User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice.

Primary tabs

Hartmann, Phillipp Chen, Peng Wang, Hui J Wang, Lirui McCole, Declan F Starkel, Peter [UCL] Schnabl, Bernd

The intestinal mucus layer protects the epithelium from noxious agents, viruses, and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin (Muc) 2, secreted by goblet cells of the intestine. Experimental alcoholic liver disease requires translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the liver and contributes to steatohepatitis. We investigated the roles of the intestinal mucus layer, and in particular Muc2, in development of experimental alcohol-associated liver disease in mice. We studied experimental alcohol-induced liver disease, induced by the Tsukamoto-French method (which involves continuous intragastric feeding of an isocaloric diet or alcohol) in wild-type and Muc2(-/-) mice. Muc2(-/-) mice showed less alcohol-induced liver injury and steatosis than developed in wild-type mice. Most notably, Muc2(-/-) mice had significantly lower plasma levels of lipopolysaccharide than wild-type mice after alcohol feeding. In contrast to wild-type mice, Muc2(-/-) mice were protected from alcohol-associated microbiome changes that are dependent on intestinal mucins. The antimicrobial proteins regenerating islet-derived 3 beta and gamma were expressed at significantly higher levels in the jejunum of Muc2(-/-) mice fed the isocaloric diet or alcohol compared with wild-type mice. Consequently, Muc2(-/-) mice showed increased killing of commensal bacteria and prevented intestinal bacterial overgrowth. Conclusion: Muc2(-/-) mice are protected from intestinal bacterial overgrowth and dysbiosis in response to alcohol feeding. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation, decreasing liver disease.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "Hepatology" - Vol. 58, no.1, p. 108-119 (2013)
Peer reviewed yes
Publisher JohnWiley & Sons, Inc. ((United States) Hoboken)
issn 0270-9139
e-issn 1527-3350
Publication status Publié
Affiliations UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie
UCL - (SLuc) Service d'hépato-gastro-entérologie
MESH Subject Alcoholism ; Lipopolysaccharides ; Liver ; Liver Diseases, Alcoholic ; Male ; Mice ; Mice, Inbred C57BL ; Mucin-2 ; Animals ; Disease Models, Animal ; Ethanol ; Fatty Liver ; Humans ; Intestinal Absorption ; Intestinal Mucosa ; Intestines
Links
  1. Kim W, Burden of liver disease in the United States: Summary of a workshop, 10.1053/jhep.2002.34734
  2. Szabo Gyongyi, Alcoholic liver disease and the gut-liver axis, 10.3748/wjg.v16.i11.1321
  3. Keshavarzian, Am J Gastroenterol, 89, 2205 (1994)
  4. Keshavarzian A., Holmes E. W., Patel M., Iber F., Fields J. Z., Pethkar S., Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage, 10.1111/j.1572-0241.1999.00797.x
  5. Ferrier Laurent, Bérard Florian, Debrauwer Laurent, Chabo Chantal, Langella Philippe, Buéno Lionel, Fioramonti Jean, Impairment of the Intestinal Barrier by Ethanol Involves Enteric Microflora and Mast Cell Activation in Rodents, 10.2353/ajpath.2006.050617
  6. Choudhry Mashkoor A., Fazal Nadeem, Goto Masakatsu, Gamelli Richard L., Sayeed Mohammed M., Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury, 10.1152/ajpgi.00235.2001
  7. Keshavarzian, J Pharmacol Exp Ther, 299, 442 (2001)
  8. Mathurin P, Exacerbation of Alcoholic Liver Injury by Enteral Endotoxin in Rats, 10.1053/jhep.2000.19621
  9. Fujimoto, Alcohol Clin Exp Res, 24, 48S (2000)
  10. HANCK C., ROSSOL S., BOCKER U., TOKUS M., SINGER M. V., PRESENCE OF PLASMA ENDOTOXIN IS CORRELATED WITH TUMOUR NECROSIS FACTOR RECEPTOR LEVELS AND DISEASE ACTIVITY IN ALCOHOLIC CIRRHOSIS, 10.1093/alcalc/33.6.606
  11. Parlesak Alexandr, Schäfer Christian, Schütz Tatjana, Bode J.Christian, Bode Christiane, Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease, 10.1016/s0168-8278(00)80242-1
  12. Urbaschek Renate, McCuskey Robert S., Rudi Volker, Becker Klaus-Peter, Stickel Felix, Urbaschek Bernhard, Seitz Helmut K., Endotoxin, Endotoxin-Neutralizing-Capacity, sCD14, sICAM-1, and Cytokines in Patients With Various Degrees of Alcoholic Liver Disease, 10.1111/j.1530-0277.2001.tb02207.x
  13. Yin M., Bradford B. U., Wheeler M. D., Uesugi T., Froh M., Goyert S. M., Thurman R. G., Reduced Early Alcohol-Induced Liver Injury in CD14-Deficient Mice, 10.4049/jimmunol.166.7.4737
  14. Uesugi T, Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice, 10.1053/jhep.2001.25350
  15. Hritz Istvan, Mandrekar Pranoti, Velayudham Arumugam, Catalano Donna, Dolganiuc Angela, Kodys Karen, Kurt-Jones Evelyn, Szabo Gyongyi, The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88, 10.1002/hep.22470
  16. Enomoto Nobuyuki, Yamashina Shunhei, Kono Hiroshi, Schemmer Peter, Rivera Chantal A., Enomoto Ayako, Nishiura Teruhiro, Nishimura Tetsuro, Brenner David A., Thurman Ronald G., Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of kupffer cells, 10.1002/hep.510290633
  17. Enomoto Nobuyuki, Ikejima Kenichi, Yamashina Shunhei, Hirose Miyoko, Shimizu Hidetake, Kitamura Tsuneo, Takei Yoshiyuki, Sato Nobuhiro, Thurman Ronald G., Kupffer Cell Sensitization by Alcohol Involves Increased Permeability to Gut-Derived Endotoxin, 10.1111/j.1530-0277.2001.tb02418.x
  18. Adachi Yukito, Moore Laura E., Bradford Blair U., Gao Wenshi, Thurman Ronald G., Antibiotics prevent liver injury in rats following long-term exposure to ethanol, 10.1016/0016-5085(95)90027-6
  19. Madrid Ana Maria, Hurtado Carmen, Venegas Mauricio, Cumsille Francisco, Defilippi Carlos, Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function, 10.1111/j.1572-0241.2001.03636.x
  20. Matsuo K, Ota H, Akamatsu T, Sugiyama A, Katsuyama T, Histochemistry of the surface mucous gel layer of the human colon., 10.1136/gut.40.6.782
  21. Johansson M. E. V., Phillipson M., Petersson J., Velcich A., Holm L., Hansson G. C., The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria, 10.1073/pnas.0803124105
  22. van Klinken, Am J Physiol, 276, G115 (1999)
  23. McGuckin Michael A., Lindén Sara K., Sutton Philip, Florin Timothy H., Mucin dynamics and enteric pathogens, 10.1038/nrmicro2538
  24. Lindén Sara K., Florin Timothy H. J., McGuckin Michael A., Mucin Dynamics in Intestinal Bacterial Infection, 10.1371/journal.pone.0003952
  25. Velcich A., Colorectal Cancer in Mice Genetically Deficient in the Mucin Muc2, 10.1126/science.1069094
  26. Van der Sluis Maria, De Koning Barbara A.E., De Bruijn Adrianus C.J.M., Velcich Anna, Meijerink Jules P.P., Van Goudoever Johannes B., Büller Hans A., Dekker Jan, Van Seuningen Isabelle, Renes Ingrid B., Einerhand Alexandra W.C., Muc2-Deficient Mice Spontaneously Develop Colitis, Indicating That MUC2 Is Critical for Colonic Protection, 10.1053/j.gastro.2006.04.020
  27. Grewal, Ann Gastroenterol, 22, 178 (2009)
  28. Yan Arthur W., E. Fouts Derrick, Brandl Johannes, Stärkel Peter, Torralba Manolito, Schott Eckart, Tsukamoto Hide, E. Nelson Karen, A. Brenner David, Schnabl Bernd, Enteric dysbiosis associated with a mouse model of alcoholic liver disease, 10.1002/hep.24018
  29. Lieber, Alcohol Res Health, 27, 220 (2003)
  30. Nagy, Exp Biol Med (Maywood), 228, 882 (2003)
  31. Vaishnava S., Yamamoto M., Severson K. M., Ruhn K. A., Yu X., Koren O., Ley R., Wakeland E. K., Hooper L. V., The Antibacterial Lectin RegIII  Promotes the Spatial Segregation of Microbiota and Host in the Intestine, 10.1126/science.1209791
  32. Gill S. R., Pop M., DeBoy R. T., Eckburg P. B., Turnbaugh P. J., Samuel B. S., Gordon J. I., Relman D. A., Fraser-Liggett C. M., Nelson K. E., Metagenomic Analysis of the Human Distal Gut Microbiome, 10.1126/science.1124234
  33. Belzer Clara, de Vos Willem M, Microbes inside—from diversity to function: the case of Akkermansia, 10.1038/ismej.2012.6
  34. Zheng Yan, Valdez Patricia A, Danilenko Dimitry M, Hu Yan, Sa Susan M, Gong Qian, Abbas Alexander R, Modrusan Zora, Ghilardi Nico, de Sauvage Frederic J, Ouyang Wenjun, Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens, 10.1038/nm1720
  35. Brandl Katharina, Plitas George, Schnabl Bernd, DeMatteo Ronald P., Pamer Eric G., MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinalListeria monocytogenesinfection, 10.1084/jem.20070563
  36. Brandl Katharina, Plitas George, Mihu Coralia N., Ubeda Carles, Jia Ting, Fleisher Martin, Schnabl Bernd, DeMatteo Ronald P., Pamer Eric G., Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits, 10.1038/nature07250
  37. Bauer Tilman Martin, Fernández Javier, Navasa Miquel, Vila Jordi, Rodés Juan, Failure of Lactobacillus spp. to prevent bacterial translocation in a rat model of experimental cirrhosis, 10.1016/s0168-8278(02)00003-x
  38. Jun Dae Won, Kim Kyung Tae, Lee Oh Young, Chae Jeong Don, Son Byoung Kwan, Kim Seong Hwan, Jo Yun Ju, Park Young Sook, Association Between Small Intestinal Bacterial Overgrowth and Peripheral Bacterial DNA in Cirrhotic Patients, 10.1007/s10620-009-0870-9
  39. Cirera Isabel, Martin Bauer Tilman, Navasa Miguel, Vila Jordi, Grande Luis, Taurá Pilar, Fuster Josep, Garcı́a-Valdecasas Juan Carlos, Lacy Antonio, Suárez Marı́a Jesús, Rimola Antoni, Rodés Juan, Bacterial translocation of enteric organisms in patients with cirrhosis, 10.1016/s0168-8278(00)00013-1
  40. Lichtman S.N., Sartor R.B., Keku J., Schwab J.H., Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth, 10.1016/0016-5085(90)90833-m
  41. Nanji A. A., Khettry U., Sadrzadeh S. M. H., Lactobacillus Feeding Reduces Endotoxemia and Severity of Experimental Alcoholic Liver (Disease), 10.3181/00379727-205-43703
  42. Forsyth Christopher B., Farhadi Ashkan, Jakate Shriram M., Tang Yueming, Shaikh Maliha, Keshavarzian Ali, Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis, 10.1016/j.alcohol.2008.12.009
  43. Bergstrom Kirk S. B., Kissoon-Singh Vanessa, Gibson Deanna L., Ma Caixia, Montero Marinieve, Sham Ho Pan, Ryz Natasha, Huang Tina, Velcich Anna, Finlay B. Brett, Chadee Kris, Vallance Bruce A., Muc2 Protects against Lethal Infectious Colitis by Disassociating Pathogenic and Commensal Bacteria from the Colonic Mucosa, 10.1371/journal.ppat.1000902
  44. Kinnebrew Melissa A., Buffie Charlie G., Diehl Gretchen E., Zenewicz Lauren A., Leiner Ingrid, Hohl Tobias M., Flavell Richard A., Littman Dan R., Pamer Eric G., Interleukin 23 Production by Intestinal CD103+CD11b+ Dendritic Cells in Response to Bacterial Flagellin Enhances Mucosal Innate Immune Defense, 10.1016/j.immuni.2011.12.011
  45. Kinnebrew Melissa A., Ubeda Carles, Zenewicz Lauren A., Smith Nichole, Flavell Richard A., Pamer Eric G., Bacterial Flagellin Stimulates Toll‐Like Receptor 5–Dependent Defense against Vancomycin‐ResistantEnterococcusInfection, 10.1086/650203
  46. Vaishnava S., Behrendt C. L., Ismail A. S., Eckmann L., Hooper L. V., Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface, 10.1073/pnas.0808723105
  47. Lacunza E., Ferretti V., Barbeito C., Segal-Eiras A., Croce M. V., Immunohistochemical evidence of Muc1 expression during rat embryonic development, 10.4081/ejh.2010.e49
Bibliographic reference Hartmann, Phillipp ; Chen, Peng ; Wang, Hui J ; Wang, Lirui ; McCole, Declan F ; et. al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice.. In: Hepatology, Vol. 58, no.1, p. 108-119 (2013)
Permanent URL http://hdl.handle.net/2078.1/136290