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An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis

BACKGROUND: The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and s...

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Autores principales: Kang, Silvia S, Bloom, Seth M, Norian, Lyse A, Geske, Michael J, Flavell, Richard A, Stappenbeck, Thaddeus S, Allen, Paul M
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270287/
https://www.ncbi.nlm.nih.gov/pubmed/18318596
http://dx.doi.org/10.1371/journal.pmed.0050041
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author Kang, Silvia S
Bloom, Seth M
Norian, Lyse A
Geske, Michael J
Flavell, Richard A
Stappenbeck, Thaddeus S
Allen, Paul M
author_facet Kang, Silvia S
Bloom, Seth M
Norian, Lyse A
Geske, Michael J
Flavell, Richard A
Stappenbeck, Thaddeus S
Allen, Paul M
author_sort Kang, Silvia S
collection PubMed
description BACKGROUND: The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. METHODS AND FINDINGS: We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics. CONCLUSIONS: Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease.
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spelling pubmed-22702872008-03-20 An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis Kang, Silvia S Bloom, Seth M Norian, Lyse A Geske, Michael J Flavell, Richard A Stappenbeck, Thaddeus S Allen, Paul M PLoS Med Research Article BACKGROUND: The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. METHODS AND FINDINGS: We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics. CONCLUSIONS: Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease. Public Library of Science 2008-03 2008-03-04 /pmc/articles/PMC2270287/ /pubmed/18318596 http://dx.doi.org/10.1371/journal.pmed.0050041 Text en : © 2008 Kang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kang, Silvia S
Bloom, Seth M
Norian, Lyse A
Geske, Michael J
Flavell, Richard A
Stappenbeck, Thaddeus S
Allen, Paul M
An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis
title An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis
title_full An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis
title_fullStr An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis
title_full_unstemmed An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis
title_short An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis
title_sort antibiotic-responsive mouse model of fulminant ulcerative colitis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270287/
https://www.ncbi.nlm.nih.gov/pubmed/18318596
http://dx.doi.org/10.1371/journal.pmed.0050041
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