Gut microbiome-based therapeutics in liver cirrhosis: Basic consideration for the next step

Journal of Clinical and Translational Hepatology

Volumn 5, Issue 3, 2017, Pages 249-260

  Fukui, Hiroshi ^a  

^a NARA MEDICAL UNIVERSITY   (Japan)

Author keywords

Dysbiosis; Endotoxemia; Liver cirrhosis; Therapeutics

Indexed keywords

EID: 85046667207     PISSN: 22250719     EISSN: 23108819     Source Type: Journal    
DOI: 10.14218/JCTH.2017.00008     Document Type: Review

References (118)

1. Fukui H, Saito H, Ueno Y, Uto H, Obara K, Sakaida I, et al. Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol 2016;51: 629–650. doi: 10.1007/s00535-016-1216-y.
2. Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139: 1246–1256, 1256.e1–5. doi: 10.1053/j.gastro.2010.06.019.
3. Fukui H. Gut microbiota and host reaction in liver diseases. Microorganisms 2015;3:759–791. doi: 10.3390/microorganisms3040759.
4. Fukui H, Wiest R. Changes of intestinal functions in liver cirrhosis. Inflamm Intest Dis 2016;1:24–40. doi: 10.1159/000444436.
5. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011;54: 562–572. doi: 10.1002/hep.24423.
6. Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59–64. doi: 10. 1038/nature13568.
7. 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 2011;61:693–703. doi: 10.1007/s00248-010-9801-8.
8. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:16731–16736. doi: 10.1073/pnas.0804812105.
9. Xu M, Wang B, Fu Y, Chen Y, Yang F, Lu H, et al. Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease. Microb Ecol 2012;63:304–313. doi: 10.1007/s00248-011-9925-5.
10. Wu ZW, Lu HF, Wu J, Zuo J, Chen P, Sheng JF, et al. 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;63:929–937. doi: 10.1007/s00248-011-9945-1.
11. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302:G168–G175. doi: 10.1152/ajpgi.00190.2011.
12. Wang HB, Wang PY, Wang X, Wan YL, Liu YC. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin1 transcription. Dig Dis Sci 2012;57:3126–3135. doi: 10.1007/s10620012-2259-4.
13. Willemsen LE, Koetsier MA, van Deventer SJ, van Tol EA. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut 2003;52:1442–1447.
14. Usami M, Miyoshi M, Yamashita H. Gut microbiota and host metabolism in liver cirrhosis. World J Gastroenterol 2015;21:11597–11608. doi: 10. 3748/wjg.v21.i41.11597.
15. Corrêa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MA. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunology 2016;5:e73. doi: 10.1038/cti.2016.17.
16. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients 2011;3:858–876. doi: 10.3390/nu3100858.
17. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014;60:940–947. doi: 10.1016/j.jhep.2013.12. 019.
18. Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012;303:G675–G685. doi: 10.1152/ajpgi.00152.2012.
19. Chen Y, Ji F, Guo J, Shi D, Fang D, Li L. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci Rep 2016;6: 34055. doi: 10.1038/srep34055.
20. Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 2015;62:1260–1271. doi: 10.1002/hep.27819.
21. Betrapally NS, Gillevet PM, Bajaj JS. Gut microbiome and liver disease. Transl Res 2017;179:49–59. doi: 10.1016/j.trsl.2016.07.005.
22. Kakiyama G, Pandak WM, Gillevet PM, Hylemon PB, Heuman DM, Daita K, et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 2013;58:949–955. doi: 10.1016/j.jhep.2013.01.003.
23. Kurdi P, Kawanishi K, Mizutani K, Yokota A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J Bacteriol 2006;188: 1979–1986. doi: 10.1128/JB.188.5.1979-1986.2006.
24. Stenman LK, Holma R, Eggert A, Korpela R. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol 2013;304:G227–G234. doi: 10.1152/ajpgi.00267.2012.
25. Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011;141:1773–1781. doi: 10.1053/j.gastro.2011.07. 046.
26. Bajaj JS. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment Pharmacol Ther 2016;43 Suppl 1:11–26. doi: 10.1111/apt. 13435.
27. Bellot P, Francés R, Such J. Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int 2013;33: 31–39. doi: 10.1111/liv.12021.
28. Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013;4: 382–387. doi: 10.4161/gmic.25723.
29. Chen Y, Qin N, Guo J, Qian G, Fang D, Shi D, et al. Functional gene arraysbased analysis of fecal microbiomes in patients with liver cirrhosis. BMC Genomics 2014;15:753. doi: 10.1186/1471-2164-15-753.
30. Wei X, Jiang S, Chen Y, Zhao X, Li H, Lin W, et al. Cirrhosis related functionality characteristic of the fecal microbiota as revealed by a metaproteomic approach. BMC Gastroenterol 2016;16:121. doi: 10.1186/s12876-0160534-0.
31. Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis. World J Gastroenterol 2014;20:14686–14695. doi: 10.3748/wjg.v20.i40.14686.
32. Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 2000;32:742–747. doi: 10.1016/S0168-8278(00)80242-1.
33. Campillo B, Pernet P, Bories PN, Richardet JP, Devanlay M, Aussel C. Intestinal permeability in liver cirrhosis: relationship with severe septic complications. Eur J Gastroenterol Hepatol 1999;11:755–759. doi: 10.1097/00042737-199907000-00013.
34. Pascual S, Such J, Esteban A, Zapater P, Casellas JA, Aparicio JR, et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology 2003;50:1482–1486.
35. Scarpellini E, Valenza V, Gabrielli M, Lauritano EC, Perotti G, Merra G, et al. Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed? Am J Gastroenterol 2010;105: 323–327. doi: 10.1038/ajg.2009.558.
36. Kim BI, Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, et al. Increased intestinal permeability as a predictor of bacterial infections in patients with decompensated liver cirrhosis and hemorrhage. J Gastroenterol Hepatol 2011;26: 550–557. doi: 10.1111/j.1440-1746.2010.06490.x.
37. Assimakopoulos SF, Tsamandas AC, Tsiaoussis GI, Karatza E, Triantos C, Vagianos CE, et al. Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability. Eur J Clin Invest 2012;42:439–446. doi: 10.1111/j.1365-2362. 2011.02609.x.
38. Pinzone MR, Celesia BM, Di Rosa M, Cacopardo B, Nunnari G. Microbial translocation in chronic liver diseases. Int J Microbiol 2012;2012:694629. doi: 10.1155/2012/694629.
39. Pijls KE, Jonkers DM, Elamin EE, Masclee AA, Koek GH. Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature. Liver Int 2013;33:1457–1469. doi: 10.1111/liv.12271.
40. Fukui H, Tsujita S, Matsumoto M, Kitano H, Hoppou K, Morimura M, et al. Endotoxemia in chronic hepatitis and cirrhosis: Epiphenomenon or of pathological relevence? In: Blum H, Bode C, Bode JC, Sartor RB, eds. Gut and the Liver. Dordrecht, Boston, London: Kluwer Academic Publishers; 1998, p. 251–262.
41. Lin RS, Lee FY, Lee SD, Tsai YT, Lin HC, Lu RH, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol 1995;22: 165–172. doi: 10.1016/0168-8278(95)80424-2.
42. Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 1988;8:232–236. doi: 10.1002/hep. 1840080207.
43. Tachiyama G, Sakon M, Kambayashi J, Iijima S, Tsujinaka T, Mori T. Endogenous endotoxemia in patients with liver cirrhosis–a quantitative analysis of endotoxin in portal and peripheral blood. Jpn J Surg 1988;18:403–408. doi: 10.1007/BF02471464.
44. Francés R, González-Navajas JM, Zapater P, Muñoz C, Caño R, Pascual S, et al. Translocation of bacterial DNA from Gram-positive microorganisms is associated with a species-specific inflammatory response in serum and ascitic fluid of patients with cirrhosis. Clin Exp Immunol 2007;150: 230–237. doi: 10.1111/j.1365-2249.2007.03494.x.
45. González-Navajas JM, Bellot P, Francés R, Zapater P, Muñoz C, García-Pagán JC, et al. Presence of bacterial-DNA in cirrhosis identifies a subgroup of patients with marked inflammatory response not related to endotoxin. J Hepatol 2008;48:61–67. doi: 10.1016/j.jhep.2007.08.012.
46. Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, et al. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence-and pH-dependent manner. Eur J Immunol 2004;34:2541–2550. doi: 10.1002/eji.200425218.
47. Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012;590:447–458. doi: 10.1113/jphysiol.2011.219691.
48. Attar BM, George M, Ion-Nedelcu N, Ramadori G, Thiel DH. Disease dependent qualitative and quantitative differences in the inflammatory response to ascites occurring in cirrhotics. World J Hepatol 2014;6:85–91. doi: 10.4254/wjh.v6.i2.85.
49. Soares JB, Pimentel-Nunes P, Afonso L, Rolanda C, Lopes P, Roncon-Albuquerque R Jr, et al. Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence. Innate Immun 2012; 18:700–708. doi: 10.1177/1753425912436762.
50. Manigold T, Böcker U, Hanck C, Gundt J, Traber P, Antoni C, et al. Differential expression of toll-like receptors 2 and 4 in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2003;15:275–282. doi: 10.1097/01.meg. 0000050010.68425.cb.
51. Riordan SM, Skinner N, Nagree A, McCallum H, McIver CJ, Kurtovic J, et al. Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology 2003;37:1154–1164. doi: 10.1053/jhep.2003.50180.
52. Tazi KA, Quioc JJ, Saada V, Bezeaud A, Lebrec D, Moreau R. Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J Hepatol 2006;45: 280–289. doi: 10.1016/j.jhep.2006.02.013.
53. González-Navajas JM. Inflammasome activation in decompensated liver cirrhosis. World J Hepatol 2016;8:207–210. doi: 10.4254/wjh.v8.i4.207.
54. Ahluwalia V, Betrapally NS, Hylemon PB, White MB, Gillevet PM, Unser AB, et al. Impaired gut-liver-brain axis in patients with cirrhosis. Sci Rep 2016; 6:26800. doi: 10.1038/srep26800.
55. Butterworth RF. Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology 2011;53:1372–1376. doi: 10.1002/hep.24228.
56. Jain L, Sharma BC, Srivastava S, Puri SK, Sharma P, Sarin S. Serum endotoxin, inflammatory mediators, and magnetic resonance spectroscopy before and after treatment in patients with minimal hepatic encephalopathy. J Gastroenterol Hepatol 2013;28:1187–1193. doi: 10.1111/jgh. 12160.
57. Luo M, Guo JY, Cao WK. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis. World J Gastroenterol 2015; 21:11815–11824. doi: 10.3748/wjg.v21.i41.11815.
58. Jayakumar AR, Rama Rao KV, Norenberg MD. Neuroinflammation in hepatic encephalopathy: mechanistic aspects. J Clin Exp Hepatol 2015;5:S21–S28. doi: 10.1016/j.jceh.2014.07.006.
59. Gupta A, Dhiman RK, Kumari S, Rana S, Agarwal R, Duseja A, et al. Roleof small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol 2010;53:849–855. doi: 10.1016/j.jhep.2010.05.017.
60. Van Thiel DH, Fagiuoli S, Wright HI, Chien MC, Gavaler JS. Gastrointestinal transit in cirrhotic patients: effect of hepatic encephalopathy and its treatment. Hepatology 1994;19:67–71.
61. Moratalla A, Ampuero J, Bellot P, Gallego-Durán R, Zapater P, Roger M, et al. Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy. Liver Int 2017;37:212–223. doi: 10.1111/liv.13200.
62. Gómez-Hurtado I, Such J, Sanz Y, Francés R. Gut microbiota-related complications in cirrhosis. World J Gastroenterol 2014;20:15624–15631. doi: 10.3748/wjg.v20.i42.15624.
63. Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441–1449. doi: 10.1002/hep.20194.
64. Campillo B, Richardet JP, Kheo T, Dupeyron C. Nosocomial spontaneous bacterial peritonitis and bacteremia in cirrhotic patients: impact of isolate type on prognosis and characteristics of infection. Clin Infect Dis 2002;35: 1–10. doi: 10.1086/340617.
65. Chang CS, Chen GH, Lien HC, Yeh HZ. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1998;28:1187–1190. doi: 10.1002/hep.510280504.
66. Such J, Francés R, Muñoz C, Zapater P, Casellas JA, Cifuentes A, et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 2002;36:135–141. doi: 10.1053/jhep.2002.33715.
67. Bellot P, García-Pagán JC, Francés R, Abraldes JG, Navasa M, Pérez-Mateo M, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010;52:2044–2052. doi: 10.1002/hep.23918.
68. Aldersley MA, Howdle PD. Intestinal permeability and liver disease. Eur J Gastroenterol Hepatol 1999;11:401–403. doi: 10.1097/00042737199904000-00007.
69. Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut 2005;54:556–563. doi: 10.1136/gut.2004.048181.
70. Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Fotopoulos A, Xourgia X, et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin Gastroenterol Hepatol 2012; 10:815–818. doi: 10.1016/j.cgh.2012.02.025.
71. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, Puri P, Sterling RK, et al. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 2014;39:1113–1125. doi: 10.1111/apt.12695.
72. Rincón D, Vaquero J, Hernando A, Galindo E, Ripoll C, Puerto M, et al. Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites. Liver Int 2014;34:1504–1512. doi: 10.1111/liv. 12539.
73. Rasaratnam B, Connelly N, Chin-Dusting J. Nitric oxide and the hyperdynamic circulation in cirrhosis: is there a role for selective intestinal decontamination? Clin Sci (Lond) 2004;107:425–434. doi: 10.1042/CS20040157.
74. Trebicka J, Krag A, Gansweid S, Appenrodt B, Schiedermaier P, Sauerbruch T, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. Eur J Gastroenterol Hepatol 2011;23:1218–1225. doi: 10.1097/MEG.0b013e32834a75dc.
75. Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004;39:746–753. doi: 10. 1002/hep.20126.
76. Lo RS, Austin AS, Freeman JG. Is there a role for probiotics in liver disease? Scientific World Journal 2014;2014:874768. doi: 10.1155/2014/874768.
77. Pannen BH, Bauer M, Zhang JX, Robotham JL, Clemens MG. Endotoxin pretreatment enhances portal venous contractile response to endothelin-1. Am J Physiol 1996;270:H7–H15.
78. Xu J, Cao H, Liu H, Wu ZY. Role of nitric oxide synthase and cyclooxygenase in hyperdynamic splanchnic circulation of portal hypertension. Hepatobiliary Pancreat Dis Int 2008;7:503–508.
79. Dong T, Aronsohn A, Gautham Reddy K, Te HS. Rifaximin decreases the incidence and severity of acute kidney injury and hepatorenal syndrome in cirrhosis. Dig Dis Sci 2016;61:3621–3626. doi: 10.1007/s10620-0164313-0.
80. Meng J, Wang Q, Liu K, Yang S, Fan X, Liu B, et al. Systemic and splanchnic lipopolysaccharide and endothelin-1 plasma levels in liver cirrhosis before and after transjugular intrahepatic portosystemic shunt. Gastroenterol Res Pract 2016;2016:8341030. doi: 10.1155/2016/8341030.
81. Aguirre Valadez JM, Rivera-Espinosa L, Méndez-Guerrero O, ChávezPacheco JL, García Juárez I, Torre A. Intestinal permeability in a patient with liver cirrhosis. Ther Clin Risk Manag 2016;12:1729–1748. doi: 10. 2147/TCRM.S115902.
82. Fukui H, Matsumoto M, Tsujita S, Takaya A, Kojima H, Matsumura M, et al. Plasma endotoxin concentration and endotoxin binding capacity of plasma acute phase proteins in cirrhotics with variceal bleeding: an analysis by new methods. J Gastroenterol Hepatol 1994;9:582–586. doi: 10.1111/j.14401746.1994.tb01565.x.
83. Bernard B, Grangé JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999;29: 1655–1661. doi: 10.1002/hep.510290608.
84. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318. doi: 10.1136/gut.2006.107789.
85. Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015;62:968–974. doi: 10.1016/j.jhep.2014.12.029.
86. Clemente C, Bosch J, Rodés J, Arroyo V, Mas A, Maragall S. Functional renal failure and haemorrhagic gastritis associated with endotoxaemia in cirrhosis. Gut 1977;18:556–560. doi: 10.1136/gut.18.7.556.
87. Wilkinson SP, Moodie H, Stamatakis JD, Kakkar VV, Williams R. Endotoxaemia and renal failure in cirrhosis and obstructive jaundice. Br Med J 1976;2: 1415–1418. doi: 10.1136/bmj.2.6049.1415.
88. Fukui H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J Hepatol 2015;7:425–442. doi: 10.4254/wjh.v7.i3. 425.
89. Barreto R, Fagundes C, Guevara M, Solà E, Pereira G, Rodríguez E, et al. Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival. Hepatology 2014;59:1505–1513. doi: 10.1002/hep.26687.
90. El-Naggar MM, Khalil el-SA, El-Daker MA, Salama MF. Bacterial DNA and its consequences in patients with cirrhosis and culture-negative, non-neutrocytic ascites. J Med Microbiol 2008;57:1533–1538. doi: 10.1099/jmm. 0.2008/001867-0.
91. Sharma BC, Singh J. Probiotics in management of hepatic encephalopathy. Metab Brain Dis 2016;31:1295–1301. doi: 10.1007/s11011-016-9826-x.
92. Shukla S, Shukla A, Mehboob S, Guha S. Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy. Aliment Pharmacol Ther 2011;33:662–671. doi: 10.1111/j.1365-2036.2010.04574.x.
93. Holte K, Krag A, Gluud LL. Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy. Hepatol Res 2012;42: 1008–1015. doi: 10.1111/j.1872-034X.2012.01015.x.
94. Xu J, Ma R, Chen LF, Zhao LJ, Chen K, Zhang RB. Effects of probiotic therapy on hepatic encephalopathy in patients with liver cirrhosis: an updated metaanalysis of six randomized controlled trials. Hepatobiliary Pancreat Dis Int 2014;13:354–360. doi: 10.1016/S1499-3872(14)60280-0.
95. McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev 2011; (11):CD008716. doi: 10.1002/14651858.CD008716.pub2.
96. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012;107: 1043–1050. doi: 10.1038/ajg.2012.113.
97. Lunia MK, Sharma BC, Sharma P, Sachdeva S, Srivastava S. Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 2014;12:1003–1008.e1. doi: 10.1016/j.cgh.2013.11.006.
98. Lebeer S, De Keersmaecker SC, Verhoeven TL, Fadda AA, Marchal K, Vanderleyden J. Functional analysis of luxS in the probiotic strain Lactobacillus rhamnosus GG reveals a central metabolic role important for growth and biofilm formation. J Bacteriol 2007;189:860–871. doi: 10.1128/JB.01394-06.
99. Dhiman RK, Rana B, Agrawal S, Garg A, Chopra M, Thumburu KK, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 2014;147:1327–1337.e3. doi: 10.1053/j.gastro.2014.08.031.
100. Malaguarnera G, Giordano M, Nunnari G, Bertino G, Malaguarnera M. Gut microbiota in alcoholic liver disease: pathogenetic role and therapeutic perspectives. World J Gastroenterol 2014;20:16639–16648. doi: 10. 3748/wjg.v20.i44.16639.
101. Riggio O, Varriale M, Testore GP, Di Rosa R, Di Rosa E, Merli M, et al. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol 1990;12:433–436. doi: 10.1097/00004836199008000-00016.
102. Chen C, Li L, Wu Z, Chen H, Fu S. Effects of lactitol on intestinal microflora and plasma endotoxin in patients with chronic viral hepatitis. J Infect 2007; 54:98–102. doi: 10.1016/j.jinf.2005.11.013.
103. Bakker-Zierikzee AM, Alles MS, Knol J, Kok FJ, Tolboom JJ, Bindels JG. Effects of infant formula containing a mixture of galacto-and fructooligosaccharides or viable Bifidobacterium animalis on the intestinal microflora during the first 4 months of life. Br J Nutr 2005;94:783–790. doi: 10. 1079/BJN20051451.
104. Malaguarnera M, Greco F, Barone G, Gargante MP, Malaguarnera M, Toscano MA. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebocontrolled study. Dig Dis Sci 2007;52:3259–3265. doi: 10.1007/s10620006-9687-y.
105. Malaguarnera M, Gargante MP, Malaguarnera G, Salmeri M, Mastrojeni S, Rampello L, et al. Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol 2010;22:199–206. doi: 10.1097/MEG. 0b013e328330a8d3.
106. Ginés P, Rimola A, Planas R, Vargas V, Marco F, Almela M, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990;12:716–724. doi: 10.1002/hep.1840120416.
107. Novella M, Solà R, Soriano G, Andreu M, Gana J, Ortiz J, et al. Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin. Hepatology 1997;25:532–536. doi: 10. 1002/hep.510250306.
108. Fernández J, Navasa M, Gómez J, Colmenero J, Vila J, Arroyo V, et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002;35:140–148. doi: 10. 1053/jhep.2002.30082.
109. Campillo B, Dupeyron C, Richardet JP. Epidemiology of hospital-acquired infections in cirrhotic patients: effect of carriage of methicillin-resistant Staphylococcus aureus and influence of previous antibiotic therapy and norfloxacin prophylaxis. Epidemiol Infect 2001;127:443–450. doi: 10. 1017/S0950268801006288.
110. Debbia EA, Maioli E, Roveta S, Marchese A. Effects of rifaximin on bacterial virulence mechanisms at supra-and sub-inhibitory concentrations. J Chemother 2008;20:186–194. doi: 10.1179/joc.2008.20.2.186.
111. Vlachogiannakos J, Saveriadis AS, Viazis N, Theodoropoulos I, Foudoulis K, Manolakopoulos S, et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther 2009;29:992–999. doi: 10.1111/j.1365-2036. 2009.03958.x.
112. Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis I, Karamanolis DG, Ladas SD. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 2013;28:450–455. doi: 10.1111/jgh.12070.
113. Kalambokis GN, Mouzaki A, Rodi M, Tsianos EV. Rifaximin for the prevention of spontaneous bacterial peritonitis. World J Gastroenterol 2012;18: 1700–1702. doi: 10.3748/wjg.v18.i14.1700.
114. Kalambokis GN, Mouzaki A, Rodi M, Tsianos EV. Rifaximin improves thrombocytopenia in patients with alcoholic cirrhosis in association with reduction of endotoxaemia. Liver Int 2012;32:467–475. doi: 10.1111/j.1478-3231. 2011.02650.x.
115. Danulescu RM, Ciobica A, Stanciu C, Trifan A. The role of rifaximine in the prevention of the spontaneous bacterial peritonitis. Rev Med Chir Soc Med Nat Iasi 2013;117:315–320.
116. Bajaj JS, Heuman DM, Sanyal AJ, Hylemon PB, Sterling RK, Stravitz RT, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One 2013;8:e60042. doi: 10. 1371/journal.pone.0060042.
117. Ahluwalia V, Wade JB, Heuman DM, Hammeke TA, Sanyal AJ, Sterling RK, et al. Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: implications for the gut-liver-brain axis. Metab Brain Dis 2014;29: 1017–1025. doi: 10.1007/s11011-014-9507-6.
118. DuPont HL. Therapeutic effects and mechanisms of action of rifaximin in gastrointestinal diseases. Mayo Clin Proc 2015;90:1116–1124. doi: 10. 1016/j.mayocp.2015.04.016.