No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Microbiota, Liver Diseases, and Alcohol

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • XML
    173.38 Kb
  • HTML
    153.76 Kb
  • PDF
    10.23 MB
  • Authors: Anne-Marie Cassard1, Philippe Gérard2, Gabriel Perlemuter3,4
  • Editors: Robert Allen Britton5, Patrice D. Cani6
    Affiliations: 1: INSERM U996 Inflammation, Chemokines and Immunopathology, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France; 2: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; 3: INSERM U996 Inflammation, Chemokines and Immunopathology, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France; 4: AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère, Clamart, France; 5: Baylor College of Medicine, Houston, TX; 6: Université catholique de Louvain, Brussels, Belgium
  • Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0007-2016
  • Received 26 September 2016 Accepted 01 December 2016 Published 25 August 2017
  • Anne-Marie Casssaard, [email protected]
image of Microbiota, Liver Diseases, and Alcohol
    Preview this microbiology spectrum article:
    Zoom in

    Microbiota, Liver Diseases, and Alcohol, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/5/4/BAD-0007-2016-1.gif /docserver/preview/fulltext/microbiolspec/5/4/BAD-0007-2016-2.gif
  • Abstract:

    Being overweight and obesity are the leading causes of liver disease in Western countries. Liver damage induced by being overweight can range from steatosis, harmless in its simple form, to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol consumption is an additional major cause of liver disease. Not all individuals who are overweight or excessively consume alcohol develop nonalcoholic fatty liver diseases (NAFLD) or alcoholic liver disease (ALD) and advanced liver disease. The role of the intestinal microbiota (IM) in the susceptibility to liver disease in this context has been the subject of recent studies. ALD and NAFLD appear to be influenced by the composition of the IM, and dysbiosis is associated with ALD and NAFLD in rodent models and human patient cohorts. Several microbial metabolites, such as short-chain fatty acids and bile acids, are specifically associated with dysbiosis. Recent studies have highlighted the causal role of the IM in the development of liver diseases, and the use of probiotics or prebiotics improves some parameters associated with liver disease. Several studies have made progress in deciphering the mechanisms associated with the modulation of the IM. These data have demonstrated the intimate relationship between the IM and metabolic liver disease, suggesting that targeting the gut microbiota could be a new preventive or therapeutic strategy for these diseases.

  • Citation: Cassard A, Gérard P, Perlemuter G. 2017. Microbiota, Liver Diseases, and Alcohol. Microbiol Spectrum 5(4):BAD-0007-2016. doi:10.1128/microbiolspec.BAD-0007-2016.


1. Perlemuter G, Bigorgne A, Cassard-Doulcier AM, Naveau S. 2007. Nonalcoholic fatty liver disease: from pathogenesis to patient care. Nat Clin Pract Endocrinol Metab 3:458–469. http://dx.doi.org/10.1038/ncpendmet0505 [PubMed]
2. Voican CS, Perlemuter G, Naveau S. 2011. Mechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update. Clin Res Hepatol Gastroenterol 35:465–474. http://dx.doi.org/10.1016/j.clinre.2011.01.017
3. Voican CS, Njiké-Nakseu M, Boujedidi H, Barri-Ova N, Bouchet-Delbos L, Agostini H, Maitre S, Prévot S, Cassard-Doulcier AM, Naveau S, Perlemuter G. 2015. Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. Liver Int 35:967–978. http://dx.doi.org/10.1111/liv.12575 [PubMed]
4. Hardy T, Oakley F, Anstee QM, Day CP. 2016. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu Rev Pathol 11:451–496. http://dx.doi.org/10.1146/annurev-pathol-012615-044224 [PubMed]
5. Bedossa P. 2013. Current histological classification of NAFLD: strength and limitations. Hepatol Int 7(Suppl 2) :765–770. http://dx.doi.org/10.1007/s12072-013-9446-z [PubMed]
6. European Association for the Study of the Liver--European Organisation for Research and Treatment of Cancer. 2012. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 56:908–943. http://dx.doi.org/10.1016/j.jhep.2011.12.001 [PubMed]
7. Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, Bedossa P, Belghiti J. 2009. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49:851–859. http://dx.doi.org/10.1002/hep.22734 [PubMed]
8. Dugum M, McCullough A. 2015. Diagnosis and management of alcoholic liver disease. J Clin Transl Hepatol 3:109–116. http://dx.doi.org/10.14218/JCTH.2015.00008 [PubMed]
9. Naveau S, Cassard-Doulcier AM, Njiké-Nakseu M, Bouchet-Delbos L, Barri-Ova N, Boujedidi H, Dauvois B, Balian A, Maitre S, Prévot S, Dagher I, Agostini H, Grangeot-Keros L, Emilie D, Perlemuter G. 2010. Harmful effect of adipose tissue on liver lesions in patients with alcoholic liver disease. J Hepatol 52:895–902. http://dx.doi.org/10.1016/j.jhep.2010.01.029 [PubMed]
10. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, Mullen KD, Cooper JN, Sheridan MJ. 2002. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123:745–750. http://dx.doi.org/10.1053/gast.2002.35354 [PubMed]
11. Musso G. 2011. The Finnish Diabetes Risk Score (FINDRISC) and other non-invasive scores for screening of hepatic steatosis and associated cardiometabolic risk. Ann Med 43:413–417. http://dx.doi.org/10.3109/07853890.2011.579152 [PubMed]
12. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. 2006. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44:865–873. http://dx.doi.org/10.1002/hep.21327 [PubMed]
13. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. 2005. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129:113–121. http://dx.doi.org/10.1053/j.gastro.2005.04.014 [PubMed]
14. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. 2015. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149:389–397.e10. [PubMed]
15. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. 2015. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 62:1148–1155. http://dx.doi.org/10.1016/j.jhep.2014.11.034 [PubMed]
16. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T. 2000. Liver fibrosis in overweight patients. Gastroenterology 118:1117–1123. http://dx.doi.org/10.1016/S0016-5085(00)70364-7 [PubMed]
17. Ertle J, Dechêne A, Sowa JP, Penndorf V, Herzer K, Kaiser G, Schlaak JF, Gerken G, Syn WK, Canbay A. 2011. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 128:2436–2443. http://dx.doi.org/10.1002/ijc.25797 [PubMed]
18. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR. 2010. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51:121–129. http://dx.doi.org/10.1002/hep.23276 [PubMed]
19. Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB, NASH CRN Research Group. 2011. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol 106:460–468, quiz 469. http://dx.doi.org/10.1038/ajg.2010.488 [PubMed]
20. Wu T, Gao X, Chen M, van Dam RM. 2009. Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss: a meta-analysis. Obes Rev 10:313–323. http://dx.doi.org/10.1111/j.1467-789X.2008.00547.x [PubMed]
21. Hardy T, Anstee QM, Day CP. 2015. Nonalcoholic fatty liver disease: new treatments. Curr Opin Gastroenterol 31:175–183. http://dx.doi.org/10.1097/MOG.0000000000000175 [PubMed]
22. Mackenzie TA, Zaha R, Smith J, Karagas MR, Morden NE. 2016. Diabetes pharmacotherapies and bladder cancer: a medicare epidemiologic study. Diabetes Ther 7:61–73. http://dx.doi.org/10.1007/s13300-016-0152-4 [PubMed]
23. Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW. 2014. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63:727–735. http://dx.doi.org/10.1136/gutjnl-2012-303839 [PubMed]
24. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, NASH Clinical Research Network. 2010. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685. http://dx.doi.org/10.1056/NEJMoa0907929 [PubMed]
25. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E, NASH Clinical Research Network. 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965. http://dx.doi.org/10.1016/S0140-6736(14)61933-4
26. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, Raverdy V, Leteurtre E, Dharancy S, Louvet A, Romon M, Duhamel A, Pattou F, Mathurin P. 2015. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 149:379–388; quiz e315–376.
27. Thursz MR, Forrest EH, Ryder S, STOPAH Investigators. 2015. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 373:282–283. [PubMed]
28. Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D, Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C, Pageaux GP, Sobesky R, Canva-Delcambre V, Dharancy S, Salleron J, Dao T. 2013. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA 310:1033–1041. http://dx.doi.org/10.1001/jama.2013.276300 [PubMed]
29. Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O’Grady J, Patch D, Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH, STOPAH Trial. 2015. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 372:1619–1628. http://dx.doi.org/10.1056/NEJMoa1412278 [PubMed]
30. Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL, AAH-NAC Study Group. 2011. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 365:1781–1789. http://dx.doi.org/10.1056/NEJMoa1101214 [PubMed]
31. Thursz M, Morgan TR. 2016. Treatment of severe alcoholic hepatitis. Gastroenterology 150:1823–1834. http://dx.doi.org/10.1053/j.gastro.2016.02.074 [PubMed]
32. Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, Castel H, Duhamel A, Pageaux GP, Leroy V, Dharancy S, Louvet A, Boleslawski E, Lucidi V, Gustot T, Francoz C, Letoublon C, Castaing D, Belghiti J, Donckier V, Pruvot FR, Duclos-Vallée JC. 2011. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 365:1790–1800. http://dx.doi.org/10.1056/NEJMoa1105703 [PubMed]
33. Zeng H, Liu J, Jackson MI, Zhao FQ, Yan L, Combs GF Jr. 2013. Fatty liver accompanies an increase in lactobacillus species in the hind gut of C57BL/6 mice fed a high-fat diet. J Nutr 143:627–631. http://dx.doi.org/10.3945/jn.112.172460 [PubMed]
34. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR. 2013. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57:601–609. http://dx.doi.org/10.1002/hep.26093 [PubMed]
35. Raman M, Ahmed I, Gillevet PM, Probert CS, Ratcliffe NM, Smith S, Greenwood R, Sikaroodi M, Lam V, Crotty P, Bailey J, Myers RP, Rioux KP. 2013. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 11:868–875.e1–3. [PubMed]
36. Jiang W, Wu N, Wang X, Chi Y, Zhang Y, Qiu X, Hu Y, Li J, Liu Y. 2015. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep 5:8096. http://dx.doi.org/10.1038/srep08096 [PubMed]
37. Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. 2013. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58:120–127. http://dx.doi.org/10.1002/hep.26319 [PubMed]
38. Wong VW, Tse CH, Lam TT, Wong GL, Chim AM, Chu WC, Yeung DK, Law PT, Kwan HS, Yu J, Sung JJ, Chan HL. 2013. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis—a longitudinal study. PLoS One 8:e62885. http://dx.doi.org/10.1371/journal.pone.0062885 [PubMed]
39. Wang B, Jiang X, Cao M, Ge J, Bao Q, Tang L, Chen Y, Li L. 2016. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci Rep 6:32002. http://dx.doi.org/10.1038/srep32002 [PubMed]
40. Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. 2011. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 140:976–986. http://dx.doi.org/10.1053/j.gastro.2010.11.049 [PubMed]
41. Gérard P. 2016. Gut microbiota and obesity. Cell Mol Life Sci 73:147–162. http://dx.doi.org/10.1007/s00018-015-2061-5 [PubMed]
42. Wang ZK, Yang YS, Chen Y, Yuan J, Sun G, Peng LH. 2014. Intestinal microbiota pathogenesis and fecal microbiota transplantation for inflammatory bowel disease. World J Gastroenterol 20:14805–14820. http://dx.doi.org/10.3748/wjg.v20.i40.14805 [PubMed]
43. Claus SP, Ellero SL, Berger B, Krause L, Bruttin A, Molina J, Paris A, Want EJ, de Waziers I, Cloarec O, Richards SE, Wang Y, Dumas ME, Ross A, Rezzi S, Kochhar S, Van Bladeren P, Lindon JC, Holmes E, Nicholson JK. 2011. Colonization-induced host-gut microbial metabolic interaction. mBio 2:e00271-10. http://dx.doi.org/10.1128/mBio.00271-10 [PubMed]
44. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. 2012. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179–185.
45. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G, Cassard-Doulcier AM, Gérard P. 2013. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62:1787–1794. http://dx.doi.org/10.1136/gutjnl-2012-303816 [PubMed]
46. Ferolla SM, Armiliato GN, Couto CA, Ferrari TC. 2014. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients 6:5583–5599. http://dx.doi.org/10.3390/nu6125583 [PubMed]
47. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A. 2009. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49:1877–1887. http://dx.doi.org/10.1002/hep.22848 [PubMed]
48. Giorgio V, Miele L, Principessa L, Ferretti F, Villa MP, Negro V, Grieco A, Alisi A, Nobili V. 2014. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis 46:556–560. http://dx.doi.org/10.1016/j.dld.2014.02.010 [PubMed]
49. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. 2007. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772. http://dx.doi.org/10.2337/db06-1491 [PubMed]
50. Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC. 2007. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50:1267–1276. http://dx.doi.org/10.1007/s00125-007-0654-8 [PubMed]
51. Ye D, Li FY, Lam KS, Li H, Jia W, Wang Y, Man K, Lo CM, Li X, Xu A. 2012. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61:1058–1067. http://dx.doi.org/10.1136/gutjnl-2011-300269 [PubMed]
52. Laugerette F, Vors C, Géloën A, Chauvin MA, Soulage C, Lambert-Porcheron S, Peretti N, Alligier M, Burcelin R, Laville M, Vidal H, Michalski MC. 2011. Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. J Nutr Biochem 22:53–59. http://dx.doi.org/10.1016/j.jnutbio.2009.11.011 [PubMed]
53. Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG. 2010. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm (Lond) 7:15. http://dx.doi.org/10.1186/1476-9255-7-15 [PubMed]
54. Verdam FJ, Rensen SS, Driessen A, Greve JW, Buurman WA. 2011. Novel evidence for chronic exposure to endotoxin in human nonalcoholic steatohepatitis. J Clin Gastroenterol 45:149–152. http://dx.doi.org/10.1097/MCG.0b013e3181e12c24 [PubMed]
55. Yuan J, Baker SS, Liu W, Alkhouri R, Baker RD, Xie J, Ji G, Zhu L. 2014. Endotoxemia unrequired in the pathogenesis of pediatric nonalcoholic steatohepatitis. J Gastroenterol Hepatol 29:1292–1298. http://dx.doi.org/10.1111/jgh.12510 [PubMed]
56. de Medeiros IC, de Lima JG. 2015. Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease? - A mechanistic hypothesis. Med Hypotheses 85:148–152. http://dx.doi.org/10.1016/j.mehy.2015.04.021 [PubMed]
57. Volynets V, Küper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, Königsrainer A, Bischoff SC, Bergheim I. 2012. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci 57:1932–1941. http://dx.doi.org/10.1007/s10620-012-2112-9 [PubMed]
58. Buchman AL, Dubin MD, Moukarzel AA, Jenden DJ, Roch M, Rice KM, Gornbein J, Ament ME. 1995. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22:1399–1403. [PubMed]
59. Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC, Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK. 2006. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci USA 103:12511–12516. http://dx.doi.org/10.1073/pnas.0601056103 [PubMed]
60. Hofmann AF, Hagey LR, Krasowski MD. 2010. Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res 51:226–246. http://dx.doi.org/10.1194/jlr.R000042 [PubMed]
61. Ridlon JM, Kang DJ, Hylemon PB. 2006. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47:241–259. http://dx.doi.org/10.1194/jlr.R500013-JLR200 [PubMed]
62. Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. 2009. Bile acids as regulatory molecules. J Lipid Res 50:1509–1520. http://dx.doi.org/10.1194/jlr.R900007-JLR200 [PubMed]
63. Gérard P. 2013. Metabolism of cholesterol and bile acids by the gut microbiota. Pathogens 3:14–24. http://dx.doi.org/10.3390/pathogens3010014 [PubMed]
64. Hofmann AF. 2004. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab Rev 36:703–722. http://dx.doi.org/10.1081/DMR-200033475 [PubMed]
65. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N. 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101. http://dx.doi.org/10.1038/nature12347 [PubMed]
66. Stenman LK, Holma R, Forsgård R, Gylling H, Korpela R. 2013. Higher fecal bile acid hydrophobicity is associated with exacerbation of dextran sodium sulfate colitis in mice. J Nutr 143:1691–1697. http://dx.doi.org/10.3945/jn.113.180810 [PubMed]
67. Lepercq P, Gérard P, Béguet F, Raibaud P, Grill JP, Relano P, Cayuela C, Juste C. 2004. Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces. FEMS Microbiol Lett 235:65–72. http://dx.doi.org/10.1111/j.1574-6968.2004.tb09568.x [PubMed]
68. Ritze Y, Bárdos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, Bischoff SC. 2014. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS One 9:e80169. http://dx.doi.org/10.1371/journal.pone.0080169 [PubMed]
69. Cano PG, Santacruz A, Trejo FM, Sanz Y. 2013. Bifidobacterium CECT 7765 improves metabolic and immunological alterations associated with obesity in high-fat diet-fed mice. Obesity (Silver Spring) 21:2310–2321. http://dx.doi.org/10.1002/oby.20330 [PubMed]
70. Gauffin Cano P, Santacruz A, Moya Á, Sanz Y. 2012. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 7:e41079. http://dx.doi.org/10.1371/journal.pone.0041079 [PubMed]
71. Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T, Matsunaga Y, Kamata H, Asahara T, Yoshida Y, Chonan O, Iwashita M, Nishimura F, Asano T. 2013. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 305:G911–G918. http://dx.doi.org/10.1152/ajpgi.00225.2013 [PubMed]
72. Nardone G, Compare D, Liguori E, Di Mauro V, Rocco A, Barone M, Napoli A, Lapi D, Iovene MR, Colantuoni A. 2010. Protective effects of Lactobacillus paracasei F19 in a rat model of oxidative and metabolic hepatic injury. Am J Physiol Gastrointest Liver Physiol 299:G669–G676. http://dx.doi.org/10.1152/ajpgi.00188.2010 [PubMed]
73. Ma X, Hua J, Li Z. 2008. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 49:821–830. http://dx.doi.org/10.1016/j.jhep.2008.05.025 [PubMed]
74. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. 2003. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37:343–350. http://dx.doi.org/10.1053/jhep.2003.50048 [PubMed]
75. Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. 2013. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 19:6911–6918. http://dx.doi.org/10.3748/wjg.v19.i40.6911 [PubMed]
76. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. 2013. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 110:9066–9071. http://dx.doi.org/10.1073/pnas.1219451110 [PubMed]
77. Pachikian BD, Essaghir A, Demoulin JB, Catry E, Neyrinck AM, Dewulf EM, Sohet FM, Portois L, Clerbaux LA, Carpentier YA, Possemiers S, Bommer GT, Cani PD, Delzenne NM. 2013. Prebiotic approach alleviates hepatic steatosis: implication of fatty acid oxidative and cholesterol synthesis pathways. Mol Nutr Food Res 57:347–359. http://dx.doi.org/10.1002/mnfr.201200364 [PubMed]
78. Foschini MP, Macchia S, Losi L, Dei Tos AP, Pasquinelli G, Di Tommaso L, Del Duca S, Roncaroli F, Dal Monte PR. 1998. Identification of mitochondria in liver biopsies. A study by immunohistochemistry, immunogold and Western blot analysis. Virchows Arch 433:267–273. http://dx.doi.org/10.1007/s004280050246
79. Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G, Galvano F. 2012. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 57:545–553. http://dx.doi.org/10.1007/s10620-011-1887-4 [PubMed]
80. Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. 2014. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr 99:535–542. http://dx.doi.org/10.3945/ajcn.113.068890 [PubMed]
81. Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. 1995. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108:218–224. http://dx.doi.org/10.1016/0016-5085(95)90027-6
82. Bode C, Kugler V, Bode JC. 1987. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol 4:8–14. http://dx.doi.org/10.1016/S0168-8278(87)80003-X
83. Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H. 2000. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 32:1008–1017. http://dx.doi.org/10.1053/jhep.2000.19621
84. Nanji AA, Khettry U, Sadrzadeh SM, Yamanaka T. 1993. Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2. Am J Pathol 142:367–373. [PubMed]
85. Keshavarzian A, Fields JZ, Vaeth J, Holmes EW. 1994. The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol 89:2205–2211. [PubMed]
86. Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. 2000. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 32:742–747. http://dx.doi.org/10.1016/S0168-8278(00)80242-1
87. Rao R. 2009. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50:638–644. http://dx.doi.org/10.1002/hep.23009 [PubMed]
88. Elamin EE, Masclee AA, Dekker J, Jonkers DM. 2013. Ethanol metabolism and its effects on the intestinal epithelial barrier. Nutr Rev 71:483–499. http://dx.doi.org/10.1111/nure.12027 [PubMed]
89. Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z. 2013. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. Am J Physiol Gastrointest Liver Physiol 305:G919–G932. http://dx.doi.org/10.1152/ajpgi.00226.2013 [PubMed]
90. Grewal RK, Mahmood A. 2009. Ethanol induced changes in glycosylation of mucins in rat intestine. Ann Gastroenterol 22:178–183.
91. Ferrier L, Bérard F, Debrauwer L, Chabo C, Langella P, Buéno L, Fioramonti J. 2006. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am J Pathol 168:1148–1154. http://dx.doi.org/10.2353/ajpath.2006.050617 [PubMed]
92. Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. 2011. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr 141:769–776. http://dx.doi.org/10.3945/jn.110.135657 [PubMed]
93. Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, Gobejishvili L, Joshi-Barve S, Ayvaz T, Petrosino J, Kong M, Barker D, McClain C, Barve S. 2013. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS One 8:e53028. http://dx.doi.org/10.1371/journal.pone.0053028 [PubMed]
94. Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. 2009. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res 33:1836–1846. http://dx.doi.org/10.1111/j.1530-0277.2009.01022.x [PubMed]
95. Yan AW, Fouts DE, Brandl J, Stärkel P, Torralba M, Schott E, Tsukamoto H, Nelson KE, Brenner DA, Schnabl B. 2011. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53:96–105. http://dx.doi.org/10.1002/hep.24018 [PubMed]
96. Mutlu EA, Gillevet PM, Rangwala H, Sikaroodi M, Naqvi A, Engen PA, Kwasny M, Lau CK, Keshavarzian A. 2012. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 302:G966–G978. http://dx.doi.org/10.1152/ajpgi.00380.2011 [PubMed]
97. Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A, Ferrere G, Puchois V, Martin JC, Lepage P, Le Roy T, Lefèvre L, Langelier B, Cailleux F, González-Castro AM, Rabot S, Gaudin F, Agostini H, Prévot S, Berrebi D, Ciocan D, Jousse C, Naveau S, Gérard P, Perlemuter G. 2016. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 65:830–839. http://dx.doi.org/10.1136/gutjnl-2015-310585 [PubMed]
98. Dorrestein PC, Mazmanian SK, Knight R. 2014. Finding the missing links among metabolites, microbes, and the host. Immunity 40:824–832. http://dx.doi.org/10.1016/j.immuni.2014.05.015 [PubMed]
99. Couch RD, Dailey A, Zaidi F, Navarro K, Forsyth CB, Mutlu E, Engen PA, Keshavarzian A. 2015. Alcohol induced alterations to the human fecal VOC metabolome. PLoS One 10:e0119362. http://dx.doi.org/10.1371/journal.pone.0119362 [PubMed]
100. Xie G, Zhong W, Li H, Li Q, Qiu Y, Zheng X, Chen H, Zhao X, Zhang S, Zhou Z, Zeisel SH, Jia W. 2013. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. FASEB J 27:3583–3593. http://dx.doi.org/10.1096/fj.13-231860 [PubMed]
101. Kakiyama G, Pandak WM, Gillevet PM, Hylemon PB, Heuman DM, Daita K, Takei H, Muto A, Nittono H, Ridlon JM, White MB, Noble NA, Monteith P, Fuchs M, Thacker LR, Sikaroodi M, Bajaj JS. 2013. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 58:949–955. http://dx.doi.org/10.1016/j.jhep.2013.01.003 [PubMed]
102. Jones ML, Martoni CJ, Ganopolsky JG, Labbé A, Prakash S. 2014. The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention. Expert Opin Biol Ther 14:467–482. http://dx.doi.org/10.1517/14712598.2014.880420 [PubMed]
103. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. 2009. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89:147–191. http://dx.doi.org/10.1152/physrev.00010.2008 [PubMed]
104. Manley S, Ding W. 2015. Role of farnesoid X receptor and bile acids in alcoholic liver disease. Acta Pharm Sin B 5:158–167. http://dx.doi.org/10.1016/j.apsb.2014.12.011 [PubMed]
105. Wu WB, Chen YY, Zhu B, Peng XM, Zhang SW, Zhou ML. 2015. Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice. Biochimie 115:86–92. http://dx.doi.org/10.1016/j.biochi.2015.05.014 [PubMed]
106. Fouts DE, Torralba M, Nelson KE, Brenner DA, Schnabl B. 2012. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 56:1283–1292. http://dx.doi.org/10.1016/j.jhep.2012.01.019 [PubMed]
107. Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, Stärkel P, Belzer C, Hellerbrand C, Tsukamoto H, Ho SB, Schnabl B. 2013. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 58:108–119. http://dx.doi.org/10.1002/hep.26321 [PubMed]
108. Wang L, Fouts DE, Stärkel P, Hartmann P, Chen P, Llorente C, DePew J, Moncera K, Ho SB, Brenner DA, Hooper LV, Schnabl B. 2016. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation. Cell Host Microbe 19:227–239. http://dx.doi.org/10.1016/j.chom.2016.01.003 [PubMed]
109. Ferrere G, Wrzosek L, Cailleux F, Turpin W, Puchois V, Spatz M, Ciocan D, Rainteau D, Humbert L, Hugot C, Gaudin F, Noordine ML, Robert V, Berrebi D, Thomas M, Naveau S, Perlemuter G, Cassard AM. 2017. Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice. J Hepatol 66:806–815. [PubMed]
110. Little TJ, Feinle-Bisset C. 2011. Effects of dietary fat on appetite and energy intake in health and obesity--oral and gastrointestinal sensory contributions. Physiol Behav 104:613–620. http://dx.doi.org/10.1016/j.physbeh.2011.04.038 [PubMed]
111. Mithieux G. 2014. Crosstalk between gastrointestinal neurons and the brain in the control of food intake. Best Pract Res Clin Endocrinol Metab 28:739–744. http://dx.doi.org/10.1016/j.beem.2014.03.004 [PubMed]
112. Bauer KC, Huus KE, Finlay BB. 2016. Microbes and the mind: emerging hallmarks of the gut microbiota-brain axis. Cell Microbiol 18:632–644. http://dx.doi.org/10.1111/cmi.12585 [PubMed]
113. Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Stärkel P, Windey K, Tremaroli V, Bäckhed F, Verbeke K, de Timary P, Delzenne NM. 2014. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA 111:E4485–E4493. http://dx.doi.org/10.1073/pnas.1415174111 [PubMed]
114. Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. 2009. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol 43:163–172. http://dx.doi.org/10.1016/j.alcohol.2008.12.009 [PubMed]
115. Nanji AA, Khettry U, Sadrzadeh SM. 1994. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 205:243–247. http://dx.doi.org/10.3181/00379727-205-43703 [PubMed]
116. Keshavarzian A, Choudhary S, Holmes EW, Yong S, Banan A, Jakate S, Fields JZ. 2001. Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats. J Pharmacol Exp Ther 299:442–448. [PubMed]
117. Wang Y, Kirpich I, Liu Y, Ma Z, Barve S, McClain CJ, Feng W. 2011. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Am J Pathol 179:2866–2875. http://dx.doi.org/10.1016/j.ajpath.2011.08.039 [PubMed]
118. Wang Y, Liu Y, Kirpich I, Ma Z, Wang C, Zhang M, Suttles J, McClain C, Feng W. 2013. Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury. J Nutr Biochem 24:1609–1615. http://dx.doi.org/10.1016/j.jnutbio.2013.02.001 [PubMed]
119. Chang B, Sang L, Wang Y, Tong J, Zhang D, Wang B. 2013. The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury. BMC Gastroenterol 13:151. http://dx.doi.org/10.1186/1471-230X-13-151 [PubMed]
120. Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C, Del Vecchio Blanco C. 2005. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 39:540–543. http://dx.doi.org/10.1097/01.mcg.0000165671.25272.0f [PubMed]
121. Zhong W, Zhou Z. 2014. Alterations of the gut microbiome and metabolome in alcoholic liver disease. World J Gastrointest Pathophysiol 5:514–522. http://dx.doi.org/10.4291/wjgp.v5.i4.514 [PubMed]
122. Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, Guy CD, Seed PC, Rawls JF, David LA, Hunault G, Oberti F, Calès P, Diehl AM. 2016. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63:764–775. http://dx.doi.org/10.1002/hep.28356 [PubMed]
123. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, Mingarelli E, Facinelli B, Magi G, Palmieri C, Marzioni M, Benedetti A, Svegliati-Baroni G. 2014. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59:1738–1749. http://dx.doi.org/10.1002/hep.26695 [PubMed]
124. Gómez-Hurtado I, Santacruz A, Peiró G, Zapater P, Gutiérrez A, Pérez-Mateo M, Sanz Y, Francés R. 2011. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS One 6:e23037. http://dx.doi.org/10.1371/journal.pone.0023037 [PubMed]
125. Cuenca S, Sanchez E, Santiago A, El Khader I, Panda S, Vidal S, Camilo Nieto J, Juárez C, Sancho F, Guarner F, Soriano G, Guarner C, Manichanh C. 2014. Microbiome composition by pyrosequencing in mesenteric lymph nodes of rats with CCl4-induced cirrhosis. J Innate Immun 6:263–271. [PubMed]
126. Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B. 2015. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 29:1043–1055. http://dx.doi.org/10.1096/fj.14-259515 [PubMed]
127. Li M, Zhu L, Xie A, Yuan J. 2015. Oral administration of Saccharomyces boulardii ameliorates carbon tetrachloride-induced liver fibrosis in rats via reducing intestinal permeability and modulating gut microbial composition. Inflammation 38:170–179. http://dx.doi.org/10.1007/s10753-014-0019-7 [PubMed]
128. Sánchez E, Nieto JC, Boullosa A, Vidal S, Sancho FJ, Rossi G, Sancho-Bru P, Oms R, Mirelis B, Juárez C, Guarner C, Soriano G. 2015. VSL#3 probiotic treatment decreases bacterial translocation in rats with carbon tetrachloride-induced cirrhosis. Liver Int 35:735–745. http://dx.doi.org/10.1111/liv.12566 [PubMed]
129. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. 2011. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54:562–572. http://dx.doi.org/10.1002/hep.24423 [PubMed]
130. Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, Guo J, Le Chatelier E, Yao J, Wu L, Zhou J, Ni S, Liu L, Pons N, Batto JM, Kennedy SP, Leonard P, Yuan C, Ding W, Chen Y, Hu X, Zheng B, Qian G, Xu W, Ehrlich SD, Zheng S, Li L. 2014. Alterations of the human gut microbiome in liver cirrhosis. Nature 513:59–64. http://dx.doi.org/10.1038/nature13568 [PubMed]
131. Wei X, Yan X, Zou D, Yang Z, Wang X, Liu W, Wang S, Li X, Han J, Huang L, Yuan J. 2013. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterol 13:175. http://dx.doi.org/10.1186/1471-230X-13-175 [PubMed]
132. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, Noble NA, Unser AB, Daita K, Fisher AR, Sikaroodi M, Gillevet PM. 2014. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 60:940–947. http://dx.doi.org/10.1016/j.jhep.2013.12.019 [PubMed]
133. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, Sikaroodi M, Gillevet PM. 2012. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 302:G168–G175. http://dx.doi.org/10.1152/ajpgi.00190.2011 [PubMed]
134. Lunia MK, Sharma BC, Sharma P, Sachdeva S, Srivastava S. 2014. Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 12:1003–1008.e1. [PubMed]
135. Jayakumar S, Carbonneau M, Hotte N, Befus AD, St Laurent C, Owen R, McCarthy M, Madsen K, Bailey RJ, Ma M, Bain V, Rioux K, Tandon P. 2013. VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis. Liver Int 33:1470–1477.
136. Bajaj JS, Betrapally NS, Hylemon PB, Thacker LR, Daita K, Kang DJ, White MB, Unser AB, Fagan A, Gavis EA, Sikaroodi M, Dalmet S, Heuman DM, Gillevet PM. 2015. Gut microbiota alterations can predict hospitalizations in cirrhosis independent of diabetes mellitus. Sci Rep 5:18559. http://dx.doi.org/10.1038/srep18559 [PubMed]
137. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, Puri P, Sterling RK, Luketic V, Stravitz RT, Siddiqui MS, Fuchs M, Thacker LR, Wade JB, Daita K, Sistrun S, White MB, Noble NA, Thorpe C, Kakiyama G, Pandak WM, Sikaroodi M, Gillevet PM. 2014. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 39:1113–1125. http://dx.doi.org/10.1111/apt.12695 [PubMed]
138. Rogers GB, van der Gast CJ, Bruce KD, Marsh P, Collins JE, Sutton J, Wright M. 2013. Ascitic microbiota composition is correlated with clinical severity in cirrhosis with portal hypertension. PLoS One 8:e74884. http://dx.doi.org/10.1371/journal.pone.0074884 [PubMed]
139. Sherman M. 2010. Epidemiology of hepatocellular carcinoma. Oncology 78(Suppl 1) :7–10. http://dx.doi.org/10.1159/000315223 [PubMed]
140. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, Lefkowitch JH, Bower M, Friedman R, Sartor RB, Rabadan R, Schwabe RF. 2012. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21:504–516. http://dx.doi.org/10.1016/j.ccr.2012.02.007 [PubMed]
141. Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, Tang L, Lin Y, He YQ, Zou SS, Wang C, Zhang HL, Cao GW, Wu MC, Wang HY. 2010. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52:1322–1333. http://dx.doi.org/10.1002/hep.23845 [PubMed]
142. Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, Lv X, Yu J, Mi S, Wang J, Hu ZW. 2013. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology 57:1869–1881. http://dx.doi.org/10.1002/hep.26234 [PubMed]
143. Eiro N, Altadill A, Juarez LM, Rodriguez M, Gonzalez LO, Atienza S, Bermudez S, Fernandez-Garcia B, Fresno-Forcelledo MF, Rodrigo L, Vizoso FJ. 2014. Toll-like receptors 3, 4 and 9 in hepatocellular carcinoma: relationship with clinicopathological characteristics and prognosis. Hepatology Res 44:769–778. [PubMed]
144. Wells JE, Hylemon PB. 2000. Identification and characterization of a bile acid 7alpha-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7alpha-dehydroxylating strain isolated from human feces. Appl Environ Microbiol 66:1107–1113. http://dx.doi.org/10.1128/AEM.66.3.1107-1113.2000 [PubMed]

Article metrics loading...



Being overweight and obesity are the leading causes of liver disease in Western countries. Liver damage induced by being overweight can range from steatosis, harmless in its simple form, to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol consumption is an additional major cause of liver disease. Not all individuals who are overweight or excessively consume alcohol develop nonalcoholic fatty liver diseases (NAFLD) or alcoholic liver disease (ALD) and advanced liver disease. The role of the intestinal microbiota (IM) in the susceptibility to liver disease in this context has been the subject of recent studies. ALD and NAFLD appear to be influenced by the composition of the IM, and dysbiosis is associated with ALD and NAFLD in rodent models and human patient cohorts. Several microbial metabolites, such as short-chain fatty acids and bile acids, are specifically associated with dysbiosis. Recent studies have highlighted the causal role of the IM in the development of liver diseases, and the use of probiotics or prebiotics improves some parameters associated with liver disease. Several studies have made progress in deciphering the mechanisms associated with the modulation of the IM. These data have demonstrated the intimate relationship between the IM and metabolic liver disease, suggesting that targeting the gut microbiota could be a new preventive or therapeutic strategy for these diseases.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...



Image of FIGURE 1

Click to view


Histology of the liver. Paraffin sections (4 μm thick) were stained with hematoxylin and eosin. Images were obtained using a Hamamatsu scanning module (Hamamatsu LX2000) and appropriate software (magnification, ×100). Healthy tissue; steatosis; steatosis with inflammation; fibrosis.

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0007-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Click to view


Intestinal microbiota in liver disease. Diet and alcohol influence the composition of the gut bacteria. Dysbiosis is associated with changes in bacterial metabolites such as SCFA and BAs. The gut barrier is also altered, leading to increased endotoxemia (LPS). Acetaldehyde is specifically produced by the gut bacteria in ALD. Modifications of BAs and activation of their receptors, FXR and TGR5, participate in the development of liver lesions.

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0007-2016
Permissions and Reprints Request Permissions
Download as Powerpoint


Generic image for table

Click to view


Main differences between ALD and NAFLD

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0007-2016
Generic image for table

Click to view


Microbiotas associated with different stages of NAFLD

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0007-2016
Generic image for table

Click to view


Comparison of healthy microbiotas and microbiotas associated with cirrhosis

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0007-2016

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error