Clinical and pathophysiological consequences of alterations in the microbiome in cirrhosis

American Journal of Gastroenterology

Volumn 110, Issue 10, 2015, Pages 1399-1410

  Macnaughtan, Jane ^a   Jalan, Rajiv ^b  

^a ROYAL FREE AND UNIVERSITY COLLEGE MEDICAL SCHOOL   (United Kingdom)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

BIODIVERSITY; COMPLICATION; DYSBIOSIS; GENETIC VARIABILITY; GENETICS; HUMAN; INTESTINE FLORA; LIVER CIRRHOSIS; METAGENOMICS; MICROBIOLOGY; PATHOPHYSIOLOGY; PHYLOGENY; PHYSIOLOGY;

BIODIVERSITY; DYSBIOSIS; GASTROINTESTINAL MICROBIOME; GENETIC VARIATION; HUMANS; LIVER CIRRHOSIS; METAGENOMICS; PHYLOGENY;

EID: 85027938997     PISSN: 00029270     EISSN: 15720241     Source Type: Journal    
DOI: 10.1038/ajg.2015.313     Document Type: Article

References (125)

1. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int 2006;26:1175-86.
2. Riordan SM, Williams R. The intestinal flora and bacterial infection in cirrhosis. J Hepatol 2006;45:744-57.
3. Fernández J, Navasa M, Planas R et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:818-24.
4. Shah N, Dhar D, El Zahraa Mohammed F et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. J Hepatol 2012;56:1047-53.
5. Thalheimer U, Triantos CK, Samonakis DN et al. Infection, coagulation, and variceal bleeding in cirrhosis. Gut 2005;54:556-63.
6. Riordan SM, Williams R. Gut flora and hepatic encephalopathy in patients with cirrhosis. N Engl J Med 2010;362:1140-2.
7. Bajaj JS, Ridlon JM, Hylemon PB et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302:G168-75.
8. Sztrymf B, Libert JM, Mougeot C et al. Cirrhotic rats with bacterial translocation have higher incidence and severity of hepatopulmonary syndrome. J Gastroenterol Hepatol 2005;20:1538-44.
9. Lin CY, Tsai IF, Ho YP et al. Endotoxemia contributes to the immune paralysis in patients with cirrhosis. J Hepatol 2007;46:816-26.
10. Albillos A, Lario M, Alvarez-Mon M et al. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014;61:1385-96.
11. González-Navajas JM, Francés R, Such J. Bacterial DNA in patients with cirrhosis and sterile ascites. Its role as a marker of bacterial translocation and prognostic tool. Rev Esp Enferm Dig 2007;99:599-603.
12. Salaspuro M. Bacteriocolonic pathway for ethanol oxidation: characteristics and implications. Ann Med 1996;28:195-200.
13. Tilg H. Obesity, metabolic syndrome, and microbiota: multiple interactions. J Clin Gastroenterol 2010;44:S16-8.
14. Chu CJ, Lee FY, Wang SS et al. Splanchnic endotoxin levels in cirrhotic rats induced by carbon tetrachloride. Zhonghua Yi Xue Za Zhi (Taipei) 2000;63:196-204.
15. Zhao HY, Wang HJ, Lu Z et al. Intestinal microflora in patients with liver cirrhosis. Chin J Dig Dis 2004;5:64-7.
16. Bajaj JS, Heuman DM, Hylemon PB et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014;60:940-7.
17. Lu H, Wu Z, Xu W et al. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb Ecol 2011;61:693-703.
18. Chen Y, Yang F, Lu H et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011;54:562-72.
19. Qin N, Yang F, Li A. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59-64.
20. Shawcross DL, Davies NA, Williams R et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-54.
21. Shawcross DL, Shabbir SS, Taylor NJ et al. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010;51:1062-9.
22. Wright G, Davies NA, Shawcross DL et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology 2007;45:1517-26.
23. Bajaj JS, Hylemon PB, Ridlon JM 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:G675-85.
24. Bajaj JS, Betrapally NS, Hylemon PB et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology; advance online publication, 29 March 2015; doi: 10.1002/ hep.27819 (e-pub ahead of print).
25. Bajaj JS, Cox IJ, Betrapally NS et al. Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function. Am J Physiol Gastrointest Liver Physiol 2014;307:G951-7.
26. Chen Y, Guo J, Qian G et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol 2015;30:1429-37.
27. Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol 2013;10:522-8.
28. Bajaj JS, Heuman DM, Sanyal AJ et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One 2013;8:e60042.
29. Gunnarsdottir SA, Sadik R, Shev S et al. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol 2003;98:1362-70.
30. Chang CS, Chen GH, Lien HC et al. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1998;28:1187-90.
31. Bode JC, Bode C, Heidelbach R et al. Jejunal microflora in patients with chronic alcohol abuse. Hepatogastroenterology 1984;31:30-4.
32. Kwon JH, Seong-Joon K, Won K et al. Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2014;29:775-81.
33. Deshpande A, Pasupuleti V, Thota P et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: A meta-analysis. J Gastroenterol Hepatol 2013;28:235-42.
34. Terg R, Casciato P, Garbe C et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: A multicenter prospective study. J Hepatol 2015;62:1056-60.
35. Alexopoulou A, Papadopoulos N, Eliopoulos DG et al. Increasing frequency of gram-positive cocci and gram-negative multidrug-resistant bacteria in spontaneous bacterial peritonitis. Liver Int 2013;33:975-81.
36. Bruns T, Peter J, Reuken PA et al. NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis. Liver Int 2012;32:223-30.
37. Appenrodt B, Grünhage F, Gentemann MG et al. Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology 2010;51:1327-33.
38. Nischalke HD, Berger C, Aldenhoff K et al. Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol 2011;55:1010-6.
39. Scarpellini E, Valenza V, Gabrielli M et al. Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed? Am J Gastroenterol 2010;105:323-7.
40. Albillos A, de la Hera A, González M et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003;37:208-17.
41. Hou MC, Lin HC, Liu TT et al. Antibiotic prophylaxis after endoscopic therapy prevents re-bleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004;39:746-53.
42. Tiso M, Schechter AN. Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions. PLoS One 2015;10:e0119712.
43. Iwakiri Y. The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol 2007;41(Suppl 3):S288-94.
44. Wei X, Yan X, Zou D et al. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterol 2013;13:175-82.
45. Kakiyama G, Pandak WM, Gillevet PM et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 2013;58:949-55.
46. Ridlon JM, Alves JM, Hylemon PB et al. Cirrhosis, bile acids and gut microbiota. Unraveling a complex relationship. Gut Microbes 4:382-7.
47. Lorenzo-Zúñiga V, Bartolí R, Planas R et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 2003;37:551-7.
48. Stenman LK, Holma R, Eggert A et al. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol 2013;304:G227-34.
49. Sayin SI, Wahlström A, Felin J et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17:225-35.
50. Hu X, Bonde Y, Eggertsen G et al. Muricholic bile acids are potent regulators of bile acid synthesis via a positive feedback mechanism. J Intern Med 2014;275:27-38
51. Degirolamo C, Rainaldi S, Bovenga F et al. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep 2014;7:12-18.
52. Seki E, De Minicis S, Osterreicher CH et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007;13:1324-32.
53. Moreau R, Jalan R, Gines P et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426-37.
54. Tritto G, Bechlis Z, Stadlbauer V et al. Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. J Hepatol 2011;55:574-81.
55. Rajkovic IA, Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology 1986;6:252-62.
56. Stadlbauer V, Mookerjee RP, Wright GA et al. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2009;296:G15-22.
57. Mookerjee RP, Stadlbauer V, Lidder S et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007;46:831-40.
58. Macnaughtan J, Davies N, Stadlbauer V et al. Evidence for compartmentalised endotoxaemia and its effect on neutrophil function in the portal circulation in cirrhosis. Hepatology 2010;52:46.
59. Albillos A, Hera Ad Ade L, Reyes E et al. Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin. J Hepatol 2004;40:624-31.
60. Granowitz EV, Porat R, Mier JW et al. Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans. J Immunol 1993;151:1637-45.
61. Wasmuth HE, Kunz D, Yagmur E et al. Patients with acute on chronic liver failure display "sepsis-like" immune paralysis. J Hepatol 2005;42: 195-201.
62. Muñoz L, Albillos A, Nieto M et al. Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis. Hepatology 2005;42:411-9.
63. Rivera CA, Adegboyega P, van Rooijen N et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 2007;47:571-9.
64. Mao TK, Lian ZX, Selmi C et al. Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology 2005;42:802-8.
65. Ma HD, Wang YH, Chang C et al. The intestinal microenvironment in liver. Autoimmun Rev 2015;14:183-91.
66. Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979;23:403-11.
67. Zapater P, Francés R, González-Navajas JM et al. Serum and ascitic fluid bacterial DNA: a new independent prognostic factor in noninfected patients with cirrhosis. Hepatology 2008;48:1924-31.
68. 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;42:200-4.
69. Bala S, Marcos M, Gattu A et al. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLoS One 2014;9:e96864.
70. Miele L, Valenza V, La Torre G et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009;49:1877-87.
71. Giofré MR, Meduri G, Pallio S et al. Gastric permeability to sucrose is increased in portal hypertensive gastropathy. Eur J Gastroenterol Hepatol 2000;12:529-33.
72. Xu WH, Wu XJ, Li JS. Influence of portal pressure change on intestinal permeability in patients with portal hypertension. Hepatobiliary Pancreat Dis Int 2002;1:510-4.
73. Senzolo M, Fries W, Buda A et al. Oral propranolol decreases intestinal permeability in patients with cirrhosis: another protective mechanism against bleeding? Am J Gastroenterol 2009;104:3115-6.
74. Senzolo M, Cholongitas E, Burra P et al. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189-93.
75. Rasaratnam B, Kaye D, Jennings G et al. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Ann Intern Med 2003;139:186-93.
76. Kalambokis GN, Mouzaki A, Rodi M et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin Gastroenterol Hepatol 2012;10:815-8.
77. Bernard B, Grangé JD, Khac EN et al. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999;29:1655-61.
78. Ginés P, Rimola A, Planas R et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990;12:716-24.
79. Dawson AM, McLaren J, Sherlock S. Neomycin in the treatment of hepatic coma. Lancet 1957;273:1262-8.
80. Morgan MH, Read AE, Speller DC. Treatment of hepatic encephalopathy with metronidazole. Gut 1982;23:1-7.
81. Bass NM, Mullen KD, Sanyal A et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362:1071-81.
82. Ng SC, Hart AL, Kamm MA et al. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis 15:300-10.
83. Bosoi CR, Parent-Robitaille C, Anderson K et al. AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats. Hepatology 53:1995-2002.
84. Bajaj JS, Sheikh MY, Chojkier M et al. AST-120 (spherical carbon adsorbent) in covert hepatic encephalopathy: results of the astute trial. Gastroenterology 2013;144:S-997.
85. Macnaughtan, Soeda J, Mouralidarane A et al. Gut Decontamination using Nanoporous Carbons reduces portal pressure and prevents liver failure in bile-duct ligated cirrhotic animals by reducing Kupffer cell activation. J Hepatol 2012;56:S230.
86. Mookerjee R, Rosselli M, Pieri G et al. O15 effects of the FXR agonist obeticholic acid on hepatic venous pressure gradient (HVPG) in alcoholic cirrhosis: A proof of concept phase 2a study. J Hepatol 2014;60:S7-8.
87. Sersté T, Francoz C, Durand F et al. Beta-blockers cause paracentesisinduced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011;55:794-9.
88. Petrasek J, Csak T, Szabo G. Toll-like receptors in liver disease. Adv Clin Chem 2013;59:155-201.
89. de Oca MM, Shah N, Dhar DK et al. Evidence of dendritic cell dysfunction in cirrhosis and its restoration by toll-like receptor 4 antagonism. Hepatology 2010;52:1018A.
90. Zhu Q, Zou L, Jagavelu K et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol 2012;56:893-9.
91. Youngster I, Russell GH, Pindar C. Oral,capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772-8.
92. Le Roy T, Llopis M, Lepage P et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013;62: 1787-94.
93. Tuomisto S, Pessi T, Collin P et al. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics. BMC Gastroenterol 2014;14:40.
94. Liu J, Wu D, Ahmed A et al. Comparison of the gut microbe profiles and numbers between patients with liver cirrhosis and healthy individuals. Curr Microbiol 2012;65:7-13.
95. Zhang Z, Zhai H, Geng J et al. Large-scale survey of gut microbiota associated with MHE via 16S rRNA-based pyrosequencing. Am J Gastroenterol 2013;108:1601-11.
96. Fernández J, Ruiz del Arbol L, Gómez C et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049-56.
97. Soriano G, Guarner C, Tomás A et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 1992;103:1267-72.
98. Kemp W, Colman J, Thompson K. Norfloxacin treatment for clinically significant portal hypertension: results of a randomised double-blind placebo-controlled crossover trial. Liver Int 2009;29:427-33.
99. Vlachogiannakos J, Viazis N, Vasianopoulou P et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 2013;28:450-5.
100. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 1993;13: 109-18.
101. Sharma BC, Sharma P, Lunia MK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013;108:1458-63.
102. Mas A, Rodés J, Sunyer L et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 2003;38:51-8.
103. Orlandi F, Freddara U, Candelaresi MT et al. Comparison between neomycin and lactulose in 173 patients with hepatic encephalopathy: a randomized clinical study. Dig Dis Sci 1981;26:498-506.
104. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial.. Am J Dig Dis 1978;23:398-406.
105. Gupta N, Kumar A, Sharma P et al. Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial. Liver Int 2013;33:1148-57.
106. Saji S, Kumar S, Thomas V. A randomized double blind placebo controlled trial of probiotics in minimal hepatic encephalopathy. Trop Gastroenterol 2011;32:128-32.
107. Loguercio C, Abbiati R, Rinaldi M et al. Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy. J Hepatol 1995;23:39-46.
108. Agrawal A, Sharma BC, Sharma P. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012;107: 1043-50.
109. Bajaj JS, Heuman DM, Hylemon PB et al. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 2014;39:1113-25.
110. Lunia MK, Sharma BC, Sharma P et al. Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 2014;12:1003-8.
111. Mittal VV, Sharma BC, Sharma P et al. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23:725-32.
112. Pereg D, Kotliroff A, Gadoth N et al. Probiotics for patients with compensated liver cirrhosis: a double-blind placebo-controlled study. Nutrition 2011;27:177-81.
113. Lata J, Juránková J, Príbramská V et al. Effect of administration of Escherichia coli Nissle (Mutaflor) on intestinal colonisation, endotoxemia, liver function and minimal hepatic encephalopathy in patients with liver cirrhosis]. Vnitr Lek 2006;52:215-9.
114. Liu Q, Duan ZP, Ha DK et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441-9.
115. Malaguarnera M, Greco F, Barone G. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 2007;52:3259-65.
116. Dhiman RK, Sawhney MS, Chawla YK et al. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000;45:1549-52.
117. Watanabe A, Sakai T, Sato S et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997;26:1410-4.
118. Horsmans Y, Solbreux PM, Daenens C et al. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997;11:165-70.
119. Elkington SG, Floch MH, Conn OH. Lactulose in the treatment of chronic portal-systemic encephalopathy-a double-blind clinical trial. N Engl J Med 1969;281:408-12.
120. Heredia D, Caballeria J, Arroyo V et al. Lactitol versus lactulose in the treatment of acute portal systemic encephalopathy (PSE). A controlled trial. J Hepatol 1987;4:293-8.
121. Morgan MY, Hawley KE, Stambuk D. Lactitol versus lactulose in the treatment of chronic hepatic encephalopathy. A double-blind, randomised, cross-over study. J Hepatol 1987;4:236-44.
122. Morencos FC, de las Heras Castaño G, Martín Ramos L et al. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig Dis Sci 1995;40:1252-6.
123. Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol 2009;249:43-54.
124. Verbeke L, Farre R, Trebicka J et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014;59:2286-98.
125. Mookerjee RP, Mehta G, Balasubramaniyan V et al. Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension. J Hepatol 2014;62:325-31.