Advertisement

Die Darm-Leber-Achse bei nichtalkoholischer Fettlebererkrankung: molekulare Mechanismen und neue Targets

The gut–liver axis in nonalcoholic fatty liver disease: molecular mechanisms and new targets

  • 23 Accesses

Zusammenfassung

Die nichtalkoholische Fettlebererkrankung (NAFLD) ist mit weiter steigender Inzidenz die weltweit häufigste Lebererkrankung. Während Adipositas der wichtigste Risikofaktor für die Entstehung einer NAFLD ist, demonstrieren aktuelle Forschungsarbeiten, dass neben genetischen Faktoren und westlicher Diät die Darm-Leber-Achse und besonders die intestinale Mikrobiota eine Schlüsselrolle während der Krankheitsprogression spielen. Eine ungünstige Komposition der Mikrobiota beeinflusst nicht nur den Leberstoffwechsel, sondern moduliert durch mikrobielle Moleküle und Metaboliten das inflammatorische Milieu in der Leber. Hier zeigen sich vielversprechende Regelkreise für die zukünftige Diagnostik und Therapie.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the world’s most common liver disease and the incidence is continuously rising. While obesity is the most important risk factor for development of NAFLD, recent data show that in addition to genetic factors and western diet, the gut–liver axis and especially the intestinal microbiota play a key role during disease progression. An unfavorable composition of the microbiota not only affects liver metabolism, but also modulates the inflammatory microenvironment in the liver through microbial molecules and metabolites. A better understanding of these molecular circuits may unearth promising targets for future diagnostics and therapy.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Abb. 1
Abb. 2

Literatur

  1. 1.

    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American association for the study of liver diseases, American college of gastroenterology, and the American gastroenterological association. Hepatology. https://doi.org/10.1002/hep.25762

  2. 2.

    Brandl K, Schnabl B (2017) Intestinal microbiota and nonalcoholic steatohepatitis. Curr Opin Gastroenterol 33:128–133

  3. 3.

    Roeb E, Steffen HM, Bantel H, Baumann U, Canbay A, Demir M et al (2015) S2k Guideline non-alcoholic fatty liver disease. Z Gastroenterol 53(7):668–723

  4. 4.

    Yki-Jarvinen H (2014) Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabet Endocrinol 2(11):901–910

  5. 5.

    Servier Medical Art by Servier (2019) Webpräsenz. https://smart.servier.com/. Zugegriffen: Oktober 2019

  6. 6.

    Brown GT, Kleiner DE (2016) Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism. https://doi.org/10.1016/j.metabol.2015.11.008

  7. 7.

    Tacke F, Kroy DC, Barreiros AP, Neumann UP (2016) Liver transplantation in Germany. Liver Transpl. https://doi.org/10.1002/lt.24461

  8. 8.

    Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E (2019) The role of the microbiome in NAFLD and NASH. EMBO Mol Med. https://doi.org/10.15252/emmm.201809302

  9. 9.

    Macpherson AJ, Heikenwalder M, Ganal-Vonarburg SC (2016) The liver at the nexus of host-microbial interactions. Cell Host Microbe 20:561–571

  10. 10.

    Schneider KM, Albers S, Trautwein C (2018) Role of bile acids in the gut-liver axis. J Hepatol 68:1083–1085. https://doi.org/10.1016/j.jhep.2017.11.025

  11. 11.

    Ursell LK, Metcalf JL, Parfrey LW, Knight R (2012) Defining the human microbiome. Nutr Rev. https://doi.org/10.1111/j.1753-4887.2012.00493.x

  12. 12.

    Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Bork P, Ehrlich SD, Wang J et al (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature. https://doi.org/10.1038/nature08821

  13. 13.

    Caussy C, Tripathi A, Humphrey G, Bassirian S, Singh S, Faulkner C, Bettencourt R, Rizo E, Richards L, Xu ZZ, Downes MR, Evans RM, Brenner DA, Sirlin CB, Knight R, Loomba R (2019) A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun. https://doi.org/10.1038/s41467-019-09455-9

  14. 14.

    Koliada A, Syzenko G, Moseiko V, Budovska L, Puchkov K, Perederiy V, Gavalko Y, Dorofeyev A, Romanenko M, Tkach S, Sineok L, Lushchak O, Vaiserman A (2017) Association between body mass index and firmicutes/bacteroidetes ratio in an adult Ukrainian population. BMC Microbiol. https://doi.org/10.1186/s12866-017-1027-1

  15. 15.

    Schwimmer JB, Johnson JS, Angeles JE, Behling C, Belt PH, Borecki I, Bross C, Durelle J, Goyal NP, Hamilton G, Holtz ML, Lavine JE, Mitreva M, Newton KP, Pan A, Simpson PM, Sirlin CB, Sodergren E, Tyagi R, Yates KP, Weinstock G, Salzman NH (2019) Microbiome signatures associated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease. Gastroenterology. https://doi.org/10.1053/j.gastro.2019.06.028

  16. 16.

    Kolodziejczyk AA, Zheng D, Elinav E (2019) Diet-microbiota interactions and personalized nutrition. Nat Rev Microbiol. https://doi.org/10.1038/s41579-019-0256-8

  17. 17.

    Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E (2017) Dysbiosis and the immune system. Nat Rev Immunol 17:219–232

  18. 18.

    Zaneveld JR, McMinds R, Thurber RV (2017) Stress and stability: applying the Anna Karenina principle to animal microbiomes. Nat Microbiol. https://doi.org/10.1038/nmicrobiol.2017.121

  19. 19.

    Chiang JYL (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966. https://doi.org/10.1194/jlr.R900010-JLR200

  20. 20.

    Wahlström A, Sayin SI, Marschall HU, Bäckhed F (2016) Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24:41–50

  21. 21.

    Begley M, Gahan CGM, Hill C (2005) The interaction between bacteria and bile. FEMS Microbiol Rev 29:625–651

  22. 22.

    Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, Di Tullio G, Palasciano G, Moustafa T, Halilbasic E, Trauner M, Moschetta A (2012) Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology. https://doi.org/10.1053/j.gastro.2011.10.028

  23. 23.

    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. https://doi.org/10.1038/nature10809

  24. 24.

    Balakrishnan A, Polli JE (2006) Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug target. Mol Pharmacol 3(3):223–230

  25. 25.

    Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. https://doi.org/10.1038/nm.3760

  26. 26.

    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. https://doi.org/10.1172/JCI76738

  27. 27.

    Chow MD, Lee YH, Guo GL (2017) The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med 56:34–44. https://doi.org/10.1016/j.mam.2017.04.004

  28. 28.

    Jiao N, Baker SS, Chapa-Rodriguez A, Liu W, Nugent CA, Tsompana M, Mastrandrea L, Buck MJ, Baker RD, Genco RJ, Zhu R, Zhu L (2018) Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut. https://doi.org/10.1136/gutjnl-2017-314307

  29. 29.

    Evans JM, Morris LS, Marchesi JR (2013) The gut microbiome: the role of a virtual organ in the endocrinology of the host. J Endocrinol 218(3):R37–47. https://doi.org/10.1530/JOE-13-0131

  30. 30.

    Arnold JW, Roach J, Azcarate-Peril MA (2016) Emerging technologies for gut microbiome research. Trends Microbiol 24(11):887–901. https://doi.org/10.1016/j.tim.2016.06.008

  31. 31.

    Rau M, Rehman A, Dittrich M, Groen AK, Hermanns HM, Seyfried F, Beyersdorf N, Dandekar T, Rosenstiel P, Geier A (2018) Fecal SCFas and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T‑cell activation and advanced disease. United European Gastroenterol J. https://doi.org/10.1177/2050640618804444

  32. 32.

    Gill PA, van Zelm MC, Muir JG, Gibson PR (2018) Review article: short chain fatty acids as potential therapeutic agents in human gastrointestinal and inflammatory disorders. Aliment Pharmacol Ther 48(1):15–34. https://doi.org/10.1111/apt.14689

  33. 33.

    Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T, Miyauchi S, Shioi G, Inoue H, Tsujimoto G (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. https://doi.org/10.1038/ncomms2852

  34. 34.

    Descamps HC, Herrmann B, Wiredu D, Thaiss CA (2019) The path toward using microbial metabolites as therapies. EBioMedicine 44:747–754. https://doi.org/10.1016/j.ebiom.2019.05.063

  35. 35.

    Thaiss CA, Itav S, Rothschild D, Meijer MT, Levy M, Moresi C, Dohnalová L, Braverman S, Rozin S, Malitsky S, Dori-Bachash M, Kuperman Y, Biton I, Gertler A, Harmelin A, Shapiro H, Halpern Z, Aharoni A, Segal E, Elinav E (2016) Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540:544–551. https://doi.org/10.1038/nature20796

  36. 36.

    Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D (2019) Fatty liver disease caused by high-alcohol-producing klebsiella pneumoniae. Cell Metab 30:675–688.e7. https://doi.org/10.1016/j.cmet.2019.08.018

  37. 37.

    Thaiss CA, Levy M, Grosheva I, Zheng D, Soffer E, Blacher E, Braverman S, Tengeler AC, Barak O, Elazar M, Ben-Zeev R, Lehavi-Regev D, Katz MN, Pevsner-Fischer M, Gertler A, Halpern Z, Harmelin A, Aamar S, Serradas P, Grosfeld A, Shapiro H, Geiger B, Elinav E (2018) Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 359:1376–1383. https://doi.org/10.1126/science.aar3318

  38. 38.

    Sorribas M, Jakob MO, Yilmaz B, Li H, Stutz D, Noser Y, de Gottardi A, Moghadamrad S, Hassan M, Albillos A, Francés R, Juanola O, Spadoni I, Rescigno M, Wiest R (2019) FxR-modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. J Hepatol. https://doi.org/10.1016/j.jhep.2019.06.017

  39. 39.

    Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S, Falony G, Raes J, Maiter D, Delzenne NM, de Barsy M, Loumaye A, Hermans MP, Thissen JP, de Vos WM, Cani PD (2019) Supplementation with akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 25(7):1096–1103. https://doi.org/10.1038/s41591-019-0495-2

  40. 40.

    Shogbesan O, Poudel DR, Victor S, Jehangir A, Fadahunsi O, Shogbesan G, Donato A (2018) A systematic review of the efficacy and safety of fecal microbiota transplant for clostridium difficile infection in Immunocompromised patients. Can J Gastroenterol Hepatol 2018:1394379. https://doi.org/10.1155/2018/1394379

  41. 41.

    Schneider KM, Bieghs V, Heymann F, Hu W, Dreymueller D, Liao L, Frissen M, Ludwig A, Gassler N, Pabst O, Latz E, Sellge G, Penders J, Tacke F, Trautwein C (2015) CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 62:1405–1416. https://doi.org/10.1002/hep.27982

  42. 42.

    Bajaj JS, Salzman NH, Acharya C, Sterling RK, White MB, Gavis EA, Fagan A, Hayward M, Holtz ML, Matherly S, Lee H, Osman M, Siddiqui MS, Fuchs M, Puri P, Sikaroodi M, Gillevet PM (2019) Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial. Hepatology. https://doi.org/10.1002/hep.30690

  43. 43.

    Parnell JA, Raman M, Rioux KP, Reimer RA (2012) The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int 32(5):701–711. https://doi.org/10.1111/j.1478-3231.2011.02730.x

  44. 44.

    Carlson JL, Erickson JM, Lloyd BB, Slavin JL (2018) Health effects and sources of prebiotic dietary fiber. Curr Dev Nutr. https://doi.org/10.1093/cdn/nzy005

  45. 45.

    Macfarlane S, Macfarlane GT, Cummings JH (2006) Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther 24(5):701–714

  46. 46.

    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

  47. 47.

    Singh V, Yeoh BS, Chassaing B, Xiao X, Saha P, Aguilera Olvera R, Lapek JD, Zhang L, Wang WB, Hao S, Flythe MD, Gonzalez DJ, Cani PD, Conejo-Garcia JR, Xiong N, Kennett MJ, Joe B, Patterson AD, Gewirtz AT, Vijay-Kumar M (2018) Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. https://doi.org/10.1016/j.cell.2018.09.004

  48. 48.

    Younossi Z, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, Bedossa P, Geier A, Beckebaum S, Newsome P, Sheridan D, Trotter J, Knapple W, Lawitz E, Kowdley K, Montano-Loza A, Boursier J, Mathurin P, Bugianesi E, Mazzella G, Olveira A, Cortez-Pinto H, Graupera I, Orr D, Gluud LL, Dufour J‑F, Shapiro D, Campagna J, Zaru L, MacConell L, Shringarpure R, Harrison S, Sanyal A (2019) GS-06-positive results from REGENERATE: a phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for NASH. J Hepatol. https://doi.org/10.1016/s0618-8278(19)30006-4

  49. 49.

    Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM (2002) A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol. https://doi.org/10.1016/S0002-9440(10)61177-7

  50. 50.

    Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, Kugelmas M, Bashir MR, Jaros MJ, Ling L, Rossi SJ, DePaoli AM, Loomba R (2018) NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. https://doi.org/10.1016/S0140-6736(18)30474-4

Download references

Author information

Correspondence to Dr. med. Dr. rer. nat. Kai Markus Schneider.

Ethics declarations

Interessenkonflikt

K.M. Schneider und C. Trautwein geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

C. Trautwein, Aachen

S. Zeuzem, Frankfurt a.M.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schneider, K.M., Trautwein, C. Die Darm-Leber-Achse bei nichtalkoholischer Fettlebererkrankung: molekulare Mechanismen und neue Targets. Gastroenterologe (2020) doi:10.1007/s11377-019-00402-0

Download citation

Schlüsselwörter

  • NASH
  • Mikrobiota
  • Bakterielle Translokation
  • Darm-Leber Achse
  • Gallensäuren

Keywords

  • NASH
  • Microbiota
  • Bacterial translocation
  • Gut-liver axis
  • Bile acids