Gut microbiota and host reaction in liver diseases

Microorganisms

Volumn 3, Issue 4, 2015, Pages 759-791

  Fukui, Hiroshi ^a  

^a NARA MEDICAL UNIVERSITY   (Japan)

Author keywords

Alcoholic liver disease; Bacterial overgrowth; Bacterial translocation; Bile acids; Dysbiosis; Endotoxin; Gut microbiota; Liver cirrhosis; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis

Indexed keywords

EID: 85014531272     PISSN: None     EISSN: 20762607     Source Type: Journal    
DOI: 10.3390/microorganisms3040759     Document Type: Review

References (178)

1. Ley, R.E.; Peterson, D.A.; Gordon, J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006, 124, 837–848, doi:10.1016/j.cell.2006.02.017.
2. Sekirov, I.; Russell, S.L.; Antunes, L.C.; Finlay, B.B. Gut microbiota in health and disease. Physiol. Rev. 2010, 90, 859–904, doi:10.1152/physrev.00045.2009.
3. Eckburg, P.B.; Bik, E.M.; Bernstein, C.N.; Purdom, E.; Dethlefsen, L.; Sargent, M.; Gill, S.R.; Nelson, K.E.; Relman, D.A. Diversity of the human intestinal microbial flora. Science 2005, 308, 1635–1638, doi:10.1126/science.1110591.
4. Frank, D.N.; St Amand, A.L.; Feldman, R.A.; Boedeker, E.C.; Harpaz, N.; Pace, N.R. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA 2007, 104, 13780–13785, doi:10.1073/pnas.0706625104.
5. Gill, S.R.; Pop, M.; Deboy, R.T.; Eckburg, P.B.; Turnbaugh, P.J.; Samuel, B.S.; Gordon, J.I.; Relman, D.A.; Fraser-Liggett, C.M.; Nelson, K.E. Metagenomic analysis of the human distal gut microbiome. Science 2006, 312, 1355–1359, doi:10.1126/science.1124234.
6. Schnabl, B.; Brenner, D.A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014, 146, 1513–1524, doi:10.1053/j.gastro.2014.01.020.
7. Gao, B.; Bataller, R. Alcoholic liver disease: Pathogenesis and new therapeutic targets. Gastroenterology 2011, 141, 1572–1585, doi:10.1053/j.gastro.2011.09.002.
8. Hartmann, P.; Seebauer, C.T.; Schnabl, B. Alcoholic liver disease: The gut microbiome and liver cross talk. Alcohol. Clin. Exp. Res. 2015, 39, 763–775, doi:10.1111/acer.12704.
9. Vassallo, G.; Mirijello, A.; Ferrulli, A.; Antonelli, M.; Landolfi, R.; Gasbarrini, A.; Addolorato, G. Review article: Alcohol and gut microbiota—The possible role of gut microbiota modulation in the treatment of alcoholic liver disease. Aliment Pharmacol. Ther. 2015, 41, 917–927, doi:10.1111/apt.13164.
10. Bode, J.C.; Bode, C.; Heidelbach, R.; Durr, H.K.; Martini, G.A. Jejunal microflora in patients with chronic alcohol abuse. Hepatogastroenterology 1984, 31, 30–34.
11. Morencos, F.C.; de las Heras Castano, G.; Martin Ramos, L.; Lopez Arias, M.J.; Ledesma, F.; Pons Romero, F. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig. Dis. Sci. 1995, 40, 1252–1256.
12. Hartmann, P.; Chen, P.; Wang, H.J.; Wang, L.; McCole, D.F.; Brandl, K.; Starkel, P.; Belzer, C.; Hellerbrand, C.; Tsukamoto, H.; et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 2013, 58, 108–119, doi:10.1002/hep.26321.
13. Yan, A.W.; Fouts, D.E.; Brandl, J.; Starkel, P.; Torralba, M.; Schott, E.; Tsukamoto, H.; Nelson, K.E.; Brenner, D.A.; Schnabl, B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011, 53, 96–105, doi:10.1002/hep.24018.
14. Bull-Otterson, L.; Feng, W.; Kirpich, I.; Wang, Y.; Qin, X.; Liu, Y.; Gobejishvili, L.; Joshi-Barve, S.; Ayvaz, T.; Petrosino, J.; et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS ONE 2013, 8, e53028, doi:10.1371/journal.pone.0053028.
15. 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.
16. Bjorkholm, B.; Olling, S.; Larsson, P.; Hagberg, L. An outbreak of diphtheria among Swedish alcoholics. Infection 1987, 15, 354–358.
17. Harnisch, J.P.; Tronca, E.; Nolan, C.M.; Turck, M.; Holmes, K.K. Diphtheria among alcoholic urban adults. A decade of experience in Seattle. Ann. Intern. Med. 1989, 111, 71–82.
18. Canesso, M.C.C.; Lacerda, N.L.; Ferreira, C.M.; Gonçalves, J.L.; Almeida, D.; Gamba, C.; Cassali, G.; Pedroso, S.H.; Moreira, C.; Martins, F.S.; et al. Comparing the effects of acute alcohol consumption in germ-free and conventional mice: The role of the gut microbiota. BMC Microbiol. 2014, 14, 240, doi:10.1186/s12866-014-0240-4.
19. Kirpich, I.A.; Solovieva, N.V.; Leikhter, S.N.; Shidakova, N.A.; Lebedeva, O.V.; Sidorov, P.I.; Bazhukova, T.A.; Soloviev, A.G.; Barve, S.S.; McClain, C.J.; et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: A pilot study. Alcohol 2008, 42, 675–682, doi:10.1016/j.alcohol.2008.08.006.
20. Mutlu, E.A.; Gillevet, P.M.; Rangwala, H.; Sikaroodi, M.; Naqvi, A.; Engen, P.A.; Kwasny, M.; Lau, C.K.; Keshavarzian, A. Colonic microbiome is altered in alcoholism. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302, G966–G978, doi:10.1152/ajpgi.00380.2011.
21. Leclercq, S.; Matamoros, S.; Cani, P.D.; Neyrinck, A.M.; Jamar, F.; Starkel, P.; Windey, K.; Tremaroli, V.; Backhed, F.; Verbeke, K.; et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc. Natl. Acad. Sci. USA 2014, 111, E4485–E4493, doi:10.1073/pnas.1415174111.
22. Sokol, H.; Pigneur, B.; Watterlot, L.; Lakhdari, O.; Bermudez-Humaran, L.G.; Gratadoux, J.J.; Blugeon, S.; Bridonneau, C.; Furet, J.P.; Corthier, G.; et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA 2008, 105, 16731–16736, doi:10.1073/pnas.0804812105.
23. Machiels, K.; Joossens, M.; Sabino, J.; de Preter, V.; Arijs, I.; Eeckhaut, V.; Ballet, V.; Claes, K.; van Immerseel, F.; Verbeke, K.; et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014, 63, 1275–1283, doi:10.1136/gutjnl-2013-304833.
24. Madsen, K.; Cornish, A.; Soper, P.; McKaigney, C.; Jijon, H.; Yachimec, C.; Doyle, J.; Jewell, L.; de Simone, C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001, 121, 580–591.
25. Chen, Y.; Yang, F.; Lu, H.; Wang, B.; Chen, Y.; Lei, D.; Wang, Y.; Zhu, B.; Li, L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011, 54, 562–572, doi:10.1002/hep.24423.
26. Kakiyama, G.; Hylemon, P.B.; Zhou, H.; Pandak, W.M.; Heuman, D.M.; Kang, D.J.; Takei, H.; Nittono, H.; Ridlon, J.M.; Fuchs, M.; et al. Colonic inflammation and secondary bile acids in alcoholic cirrhosis. Am. J. Physiol. Gastrointest. Liver. Physiol. 2014, 306, G929–G937, doi:10.1152/ajpgi.00315.2013.
27. Brandl, K.; Plitas, G.; Schnabl, B.; DeMatteo, R.P.; Pamer, E.G. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 2007, 204, 1891–1900, doi:10.1084/jem.20070563.
28. Brandl, K.; Plitas, G.; Mihu, C.N.; Ubeda, C.; Jia, T.; Fleisher, M.; Schnabl, B.; DeMatteo, R.P.; Pamer, E.G. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 2008, 455, 804–807, doi:10.1038/nature07250.
29. Dessein, R.; Gironella, M.; Vignal, C.; Peyrin-Biroulet, L.; Sokol, H.; Secher, T.; Lacas-Gervais, S.; Gratadoux, J.J.; Lafont, F.; Dagorn, J.C.; et al. Toll-like receptor 2 is critical for induction of Reg3 beta expression and intestinal clearance of Yersinia pseudotuberculosis. Gut 2009, 58, 771–776, doi:10.1136/gut.2008.168443.
30. Zhao, H.Y.; Wang, H.J.; Lu, Z.; Xu, S.Z. Intestinal microflora in patients with liver cirrhosis. Chin. J. Dig. Dis. 2004, 5, 64–67.
31. Bjarnason, I.; Peters, T.J.; Wise, R.J. The leaky gut of alcoholism: Possible route of entry for toxic compounds. Lancet 1984, 1, 179–182.
32. Keshavarzian, A.; Holmes, E.W.; Patel, M.; Iber, F.; Fields, J.Z.; Pethkar, S. Leaky gut in alcoholic cirrhosis: A possible mechanism for alcohol-induced liver damage. Am. J. Gastroenterol. 1999, 94, 200–207, doi:10.1111/j.1572-0241.1999.00797.x.
33. 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.
34. Parlesak, A.; Schafer, C.; Schutz, T.; Bode, J.C.; 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.
35. Purohit, V.; Bode, J.C.; Bode, C.; Brenner, D.A.; Choudhry, M.A.; Hamilton, F.; Kang, Y.J.; Keshavarzian, A.; Rao, R.; Sartor, R.B.; et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: Summary of a symposium. Alcohol 2008, 42, 349–361, doi:10.1016/j.alcohol.2008.03.131.
36. Keshavarzian, A.; Fields, J.Z.; Vaeth, J.; Holmes, E.W. The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am. J. Gastroenterol. 1994, 89, 2205–2211.
37. Elamin, E.; Masclee, A.; Troost, F.; Pieters, H.J.; Keszthelyi, D.; Aleksa, K.; Dekker, J.; Jonkers, D. Ethanol impairs intestinal barrier function in humans through mitogen activated protein kinase signaling: A combined in vivo and in vitro approach. PLoS ONE 2014, 9, e107421, doi:10.1371/journal.pone.0107421
38. Kalaitzakis, E. Gastrointestinal dysfunction in liver cirrhosis. World J. Gastroenterol. 2014, 20, 14686–14695, doi:10.3748/wjg.v20.i40.14686.
39. Elamin, E.E.; Masclee, A.A.; Dekker, J.; Jonkers, D.M. Ethanol metabolism and its effects on the intestinal epithelial barrier. Nutr. Rev. 2013, 71, 483–499, doi:10.1111/nure.12027.
40. Tang, Y.; Forsyth, C.B.; Farhadi, A.; Rangan, J.; Jakate, S.; Shaikh, M.; Banan, A.; Fields, J.Z.; Keshavarzian, A. 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.
41. Pijls, K.E.; Jonkers, D.M.; Elamin, E.E.; Masclee, A.A.; Koek, G.H. Intestinal epithelial barrier function in liver cirrhosis: An extensive review of the literature. Liver Int. 2013, 33, 1457–1469, doi:10.1111/liv.12271.
42. Fukui, H.; Brauner, B.; Bode, J.C.; Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: Reevaluation with an improved chromogenic assay. J. Hepatol. 1991, 12, 162–169.
43. 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.
44. Guo, J.; Friedman, S.L. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenes. Tissue Repair 2010, 3, 21, doi:10.1186/1755-1536-3-21.
45. Seo, Y.S.; Shah, V.H. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin. Mol. Hepatol. 2012, 18, 337–346, doi:10.3350/cmh.2012.18.4.337.
46. Wang, Y.; Kirpich, I.; Liu, Y.; Ma, Z.; Barve, S.; McClain, C.J.; Feng, W. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Am. J. Pathol. 2011, 179, 2866–2875, doi:10.1016/j.ajpath.2011.08.039.
47. Fujimoto, M.; Uemura, M.; Nakatani, Y.; Tsujita, S.; Hoppo, K.; Tamagawa, T.; Kitano, H.; Kikukawa, M.; Ann, T.; Ishii, Y.; et al. Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: Relation to severity of liver disturbance. Alcohol. Clin. Exp. Res. 2000, 24, 48S–54S.
48. Fukui, H. Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure. Alcohol. Clin. Exp. Res. 2005, 29, 172S–179S.
49. Miele, L.; Valenza, V.; la Torre, G.; Montalto, M.; Cammarota, G.; Ricci, R.; Masciana, R.; Forgione, A.; Gabrieli, M.L.; Perotti, G.; et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009, 49, 1877–1887, doi:10.1002/hep.22848.
50. Aron-Wisnewsky, J.; Gaborit, B.; Dutour, A.; Clement, K. Gut microbiota and non-alcoholic fatty liver disease: New insights. Clin. Microbiol. Infect. 2013, 19, 338–348, doi:10.1111/1469-0691.12140.
51. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 2006, 444, 860–867, doi:10.1038/nature05485.
52. Nath, B.; Levin, I.; Csak, T.; Petrasek, J.; Mueller, C.; Kodys, K.; Catalano, D.; Mandrekar, P.; Szabo, G. Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology 2011, 53, 1526–1537, doi:10.1002/hep.24256.
53. Ilan, Y. Leaky gut and the liver: A role for bacterial translocation in nonalcoholic steatohepatitis. World J. Gastroenterol. 2012, 18, 2609–2618, doi:10.3748/wjg.v18.i21.2609.
54. Othman, M.; Aguero, R.; Lin, H.C. Alterations in intestinal microbial flora and human disease. Curr. Opin. Gastroenterol. 2008, 24, 11–16, doi:10.1097/MOG.0b013e3282f2b0d7.
55. Wigg, A.J.; Roberts-Thomson, I.C.; Dymock, R.B.; McCarthy, P.J.; Grose, R.H.; Cummins, A.G. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001, 48, 206–211.
56. Sajjad, A.; Mottershead, M.; Syn, W.K.; Jones, R.; Smith, S.; Nwokolo, C.U. Ciprofloxacin suppresses bacterial overgrowth, increases fasting insulin but does not correct low acylated ghrelin concentration in non-alcoholic steatohepatitis. Aliment Pharmacol. Ther. 2005, 22, 291–299, doi:10.1111/j.1365-2036.2005.02562.x.
57. Shanab, A.A.; Scully, P.; Crosbie, O.; Buckley, M.; O’Mahony, L.; Shanahan, F.; Gazareen, S.; Murphy, E.; Quigley, E.M. Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: Association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig. Dis. Sci. 2011, 56, 1524–1534, doi:10.1007/s10620-010-1447-3.
58. Volynets, V.; Kuper, M.A.; Strahl, S.; Maier, I.B.; Spruss, A.; Wagnerberger, S.; Konigsrainer, A.; Bischoff, S.C.; Bergheim, I. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig. Dis. Sci. 2012, 57, 1932–1941, doi:10.1007/s10620-012-2112-9.
59. Ferolla, S.M.; Armiliato, G.N.; Couto, C.A.; Ferrari, T.C. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients 2014, 6, 5583–5599, doi:10.3390/nu6125583.
60. Mouzaki, M.; Comelli, E.M.; Arendt, B.M.; Bonengel, J.; Fung, S.K.; Fischer, S.E.; McGilvray, I.D.; Allard, J.P. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013, 58, 120–127, doi:10.1002/hep.26319.
61. Ley, R.E.; Turnbaugh, P.J.; Klein, S.; Gordon, J.I. Microbial ecology: Human gut microbes associated with obesity. Nature 2006, 444, 1022–1023, doi:10.1038/4441022a.
62. Clarke, S.F.; Murphy, E.F.; Nilaweera, K.; Ross, P.R.; Shanahan, F.; O’Toole, P.W.; Cotter, P.D. The gut microbiota and its relationship to diet and obesity: New insights. Gut Microbes 2012, 3, 186–202, doi:10.4161/gmic.20168.
63. Turnbaugh, P.J.; Ley, R.E.; Mahowald, M.A.; Magrini, V.; Mardis, E.R.; Gordon, J.I. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444, 1027–1031, doi:10.1038/nature05414.
64. Turnbaugh, P.J.; Backhed, F.; Fulton, L.; Gordon, J.I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008, 3, 213–223. doi:10.1016/j.chom.2008.02.015.
65. Hildebrandt, M.A.; Hoffmann, C.; Sherrill-Mix, S.A.; Keilbaugh, S.A.; Hamady, M.; Chen, Y.Y.; Knight, R.; Ahima, R.S.; Bushman, F.; Wu, G.D. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009, 137, 1716–1724.e1–e2, doi:10.1053/j.gastro.2009.08.042.
66. He, W.; Wang, M.L.; Jiang, H.Q.; Steppan, C.M.; Shin, M.E.; Thurnheer, M.C.; Cebra, J.J.; Lazar, M.A.; Wu, G.D. Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology 2003, 125, 1388–1397.
67. Shojima, N.; Ogihara, T.; Inukai, K.; Fujishiro, M.; Sakoda, H.; Kushiyama, A.; Katagiri, H.; Anai, M.; Ono, H.; Fukushima, Y.; et al. Serum concentrations of resistin-like molecules beta and gamma are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow. Diabetologia 2005, 48, 984–992, doi:10.1007/s00125-005-1735-1.
68. Turnbaugh, P.J.; Ridaura, V.K.; Faith, J.J.; Rey, F.E.; Knight, R.; Gordon, J.I. The effect of diet on the human gut microbiome: A metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 2009, 1, 6ra14, doi:10.1126/scitranslmed.3000322.
69. Turnbaugh, P.J.; Hamady, M.; Yatsunenko, T.; Cantarel, B.L.; Duncan, A.; Ley, R.E.; Sogin, M.L.; Jones, W.J.; Roe, B.A.; Affourtit, J.P.; et al. A core gut microbiome in obese and lean twins. Nature 2009, 457, 480–484, doi:10.1038/nature07540.
70. Armougom, F.; Henry, M.; Vialettes, B.; Raccah, D.; Raoult, D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLoS ONE 2009, 4, e7125, doi:10.1371/journal.pone.0007125.
71. Santacruz, A.; Collado, M.C.; Garcia-Valdes, L.; Segura, M.T.; Martin-Lagos, J.A.; Anjos, T.; Marti-Romero, M.; Lopez, R.M.; Florido, J.; Campoy, C.; et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br. J. Nutr. 2010, 104, 83–92, doi:10.1017/S0007114510000176.
72. Zhu, L.; Baker, S.S.; Gill, C.; Liu, W.; Alkhouri, R.; Baker, R.D.; Gill, S.R. 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.
73. Yuan, J.; Baker, S.S.; Liu, W.; Alkhouri, R.; Baker, R.D.; Xie, J.; Ji, G.; Zhu, L. Endotoxemia unrequired in the pathogenesis of pediatric nonalcoholic steatohepatitis. J. Gastroenterol. Hepatol. 2014, 29, 1292–1298, doi:10.1111/jgh.12510.
74. Schwiertz, A.; Taras, D.; Schafer, K.; Beijer, S.; Bos, N.A.; Donus, C.; Hardt, P.D. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 2010, 18, 190–195, doi:10.1038/oby.2009.167.
75. Zhang, H.; DiBaise, J.K.; Zuccolo, A.; Kudrna, D.; Braidotti, M.; Yu, Y.; Parameswaran, P.; Crowell, M.D.; Wing, R.; Rittmann, B.E.; et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl. Acad. Sci. USA 2009, 106, 2365–2370, doi:10.1073/pnas.0812600106.
76. Collado, M.C.; Isolauri, E.; Laitinen, K.; Salminen, S. Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am. J. Clin. Nutr. 2008, 88, 894–899.
77. Million, M.; Maraninchi, M.; Henry, M.; Armougom, F.; Richet, H.; Carrieri, P.; Valero, R.; Raccah, D.; Vialettes, B.; Raoult, D. Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii. Int. J. Obes. (Lond.) 2012, 36, 817–825, doi:10.1038/ijo.2011.153.
78. Raman, M.; Ahmed, I.; Gillevet, P.M.; Probert, C.S.; Ratcliffe, N.M.; Smith, S.; Greenwood, R.; Sikaroodi, M.; Lam, V.; Crotty, P.; et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2013, 11, 868–875.e1–e3, doi:10.1016/j.cgh.2013.02.015.
79. Wong, V.W.; Tse, C.H.; Lam, T.T.; Wong, G.L.; Chim, A.M.; Chu, W.C.; Yeung, D.K.; Law, P.T.; Kwan, H.S.; Yu, J.; et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis—A longitudinal study. PLoS ONE 2013, 8, e62885, doi:10.1371/journal.pone.0062885.
80. Henao-Mejia, J.; Elinav, E.; Jin, C.; Hao, L.; Mehal, W.Z.; Strowig, T.; Thaiss, C.A.; Kau, A.L.; Eisenbarth, S.C.; Jurczak, M.J.; et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012, 482, 179–185, doi:10.1038/nature10809.
81. Elinav, E.; Strowig, T.; Kau, A.L.; Henao-Mejia, J.; Thaiss, C.A.; Booth, C.J.; Peaper, D.R.; Bertin, J.; Eisenbarth, S.C.; Gordon, J.I.; et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011, 145, 745–757, doi:10.1016/j.cell.2011.04.022.
82. Vos, B.; Moreno, C.; Nagy, N.; Fery, F.; Cnop, M.; Vereerstraeten, P.; Deviere, J.; Adler, M. Lean non-alcoholic fatty liver disease (Lean-NAFLD): A major cause of cryptogenic liver disease. Acta Gastroenterol. Belg. 2011, 74, 389–394.
83. Van Best, N.; Jansen, P.L.; Rensen, S.S. The gut microbiota of nonalcoholic fatty liver disease: Current methods and their interpretation. Hepatol. Int. 2015, 9, 406–415, doi:10.1007/s12072-015-9640-2.
84. Everard, A.; Belzer, C.; Geurts, L.; Ouwerkerk, J.P.; Druart, C.; Bindels, L.B.; Guiot, Y.; Derrien, M.; Muccioli, G.G.; Delzenne, N.M.; et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 2013, 110, 9066–9071, doi:10.1073/pnas.1219451110.
85. Topping, D.L.; Clifton, P.M. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 2001, 81, 1031–1064.
86. Wolever, T.M.; Brighenti, F.; Royall, D.; Jenkins, A.L.; Jenkins, D.J. Effect of rectal infusion of short chain fatty acids in human subjects. Am. J. Gastroenterol. 1989, 84, 1027–1033.
87. Ridlon, J.M.; Kang, D.J.; Hylemon, P.B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 2006, 47, 241–259, doi:10.1194/jlr.R500013-JLR200.
88. De Filippo, C.; Cavalieri, D.; di Paola, M.; Ramazzotti, M.; Poullet, J.B.; Massart, S.; Collini, S.; Pieraccini, G.; Lionetti, P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl. Acad. Sci. USA 2010, 107, 14691–14696, doi:10.1073/pnas.1005963107.
89. Zhu, L.; Baker, R.D.; Baker, S.S. Gut microbiome and nonalcoholic fatty liver diseases. Pediatr. Res 2015, 77, 245–251, doi:10.1038/pr.2014.157.
90. Karaki, S.; Mitsui, R.; Hayashi, H.; Kato, I.; Sugiya, H.; Iwanaga, T.; Furness, J.B.; Kuwahara, A. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 2006, 324, 353–360, doi:10.1007/s00441-005-0140-x.
91. Tazoe, H.; Otomo, Y.; Kaji, I.; Tanaka, R.; Karaki, S.I.; Kuwahara, A. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J. Physiol. Pharmacol. 2008, 59 (Suppl. 2), 251–262.
92. Bjursell, M.; Admyre, T.; Goransson, M.; Marley, A.E.; Smith, D.M.; Oscarsson, J.; Bohlooly, Y.M. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 2011, 300, E211–E220, doi:10.1152/ajpendo.00229.2010.
93. Ridlon, J.M.; Alves, J.M.; Hylemon, P.B.; Bajaj, J.S. Cirrhosis, bile acids and gut microbiota: Unraveling a complex relationship. Gut Microbes 2013, 4, 382–387, doi:10.4161/gmic.25723.
94. Wang, H.; Chen, J.; Hollister, K.; Sowers, L.C.; Forman, B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 1999, 3, 543–553.
95. Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Nakamura, T.; Itadani, H.; Tanaka, K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 2002, 298, 714–719.
96. Keitel, V.; Haussinger, D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin. Res. Hepatol. Gastroenterol. 2012, 36, 412–419, doi:10.1016/j.clinre.2012.03.008.
97. Matsubara, T.; Li, F.; Gonzalez, F.J. FXR signaling in the enterohepatic system. Mol. Cell. Endocrinol. 2013, 368, 17–29, doi:10.1016/j.mce.2012.05.004.
98. Stanimirov, B.; Stankov, K.; Mikov, M. Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases. Hepatobiliary Pancreat. Dis. Int. 2015, 14, 18–33.
99. Haub, S.; Kanuri, G.; Volynets, V.; Brune, T.; Bischoff, S.C.; Bergheim, I. Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2010, 298, G335–G344, doi:10.1152/ajpgi.00088.2009.
100. Wang, Y.D.; Chen, W.D.; Wang, M.; Yu, D.; Forman, B.M.; Huang, W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008, 48, 1632–1643, doi;10.1002/hep.22519.
101. Zhang, S.; Wang, J.; Liu, Q.; Harnish, D.C. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J. Hepatol. 2009, 51, 380–388, doi:10.1016/j.jhep.2009.03.025.
102. Cipriani, S.; Mencarelli, A.; Palladino, G.; Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid Res. 2010, 51, 771–784, doi:10.1194/jlr.M001602.
103. Wang, Y.D.; Chen, W.D.; Yu, D.; Forman, B.M.; Huang, W. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-kappaB) in mice. Hepatology 2011, 54, 1421–1432, doi:10.1002/hep.24525.
104. McMahan, R.H.; Wang, X.X.; Cheng, L.L.; Krisko, T.; Smith, M.; El Kasmi, K.; Pruzanski, M.; Adorini, L.; Golden-Mason, L.; Levi, M.; et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J. Biol. Chem. 2013, 288, 11761–11770, doi:10.1074/jbc.M112.446575.
105. Mudaliar, S.; Henry, R.R.; Sanyal, A.J.; Morrow, L.; Marschall, H.U.; Kipnes, M.; Adorini, L.; Sciacca, C.I.; Clopton, P.; Castelloe, E.; et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013, 145, 574.e1–582.e1, doi:10.1053/j.gastro.2013.05.042.
106. Abdelmegeed, M.A.; Banerjee, A.; Jang, S.; Yoo, S.H.; Yun, J.W.; Gonzalez, F.J.; Keshavarzian, A.; Song, B.J. CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. Free Radic. Biol. Med. 2013, 65, 1238–1245, doi:10.1016/j.freeradbiomed.2013.09.009.
107. Ali, A.H.; Carey, E.J.; Lindor, K.D. Recent advances in the development of farnesoid X receptor agonists. Ann. Transl. Med. 2015, 3, 5, doi:10.3978/j.issn.2305-5839.2014.12.06.
108. Neuschwander-Tetri, B.A.; Loomba, R.; Sanyal, A.J.; Lavine, J.E.; van Natta, M.L.; Abdelmalek, M.F.; Chalasani, N.; Dasarathy, S.; Diehl, A.M.; Hameed, B.; et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial. Lancet 2015, 385, 956–965, doi:10.1016/S0140-6736(14)61933-4.
109. Dumas, M.E.; Barton, R.H.; Toye, A.; Cloarec, O.; Blancher, C.; Rothwell, A.; Fearnside, J.; Tatoud, R.; Blanc, V.; Lindon, J.C.; et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl. Acad. Sci. USA 2006, 103, 12511–12516, doi;10.1073/pnas.0601056103.
110. Jiang, X.C.; Li, Z.; Liu, R.; Yang, X.P.; Pan, M.; Lagrost, L.; Fisher, E.A.; Williams, K.J. Phospholipid transfer protein deficiency impairs apolipoprotein-B secretion from hepatocytes by stimulating a proteolytic pathway through a relative deficiency of vitamin E and an increase in intracellular oxidants. J. Biol. Chem. 2005, 280, 18336–18340, doi:10.1074/jbc.M500007200.
111. Giorgio, V.; Miele, L.; Principessa, L.; Ferretti, F.; Villa, M.P.; Negro, V.; Grieco, A.; Alisi, A.; Nobili, V. 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.
112. Alisi, A.; Manco, M.; Devito, R.; Piemonte, F.; Nobili, V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J. Pediatr. Gastroenterol. Nutr. 2010, 50, 645–649, doi:10.1097/MPG.0b013e3181c7bdf1.
113. Farhadi, A.; Gundlapalli, S.; Shaikh, M.; Frantzides, C.; Harrell, L.; Kwasny, M.M.; Keshavarzian, A. Susceptibility to gut leakiness: A possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int. 2008, 28, 1026–1033, doi:10.1111/j.1478-3231.2008.01723.x.
114. Kapil, S.; Duseja, A.; Sharma, B.K.; Singla, B.; Chakraborti, A.; Das, A.; Ray, P.; Dhiman, R.K.; Chawla, Y. Small intestinal bacterial overgrowth and toll like receptor signaling in patients with nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2015, doi:10.1111/jgh.13058.
115. Sharifnia, T.; Antoun, J.; Verriere, T.G.; Suarez, G.; Wattacheril, J.; Wilson, K.T.; Peek, R.M., Jr.; Abumrad, N.N.; Flynn, C.R. Hepatic TLR4 Signaling in Obese NAFLD. Am. J. Physiol. Gastrointest. Liver Physiol. 2015, 309, G270–G278, doi:10.1152/ajpgi.00304.2014.
116. Kiziltas, S.; Ata, P.; Colak, Y.; Mesci, B.; Senates, E.; Enc, F.; Ulasoglu, C.; Tuncer, I.; Oguz, A. TLR4 gene polymorphism in patients with nonalcoholic fatty liver disease in comparison to healthy controls. Metab. Syndr. Relat. Disord. 2014, 12, 165–170, doi:10.1089/met.2013.0120.
117. Brun, P.; Castagliuolo, I.; di Leo, V.; Buda, A.; Pinzani, M.; Palu, G.; Martines, D. Increased intestinal permeability in obese mice: New evidence in the pathogenesis of nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 292, G518–G525, doi:10.1152/ajpgi.00024.2006.
118. Amar, J.; Chabo, C.; Waget, A.; Klopp, P.; Vachoux, C.; Bermudez-Humaran, L.G.; Smirnova, N.; Berge, M.; Sulpice, T.; Lahtinen, S.; et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: Molecular mechanisms and probiotic treatment. EMBO Mol. Med. 2011, 3, 559–572, doi:10.1002/emmm.201100159.
119. Burcelin, R.; Garidou, L.; Pomie, C. Immuno-microbiota cross and talk: The new paradigm of metabolic diseases. Semin. Immunol. 2012, 24, 67–74, doi:10.1016/j.smim.2011.11.011.
120. Ruiz, A.G.; Casafont, F.; Crespo, J.; Cayon, A.; Mayorga, M.; Estebanez, A.; Fernadez-Escalante, J.C.; Pons-Romero, F. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: Evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes. Surg. 2007, 17, 1374–1380, doi:10.1007/s11695-007-9243-7.
121. Baker, S.S.; Baker, R.D.; Liu, W.; Nowak, N.J.; Zhu, L. Role of alcohol metabolism in non-alcoholic steatohepatitis. PLoS ONE 2010, 5, e9570, doi:10.1371/journal.pone.0009570.
122. Miura, K.; Kodama, Y.; Inokuchi, S.; Schnabl, B.; Aoyama, T.; Ohnishi, H.; Olefsky, J.M.; Brenner, D.A.; Seki, E. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 2010, 139, 323–334.e7, doi:10.1053/j.gastro.2010.03.052.
123. Rivera, C.A.; Adegboyega, P.; van Rooijen, N.; Tagalicud, A.; Allman, M.; Wallace, M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 2007, 47, 571–579, doi:10.1016/j.jhep.2007.04.019.
124. De Minicis, S.; Rychlicki, C.; Agostinelli, L.; Saccomanno, S.; Candelaresi, C.; Trozzi, L.; Mingarelli, E.; Facinelli, B.; Magi, G.; Palmieri, C.; et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 2014, 59, 1738–1749, doi:10.1002/hep.26695.
125. Kawaratani, H.; Tsujimoto, T.; Kitazawa, T.; Kitade, M.; Yoshiji, H.; Uemura, M.; Fukui, H. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World J. Gastroenterol. 2008, 14, 6655–6661.
126. Tsujimoto, T.; Kawaratani, H.; Kitazawa, T.; Hirai, T.; Ohishi, H.; Kitade, M.; Yoshiji, H.; Uemura, M.; Fukui, H. Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model. World J. Gastroenterol. 2008, 14, 6036–6043.
127. Tsujimoto, T.; Kawaratani, H.; Kitazawa, T.; Uemura, M.; Fukui, H. Innate immune reactivity of the ileum-liver axis in nonalcoholic steatohepatitis. Dig. Dis. Sci. 2012, 57, 1144–1151, doi:10.1007/s10620-012-2073-z.
128. Imajo, K.; Yoneda, M.; Ogawa, Y.; Wada, K.; Nakajima, A. Microbiota and nonalcoholic steatohepatitis. Semin. Immunopathol. 2014, 36, 115–132, doi:10.1007/s00281-013-0404-6.
129. Dunzendorfer, S.; Lee, H.K.; Soldau, K.; Tobias, P.S. TLR4 is the signaling but not the lipopolysaccharide uptake receptor. J. Immunol. 2004, 173, 1166–1170.
130. Douhara, A.; Moriya, K.; Yoshiji, H.; Noguchi, R.; Namisaki, T.; Kitade, M.; Kaji, K.; Aihara, Y.; Nishimura, N.; Takeda, K.; et al. Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model. Mol. Med. Rep. 2015, 11, 1693–1700, doi:10.3892/mmr.2014.2995.
131. Tsukumo, D.M.; Carvalho-Filho, M.A.; Carvalheira, J.B.; Prada, P.O.; Hirabara, S.M.; Schenka, A.A.; Araujo, E.P.; Vassallo, J.; Curi, R.; Velloso, L.A.; et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 2007, 56, 1986–1998, doi:10.2337/db06-1595.
132. Csak, T.; Velayudham, A.; Hritz, I.; Petrasek, J.; Levin, I.; Lippai, D.; Catalano, D.; Mandrekar, P.; Dolganiuc, A.; Kurt-Jones, E.; et al. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2011, 300, G433–G441, doi:10.1152/ajpgi.00163.2009.
133. Roth, C.L.; Elfers, C.T.; Figlewicz, D.P.; Melhorn, S.J.; Morton, G.J.; Hoofnagle, A.; Yeh, M.M.; Nelson, J.E.; Kowdley, K.V. Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation. Hepatology 2012, 55, 1103–1111, doi:10.1002/hep.24737.
134. Miura, K.; Ohnishi, H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J. Gastroenterol. 2014, 20, 7381–7391, doi:10.3748/wjg.v20.i23.7381.
135. Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat. Immunol. 2010, 11, 373–384, doi:10.1038/ni.1863.
136. Miura, K.; Yang, L.; van Rooijen, N.; Brenner, D.A.; Ohnishi, H.; Seki, E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 2013, 57, 577–589, doi:10.1002/hep.26081.
137. Pinzani, M.; Rosselli, M.; Zuckermann, M. Liver cirrhosis. Best Pract. Res. Clin. Gastroenterol. 2011, 25, 281–290, doi:10.1016/j.bpg.2011.02.009.
138. Tandon, P.; Garcia-Tsao, G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin. Liver Dis. 2008, 28, 26–42, doi:10.1055/s-2008-1040319.
139. Arvaniti, V.; D’Amico, G.; Fede, G.; Manousou, P.; Tsochatzis, E.; Pleguezuelo, M.; Burroughs, A.K. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010, 139, 1246–1256.e1–e5.
140. Campillo, B.; Richardet, J.P.; 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.
141. Bajaj, J.S.; Heuman, D.M.; Hylemon, P.B.; Sanyal, A.J.; White, M.B.; Monteith, P.; Noble, N.A.; Unser, A.B.; Daita, K.; Fisher, A.R.; et al. The Cirrhosis Dysbiosis Ratio Defines Changes in the Gut Microbiome Associated with Cirrhosis and its Complications. J. Hepatol. 2014, 60, 940–947, doi:10.1016/j.jhep.2013.12.019.
142. Bauer, T.M.; Schwacha, H.; Steinbruckner, B.; Brinkmann, F.E.; Ditzen, A.K.; Aponte, J.J.; Pelz, K.; Berger, D.; Kist, M.; Blum, H.E. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am. J. Gastroenterol. 2002, 97, 2364–2370, doi:10.1111/j.1572-0241.2002.05791.x.
143. Gupta, A.; Dhiman, R.K.; Kumari, S.; Rana, S.; Agarwal, R.; Duseja, A.; Chawla, Y. Role of 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.
144. Sadik, R.; Abrahamsson, H.; Bjornsson, E.; Gunnarsdottir, A.; Stotzer, P.O. Etiology of portal hypertension may influence gastrointestinal transit. Scand. J. Gastroenterol. 2003, 38, 1039–1044.
145. Pardo, A.; Bartoli, R.; Lorenzo-Zuniga, V.; Planas, R.; Vinado, B.; Riba, J.; Cabre, E.; Santos, J.; Luque, T.; Ausina, V.; et al. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis. Hepatology 2000, 31, 858–863, doi:10.1053/he.2000.5746.
146. Van Thiel, D.H.; Fagiuoli, S.; Wright, H.I.; Chien, M.C.; Gavaler, J.S. Gastrointestinal transit in cirrhotic patients: Effect of hepatic encephalopathy and its treatment. Hepatology 1994, 19, 67–71.
147. Qin, N.; Yang, F.; Li, A.; Prifti, E.; Chen, Y.; Shao, L.; Guo, J.; Le Chatelier, E.; Yao, J.; Wu, L.; et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014, 513, 59–64, doi:10.1038/nature13568.
148. Bajaj, J.S.; Ridlon, J.M.; Hylemon, P.B.; Thacker, L.R.; Heuman, D.M.; Smith, S.; Sikaroodi, M.; Gillevet, P.M. 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.
149. 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.
150. Xu, M.; Wang, B.; Fu, Y.; Chen, Y.; Yang, F.; Lu, H.; Chen, Y.; Xu, J.; Li, L. 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.
151. Wu, Z.W.; Lu, H.F.; Wu, J.; Zuo, J.; Chen, P.; Sheng, J.F.; Zheng, S.S.; Li, L.J. 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.
152. Bajaj, J.S.; Hylemon, P.B.; Ridlon, J.M.; Heuman, D.M.; Daita, K.; White, M.B.; Monteith, P.; Noble, N.A.; Sikaroodi, M.; Gillevet, P.M. 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.
153. Nava, G.M.; Stappenbeck, T.S. Diversity of the autochthonous colonic microbiota. Gut Microbes 2011, 2, 99–104, doi:10.4161/gmic.2.2.15416.
154. Dabard, J.; Bridonneau, C.; Phillipe, C.; Anglade, P.; Molle, D.; Nardi, M.; Ladire, M.; Girardin, H.; Marcille, F.; Gomez, A.; et al. Ruminococcin A, a new lantibiotic produced by a Ruminococcus gnavus strain isolated from human feces. Appl. Environ. Microbiol. 2001, 67, 4111–4118.
155. Gomez-Hurtado, I.; Such, J.; Sanz, Y.; Frances, R. Gut microbiota-related complications in cirrhosis. World J. Gastroenterol. 2014, 20, 15624–15631, doi:10.3748/wjg.v20.i42.15624.
156. Liu, Q.; Duan, Z.P.; Ha, D.K.; Bengmark, S.; Kurtovic, J.; Riordan, S.M. Synbiotic modulation of gut flora: Effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004, 39, 1441–1449, doi:10.1002/hep.20194.
157. Kakiyama, G.; Pandak, W.M.; Gillevet, P.M.; Hylemon, P.B.; Heuman, D.M.; Daita, K.; Takei, H.; Muto, A.; Nittono, H.; Ridlon, J.M.; 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.
158. Bellot, P.; Frances, R.; Such, J. Pathological bacterial translocation in cirrhosis: Pathophysiology, diagnosis and clinical implications. Liver Int. 2013, 33, 31–39, doi:10.1111/liv.12021.
159. Clements, W.D.; Parks, R.; Erwin, P.; Halliday, M.I.; Barr, J.; Rowlands, B.J. Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 1996, 39, 587–593.
160. Lorenzo-Zuniga, V.; Bartoli, R.; Planas, R.; Hofmann, A.F.; Vinado, B.; Hagey, L.R.; Hernandez, J.M.; Mane, J.; Alvarez, M.A.; Ausina, V.; et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 2003, 37, 551–557, doi:10.1053/jhep.2003.50116.
161. Renga, B.; Mencarelli, A.; Cipriani, S.; D’Amore, C.; Zampella, A.; Monti, M.C.; Distrutti, E.; Fiorucci, S. The nuclear receptor FXR regulates hepatic transport and metabolism of glutamine and glutamate. Biochim. Biophys. Acta 2011, 1812, 1522–1531, doi:10.1016/j.bbadis.2011.06.009.
162. Verbeke, L.; Farre, R.; Trebicka, J.; Komuta, M.; Roskams, T.; Klein, S.; Elst, I.V.; Windmolders, P.; Vanuytsel, T.; Nevens, F.; et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014, 59, 2286–2298, doi:10.1002/hep.26939.
163. Verbeke, L.; Farre, R.; Verbinnen, B.; Covens, K.; Vanuytsel, T.; Verhaegen, J.; Komuta, M.; Roskams, T.; Chatterjee, S.; Annaert, P.; et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am. J. Pathol. 2015, 185, 409–419, doi:10.1016/j.ajpath.2014.10.009.
164. Chen, Y.; Qin, N.; Guo, J.; Qian, G.; Fang, D.; Shi, D.; Xu, M.; Yang, F.; He, Z.; van Nostrand, J.D.; et al. Functional gene arrays-based analysis of fecal microbiomes in patients with liver cirrhosis. BMC Genom. 2014, 15, 753, doi:10.1186/1471-2164-15-753.
165. Campillo, B.; Pernet, P.; Bories, P.N.; Richardet, J.P.; Devanlay, M.; Aussel, C. Intestinal permeability in liver cirrhosis: Relationship with severe septic complications. Eur. J. Gastroenterol. Hepatol. 1999, 11, 755–759.
166. Pascual, S.; Such, J.; Esteban, A.; Zapater, P.; Casellas, J.A.; Aparicio, J.R.; Girona, E.; Gutierrez, A.; Carnices, F.; Palazon, J.M.; et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology 2003, 50, 1482–1486.
167. Scarpellini, E.; Valenza, V.; Gabrielli, M.; Lauritano, E.C.; Perotti, G.; Merra, G.; dal Lago, A.; Ojetti, V.; Ainora, M.E.; Santoro, M.; 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.
168. Fink, D.; Romanowski, K.; Valuckaite, V.; Babrowski, T.; Kim, M.; Matthews, J.B.; Liu, D.; Zaborina, O.; Alverdy, J.C. Pseudomonas aeruginosa potentiates the lethal effect of intestinal ischemia-reperfusion injury: The role of in vivo virulence activation. J. Trauma 2011, 71, 1575–1582, doi:10.1097/TA.0b013e31821cb7e5.
169. Pijls, K.E.; Koek, G.H.; Elamin, E.E.; de Vries, H.; Masclee, A.A.; Jonkers, D.M. Large intestine permeability is increased in patients with compensated liver cirrhosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2014, 306, G147–G153, doi:10.1152/ajpgi.00330.2013.
170. Zhang, W.; Gu, Y.; Chen, Y.; Deng, H.; Chen, L.; Chen, S.; Zhang, G.; Gao, Z. Intestinal flora imbalance results in altered bacterial translocation and liver function in rats with experimental cirrhosis. Eur. J. Gastroenterol. Hepatol. 2010, 22, 1481–1486, doi:10.1097/MEG.0b013e32833eb8b0.
171. Jun, D.W.; Kim, K.T.; Lee, O.Y.; Chae, J.D.; Son, B.K.; Kim, S.H.; Jo, Y.J.; Park, Y.S. Association between small intestinal bacterial overgrowth and peripheral bacterial DNA in cirrhotic patients. Dig. Dis. Sci. 2010, 55, 1465–1471, doi:10.1007/s10620-009-0870-9.
172. Fukui, H.; Tsujita, S.; Matsumoto, M.; Morimura, M.; Kitano, H.; Kinoshita, K.; Kikuchi, E.; Okamoto, Y.; Tsujii, T. Endotoxin inactivating action of plasma in patients with liver cirrhosis. Liver 1995, 15, 104–109.
173. Nakatani, Y.; Fukui, H.; Kitano, H.; Nagamoto, I.; Tsujimoto, T.; Kuriyama, S.; Kikuchi, E.; Hoppou, K.; Tsujii, T. Endotoxin clearance and its relation to hepatic and renal disturbances in rats with liver cirrhosis. Liver 2001, 21, 64–70.
174. Guarner, C.; Soriano, G.; Tomas, A.; Bulbena, O.; Novella, M.T.; Balanzo, J.; Vilardell, F.; Mourelle, M.; Moncada, S. Increased serum nitrite and nitrate levels in patients with cirrhosis: Relationship to endotoxemia. Hepatology 1993, 18, 1139–1143.
175. Albillos, A.; de la Hera, A.; Gonzalez, M.; Moya, J.L.; Calleja, J.L.; Monserrat, J.; Ruiz-del-Arbol, L.; Alvarez-Mon, M. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003, 37, 208–217, doi:10.1053/jhep.2003.50038.
176. Such, J.; Frances, R.; Munoz, C.; Zapater, P.; Casellas, J.A.; Cifuentes, A.; Rodriguez-Valera, F.; Pascual, S.; Sola-Vera, J.; Carnicer, F.; 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.
177. Guarner, C.; Gonzalez-Navajas, J.M.; Sanchez, E.; Soriando, G.; Frances, R.; Chiva, M.; Zapater, P.; Benlloch, S.; Munoz, C.; Pascual, S.; et al. The detection of bacterial DNA in blood of rats with CCl4-induced cirrhosis with ascites represents episodes of bacterial translocation. Hepatology 2006, 44, 633–639, doi:10.1002/hep.21286.
178. Wiest, R.; Lawson, M.; Geuking, M. Pathological bacterial translocation in liver cirrhosis. J. Hepatol. 2014, 60, 197–209, doi:10.1016/j.jhep.2013.07.044.