肠道菌群在自身免疫性肝病发生发展及治疗中的作用
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摘要
肠道细菌过度生长、肠道菌群变化、细菌及其产物的易位与胆汁酸代谢的相互作用等是多种肝病发生发展的重要共同途径。肝细胞通过门静脉系统持续的暴露于肠道代谢产物及各种抗原抗体之下,某些肠道细菌成分或代谢物可通过"分子模拟"等多个机制启动针对肝细胞的自身免疫机制。因此肠道菌群在自身免疫性肝病,包括自身免疫性肝炎、原发性胆汁性胆管炎和原发性硬化性胆管炎的发生发展及治疗过程中发挥了重要作用,对近年来的相关研究进展进行了阐述和总结。
Overgrowth of intestinal bacteria,change in intestinal flora,translocation between bacteria and their products,and bile acid metabolism are the important pathways for the development and progression of liver diseases. Hepatocytes are persistently exposed to intestinal metabolites and various antigens and antibodies via the portal vein system,and the constituents or metabolites of some intestinal bacteria can activate the autoimmune mechanism targeting hepatocytes through several mechanisms,including molecular mimicry. Therefore,intestinal flora plays an important role in the development/progression and treatment of autoimmune liver diseases,including autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis. This article reviews the related research advances in recent years.
Overgrowth of intestinal bacteria,change in intestinal flora,translocation between bacteria and their products,and bile acid metabolism are the important pathways for the development and progression of liver diseases. Hepatocytes are persistently exposed to intestinal metabolites and various antigens and antibodies via the portal vein system,and the constituents or metabolites of some intestinal bacteria can activate the autoimmune mechanism targeting hepatocytes through several mechanisms,including molecular mimicry. Therefore,intestinal flora plays an important role in the development/progression and treatment of autoimmune liver diseases,including autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis. This article reviews the related research advances in recent years.
引文
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[2]FUKUI H.Gut microbiota and host reaction in liver diseases[J].Microorganisms,2015,3(4):759-791.
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[16]WEINGARDEN AR,CHEN C,ZHANG N,et al.Ursodeoxycholic acid inhibits clostridium difficile spore germination and vegetative growth,and prevents the recurrence of ileal pouchitis associated with the infection[J].J Clin Gastroenterol,2016,50(8):624-630.
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[22]CHEN XM,O'HARA SP,LARUSSO NF.The immunobiology of cholangiocytes[J].Immunol Cell Biol,2008,86(6):497-505.
[23]LICHTMAN SN,OKORUWA EE,KEKU J,et al.Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth[J].J Clin Invest,1992,90(4):1313-1322.
[24]LICHTMAN SN,WANG J,CLARK RL.A microcholangiographic study of liver disease models in rats[J].Acad Radiol,1995,2(6):515-521.
[25]O'HARA SP,TABIBIAN JH,SPLINTER PL,et al.The dynamic biliary epithelia:Molecules,pathways,and disease[J].JHepatol,2013,58(3):575-582.
[26]TORNAI T,PALYU E,VITALIS Z,et al.Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis[J].World J Gastroenterol,2017,23(29):5412-5421.
[27]TABIBIAN JH,WEEDING E,JORGENSEN RA,et al.Randomised clinical trial:Vancomycin or metronidazole in patients with primary sclerosing cholangitis-a pilot study[J].Aliment Pharmacol Ther,2013,37(6):604-612.
[28]MUELLER T,BEUTLER C,PICO AH,et al.Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis[J].Liver Int,2011,31(10):1574-1588.
[29]LINDOR KD,KOWDLEY KV,HARRISON ME,et al.ACG clinical guideline:Primary sclerosing cholangitis[J].Am J Gastroenterol,2015,110(5):646-660.
[30]TIBIAN JH,WEEDING E,JORGENSEN RA,et al.Randomised clinical trial:Vancomycin or metronidazole in patients with primary sclerosing cholangitis:A pilot study[J].Aliment Pharmacol Ther,2013,37(6):604-612.
[31]ABARBANEL DN,SEKI SM,DAVIES Y,et al.Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing eholangitis[J].J Clin Immunol,2013,33(2):397-406.
[32]YETAILE NEZT,ZHENG S.Application of oral vancomycin in children with primary sclerosing cholangitis[J].Chin J Appl Clin Pediatr,2018,33(7):556-558.(in Chinese)叶勒泰·努尔扎提,郑珊.口服万古霉素在小儿原发性硬化性胆管炎中的应用[J].中华实用儿科临床杂志,2018,33(7):556-558.
[2]FUKUI H.Gut microbiota and host reaction in liver diseases[J].Microorganisms,2015,3(4):759-791.
[3]LI B,SELMI C,TANG R,et al.The microbiome and autoimmunity:A paradigm from the gut-liver axis[J].Cell Mol Immunol,2018.[Epub ahead of print]
[4]LI YQ,DONG HJ,LIU XW,et al.Latest clinical advances in autoimmune hepatitis in special populations and special types of autoimmune hepatitis[J].J Clin Hepatol,2018,34(6):1338-1342.(in Chinese)李艳清,董洪静,刘晓雯,等.特殊人群及特殊类型自身免疫性肝炎的临床新进展[J].临床肝胆病杂志,2018,34(6):1338-1342.
[5]CZAJA AJ.Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis[J].World J Gastroenterol,2016,22(42):9257-9278.
[6]YUKSEL M,WANG Y,TAI N,et al.A novel“humanized mouse”model for autoimmune hepatitis and the association of gut microbiota with liver inflammation[J].Hepatology,2015,62(5):1536-1550.
[7]LIN R,ZHOU L,ZHANG J,et al.Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis[J].Int J Clin Exp Pathol,2015,8(5):5153-5160.
[8]CAI W,RAN Y,LI Y,et al.Intestinal microbiome and permeability in patients with autoimmune hepatitis[J].Best Pract Res Clin Gastroenterol,2017,31(6):669-673.
[9]HUANG EY,INOUE T,LEONE VA,et al.Using corticosteroids to reshape the gut microbiome:Implications for inflammatory bowel diseases[J].Inflamm Bowel Dis,2015,21(5):963-972.
[10]GERSHWIN ME,SELMI C,WORMANH J,et al.Risk factors and comorbidities in primary biliary cirrhosis:A controlled interview-based study of 1032 patients[J].Hepatology,2005,42(5):1194-1202.
[11]CORPECHOT C,CHRETIEN Y,CHAZOUILLRES O,et al.Demographic,lifestyle,medical and familial factors associated with primary biliary cirrhosis[J].J Hepatol,2010,53(1):162-169.
[12]MATTNER J.Impact of microbes on the pathogenesis of primary biliary cirrhosis(PBC)and primary sclerosing cholangitis(PSC)[J].Int J Mol Sci,2016,17(11):1864.
[13]SELMI C,BALKWILL DL,INVERNIZZI P,et al.Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium[J].Hepatology,2003,38(5):1250-1257.
[14]BOGDANOS DP,PARES A,BAUM H,et al.Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis[J].J Autoimmun,2004,22(4):353-362.
[15]LV LX,FANG DQ,SHI D,et al.Alterations and correlations of the gut microbiome,metabolism and immunity in patients with primary biliary cirrhosis[J].EnvironMicrobiol,2016,18(7):2272-2286.
[16]WEINGARDEN AR,CHEN C,ZHANG N,et al.Ursodeoxycholic acid inhibits clostridium difficile spore germination and vegetative growth,and prevents the recurrence of ileal pouchitis associated with the infection[J].J Clin Gastroenterol,2016,50(8):624-630.
[17]TANG R,WEI Y,LI Y,et al.Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCAtherapy[J].Gut,2018,67(3):534-541.
[18]LI QQ,ZHOU XM,QI XS,et al.Recommendations for The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines(2018)[J].J Clin Hepatol,2018,34(6):1191-1192.(in Chinese)李谦谦,周新苗,祁兴顺,等.《2018年英国胃肠病学会/英国PBC协作组原发性胆汁性胆管炎治疗及管理指南》推荐意见[J].临床肝胆病杂志,2018,34(6):1191-1192.
[19]KUGELMAS M,SPIEGELMAN P,OSGOOD MJ,et al.Different immunosuppressive regimens and recurrence of primary sclerosing cholangitis after liver transplantation[J].Liver Transpl,2003,9(7):727-732.
[20]BUHNER S,BUNING C,GENSCHEL J,et al.Genetic basis for increased intestinal permeability in families with Crohn's disease:Role of CARD15 3020insC mutation?[J].Gut,2006,55(3):342-347.
[21]YOKOYAMA T,KOMORI A,NAKAMURA M,et al.Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-kappaB and-MAPKsignaling pathways[J].Liver Int,2006,26(4):467-476.
[22]CHEN XM,O'HARA SP,LARUSSO NF.The immunobiology of cholangiocytes[J].Immunol Cell Biol,2008,86(6):497-505.
[23]LICHTMAN SN,OKORUWA EE,KEKU J,et al.Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth[J].J Clin Invest,1992,90(4):1313-1322.
[24]LICHTMAN SN,WANG J,CLARK RL.A microcholangiographic study of liver disease models in rats[J].Acad Radiol,1995,2(6):515-521.
[25]O'HARA SP,TABIBIAN JH,SPLINTER PL,et al.The dynamic biliary epithelia:Molecules,pathways,and disease[J].JHepatol,2013,58(3):575-582.
[26]TORNAI T,PALYU E,VITALIS Z,et al.Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis[J].World J Gastroenterol,2017,23(29):5412-5421.
[27]TABIBIAN JH,WEEDING E,JORGENSEN RA,et al.Randomised clinical trial:Vancomycin or metronidazole in patients with primary sclerosing cholangitis-a pilot study[J].Aliment Pharmacol Ther,2013,37(6):604-612.
[28]MUELLER T,BEUTLER C,PICO AH,et al.Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis[J].Liver Int,2011,31(10):1574-1588.
[29]LINDOR KD,KOWDLEY KV,HARRISON ME,et al.ACG clinical guideline:Primary sclerosing cholangitis[J].Am J Gastroenterol,2015,110(5):646-660.
[30]TIBIAN JH,WEEDING E,JORGENSEN RA,et al.Randomised clinical trial:Vancomycin or metronidazole in patients with primary sclerosing cholangitis:A pilot study[J].Aliment Pharmacol Ther,2013,37(6):604-612.
[31]ABARBANEL DN,SEKI SM,DAVIES Y,et al.Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing eholangitis[J].J Clin Immunol,2013,33(2):397-406.
[32]YETAILE NEZT,ZHENG S.Application of oral vancomycin in children with primary sclerosing cholangitis[J].Chin J Appl Clin Pediatr,2018,33(7):556-558.(in Chinese)叶勒泰·努尔扎提,郑珊.口服万古霉素在小儿原发性硬化性胆管炎中的应用[J].中华实用儿科临床杂志,2018,33(7):556-558.