробиоценоза при вирусных гепатитах и возможности его коррекции. Актуальная инфектология. 2014. № 2 (3). С. 7–11. [Yershova I.B. Features of intestinal microbiocenosis in viral hepatitis and possible correction. Aktual’naya infektologiya = Actual Infectology, 2014, no. 2 (3), pp. 7–11. (In Russ.)]
  5. Закиров И.Г. Дисбактериоз кишечника при хронических вирусных гепатитах. Казань: ЗАО «Новое знание», 2002. 102 с. [Zakirov I.G. Disbakterioz kishechnika pri khronicheskikh virusnykh gepatitakh [Intestinal dysbiosis in chronic viral hepatitis]. Kazan: JSC “New knowledge”, 2002. 102 p. (In Russ.)]
  6. Закиров И.Г. Микроэкология толстого кишечника больных хроническим вирусным гепатитом // Казанский медицинский журнал. 2002. № 1. C. 38–40. [Zakirov I.G. Microecology colon of patients with chronic viral hepatitis. Kazanskii meditsinskii zhurnal = Kazan Medical Journal, 2002, no. 1, pp. 38–40. (In Russ.)]
  7. Ильченко А.А. Желчные кислоты в норме и при патологии // Здоров’я України. 2011. № 9. C. 22–24. [Ilchenko A.A. Bile acids in health and disease. Zdorov’ya Ukraїni = Health Protection of Ukraine, 2011, no. 9, рр. 22–24. (In Russ.)]
  8. Кляритская И.Л., Кривой В.В., Матрау С. Значение бактерий рода Helicobacter рylorі у пациентов с хронической вирусной патологией печени // Кримський терапевтичний журнал. 2014. № 1. C. 162–171. [Klyaritskaya I.L, Krivy V.V., Matrau S. The role of Helicobacter рylorі in patients with chronic hepatitis and liver cirrhosis associate with HCV. Krims’kii terapevtichnii zhurnal = Crimean Therapeutic Journal, 2014, no. 1, pp. 162–171. (In Russ.)]
  9. Князькина О.В. Микрофлора кишечника у больных вирусными гепатитами // Информационный архив. 2010. Т. 4, № 2. C. 130–131. [Knyazkina O.V. Intestinal microflora in patients with viral hepatitis. Informatsionnyi arkhiv = Information Archive, 2010, vol. 4, no. 2, pp. 130–131. (In Russ.)]
  10. Порохницький В.Г., Топольницький В.С. Вірусні гепатити. Київ: Книга плюс, 2010. 425 p. [Porohnitsky V.G., Topolnitsky V.S. Vіrusnі gepatiti [Viral hepatitis]. Kiev: Book Plus, 2010. 425 p.]
  11. Радченко В.Г., Селиверстов П.В., Тетерина Л.А. Дисбиоз кишечника и хронические заболевания печени // Санкт-Петербургские врачебные ведомости. 2010. № 2. C. 61–65. [Radchenko V.G., Seliverstov P.V., Teterina L.A. Intestinal dysbiosis and chronic liver disease. Sankt-Peterburgskie vrachebnye vedomosti = St. Petersburg Medical Statements, 2010, no. 2, pp. 61–65. (In Russ.)]
  12. Соловьева Н.В. Механизмы нарушений функций печени и микробиоценоза толстой кишки при хронических вирусных гепатитах В и С и их пробиотическая коррекция // Ученые записки Петрозаводского государственного университета. 2014. Т. 1, № 8. C. 52–58. [Solovievа N.V. Mechanisms of violations of liver functions and colon microbiocenosis in chronic viral hepatitis B and C and their probiotic correction. Uchenye zapiski Petrozavodskogo gosudarstvennogo universiteta = Scientific Notes of Petrozavodsk State University, 2014, vol. 1, no. 8, pp. 52–58. (In Russ.)]
  13. Ткач С.М., Левченко А.Р., Онищук Л.О. Інфекція Helicobacter pylori і позашлункові захворювання. Сучасна гастро-ентерологія. 2015. № 6 (86). C. 89–95. [Weaver S., Levchenko A.R., Onischuk L.A. Helicobacter pylori infection and out gastric disease. Suchasna gastroenterologіya = Current Gastroenterology, 2015, no. 6 (86), pp. 89–95.]
  14. Шейбак В.М. Микробиом кишечника человека и его влияние на метаболизм // Журнал Гродненского государственного медицинского университета. 2015. № 2. C. 37–43. [Sheibak V.M. Human intestinal microbiom and its effect on the metabolism. Zhurnal Grodnenskogo gosudarstvennogo meditsinskogo universiteta = Journal of Grodno State Medical University, 2015, no. 2, pp. 37–43. (In Russ.)]
  15. Abbeele P., Belzer C., Goossens M., Kleerebezem M., Vos W., Thas O., Weirdt R., Kerckhof F., Wiele T. Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model. ISME J., 2013, vol. 7, no. 5, pp. 949–961. doi: 10.1038/ismej.2012.158
  16. Andoh A., Bamba T., Saski M. Physiological and anti-infl ammatory roles of dietary fiber and butyrate in intestinal functions. J. Parent. Enteral. Nutr., 1999, vol. 23, pp. 70–73.
  17. Avenaud P., Castoviejo M., Claret S., Mégraud F., Ménard A. Expression and activity of the cytoletal distending toxin of Helicobacter hepaticus. Biochem. Biophys. Pes. Commun., 2004, vol. 318, no. 3, pp. 739–745.
  18. Belkaid Y., Hand T. Role of the microbiota in immunity and inflammation. Cell, 2014, vol. 157, no. 1, pp. 121–141. doi: 10.1016/j.cell.2014.03.011
  19. Belkaid Y., Naik S. Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol., 2013, vol. 14, no. 7, pp. 646–653. doi: 10.1038/ni.2604
  20. Boettler T., Panther E., Bengsch B., Nazarova N., Spangenberg H.C., Blum H.E., Thimme R. Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J. Virol., 2006, vol. 80, no. 7, pp. 3532–3540. doi: 10.1128/JVI.80.7.3532-3540.2006
  21. Boettler T., Spangenberg H.C., Neumann-Haefelin C., Panther E., Urbani S., Ferrari C., Blum H.E., Weizsacker F., Timme R. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J. Virol., 2005, vol. 79, no. 12, pp. 7860–7867. doi: 10.1128/JVI.79.12.7860-7867.2005
  22. Boni C., Fisicaro P., Valdatta C., Amadei B., Di Vincenzo P., Giuberti T., Laccabue D., Zerbini A., Cavalli A., Missale G., Bertoletti A., Ferrari C. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol., 2007, vol. 81, no. 8, pp. 4215–4225. doi: 10.1128/JVI.02844-06
  23. Brogden K.A., Guthmiller J.M. Polymicrobial diseases. mixed infections of intestinal viruses and bacteria in humans. Ed. J.A. Marshall. Washington (DC): ASM Press; 2002. 427 p.
  24. Chen Y., Yang F., Lu H., Wang B., Chen Y., Lei D., Wang Y., Zhu B., Li L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology, 2011, vol. 54, no. 2, pp. 562–572. doi: 10.1002/hep.24423
  25. Chou H.H., Chien W.H., Wu L.L., Cheng C.H., Chung C.H., Horng J.H., Ni Y.H., Tseng H.T., Wu D., Lu X.I., Wang H.Y., Chen P.J., Chen D.S. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. PNAS, 2015, vol. 112, no. 7, pp. 2175–2180. doi: 10.1073/pnas.1424775112
  26. Cowie B.C., Carville K.S., MacLachlan J.H. Mortality due to viral hepatitis in the Global Burden of Disease Study 2010: new evidence of an urgent global public health priority demanding action. Antivir. Ther., 2013, vol. 18, no. 8, pp. 953–954. doi: 10.3851/ IMP2654
  27. El-Masry S., El-Shahat M., Badra G., Aboel-Nour M., Lotfy M. Helicobacter pylori and hepatitis C virus coinfection in egyptian patients. J. Glob. Infect. Dis., 2010, vol. 2, no. 1, pp. 4–9. doi: 10.4103/0974-777X.59244
  28. Esmat G., El-Bendary M., Zakarya S., Ela M., Zalata K. Role of Helicobacter pylori in patients with HCV-related chronic hepatitis and cirrhosis with or without hepatocellular carcinoma: possible association with disease progression. J. Viral Hepat., 2012, vol. 19, no. 7, pp. 473–479. doi: 10.1111/j.1365-2893.2011.01567.x
  29. European Association for the Study of the Liver (EASL). Clinical Practice Guidelines: Management of chronic hepatitis B. J. Hepatol., 2012, vol. 57, no. 1, pp. 167–185. doi: 10.106/j.hep.2012.02.010
  30. Fagoonee S., Pellicano R., Rizzetto M., Ponzetto A. The journey from hepatitis to hepatocellular carcinoma. Bridging role of Helicobacter species. Panminerva Med., 2001, vol. 43, no. 4, pp. 279–282.
  31. Fisicaro P., Valdatta C., Massari M., Loggi E., Ravanetti L., Urbani S., Giuberti T., Cavalli A., Vandelli C., Andreone P., Missale G., Ferrari C. Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology, 2012, vol. 143, no. 6, pp. 1576–1585. doi: 10.1053/j.gastro.2012.08.041
  32. Haque T.R., Barritt IV A.S. Intestinal microbiota in liver disease. Best Pract. Res. Clin. Gastroenterol., 2016, vol. 30, no. 1, pp. 133– 142. doi: 10.1016/j.bpg.2016.02.004
  33. Hu C.E., Gan J., Zhang R.D., Cheng Y.R., Huang G.J. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand. J. Gastroenterol., 2011, vol. 46, no. 2, pp. 156–164. doi: 10.3109/00365521.2010.516450
  34. Kakiyama G., Hylemon P.B., Zhou H., Pandak W.M., Heuman D.M., Kang D.J., Takei H., Nittono H., Ridlon J.M., Fuchs M., Gurley E.C., Wang Y., Liu R., Sanyal A.J., Gillevet P.M., Bajaj J.S. Colonic inflammation and secondary bile acids in alcoholic cirrhosis. Am. J. Physiol. Gastrointest. Liver Physiol., 2014, vol. 306, no. 11, pp. 929–937. doi: 10.1152/ajpgi.00315.2013
  35. Kakiyama G., Pandak W.M., Gillevet P.M., Hylemon P.B., Heuman D.M., Daita K., Takei H., Muto A., Nittono H., Ridlon J.M., White M.B., Noble N.A., Monteith P., Fuchs M., Thacker L.R., Sikaroodi M., Bajaj J.S. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J. Hepatol., 2013, vol. 58, no. 5, pp. 949–955. doi: 10.1016/j.jhep.2013.01.003
  36. Kamada N., Seo S.U., Chen G.Y., Núñez G. Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol., 2013, vol. 13, no. 5, pp. 321–335. doi: 10.1038/nri3430
  37. Kosiewicz M.M., Zirnheld A.L., Alard P. Gut microbiota, immunity, and disease: a complex relationship. Front. Microbiol., 2011, vol. 2, article 180, pp. 1–11. doi: 10.3389/fmicb.2011.00180
  38. Kostic A.D., Xavier R.J., Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology, 2014, vol. 146, no. 6, pp. 1489–1499. doi: 10.1053/j.gastro.2014.02.009
  39. Krüttgen A., Horz H.P., Weber-Heynemann J., Vucur M., Trautwein C., Haase G., Luedde T., Roderburg C. Study on the association of helicobacter species with viral hepatitis-induced hepatocellular carcinoma. Gut Microbes., 2012, vol. 3, no. 3, pp. 228–233. doi: 10.4161/gmic.19922
  40. Lee K., Kang J.Y., Shin H.S., Park I.H., Ha N.J. Antiviral activity of Bifidobacterium adolescentis SPM0212 against Hepatitis B virus. Arch. Pharm. Res., 2013, vol. 36, no. 12, pp. 1525–1532. doi: 10.1007/s12272-013-0141-3
  41. Li G., Guo G.L. Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration. Acta Pharm. Sin. B, 2015, vol. 5, no. 2, pp. 93–98. doi: 10.1016/j.apsb.2015.01.005
  42. Livesey G., Elia M. Short-chain fatty acids as an energy source in the colon: metabolism and clinical implications. Physiological and clinical aspects of short-chain fatty acids. Ed. Cummings J.Y., Rombeau J.L., Sakata T. Cambridge University Press, 2004, pp. 427–482.
  43. Lu H., Wu Z., Xu W., Yang J., Chen Y., Li L.. Intestinal microbiota was assessed in cirrhotic patients with hepatitis b virus infection: intestinal microbiota of HBV cirrhotic patients. Microb. Ecol., vol. 61, no. 3, pp. 693–703. doi: 10.1007/s00248-010-9801-8
  44. Mazmanian S.K., Round J.L., Kasper D.L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature, 2008, no. 453, рр. 620–625. doi: 10.1038/nature07008
  45. Minemura M., Shimizu Y. Gut microbiota and liver diseases. World J. Gastroenterol., 2015, vol. 21, no. 6, pp. 1691–1702. doi: 10.3748/wjg.v21.i6.1691
  46. Miquel S., Martín R., Rossi O., Bermúdez-Humarán L.G., Chatel J.M., Sokol H., Thomas M., Wells J.M., Langella P. Faecalibacterium prausnitzii and human intestinal health. Curr. Opin. Microbiol., vol. 16, no. 3, pp. 255–261. doi: 10.1016/j.mib.2013.06.003
  47. Mirpuri J., Sotnikov I., Myers L., Denning T.L., Yarovinsky F., Parkos C.A., Denning P.W., Louis N.A. Lactobacillus rhamnosus (LGG) regulates IL-10 signaling in the developing murine colon through upregulation of the IL-10R2 receptor subunit. PLoS One, 2012, vol. 7, no. 12. e. 51955. doi: 10.1371/journal.pone.0051955
  48. Molloy M.J., Bouladoux N., Belkaid Y. Intestinal microbiota: shaping local and systemic immune responses. Semin. Immunol., 2012, vol. 24, no. 1, pp. 58–66. doi: 10.1016/j.smim.2011.11.008
  49. Neish A.S. Microbes in gastrointestinal health and disease. Gastroenterology, 2009, vol. 136, no. 1, pp. 65–80. doi: 10.1053/j.gastro.2008.10.080
  50. Pellicano R., Ménard A., Rizzetto M., Mégraud F. Helicobacter species and liver diseases: association or causation? Lancet Infect. Dis., 2008, vol. 8, no. 4, pp. 254–260. doi: 10.1016/S1473-3099(08)70066-5
  51. Rai R., Saraswat V.A., Dhiman R.D. Gut microbiota: its role in hepatic encephalopathy. J. Clin. Exp. Hepatol., 2015, vol. 5, no. 1, pp. 29–36. doi: 10.1016/j.jceh.2014.12.003
  52. Ridlon J.M., Alves J.M., Hylemon P.B., Bajaj J.S. Cirrhosis, bile acids and gut microbiota. Unraveling a complex relationship. Gut Microbes, 2013, vol. 4, no. 5, pp. 382–387. doi: 10.4161/gmic.25723
  53. Ridlon J.M., Bajaj J.S. The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics. Acta Pharm. Sin. B, 2015, vol. 5, no. 2, pp. 99–105. doi: 10.1016/j.apsb.2015.01.006
  54. Rocha M., Avenaud P., Ménard A., Le Bail B., Balabaud C., Bioulac-Sage P., De Magalhães Queiroz D.M., Mégraud F. Association of Helicobacter species with hepatitis C cirrhosis with or without hepatocellular carcinoma. Gut, 2005, vol. 54, no. 3, pp. 396–401.
  55. Roderburg C., Luedde T. The role of the gut microbiome in the development and progression of liver cirrhosis and hepatocellular carcinoma. Gut Microbes, 2014, vol. 5, no. 4, pp. 441–445. doi: 10.4161/gmic.29599
  56. Schnabl B. Linking intestinal homeostasis and liver disease. Curr. Opin. Gastroenterol., 2013, vol. 29, no. 3. pp. 264–270. doi: 10.1097/MOG.0b013e32835ff948
  57. Semmo N., Day C.L., Ward S.M., Lucas M., Harcourt G., Loughry A., Klenerman P. Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection. Hepatology, 2005, vol. 41, no. 5, pp. 1019–1028. doi: 10.1002/hep.20669
  58. Shuai Z., Leung M., He X., Zhang W., Yang G., Leung P., Gershwin M. Adaptive immunity in the liver. Cell. Mol. Immunol., 2016, vol. 13, no. 3, pp. 354–368. doi: 10.1038/cmi.2016.4
  59. Wei X., Yan X., Zou D., Yang Z., Wang X., Liu W., Wang S., Li X., Han J., Huang L., Yuan J. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterol., 2013, vol. 175, no. 13, pp. 175–185. doi: 10.1186/1471-230X-13-175
  60. Wells J.E., Hylemon P.B. Identification and characterization of a bile acid 7alpha-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7alpha-dehydroxylating strain isolated from human feces. Appl. Environ. Microbiol., 2000. vol. 66, no. 3, рp. 1107–1113.
  61. Wu Z.W., Lu H.F., Wu J., Zuo J., Chen P., Sheng J.F., Zheng S.S., Li L.J. Assessment of the fecal lactobacilli population in patients with hepatitis B virus-related decompensated cirrhosis and hepatitis B cirrhosis treated with liver transplant. Microb. Ecol. 2012, vol. 63, no. 4, pp. 929–937. doi: 10.1007/s00248-011-9945-1
  62. Xu D., Huang Y., Wang J. Gut microbiota modulate the immune effect against hepatitis B virus infection. Eur. J. Clin. Microbiol. Infect. Dis., 2015, vol. 34, no. 11, pp. 2139–2147. doi: 10.1007/s10096-015-2464-0
  63. Xu M., Wang B, Fu Y., Chen Y., Yang F., Lu H., Chen Y., Xu J., Li L. Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease. Microb. Ecol., 2012, vol. 63, no. 2, pp. 304–313. doi: 10.1007/s00248-011-9925-5
  64. Zhou Z., Xu M.J., Gao B. Hepatocytes: a key cell type for innate immunity. Cell. Mol. Immunol., 2016, vol. 13, no. 3, pp. 301–315. doi: 10.1038/cmi.2015.97

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