Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice

Ki Jong Rhee, Shaoguang Wu, Xinqun Wu, David L. Huso, Baktiar Karim, Augusto A. Franco, Shervin Rabizadeh, Jonathan E. Golub, Lauren E. Mathews, Jai Shin, R. Balfour Sartor, Douglas Golenbock, Abdel R. Hamad, Christine M. Gan, Franck Housseau, Cynthia L. Sears

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Abstract

Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.

Original languageEnglish
Pages (from-to)1708-1718
Number of pages11
JournalInfection and Immunity
Volume77
Issue number4
DOIs
Publication statusPublished - 2009 Apr 1

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Bacteroides fragilis
Colitis
Inbred C57BL Mouse
Specific Pathogen-Free Organisms
Cadherins
Epithelial Cells
Toll-Like Receptors
Virulence Factors
Interleukin-8
Inflammatory Bowel Diseases
Dendritic Cells
Abscess
Colorectal Neoplasms
Diarrhea
Cell Proliferation
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Rhee, Ki Jong ; Wu, Shaoguang ; Wu, Xinqun ; Huso, David L. ; Karim, Baktiar ; Franco, Augusto A. ; Rabizadeh, Shervin ; Golub, Jonathan E. ; Mathews, Lauren E. ; Shin, Jai ; Balfour Sartor, R. ; Golenbock, Douglas ; Hamad, Abdel R. ; Gan, Christine M. ; Housseau, Franck ; Sears, Cynthia L. / Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. In: Infection and Immunity. 2009 ; Vol. 77, No. 4. pp. 1708-1718.
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title = "Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice",
abstract = "Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.",
author = "Rhee, {Ki Jong} and Shaoguang Wu and Xinqun Wu and Huso, {David L.} and Baktiar Karim and Franco, {Augusto A.} and Shervin Rabizadeh and Golub, {Jonathan E.} and Mathews, {Lauren E.} and Jai Shin and {Balfour Sartor}, R. and Douglas Golenbock and Hamad, {Abdel R.} and Gan, {Christine M.} and Franck Housseau and Sears, {Cynthia L.}",
year = "2009",
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Rhee, KJ, Wu, S, Wu, X, Huso, DL, Karim, B, Franco, AA, Rabizadeh, S, Golub, JE, Mathews, LE, Shin, J, Balfour Sartor, R, Golenbock, D, Hamad, AR, Gan, CM, Housseau, F & Sears, CL 2009, 'Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice', Infection and Immunity, vol. 77, no. 4, pp. 1708-1718. https://doi.org/10.1128/IAI.00814-08

Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. / Rhee, Ki Jong; Wu, Shaoguang; Wu, Xinqun; Huso, David L.; Karim, Baktiar; Franco, Augusto A.; Rabizadeh, Shervin; Golub, Jonathan E.; Mathews, Lauren E.; Shin, Jai; Balfour Sartor, R.; Golenbock, Douglas; Hamad, Abdel R.; Gan, Christine M.; Housseau, Franck; Sears, Cynthia L.

In: Infection and Immunity, Vol. 77, No. 4, 01.04.2009, p. 1708-1718.

Research output: Contribution to journalArticle

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T1 - Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice

AU - Rhee, Ki Jong

AU - Wu, Shaoguang

AU - Wu, Xinqun

AU - Huso, David L.

AU - Karim, Baktiar

AU - Franco, Augusto A.

AU - Rabizadeh, Shervin

AU - Golub, Jonathan E.

AU - Mathews, Lauren E.

AU - Shin, Jai

AU - Balfour Sartor, R.

AU - Golenbock, Douglas

AU - Hamad, Abdel R.

AU - Gan, Christine M.

AU - Housseau, Franck

AU - Sears, Cynthia L.

PY - 2009/4/1

Y1 - 2009/4/1

N2 - Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.

AB - Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.

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