Кишкова мікробіота при захворюваннях печінки: сучасний стан проблеми
DOI:
https://doi.org/10.30978/MG-2019-3-79Ключові слова:
мікробіота, дисбіоз кишечника, синдром надмірного бактеріального росту, кишкова проникність, захворювання печінки, патогенез, лікуванняАнотація
Проаналізовано дані сучасної літератури, результати експериментальних і клінічних досліджень, які розкривають роль кишкової мікробіоти у патогенезі різних захворювань печінки: вірусних гепатитів, алкогольної хвороби печінки, неалкогольної жирової хвороби печінки, первинного склерозувального холангіту, цирозу печінки та гепатоцелюлярної карциноми. Особливу увагу приділено підвищенню кишкової проникності, що створює умови для транслокації бактерій, активації системної запальної відповіді, посилення гіпердинамічного кровотоку і погіршення функціонального стану печінки. Як приклад впливу кишкової мікробіоти на стан печінки наведено дані щодо синдрому надмірного бактеріального росту. Відзначено високу частоту розвитку синдрому надмірного бактеріального росту при хронічних захворюваннях печінки, залежність між підвищенням кишкової проникності та ступенем тяжкості порушення функцій печінки, розвитком і ступенем виразності печінкової енцефалопатії, ймовірністю виникнення спонтанного бактеріального перитоніту. Обговорюється роль кишкової мікробіоти у розвитку бактеріальних ускладнень цирозу печінки, зокрема спонтанного бактеріального перитоніту. Показано, що кишковий дисбіоз бере участь у дисрегуляції клітинного балансу загибель/регенерація, який лежить в основі канцерогенезу. Зроблено висновок щодо доцільності включення до складу терапії кількох захворювань печінки препаратів, які коригують склад кишкової мікробіоти. Описано переваги призначення рифаксиміну для поліпшення функціонального стану печінки при неалкогольному стеатогепатиті та печінковій енцефалопатії за допомогою корекції складу кишкового мікробіому.
Посилання
Babak OYa, Kolesnikova YeV. Liver cirrhosis and its complications. Kyiv: Health of Ukraine, 2011:576.
Gubergits NB, Kharchenko NV. Chronic hepatitis and liver cirrhosis. Modern classification, diagnosis and treatment. Kirovograd: Polium, 2015:286.
Joshi D, Keane G, Brind A. Hepatology at a Glance / Transl. by Yu. O. Shulpekova; ed. by Ch. S. Pavlov. Moscow: Geotar-Media, 2018:168.
Ivashkin VT, Mayevskaya MV, Zharkova MS et al. Diagnostic and treatment algorithms in hepatology. Moscow: Medpress-inform, 2016:176.
Kucheryaviy YuA, Maevskaya YeA, Akhtayeva ML, Krasnyakova YeA. Non-alcoholic steatohepatitis and intestinal microflora: is there potential for prebiotic drugs in treatment?. Medical advice. 2013;No 3:46 — 51.
Plotnikova YeYu. What is common between microbial intestinal landscape and metabolic syndrome?. Herald of Pancreatic Club. 2016;No 2:63-72.
Podymova SD. Liver diseases: guidelines for physicians. Moscow: Medical Information Agency, 2018:984.
Tkach SM, Puchkov KS, Sizenko AK. Intestinal microbiota in health and pathology. Modern approaches to the diagnosis and correction of intestinal dysbiosis. Kyiv, 2014:149.
Schiff ER, Sorrell MF, Maddrey WC. Schiff’s Diseases of the Liver: Introduction to Hepatology: Transl. from Eng. Moscow: Geotar-Media, 2011;1:704.
Alisi A, Ceccarelli S, Panera N et al. Causative role of gut microbiota in non-alcoholic fatty liver disease pathogenesis. Front Cell Infect Microbiol. 2012;N 2:132. DOI: 10.3389/fcimb.2012.00132.
Anderson P, Cremona A, Paton A, Turner C, Wallace P. The risk of alcohol. Addiction. 1993;88:1493— 1508. PMID: 8286995.
Bajaj JS, Barbara G, DuPont HL et al. New concepts on intestinal microbiota and the role of the non-absorbable antibiotics with special reference to rifaximin in digestive diseases. Dig Liver Dis. 2018;50(8):741 — 749. DOI: 10.1016/j.dld.2018.04.020.
Bode C, Bode JC. Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol. 2003;17:575— 592. PMID: 12828956.
Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761 — 1772. DOI: 10.2337/db06-1491.
Caradonna L, Mastronardi ML, Magrone T et al. Biological and clinical significance of endotoxemia in the course of hepatitis C virus infection. Curr Pharm Des. 2002;N 8:995 — 1005. PMID: 11945146.
Cariello R, Federico A, Sapone A et al. Intestinal permeability in patients with chronic liver diseases: Its relationship with the aetiology and the entity of liver damage. Dig Liver Dis. 2010;42:200 — 204. DOI: 10.1016/j.dld.2009.05.001.
Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology. 2014;59:328— 339. DOI: 10.1002/hep.26494.
Chavez-Tapia NC, Barrientos-Gutierrez T et al. Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding — an updated Cochrane review. Aliment Pharmacol Ther. 2011;34:509 — 518. DOI: 10.1111/j.1365-2036.2011.04746.x.
Chen P, Miyamoto Y, Mazagova M et al. Microbiota protects mice against a cute alcohol-induced liver injury. Alcohol Clin Exp Res. 2015;39:2313 — 2323. DOI: 10.1111/acer.12900.
Chou HH, Chien WH, Wu LL et al. Age-related immune clearance of hepatitis В virus infection requires the establishment of gut microbiota. Proc Natl Acad Sci USA. 2015;112:2175 — 2180. DOI: 10.1073/pnas.1424775112.
Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 2000;119:1340— 1347. PMID: 11054393.
Damms-Machado A, Louis S, Schnitzer A et al. Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction. Am J Clin Nutr. 2017;105:127 — 135. DOI: 10.3945/ajcn.116.131110.
Dapito DH, Mencin A, Gwak GY et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504 — 516. DOI: 10.1016/j.ccr.2012.02.007.
Dolganiuc A, Norkina O, Kodys K et al. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology. 2007;133:1627 — 1636. DOI: 10.1053/j.gastro.2007.08.003.
Farhadi A, Gundlapalli S, Shaikh M et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in nonalcoholic steatohepatitis. Liver Int- — 2008;28:1026— 1033. DOI: 10.1111/j.1478-3231.2008.01723.x.
Federico A, Dallio M, Tolone S et al. Gastrointestinal hormones, intestinal microbiota and metabolic homeostasis in obese patients: effect of bariatric surgery. In Vivo. 2016;30:321 — 330. PMID: 27107092.
Fiebiger U, Bereswill S, Heimesaat MM. Dissecting the interplay between intestinal microbiota and host immunity in health and disease: lessons learned from germfree and gnotobiotic animal models. Eur J Microbiol Immunol (Bp). 2016;N 6:253 — 271. DOI: 10.1556/1886.2016.00036.
Forbes SJ, Parola M. Liver fibrogenic cells. Best Pract Res Clin Gastroenterol. 2011;25:207 — 217. DOI: 10.1016/j.bpg.2011.02.006.
Gatta L, Scarpignato C. Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth. Aliment Pharmacol Ther. 2017;45(5):604 — 616. DOI: 10.1111/apt.13928.
Giorgio V, Miele L, Principessa L et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis. 2014;46:556 — 560. DOI: 10.1016/j.dld.2014.02.010.
Goulis J, Armonis A, Patch D et al. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology. 1998;27:1207 — 1212. DOI: 10.1002/hep.510270504.
Hanck C, Rossol S, Bocker U, Tokus M, Singer MV. Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis. Alcohol Alcohol. 1998;33:606 — 608. DOI: 10.1093/alcalc/33.6.606.
Hov JR, Kummen M. Intestinal microbiota in primary sclerosing cholangitis. Curr Opin Gastroenterol. 2017;33(2):85 — 92. DOI: 10.1097/MOG.0000000000000334.
Howe KL, Reardon C, Wang A, Nazli A, McKay DM. Transforming growth factor-beta regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli 0157. P.H7-induced increased permeability. Am J Pathol. 2005;167:1587— 1597. PMID: 16314472.
Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012;21(8):2609 — 2618. DOI: 10.3748/wjg.v18.i21.2609.
Jakobsson HE, Rodriguez-Pineiro AM, Schiitte A et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 2015;16:164 — 177. DOI: 10.15252/embr.201439263.
Karczewski J, Troost FJ, Konings I et al. Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. Am J Physiol Gastrointest Liver Physiol. 2010;298:851— 859. DOI: 10.1152/ajpgi.00327.2009.
Kelly CJ, Zheng L, Campbell EL et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17:662 — 671. DOI: 10.1016/j.chom.2015.03.005.
Konig J, Wells J, Cani PD et al. Human intestinal barrier function in health and disease. Clin Transl Gastroenterol. 2016;N 7. el96. DOI: 10.1038/ctg.2016.54.
Kummen M, Holm K, Anmarkrud JA et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut. 2017;66:611 — 619. DOI: 10.1136/gutjnl-2015-310500.
Le Chatelier E, Nielsen T, Qin J et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541 — 546. DOI: 10.1038/nature12506.
Le Roy T, Llopis M, Lepage P et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62:1787 — 1794. DOI: 10.1136/gutjnl-2012-303816.
Leclercq S, Matamoros S, Cani PD et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA. 2014;111. E4485— 4493. DOI: 10.1073/pnas.1415174111.
Li J, Jia H, Cai X et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol. 2014;32:834 — 841. DOI: 10.1038/nbt.2942.
Loguericio C. Gut microbiota and gastrointestinal tract, liver and pancreas: from phisiology to pathology. Torino: Edizioni Minerva Medica, 2018:123.
Lopetuso LR, Petito V, Scaldaferri F, Gasbarrini A. Gut microbiota modulation and mucosal immunity: focus on rifaximin. Mini Rev Med Chem. 2015;16(3):179 — 185. PMID: 26643042.
Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Envir Microbiol. 2017;19:29 — 41. DOI: 10.1111/1462-2920.13589.
Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428 — 435. DOI: 10.1038/nature07201.
Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut. 2009;58:704— 720. DOI: 10.1136/gut.2008.156307.
Mullen KD, Sanyal AJ, Bass NM et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clinical Gastroenterology and Hepatology. 2014;N 12:1390 — 1397. DOI: 10.1016/j.cgh.2013.12.021.
Mutlu EA, Gillevet PM, Rangwala H et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol. 2012;302. P. G966 — 978. DOI: 10.1152/ajpgi.00380.2011.
Nair S, Cope K, Risby TH, Diehl AM. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:1200— 1204. DOI: 10.1111/j.1572-0241.2001.03702.x.
Nanji AA, Jokelainen K, Fotouhinia M et al. Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines. Am J Physiol Gastrointest Liver Physiol. 2001;281:1348 — 1356. DOI: 10.1152/ajpgi.2001.281.6.G1348.
Park B, Lee HR, Lee YJ. Alcoholic liver disease: focus on prodromal gut health. J Dig Dis. 2016;17:493 — 500. DOI: 10.1111/1751-2980.12375.
Peng L, He Z, Chen W, Holzman IR, Lin J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res. 2007;61:37— 41. DOI: 10.1203/01.pdr.0000250014.92242.f3.
Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Therapy. 2007;25(1):3— 9. DOI: 10.1111/j.1746-6342.2006.03215.x.
Quigley EM. Gut bacteria in health and disease. Gastroenterol Hepatol. 2013;N 9:560 — 569. PMID: 24729765.
Quigley EM, Stanton C, Murphy EF. The gut microbiota and the liver. Pathophysiological and clinical implications. J Hepatol. 2013;58(5):1020 — 1027. DOI: 10.1016/j.jhep.2012.11.023.
Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43:54 — 62. DOI: 10.1002/hep.21060.
Rao RK. Acetaldehyde-induced barrier disruption and paracellular permeability in Caco-2 cell monolayer. Methods Mol Biol. 2008;447:171 — 183. DOI: 10.1007/978-1-59745-242-7_13.
Rao RK, Seth A, Sheth P. Recent advances in alcoholic liver disease. I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol. 2004;286:881 — 884. DOI: 10.1152/ajpgi.00006.2004.
Reiberger T, Ferlitsch A, Payer BA et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol. 2013;58:911 — 921. DOI: 10.1016/j.jhep.2012.12.011.
Rossen NG, Fuentes S, Boonstra K et al. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J Crohns Colitis. 2015;N 9:342 — 348. DOI: 10.1093/ecco-jcc/jju023.
Sabino J, Vieira-Silva S, Machiels K et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut. 2016;65:1681 — 1689. DOI: 10.1136/gutjnl-2015-311004.
Sarkola T, Eriksson CJ. Effect of 4-methylpyrazole on endogenous plasma ethanol and methanol levels in humans. Alcohol Clin Exp Res. 2001;25:513 — 516. PMID: 11329490.
Scarpellini E, Gabrielli M, Lauritano CE et al. High dosage rifaximin for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2007;25(7):781— 786. DOI: 10.1111/j.1365-2036.2007.03259.x.
Scarpignato C, Pelosini I. Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy. 2005;51, 1:36 — 66. DOI: 10.1159/000081990.
Schnabl B, Purbeck CA, Choi YH et al. Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology. 2003;37:653 — 664. DOI: 10.1053/jhep.2003.50097.
Seki E, De Minicis S, Osterreicher CH et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:1324 — 1332. DOI: 10.1038/nm1663.
Shawcross DL, Sharifi Y, Canavan JB et al. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011;54:640 — 649. DOI: 10.1016/j.jhep.2010.07.045.
Sibley D, Jerrells TR. Alcohol consumption by C57BL/6 mice is associated with depletion of lymphoid cells from the gutassociated lymphoid tissues and altered resistance to oral infections with Salmonella typhimurium. J Infect Dis. 2000;182:482 — 489. DOI: 10.1086/315728.
Sozinov AS. Systemic endotoxemia during chronic viral hepatitis. Bull Exp Biol Med. 2002;133:153— 155. PMID: 12428283.
Starkel P, Schnabl B. Bidirectional communication between liver and gut during alcoholic liver disease. Semin Liver Dis. 2016;36:331 — 339. DOI: 10.1055/s-0036-1593882.
Tabibian H, O’Hara SP, Trussoni CE et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology. 2016;63:185 — 196. DOI: 10.1002/hep.27927.
Tang Y, Forsyth CB, Farhadi A et al. Nitric oxide-mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage. Alcohol Clin Exp Res. 2009;33:1220 — 1230. DOI: 10.1111/j.1530-0277.2009.00946.x.
Wang L, Fouts DE, Starkel P et al. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosaassociated microbiota and preventing bacterial translocation. Cell Host Microbe. 2016;19:227 — 239. DOI: 10.1016/j.chom.2016.01.003.
Yang CY, Chang CS, Chen GH. Small-intestinal bacterial overgrowth in patients with liver cirrhosis, diagnosed with glucose H2 or CH4 breath tests. Scand J Gastroenterol. 1998;33:867 — 871. PMID: 9754736.
Yoshimoto S, Loo TM, Atarashi K et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97 — 101. DOI: 10.1038/nature12347.
Zhu L, Baker SS, Gill C et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57:601 — 609. DOI: 10.1002/hep.26093].
