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The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD)

Abstract

NAFLD is currently the main cause of chronic liver disease in developed countries, and the number of NAFLD patients is growing worldwide. NAFLD often has similar symptoms to other metabolic disorders, including type 2 diabetes and obesity. Recently, the role of the gut microbiota in the pathophysiology of many diseases has been revealed. Regarding NAFLD, experiments using gut microbiota transplants to germ-free animal models showed that fatty liver disease development is determined by gut bacteria. Moreover, the perturbation of the composition of the gut microbiota has been observed in patients suffering from NAFLD. Numerous mechanisms relating the gut microbiome to NAFLD have been proposed, including the dysbiosis-induced dysregulation of gut endothelial barrier function that allows for the translocation of bacterial components and leads to hepatic inflammation. In addition, the various metabolites produced by the gut microbiota may impact the liver and thus modulate NAFLD susceptibility. Therefore, the manipulation of the gut microbiome by probiotics, prebiotics or synbiotics was shown to improve liver phenotype in NAFLD patients as well as in rodent models. Hence, further knowledge about the interactions among dysbiosis, environmental factors, and diet and their impacts on the gut–liver axis can improve the treatment of this life-threatening liver disease and its related disorders.

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Abbreviations

AMPK:

AMP-activated protein kinase

ANGPTL4:

Angiopoietin-like 4

CV:

Conventional

FMT:

Faecal microbiota transplantation

FOS:

Fructooligosaccharides

FXR:

Farnesoid X receptor

GF:

Germ free

GI:

Gastrointestinal

GLP:

Glucagon-like peptide

HBV:

Hepatitis B virus

HFD:

High-fat diet

LPS:

Lipopolysaccharides

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

PAMPs:

Pathogen-associated molecular patterns

PEMT:

Phosphatidylethanolamine methyltransferase

SCFA:

Short-chain fatty acid

TJ:

Tight junction

TMA:

Trimethylamine

References

  1. 1.

    Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Reddy DN (2015) Role of the normal gut microbiota. WJG 21(29):8787–8803. https://doi.org/10.3748/wjg.v21.i29.8787

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444(7122):1022–1023. https://doi.org/10.1038/4441022a

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Huttenhower C, Gevers D, Knight R, Abubucker S, Badger JH, Chinwalla AT, Creasy HH, Earl AM, FitzGerald MG, Fulton RS, Giglio MG (2012) Structure, function and diversity of the healthy human microbiome. Nature 486(7402):207–214. https://doi.org/10.1038/nature11234

    CAS  Article  Google Scholar 

  4. 4.

    Gillespie JJ, Wattam AR, Cammer SA, Gabbard JL, Shukla MP, Dalay O, Driscoll T, Hix D, Mane SP, Mao C, Nordberg EK, Scott M, Schulman JR, Snyder EE, Sullivan DE, Wang C, Warren A, Williams KP, Xue T, Yoo HS, Zhang C, Zhang Y, Will R, Kenyon RW, Sobral BW (2011) PATRIC: the comprehensive bacterial bioinformatics resource with a focus on human pathogenic species. Infect Immun 79(11):4286–4298. https://doi.org/10.1128/iai.00207-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hollister EB, Gao C, Versalovic J (2014) Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology 146(6):1449–1458. https://doi.org/10.1053/j.gastro.2014.01.052

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Swidsinski A, Loening-Baucke V, Lochs H, Hale LP (2005) Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J Gastroenterol 11(8):1131–1140

    Article  Google Scholar 

  7. 7.

    Brown CT, Sharon I, Thomas BC, Castelle CJ, Morowitz MJ, Banfield JF (2013) Genome resolved analysis of a premature infant gut microbial community reveals a Varibaculum cambriense genome and a shift towards fermentation-based metabolism during the third week of life. Microbiome 1(1):30. https://doi.org/10.1186/2049-2618-1-30

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Clemente JC, Ursell LK, Parfrey LW, Knight R (2012) The impact of the gut microbiota on human health: an integrative view. Cell 148(6):1258–1270. https://doi.org/10.1016/j.cell.2012.01.035

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Macpherson AJ, de Aguero MG, Ganal-Vonarburg SC (2017) How nutrition and the maternal microbiota shape the neonatal immune system. Nat Rev Immunol 17(8):508–517. https://doi.org/10.1038/nri.2017.58

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Vaahtovuo J, Toivanen P, Eerola E (2003) Bacterial composition of murine fecal microflora is indigenous and genetically guided. FEMS Microbiol Ecol 44(1):131–136. https://doi.org/10.1016/s0168-6496(02)00460-9

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Kovacs A, Ben-Jacob N, Tayem H, Halperin E, Iraqi FA, Gophna U (2011) Genotype is a stronger determinant than sex of the mouse gut microbiota. Microb Ecol 61(2):423–428. https://doi.org/10.1007/s00248-010-9787-2

    Article  PubMed  Google Scholar 

  12. 12.

    Benson AK, Kelly SA, Legge R, Ma F, Low SJ, Kim J, Zhang M, Oh PL, Nehrenberg D, Hua K, Kachman SD, Moriyama EN, Walter J, Peterson DA, Pomp D (2010) Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors. Proc Natl Acad Sci 107(44):18933

    CAS  Article  Google Scholar 

  13. 13.

    Frank DN, Robertson CE, Hamm CM, Kpadeh Z, Zhang T, Chen H, Zhu W, Sartor RB, Boedeker EC, Harpaz N, Pace NR, Li E (2011) Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 17(1):179–184. https://doi.org/10.1002/ibd.21339

    Article  PubMed  Google Scholar 

  14. 14.

    Khachatryan ZA, Ktsoyan ZA, Manukyan GP, Kelly D, Ghazaryan KA, Aminov RI (2008) Predominant role of host genetics in controlling the composition of gut microbiota. PLoS One 3(8):e3064. https://doi.org/10.1371/journal.pone.0003064

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H, Kobayashi KS (2009) Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci USA 106(37):15813–15818. https://doi.org/10.1073/pnas.0907722106

    Article  PubMed  Google Scholar 

  16. 16.

    Wacklin P, Tuimala J, Nikkila J, Sebastian T, Makivuokko H, Alakulppi N, Laine P, Rajilic-Stojanovic M, Paulin L, de Vos WM, Matto J (2014) Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status. PLoS One 9(4):e94863. https://doi.org/10.1371/journal.pone.0094863

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Zhang C, Zhang M, Wang S, Han R, Cao Y, Hua W, Mao Y, Zhang X, Pang X, Wei C, Zhao G, Chen Y, Zhao L (2010) Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J 4(2):232–241. https://doi.org/10.1038/ismej.2009.112

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1(6):6ra14. https://doi.org/10.1126/scitranslmed.3000322

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI (2012) Human gut microbiome viewed across age and geography. Nature 486(7402):222–227. https://doi.org/10.1038/nature11053

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472(7341):57–63. https://doi.org/10.1038/nature09922

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Ley RE (2010) Obesity and the human microbiome. Curr Opin Gastroenterol 26(1):5–11. https://doi.org/10.1097/MOG.0b013e328333d751

    Article  PubMed  Google Scholar 

  22. 22.

    Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Al-Soud WA, Sorensen SJ, Hansen LH, Jakobsen M (2010) Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 5(2):e9085. https://doi.org/10.1371/journal.pone.0009085

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490(7418):55–60. https://doi.org/10.1038/nature11450

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Cani PD, Delzenne NM (2009) The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 15(13):1546–1558

    CAS  Article  Google Scholar 

  25. 25.

    Murphy EF, Cotter PD, Hogan A, O’Sullivan O, Joyce A, Fouhy F, Clarke SF, Marques TM, O’Toole PW, Stanton C, Quigley EM, Daly C, Ross PR, O’Doherty RM, Shanahan F (2013) Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut 62(2):220–226. https://doi.org/10.1136/gutjnl-2011-300705

    Article  PubMed  Google Scholar 

  26. 26.

    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 (Baltimore, MD) 59(5):1738–1749. https://doi.org/10.1002/hep.26695

    CAS  Article  Google Scholar 

  27. 27.

    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(7384):179–185. https://doi.org/10.1038/nature10809

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    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, Gerard P (2013) Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62(12):1787–1794. https://doi.org/10.1136/gutjnl-2012-303816

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, MD) 64(1):73–84. https://doi.org/10.1002/hep.28431

    Article  Google Scholar 

  30. 30.

    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology (Baltimore, MD) 40(6):1387–1395. https://doi.org/10.1002/hep.20466

    Article  Google Scholar 

  31. 31.

    Saab S, Manne V, Nieto J, Schwimmer JB, Chalasani NP (2016) Nonalcoholic Fatty Liver Disease in Latinos. Clin Gastroenterol Hepatol 14(1):5–12. https://doi.org/10.1016/j.cgh.2015.05.001

    Article  PubMed  Google Scholar 

  32. 32.

    Boccuto L, Abenavoli L (2017) The impact of genetic polymorphisms on liver diseases: entering the era of personalized medicine. Eur J Gastroenterol Hepatol 29(9):1102–1103. https://doi.org/10.1097/meg.0000000000000917

    Article  PubMed  Google Scholar 

  33. 33.

    Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ (2009) A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 50(10):2111–2116. https://doi.org/10.1194/jlr.P900013-JLR200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kleiner DE, Makhlouf HR (2016) Histology of NAFLD and NASH in adults and children. Clin Liver Dis 20(2):293–312. https://doi.org/10.1016/j.cld.2015.10.011

    Article  PubMed  Google Scholar 

  35. 35.

    Zatloukal K, French SW, Stumptner C, Strnad P, Harada M, Toivola DM, Cadrin M, Omary MB (2007) From Mallory to Mallory-Denk bodies: what, how and why? Exp Cell Res 313(10):2033–2049. https://doi.org/10.1016/j.yexcr.2007.04.024

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845

    CAS  Article  Google Scholar 

  37. 37.

    Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, Cartenì M, Nardone G (2012) Gut–liver axis: The impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 22(6):471–476. https://doi.org/10.1016/j.numecd.2012.02.007

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Henao-Mejia J, Elinav E, Thaiss CA, Licona-Limon P, Flavell RA (2013) Role of the intestinal microbiome in liver disease. J Autoimmun 46:66–73. https://doi.org/10.1016/j.jaut.2013.07.001

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Bieghs V, Trautwein C (2014) Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease. Hepatobiliary Surg Nutr 3(6):377–385. https://doi.org/10.3978/j.issn.2304-3881.2014.12.04

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Pedra JH, Cassel SL, Sutterwala FS (2009) Sensing pathogens and danger signals by the inflammasome. Curr Opin Immunol 21(1):10–16. https://doi.org/10.1016/j.coi.2009.01.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820. https://doi.org/10.1016/j.cell.2010.01.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Walkey CJ, Yu L, Agellon LB, Vance DE (1998) Biochemical and evolutionary significance of phospholipid methylation. J Biol Chem 273(42):27043–27046

    CAS  Article  Google Scholar 

  43. 43.

    Waite KA, Cabilio NR, Vance DE (2002) Choline deficiency-induced liver damage is reversible in Pemt−/− mice. J Nutr 132(1):68–71. https://doi.org/10.1093/jn/132.1.68

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Song J, da Costa KA, Fischer LM, Kohlmeier M, Kwock L, Wang S, Zeisel SH (2005) Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). Faseb J 19(10):1266–1271. https://doi.org/10.1096/fj.04-3580com

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Drenick EJ, Fisler J, Johnson D (1982) Hepatic steatosis after intestinal bypass–prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology 82(3):535–548

    CAS  PubMed  Google Scholar 

  46. 46.

    Gerard P (2016) Gut microbiota and obesity. Cell Mol Life Sci 73(1):147–162. https://doi.org/10.1007/s00018-015-2061-5

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Backhed F, Manchester JK, Semenkovich CF, Gordon JI (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 104(3):979–984. https://doi.org/10.1073/pnas.0605374104

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Rabot S, Membrez M, Bruneau A, Gerard P, Harach T, Moser M, Raymond F, Mansourian R, Chou CJ (2010) Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. Faseb J 24(12):4948–4959. https://doi.org/10.1096/fj.10-164921

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Fleissner CK, Huebel N, Abd El-Bary MM, Loh G, Klaus S, Blaut M (2010) Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br J Nutr 104(6):919–929. https://doi.org/10.1017/s0007114510001303

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI (2008) Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA 105(43):16767–16772. https://doi.org/10.1073/pnas.0808567105

    Article  PubMed  Google Scholar 

  51. 51.

    Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101(44):15718–15723. https://doi.org/10.1073/pnas.0407076101

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Björkholm B, Bok CM, Lundin A, Rafter J, Hibberd ML, Pettersson S (2009) Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS One 4(9):e6958. https://doi.org/10.1371/journal.pone.0006958

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    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(3):1043–1055. https://doi.org/10.1096/fj.14-259515

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Celaj S, Gleeson MW, Deng J, O’Toole GA, Hampton TH, Toft MF, Morrison HG, Sogin ML, Putra J, Suriawinata AA, Gorham JD (2014) The microbiota regulates susceptibility to Fas-mediated acute hepatic injury. Lab Invest 94(9):938–949. https://doi.org/10.1038/labinvest.2014.93

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    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 (Baltimore, MD) 58(1):120–127. https://doi.org/10.1002/hep.26319

    CAS  Article  Google Scholar 

  56. 56.

    Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG (2001) The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48(2):206–211

    CAS  Article  Google Scholar 

  57. 57.

    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 (Baltimore, MD) 57(2):601–609. https://doi.org/10.1002/hep.26093

    CAS  Article  Google Scholar 

  58. 58.

    Eslamparast T, Eghtesad S, Poustchi H, Hekmatdoost A (2015) Recent advances in dietary supplementation, in treating non-alcoholic fatty liver disease. World J Hepatol 7(2):204–212. https://doi.org/10.4254/wjh.v7.i2.204

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    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(3):535–542. https://doi.org/10.3945/ajcn.113.068890

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Rahimlou M, Ahmadnia H, Hekmatdoost A (2015) Dietary supplements and pediatric non-alcoholic fatty liver disease: Present and the future. World J Hepatol 7(25):2597–2602. https://doi.org/10.4254/wjh.v7.i25.2597

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Shavakhi A, Minakari M, Firouzian H, Assali R, Hekmatdoost A, Ferns G (2013) Effect of a probiotic and metformin on liver aminotransferases in non-alcoholic steatohepatitis: a double blind randomized clinical trial. Int J Prev Med 4(5):531–537

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Yari Z, Rahimlou M, Eslamparast T, Ebrahimi-Daryani N, Poustchi H, Hekmatdoost A (2016) Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study. Int J Food Sci Nutr 67(4):461–469. https://doi.org/10.3109/09637486.2016.1161011

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    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(3):976–986. https://doi.org/10.1053/j.gastro.2010.11.049

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    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. https://doi.org/10.1038/srep32002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Michail S, Lin M, Frey MR, Fanter R, Paliy O, Hilbush B, Reo NV (2015) Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol 91(2):1–9. https://doi.org/10.1093/femsec/fiu002

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    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(7):868–875. https://doi.org/10.1016/j.cgh.2013.02.015

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Del Chierico F, Nobili V, Vernocchi P, Russo A, Stefanis C, Gnani D, Furlanello C, Zandona A, Paci P, Capuani G, Dallapiccola B, Miccheli A, Alisi A, Putignani L (2017) Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology (Baltimore, MD) 65(2):451–464. https://doi.org/10.1002/hep.28572

    CAS  Article  Google Scholar 

  68. 68.

    Jiang C, Xie C, Li F, Zhang L, Nichols RG, Krausz KW, Cai J, Qi Y, Fang ZZ, Takahashi S, Tanaka N, Desai D, Amin SG, Albert I, Patterson AD, Gonzalez FJ (2015) Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125(1):386–402. https://doi.org/10.1172/jci76738

    Article  PubMed  Google Scholar 

  69. 69.

    Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, Dulai PS, Caussy C, Bettencourt R, Highlander SK, Jones MB, Sirlin CB, Schnabl B, Brinkac L, Schork N, Chen CH, Brenner DA, Biggs W, Yooseph S, Venter JC, Nelson KE (2017) Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab 25(5):1054–1062.e1055. https://doi.org/10.1016/j.cmet.2017.04.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    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, Cales 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 (Baltimore, MD) 63(3):764–775. https://doi.org/10.1002/hep.28356

    CAS  Article  Google Scholar 

  71. 71.

    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(4):e62885. https://doi.org/10.1371/journal.pone.0062885

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L (2011) Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb Ecol 61(3):693–703. https://doi.org/10.1007/s00248-010-9801-8

    Article  PubMed  Google Scholar 

  73. 73.

    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 (Baltimore, MD) 54(2):562–572. https://doi.org/10.1002/hep.24423

    Article  Google Scholar 

  74. 74.

    Xu M, Wang B, Fu Y, Chen Y, Yang F, Lu H, Chen Y, Xu J, Li L (2012) Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease. Microb Ecol 63(2):304–313. https://doi.org/10.1007/s00248-011-9925-5

    Article  PubMed  Google Scholar 

  75. 75.

    Wu Z-W, Lu H-F, Wu J, Zuo J, Chen P, Sheng J-F, Zheng S-S, Li L-J (2012) 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 63(4):929–937. https://doi.org/10.1007/s00248-011-9945-1

    Article  PubMed  Google Scholar 

  76. 76.

    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(1):G168–175. https://doi.org/10.1152/ajpgi.00190.2011

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM (2012) 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 303(6):G675–685. https://doi.org/10.1152/ajpgi.00152.2012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    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(6):556–560. https://doi.org/10.1016/j.dld.2014.02.010

    Article  PubMed  Google Scholar 

  79. 79.

    Luther J, Garber JJ, Khalili H, Dave M, Bale SS, Jindal R, Motola DL, Luther S, Bohr S, Jeoung SW, Deshpande V, Singh G, Turner JR, Yarmush ML, Chung RT, Patel SJ (2015) Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell Mol Gastroenterol Hepatol 1(2):222–232.e222. https://doi.org/10.1016/j.jcmgh.2015.01.001

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana 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 (Baltimore, MD) 49(6):1877–1887. https://doi.org/10.1002/hep.22848

    CAS  Article  Google Scholar 

  81. 81.

    Alisi A, Manco M, Devito R, Piemonte F, Nobili V (2010) Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 50(6):645–649. https://doi.org/10.1097/MPG.0b013e3181c7bdf1

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Konigsrainer A, Maier KP, Bischoff SC, Bergheim I (2008) Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 138(8):1452–1455. https://doi.org/10.1093/jn/138.8.1452

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Volynets V, Machann J, Küper MA, Maier IB, Spruss A, Königsrainer A, Bischoff SC, Bergheim I (2013) A moderate weight reduction through dietary intervention decreases hepatic fat content in patients with non-alcoholic fatty liver disease (NAFLD): a pilot study. Eur J Nutr 52(2):527–535. https://doi.org/10.1007/s00394-012-0355-z

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    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(2):149–152. https://doi.org/10.1097/MCG.0b013e3181e12c24

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Zhou X, Han D, Xu R, Li S, Wu H, Qu C, Wang F, Wang X, Zhao Y (2014) A model of metabolic syndrome and related diseases with intestinal endotoxemia in rats fed a high fat and high sucrose diet. PLoS One 9(12):e115148. https://doi.org/10.1371/journal.pone.0115148

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Boulange CL, Neves AL, Chilloux J, Nicholson JK, Dumas ME (2016) Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med 8(1):42. https://doi.org/10.1186/s13073-016-0303-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM (1997) Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci USA 94(6):2557–2562

    CAS  Article  Google Scholar 

  88. 88.

    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772. https://doi.org/10.2337/db06-1491

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, Catalano D, Mandrekar P, Dolganiuc A, Kurt-Jones E, Szabo G (2011) 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 300(3):G433–441. https://doi.org/10.1152/ajpgi.00163.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I (2009) Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology (Baltimore, MD) 50(4):1094–1104. https://doi.org/10.1002/hep.23122

    CAS  Article  Google Scholar 

  91. 91.

    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(7):1058–1067. https://doi.org/10.1136/gutjnl-2011-300269

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, Olefsky JM, Brenner DA, Seki E (2010) Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139(1):323–334.e327. https://doi.org/10.1053/j.gastro.2010.03.052

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Krajmalnik-Brown R, Ilhan Z-E, Kang D-W, DiBaise JK (2012) Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract 27(2):201–214. https://doi.org/10.1177/0884533611436116

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027. https://doi.org/10.1038/nature05414

    Article  PubMed  Google Scholar 

  95. 95.

    Lichtman SN, Keku J, Schwab JH, Sartor RB (1991) Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 100(2):513–519

    CAS  Article  Google Scholar 

  96. 96.

    Al Rajabi A, Castro GS, da Silva RP, Nelson RC, Thiesen A, Vannucchi H, Vine DF, Proctor SD, Field CJ, Curtis JM, Jacobs RL (2014) Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet. J Nutr 144(3):252–257. https://doi.org/10.3945/jn.113.185389

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Smallwood T, Allayee H, Bennett BJ (2016) Choline metabolites: gene by diet interactions. Curr Opin Lipidol 27(1):33–39. https://doi.org/10.1097/mol.0000000000000259

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Zeisel SH, daCosta KA, Youssef M, Hensey S (1989) Conversion of dietary choline to trimethylamine and dimethylamine in rats: dose-response relationship. J Nutr 119(5):800–804. https://doi.org/10.1093/jn/119.5.800

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    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(33):12511–12516. https://doi.org/10.1073/pnas.0601056103

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Gérard P (2014) Metabolism of cholesterol and bile acids by the gut microbiota. Pathogens 3(1):14–24. https://doi.org/10.3390/pathogens3010014

    CAS  Article  Google Scholar 

  101. 101.

    Hofmann AF, Hagey LR, Krasowski MD (2010) Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res 51(2):226–246. https://doi.org/10.1194/jlr.R000042

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E (2011) Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA 108(Suppl 1):4523–4530. https://doi.org/10.1073/pnas.1006734107

    Article  PubMed  Google Scholar 

  103. 103.

    Gonzalez FJ, Jiang C, Patterson AD (2016) An intestinal microbiota–farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151(5):845–859. https://doi.org/10.1053/j.gastro.2016.08.057

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Mouzaki M, Wang AY, Bandsma R, Comelli EM, Arendt BM, Zhang L, Fung S, Fischer SE, McGilvray IG, Allard JP (2016) Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS One 11(5):e0151829. https://doi.org/10.1371/journal.pone.0151829

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Wahlstrom A, Sayin SI, Marschall HU, Backhed F (2016) Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24(1):41–50. https://doi.org/10.1016/j.cmet.2016.05.005

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17(2):225–235. https://doi.org/10.1016/j.cmet.2013.01.003

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    de Wit N, Derrien M, Bosch-Vermeulen H, Oosterink E, Keshtkar S, Duval C, de Vogel-van den Bosch J, Kleerebezem M, Muller M, van der Meer R (2012) Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am J Physiol Gastrointest Liver Physiol 303(5):G589–599. https://doi.org/10.1152/ajpgi.00488.2011

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC Jr, Pares A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Bohm O, Shapiro D (2015) Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148(4):751–761.e758. https://doi.org/10.1053/j.gastro.2014.12.005

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Verbeke L, Mannaerts I, Schierwagen R, Govaere O, Klein S, Vander Elst I, Windmolders P, Farre R, Wenes M, Mazzone M, Nevens F, van Grunsven LA, Trebicka J, Laleman W (2016) FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 6:33453. https://doi.org/10.1038/srep33453

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Janssen AWF, Houben T, Katiraei S, Dijk W, Boutens L, van der Bolt N, Wang Z, Brown JM, Hazen SL, Mandard S, Shiri-Sverdlov R, Kuipers F, Willems van Dijk K, Vervoort J, Stienstra R, Hooiveld G, Kersten S (2017) Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids. J Lipid Res 58(7):1399–1416. https://doi.org/10.1194/jlr.M075713

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Nie Y-f HuJ, X-h Yan (2015) Cross-talk between bile acids and intestinal microbiota in host metabolism and health. J Zhejiang Univ Sci B 16(6):436–446. https://doi.org/10.1631/jzus.B1400327

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Cope K, Risby T, Diehl AM (2000) Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 119(5):1340–1347

    CAS  Article  Google Scholar 

  113. 113.

    Ferolla SM, Armiliato GNdA, Couto CA, Ferrari TCA (2015) Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease. World J Hepatol 7(3):559–565. https://doi.org/10.4254/wjh.v7.i3.559

    Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Shen W, Gaskins HR, McIntosh MK (2014) Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem 25(3):270–280. https://doi.org/10.1016/j.jnutbio.2013.09.009

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Tarantino G, Finelli C (2015) Systematic review on intervention with prebiotics/probiotics in patients with obesity-related nonalcoholic fatty liver disease. Future Microbiol 10(5):889–902. https://doi.org/10.2217/fmb.15.13

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Dethlefsen L, Huse S, Sogin ML, Relman DA (2008) The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6(11):e280. https://doi.org/10.1371/journal.pbio.0060280

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Madrid AM, Hurtado C, Venegas M, Cumsille F, Defilippi C (2001) Long-Term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am J Gastroenterol 96(4):1251–1255. https://doi.org/10.1111/j.1572-0241.2001.03636.x

    CAS  Article  PubMed  Google Scholar 

  118. 118.

    Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC (2008) Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 48(6):983–992. https://doi.org/10.1016/j.jhep.2008.01.035

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Vos MB, Lavine JE (2013) Dietary fructose in nonalcoholic fatty liver disease. Hepatology (Baltimore, MD) 57(6):2525–2531. https://doi.org/10.1002/hep.26299

    CAS  Article  Google Scholar 

  120. 120.

    Roberfroid M (2007) Prebiotics: the concept revisited. J Nutr 137(3 Suppl 2):830s–837s. https://doi.org/10.1093/jn/137.3.830S

    CAS  Article  PubMed  Google Scholar 

  121. 121.

    Macfarlane S, Macfarlane GT, Cummings JH (2006) Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther 24(5):701–714. https://doi.org/10.1111/j.1365-2036.2006.03042.x

    CAS  Article  PubMed  Google Scholar 

  122. 122.

    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(2):347–359. https://doi.org/10.1002/mnfr.201200364

    CAS  Article  PubMed  Google Scholar 

  123. 123.

    Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM (2005) Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur J Clin Nutr 59(5):723–726. https://doi.org/10.1038/sj.ejcn.1602127

    CAS  Article  PubMed  Google Scholar 

  124. 124.

    Delzenne NM, Williams CM (2002) Prebiotics and lipid metabolism. Curr Opin Lipidol 13(1):61–67

    CAS  Article  Google Scholar 

  125. 125.

    Kok N, Roberfroid M, Delzenne N (1996) Dietary oligofructose modifies the impact of fructose on hepatic triacylglycerol metabolism. Metabolism 45(12):1547–1550

    CAS  Article  Google Scholar 

  126. 126.

    Sugatani J, Wada T, Osabe M, Yamakawa K, Yoshinari K, Miwa M (2006) Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet: association with the suppression of hepatic cytochrome P450 and hepatocyte nuclear factor 4α expression. Drug Metab Dispos 34(10):1677

    CAS  Article  Google Scholar 

  127. 127.

    Daubioul CA, Taper HS, De Wispelaere LD, Delzenne NM (2000) Dietary oligofructose lessens hepatic steatosis, but does not prevent hypertriglyceridemia in obese zucker rats. J Nutr 130(5):1314–1319. https://doi.org/10.1093/jn/130.5.1314

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Delzenne NM, Kok N (2001) Effects of fructans-type prebiotics on lipid metabolism. Am J Clin Nutr 73(2 Suppl):456s–458s

    CAS  Article  Google Scholar 

  129. 129.

    Fiordaliso M, Kok N, Desager JP, Goethals F, Deboyser D, Roberfroid M, Delzenne N (1995) Dietary oligofructose lowers triglycerides, phospholipids and cholesterol in serum and very low density lipoproteins of rats. Lipids 30(2):163–167

    CAS  Article  Google Scholar 

  130. 130.

    Neyrinck AM, Possemiers S, Verstraete W, De Backer F, Cani PD, Delzenne NM (2012) Dietary modulation of clostridial cluster XIVa gut bacteria (Roseburia spp.) by chitin-glucan fiber improves host metabolic alterations induced by high-fat diet in mice. J Nutr Biochem 23(1):51–59. https://doi.org/10.1016/j.jnutbio.20

    CAS  Article  PubMed  Google Scholar 

  131. 131.

    Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, Caropreso M, Vallone G, Meli R (2011) Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 52(6):740–743. https://doi.org/10.1097/MPG.0b013e31821f9b85

    Article  PubMed  Google Scholar 

  132. 132.

    Famouri F, Shariat Z, Hashemipour M, Keikha M, Kelishadi R (2017) Effects of probiotics on nonalcoholic fatty liver disease in obese children and adolescents. J Pediatr Gastroenterol Nutr 64(3):413–417. https://doi.org/10.1097/mpg.0000000000001422

    CAS  Article  PubMed  Google Scholar 

  133. 133.

    Alisi A, Bedogni G, Baviera G, Giorgio V, Porro E, Paris C, Giammaria P, Reali L, Anania F, Nobili V (2014) Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 39(11):1276–1285. https://doi.org/10.1111/apt.12758

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Jones RB, Alderete TL, Martin AA, Geary BA, Hwang DH, Palmer SL, Goran MI (2018) Probiotic supplementation increases obesity with no detectable effects on liver fat or gut microbiota in obese Hispanic adolescents: a 16-week, randomized, placebo-controlled trial. Pediatr Obes 13(11):705–714. https://doi.org/10.1111/ijpo.12273

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, De La Fuente B, Gonzalez J (2011) Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 15(9):1090–1095

    CAS  PubMed  Google Scholar 

  136. 136.

    Sawas T, Al Halabi S, Hernaez R, Carey WD, Cho WK (2015) Patients receiving prebiotics and probiotics before liver transplantation develop fewer infections than controls: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 13(9):1567–1574. https://doi.org/10.1016/j.cgh.2015.05.027 (quiz e1143–1564)

    Article  PubMed  Google Scholar 

  137. 137.

    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(12):G911–918. https://doi.org/10.1152/ajpgi.00225.2013

    CAS  Article  PubMed  Google Scholar 

  138. 138.

    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 (Baltimore, MD) 37(2):343–350. https://doi.org/10.1053/jhep.2003.50048

    CAS  Article  Google Scholar 

  139. 139.

    Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, Chan HL (2013) Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 12(2):256–262

    CAS  Article  Google Scholar 

  140. 140.

    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, Md) 21(11):2310–2321. https://doi.org/10.1002/oby.20330

    CAS  Article  Google Scholar 

  141. 141.

    Gauffin Cano P, Santacruz A, Moya A, Sanz Y (2012) Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 7(7):e41079. https://doi.org/10.1371/journal.pone.0041079

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Wu W, Lv L, Shi D, Ye J, Fang D, Guo F, Li Y, He X, Li L (2017) Protective effect of akkermansia muciniphila against immune-mediated liver injury in a mouse model. Front Microbiol 8:1804. https://doi.org/10.3389/fmicb.2017.01804

    Article  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Ritze Y, Bardos 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(1):e80169. https://doi.org/10.1371/journal.pone.0080169

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144.

    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(2):545–553. https://doi.org/10.1007/s10620-011-1887-4

    Article  PubMed  Google Scholar 

  145. 145.

    Safavi M, Farajian S, Kelishadi R, Mirlohi M, Hashemipour M (2013) The effects of synbiotic supplementation on some cardio-metabolic risk factors in overweight and obese children: a randomized triple-masked controlled trial. Int J Food Sci Nutr 64(6):687–693. https://doi.org/10.3109/09637486.2013.775224

    CAS  Article  PubMed  Google Scholar 

  146. 146.

    Ipar N, Aydogdu SD, Yildirim GK, Inal M, Gies I, Vandenplas Y, Dinleyici EC (2015) Effects of synbiotic on anthropometry, lipid profile and oxidative stress in obese children. Benef Microb 6(6):775–782. https://doi.org/10.3920/bm2015.0011

    CAS  Article  Google Scholar 

  147. 147.

    Bomhof MR, Saha DC, Reid DT, Paul HA, Reimer RA (2014) Combined effects of oligofructose and Bifidobacterium animalis on gut microbiota and glycemia in obese rats. Obesity (Silver Spring, Md) 22(3):763–771. https://doi.org/10.1002/oby.20632

    CAS  Article  Google Scholar 

  148. 148.

    Carmody RN, Gerber GK, Luevano JM Jr, Gatti DM, Somes L, Svenson KL, Turnbaugh PJ (2015) Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17(1):72–84. https://doi.org/10.1016/j.chom.2014.11.010

    CAS  Article  PubMed  Google Scholar 

  149. 149.

    Hekmatdoost A, Feizabadi MM, Djazayery A, Mirshafiey A, Eshraghian MR, Yeganeh SM, Sedaghat R, Jacobson K (2008) The effect of dietary oils on cecal microflora in experimental colitis in mice. Indian J Gastroenterol 27(5):186–189

    PubMed  Google Scholar 

  150. 150.

    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(5):627–631. https://doi.org/10.3945/jn.112.172460

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Yin X, Peng J, Zhao L, Yu Y, Zhang X, Liu P, Feng Q, Hu Y, Pang X (2013) Structural changes of gut microbiota in a rat non-alcoholic fatty liver disease model treated with a Chinese herbal formula. Syst Appl Microbiol 36(3):188–196. https://doi.org/10.1016/j.syapm.2012.12.009

    Article  PubMed  Google Scholar 

  152. 152.

    Scheppach W, Bartram P, Richter A, Richter F, Liepold H, Dusel G, Hofstetter G, Rüthlein J, Kasper H (1992) Effect of short-chain fatty acids on the human colonic mucosa in vitro. J Parent Enter Nutr 16(1):43–48. https://doi.org/10.1177/014860719201600143

    CAS  Article  Google Scholar 

  153. 153.

    Abenavoli L, Di Renzo L, Boccuto L, Alwardat N, Gratteri S, De Lorenzo A (2018) Health benefits of Mediterranean diet in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 12(9):873–881. https://doi.org/10.1080/17474124.2018.1503947

    CAS  Article  PubMed  Google Scholar 

  154. 154.

    Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M (2013) Therapeutic potential of fecal microbiota transplantation. Gastroenterology 145(5):946–953. https://doi.org/10.1053/j.gastro.2013.08.058

    Article  PubMed  Google Scholar 

  155. 155.

    Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143(4):913–916.e917. https://doi.org/10.1053/j.gastro.2012.06.031

    CAS  Article  PubMed  Google Scholar 

  156. 156.

    Zhou D, Pan Q, Shen F, H-x Cao, W-j Ding, Y-w Chen, J-g Fan (2017) Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep 7(1):1529. https://doi.org/10.1038/s41598-017-01751-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Fecal microbiota transplantation (FMT) in nonalcoholic steatohepatitis (NASH). A Pilot Study. NihGov, Bethesda. https://clinicaltrials.gov/ct2/show/NCT02469272

    Google Scholar 

  158. 158.

    Silverman M (2016) Transplantation of microbes for treatment of metabolic syndrome and NAFLD (FMT). NihGov, vol NCT02496390.

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Acknowledgements

This work was supported by Austrian Science Fund (FWF) Projects and the Doctoral School “DK Metabolic and Cardiovascular Disease”.

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Safari, Z., Gérard, P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell. Mol. Life Sci. 76, 1541–1558 (2019). https://doi.org/10.1007/s00018-019-03011-w

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Keywords

  • Gut microbiota
  • Non-alcoholic fatty liver disease
  • Germ-free animals
  • Dysbiosis
  • Metabolic syndrome
  • Bile acids
  • Intestinal permeability
  • Antibiotics
  • Probiotics
  • Prebiotics