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Infection and Immunity, April 2009, p. 1708-1718, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00814-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Induction of Persistent Colitis by a Human Commensal, Enterotoxigenic Bacteroides fragilis, in Wild-Type C57BL/6 Mice{triangledown}

Ki-Jong Rhee,1* Shaoguang Wu,1 XinQun Wu,1 David L. Huso,2,6 Baktiar Karim,2 Augusto A. Franco,1 Shervin Rabizadeh,4 Jonathan E. Golub,1 Lauren E. Mathews,1 Jai Shin,1 R. Balfour Sartor,7 Douglas Golenbock,8 Abdel R. Hamad,3 Christine M. Gan,5 Franck Housseau,5,6 and Cynthia L. Sears1,5,6

Departments of Medicine,1 Molecular and Comparative Pathobiology,2 Pathology,3 Pediatrics,4 Oncology,5 the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231,6 Departments of Medicine, Microbiology, and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina,7 Department of Medicine, University of Massachusetts School of Medicine, Worchester, Massachusetts8

Received 1 July 2008/ Returned for modification 16 October 2008/ Accepted 16 January 2009

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.

* Corresponding author. Present address: Section of Digestive Diseases and Nutrition (MC716), Department of Medicine, University of Illinois at Chicago, Room 741, Clinical Sciences Building, 840 South Wood Street, Chicago, IL 60612-7323. Phone: (312) 355-4945. Fax: (312) 996-5103. E-mail: kjrhee{at}uic.edu

{triangledown} Published ahead of print on 2 February 2009.

Editor: V. J. DiRita

Infection and Immunity, April 2009, p. 1708-1718, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00814-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sears, C. L. (2009). Enterotoxigenic Bacteroides fragilis: a Rogue among Symbiotes. Clin. Microbiol. Rev. 22: 349-369 [Abstract] [Full Text]  


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