肠道微生物群与慢性肝病
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摘要
近年来,慢性肝病的发病率、死亡率持续上升,肝脏直接从富含微生物群及其代谢产物的肠道接收大量血液供应,因此肠道微生物群与肝脏的健康情况息息相关。越来越多的研究证明,肠道微生物群失衡参与了慢性肝病的发生、发展,而且肠道菌群在不同疾病中的改变情况不尽相同。本文将从肠道微生物群在慢性肝病发生、发展中的作用及目前可用治疗策略等方面作一概述。
In recent years, the morbidity and mortality of chronic liver disease have been increasing, and the liver receives a large amount of blood directly from the gut which carries the microbiota and its metabolites. Therefore, gut microbiota is closely related to the health of the liver. More and more studies have shown that gut microbiota imbalance is involved in the occurrence and development of chronic liver disease, and the changes in intestinal microflora are different in different diseases. This article reviewed the role of gut microbiota in the development of chronic liver disease and the available therapeutic strategies.
In recent years, the morbidity and mortality of chronic liver disease have been increasing, and the liver receives a large amount of blood directly from the gut which carries the microbiota and its metabolites. Therefore, gut microbiota is closely related to the health of the liver. More and more studies have shown that gut microbiota imbalance is involved in the occurrence and development of chronic liver disease, and the changes in intestinal microflora are different in different diseases. This article reviewed the role of gut microbiota in the development of chronic liver disease and the available therapeutic strategies.
引文
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[5] FENG Q, LIU W, BAKER S S, et al. Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of non-alcoholic fatty liver disease [J]. Oncotarget, 2017, 8(17): 27820-27838. DOI: 10.18632/oncotarget.15482.
[6] ENGSTLER A J, AUMILLER T, DEGEN C, et al. Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease [J]. Gut, 2016, 65(9): 1564-1571. DOI: 10.1136/gutjnl-2014-308379.
[7] DE MEDEIROS I C, DE LIMA J G. Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease-a mechanistic hypothesis [J]. Med Hypotheses, 2015, 85(2): 148-152. DOI: 10.1016/j.mehy.2015.04.021.
[8] LLOPIS M, CASSARD A M, WRZOSEK L, et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease [J]. Gut, 2016, 65(5): 830-839. DOI: 10.1136/gutjnl-2015-310585.
[9] FERRERE G, WRZOSEK L, CAILLEUX F, et al. Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice [J]. J Hepatol, 2017, 66(4): 806-815. DOI: 10.1016/j.jhep.2016.11.008.
[10] LOWE P P, GYONGYOSI B, SATISHCHANDRAN A, et al. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice [J]. PLoS One, 2017, 12(3): e0174544. DOI: 10.1371/journal.pone.0174544.
[11] HARTMANN P, HOCHRATH K, HORVATH A, et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice [J]. Hepatology, 2018, 67(6): 2150-2166.DOI: 10.1002/hep.29676.
[12] YANG A M, INAMINE T, HOCHRATH K, et al. Intestinal fungi contribute to development of alcoholic liver disease [J]. J Clin Invest, 2017, 127(7): 2829-2841. DOI: 10.1172/JCI90562.
[13] SABINO J, VIEIRA-SILVA S, MACHIELS K, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD [J]. Gut, 2016, 65(10): 1681-1689. DOI: 10.1136/gutjnl-2015-311004.
[14] KUMMEN M, HOLM K, ANMARKRUD J A, 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 [J]. Gut, 2017, 66(4): 611-619. DOI: 10.1136/gutjnl-2015-310500.
[15] TORRES J, PALMELA C, BRITO H, et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease [J]. United European Gastroenterol J, 2018, 6(1): 112-122. DOI: 10.1177/2050640617708953.
[16] ROSSEN N G, 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]. J Crohns Colitis, 2015, 9(4): 342-348. DOI: 10.1093/ecco-jcc/jju023.
[17] QIN N, YANG F, LI A, et al. Alterations of the human gut microbiome in liver cirrhosis [J]. Nature, 2014, 513(7516): 59-64. DOI: 10.1038/nature13568.
[18] BAJAJ J S, HEUMAN D M, HYLEMON P B, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications [J]. J Hepatol, 2014, 60(5): 940-947. DOI: 10.1016/j.jhep.2013.12.019.
[19] BAJAJ J S, BETRAPALLY N S, HYLEMON P B, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy [J]. Hepatology, 2015, 62(4): 1260-1271. DOI: 10.1002/hep.27819.
[20] FUKUI H. Gut microbiome-based therapeutics in liver cirrhosis: basic consideration for the next step [J]. J Clin Transl Hepatol, 2017, 5(3): 249-260. DOI: 10.14218/JCTH.2017.00008.
[21] CHEN Y, JI F, GUO J, et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology [J]. Sci Rep, 2016, 6: 34055. DOI: 10.1038/srep34055.
[22] ARAB J P, MARTIN-MATEOS R M, SHAH V H. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg [J]. Hepatol Int, 2018, 12(Suppl 1): 24-33. DOI: 10.1007/s12072-017-9798-x.
[23] OIKONOMOU T, PAPATHEODORIDIS G V, SAMARKOSM, et al. Clinical impact of microbiome in patients with decompensated cirrhosis [J]. World J Gastroenterol, 2018 , 24(34): 3813-3820. DOI: 10.3748/wjg.v24.i34.3813.
[24] WOODHOUSE C A, PATEL V C, SINGANAYAGAM A, et al. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease [J]. Aliment Pharmacol Ther, 2018, 47(2): 192-202. DOI: 10.1111/apt.14397.
[25] DE LORENZO-PINTO A, GARCíA-SáNCHEZ R, LORENZO-SALINAS A. Lactulose enemas in the treatment of hepatic encephalopathy. Do we help or harm?[J]. Rev Esp Enferm Dig, 2017, 109(10): 736-737. DOI: 10.17235/reed.2017.5106/2017.
[26] GLUUD L L,VILSTRUP H, MORGAN M Y. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis [J]. Cochrane Database Syst Rev, 2016, (5): CD003044. DOI: 10.1002/14651858.CD003044.pub4.
[27] LOWE P P, GYONGYOSI B, SATISHCHANDRAN A, et al. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice [J]. PLoS One, 2017, 12(3): e0174544. DOI: 10.1371/journal.pone.0174544.
[28] BAJAJ J S. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis [J]. Aliment Pharmacol Ther, 2016, 43 Suppl 1: 11-26. DOI: 10.1111/apt.13435.
[29] KAJI K,TAKAYA H, SAIKAWA S, et al. Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity [J]. World J Gastroenterol, 2017, 23(47): 8355-8366. DOI: 10.3748/wjg.v23.i47.8355.
[30] HONG M, HAN D H, HONG J. Are probiotics effective in targeting alcoholic liver diseases [J]. Probiotics Antimicrob Proteins, 2018, 23. DOI: 10.1007/s12602-018-9419-6
[31] ELZOUKI A N. Probiotics and liver disease: where are we now and where are we going?[J]. J Clin Gastroenterol, 2016, 50 Suppl 2: 188-190.
[32] ZHAO L N, YU T, LAN S Y, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy: an update meta-analysis [J]. Clin Res Hepatol Gastroenterol, 2015, 39(6): 674-682. DOI: 10.1016/j.clinre.2015.03.008.
[33] V?H?MIKO S, LAIHO A, LUND R, et al. The impact of probiotic supplementation during pregnancy on DNA methylation of obesity-related genes in mothers and their children [J]. Eur J Nutr, 2018. DOI: 10.1007/s00394-017-1601-1.
[34] LIU J P, ZOU W L, CHEN S J, et al. Effects of different diets on intestinal microbiota and nonalcoholic fatty liver disease development [J]. World J Gastroenterol, 2016, 22(32): 7353-7364. DOI: 10.3748/wjg.v22.i32.7353.
[35] ANANIA C, PERLA F M, OLIVERO F, et al. Mediterranean diet and nonalcoholic fatty liver disease [J]. World J Gastroenterol, 2018, 24(19): 2083-2094. DOI: 10.3748/wjg.v24.i19.2083.
[36] JEGATHEESAN P, DE BANDT J P. Fructose and NAFLD: the multifaceted aspects of fructose metabolism [J]. Nutrients, 2017, 9(3). pii: E230. DOI: 10.3390/nu9030230.
[37] MCDONALD L C, GERDING D N, JOHNSON S, et al. Clinical practice guidelines for clostridium difficile infection in adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) [J]. Clin Infect Dis, 2018, 66(7): 987-994. DOI: 10.1093/cid/ciy149.
[38] BAJAJ J S, KASSAM Z, FAGAN A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial [J]. Hepatology, 2017, 66(6): 1727-1738. DOI: 10.1002/hep.29306.
[39] FERNáNDEZ J, TANDON P, MENSA J, et al. Antibiotic prophylaxis in cirrhosis: good and bad [J]. Hepatology, 2016 , 63(6): 2019-2031. DOI: 10.1002/hep.28330.
[40] BAJAJ J S, MOREAU R, KAMATH P S, et al. Acute-on-chronic liver failure: getting ready for prime time [J]. Hepatology, 2018, 68(4): 1621-1632. DOI: 10.1002/hep.30056.
[41] VAUGHN B P, RANK K M, KHORUTS A. Fecal microbiota transplantation: current status in treatment of GI and liver disease [J]. Clin Gastroenterol Hepatol, 2019, 17(2): 353-361. DOI: 10.1016/j.cgh.2018.07.026.
[2] SCHWENGER K J P, CHEN L, CHELLIAH A, et al. Markers of activated inflammatory cells are associated with disease severity and intestinal microbiota in adults with nonalcoholic fatty liver disease [J]. Int J Mol Med, 2018, 42(4): 2229-2237. DOI: 10.3892/ijmm.2018.3800.
[3] ZHOU Y, ZHENG T, CHEN H, et al. Microbial intervention as a novel target in treatment of non-alcoholic fatty liver disease progression [J]. Cell Physiol Biochem, 2018, 51(5): 2123-2135. DOI: 10.1159/000495830.
[4] GHOLIZADEH P, MAHALLEI M, PORMOHAMMAD A, et al. Microbial balance in the intestinal microbiota and its association with diabetes, obesity and allergic disease [J]. Microb Pathog, 2018, 127: 48-55. DOI: 10.1016/j.micpath.2018.11.031.
[5] FENG Q, LIU W, BAKER S S, et al. Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of non-alcoholic fatty liver disease [J]. Oncotarget, 2017, 8(17): 27820-27838. DOI: 10.18632/oncotarget.15482.
[6] ENGSTLER A J, AUMILLER T, DEGEN C, et al. Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease [J]. Gut, 2016, 65(9): 1564-1571. DOI: 10.1136/gutjnl-2014-308379.
[7] DE MEDEIROS I C, DE LIMA J G. Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease-a mechanistic hypothesis [J]. Med Hypotheses, 2015, 85(2): 148-152. DOI: 10.1016/j.mehy.2015.04.021.
[8] LLOPIS M, CASSARD A M, WRZOSEK L, et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease [J]. Gut, 2016, 65(5): 830-839. DOI: 10.1136/gutjnl-2015-310585.
[9] FERRERE G, WRZOSEK L, CAILLEUX F, et al. Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice [J]. J Hepatol, 2017, 66(4): 806-815. DOI: 10.1016/j.jhep.2016.11.008.
[10] LOWE P P, GYONGYOSI B, SATISHCHANDRAN A, et al. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice [J]. PLoS One, 2017, 12(3): e0174544. DOI: 10.1371/journal.pone.0174544.
[11] HARTMANN P, HOCHRATH K, HORVATH A, et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice [J]. Hepatology, 2018, 67(6): 2150-2166.DOI: 10.1002/hep.29676.
[12] YANG A M, INAMINE T, HOCHRATH K, et al. Intestinal fungi contribute to development of alcoholic liver disease [J]. J Clin Invest, 2017, 127(7): 2829-2841. DOI: 10.1172/JCI90562.
[13] SABINO J, VIEIRA-SILVA S, MACHIELS K, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD [J]. Gut, 2016, 65(10): 1681-1689. DOI: 10.1136/gutjnl-2015-311004.
[14] KUMMEN M, HOLM K, ANMARKRUD J A, 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 [J]. Gut, 2017, 66(4): 611-619. DOI: 10.1136/gutjnl-2015-310500.
[15] TORRES J, PALMELA C, BRITO H, et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease [J]. United European Gastroenterol J, 2018, 6(1): 112-122. DOI: 10.1177/2050640617708953.
[16] ROSSEN N G, 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]. J Crohns Colitis, 2015, 9(4): 342-348. DOI: 10.1093/ecco-jcc/jju023.
[17] QIN N, YANG F, LI A, et al. Alterations of the human gut microbiome in liver cirrhosis [J]. Nature, 2014, 513(7516): 59-64. DOI: 10.1038/nature13568.
[18] BAJAJ J S, HEUMAN D M, HYLEMON P B, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications [J]. J Hepatol, 2014, 60(5): 940-947. DOI: 10.1016/j.jhep.2013.12.019.
[19] BAJAJ J S, BETRAPALLY N S, HYLEMON P B, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy [J]. Hepatology, 2015, 62(4): 1260-1271. DOI: 10.1002/hep.27819.
[20] FUKUI H. Gut microbiome-based therapeutics in liver cirrhosis: basic consideration for the next step [J]. J Clin Transl Hepatol, 2017, 5(3): 249-260. DOI: 10.14218/JCTH.2017.00008.
[21] CHEN Y, JI F, GUO J, et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology [J]. Sci Rep, 2016, 6: 34055. DOI: 10.1038/srep34055.
[22] ARAB J P, MARTIN-MATEOS R M, SHAH V H. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg [J]. Hepatol Int, 2018, 12(Suppl 1): 24-33. DOI: 10.1007/s12072-017-9798-x.
[23] OIKONOMOU T, PAPATHEODORIDIS G V, SAMARKOSM, et al. Clinical impact of microbiome in patients with decompensated cirrhosis [J]. World J Gastroenterol, 2018 , 24(34): 3813-3820. DOI: 10.3748/wjg.v24.i34.3813.
[24] WOODHOUSE C A, PATEL V C, SINGANAYAGAM A, et al. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease [J]. Aliment Pharmacol Ther, 2018, 47(2): 192-202. DOI: 10.1111/apt.14397.
[25] DE LORENZO-PINTO A, GARCíA-SáNCHEZ R, LORENZO-SALINAS A. Lactulose enemas in the treatment of hepatic encephalopathy. Do we help or harm?[J]. Rev Esp Enferm Dig, 2017, 109(10): 736-737. DOI: 10.17235/reed.2017.5106/2017.
[26] GLUUD L L,VILSTRUP H, MORGAN M Y. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis [J]. Cochrane Database Syst Rev, 2016, (5): CD003044. DOI: 10.1002/14651858.CD003044.pub4.
[27] LOWE P P, GYONGYOSI B, SATISHCHANDRAN A, et al. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice [J]. PLoS One, 2017, 12(3): e0174544. DOI: 10.1371/journal.pone.0174544.
[28] BAJAJ J S. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis [J]. Aliment Pharmacol Ther, 2016, 43 Suppl 1: 11-26. DOI: 10.1111/apt.13435.
[29] KAJI K,TAKAYA H, SAIKAWA S, et al. Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity [J]. World J Gastroenterol, 2017, 23(47): 8355-8366. DOI: 10.3748/wjg.v23.i47.8355.
[30] HONG M, HAN D H, HONG J. Are probiotics effective in targeting alcoholic liver diseases [J]. Probiotics Antimicrob Proteins, 2018, 23. DOI: 10.1007/s12602-018-9419-6
[31] ELZOUKI A N. Probiotics and liver disease: where are we now and where are we going?[J]. J Clin Gastroenterol, 2016, 50 Suppl 2: 188-190.
[32] ZHAO L N, YU T, LAN S Y, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy: an update meta-analysis [J]. Clin Res Hepatol Gastroenterol, 2015, 39(6): 674-682. DOI: 10.1016/j.clinre.2015.03.008.
[33] V?H?MIKO S, LAIHO A, LUND R, et al. The impact of probiotic supplementation during pregnancy on DNA methylation of obesity-related genes in mothers and their children [J]. Eur J Nutr, 2018. DOI: 10.1007/s00394-017-1601-1.
[34] LIU J P, ZOU W L, CHEN S J, et al. Effects of different diets on intestinal microbiota and nonalcoholic fatty liver disease development [J]. World J Gastroenterol, 2016, 22(32): 7353-7364. DOI: 10.3748/wjg.v22.i32.7353.
[35] ANANIA C, PERLA F M, OLIVERO F, et al. Mediterranean diet and nonalcoholic fatty liver disease [J]. World J Gastroenterol, 2018, 24(19): 2083-2094. DOI: 10.3748/wjg.v24.i19.2083.
[36] JEGATHEESAN P, DE BANDT J P. Fructose and NAFLD: the multifaceted aspects of fructose metabolism [J]. Nutrients, 2017, 9(3). pii: E230. DOI: 10.3390/nu9030230.
[37] MCDONALD L C, GERDING D N, JOHNSON S, et al. Clinical practice guidelines for clostridium difficile infection in adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) [J]. Clin Infect Dis, 2018, 66(7): 987-994. DOI: 10.1093/cid/ciy149.
[38] BAJAJ J S, KASSAM Z, FAGAN A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial [J]. Hepatology, 2017, 66(6): 1727-1738. DOI: 10.1002/hep.29306.
[39] FERNáNDEZ J, TANDON P, MENSA J, et al. Antibiotic prophylaxis in cirrhosis: good and bad [J]. Hepatology, 2016 , 63(6): 2019-2031. DOI: 10.1002/hep.28330.
[40] BAJAJ J S, MOREAU R, KAMATH P S, et al. Acute-on-chronic liver failure: getting ready for prime time [J]. Hepatology, 2018, 68(4): 1621-1632. DOI: 10.1002/hep.30056.
[41] VAUGHN B P, RANK K M, KHORUTS A. Fecal microbiota transplantation: current status in treatment of GI and liver disease [J]. Clin Gastroenterol Hepatol, 2019, 17(2): 353-361. DOI: 10.1016/j.cgh.2018.07.026.