An antibiotic-responsive mouse model of fulminant ulcerative colitis

Sylvia Kang, Seth M. Bloom, Lyse A. Norian, Michael J. Geske, Richard A. Flavell, Thaddeus S. Stappenbeck, Paul M. Allen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere41
Pages (from-to)424-439
Number of pages16
JournalPLoS Medicine
Volume5
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

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Ulcerative Colitis
Anti-Bacterial Agents
Inflammatory Bowel Diseases
Crohn Disease
Pathology
Cytokines
Inborn Genetic Diseases
Genetic Models
Immunologic Factors
Colitis
Interleukin-10
Intestines
Immune System
Therapeutics
T-Lymphocytes
Antibodies
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kang, S., Bloom, S. M., Norian, L. A., Geske, M. J., Flavell, R. A., Stappenbeck, T. S., & Allen, P. M. (2008). An antibiotic-responsive mouse model of fulminant ulcerative colitis. PLoS Medicine, 5(3), 424-439. [e41]. https://doi.org/10.1371/journal.pmed.0050041

An antibiotic-responsive mouse model of fulminant ulcerative colitis. / Kang, Sylvia; Bloom, Seth M.; Norian, Lyse A.; Geske, Michael J.; Flavell, Richard A.; Stappenbeck, Thaddeus S.; Allen, Paul M.

In: PLoS Medicine, Vol. 5, No. 3, e41, 03.2008, p. 424-439.

Research output: Contribution to journalArticle

Kang, S, Bloom, SM, Norian, LA, Geske, MJ, Flavell, RA, Stappenbeck, TS & Allen, PM 2008, 'An antibiotic-responsive mouse model of fulminant ulcerative colitis', PLoS Medicine, vol. 5, no. 3, e41, pp. 424-439. https://doi.org/10.1371/journal.pmed.0050041
Kang S, Bloom SM, Norian LA, Geske MJ, Flavell RA, Stappenbeck TS et al. An antibiotic-responsive mouse model of fulminant ulcerative colitis. PLoS Medicine. 2008 Mar;5(3):424-439. e41. https://doi.org/10.1371/journal.pmed.0050041
Kang, Sylvia ; 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. In: PLoS Medicine. 2008 ; Vol. 5, No. 3. pp. 424-439.
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