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

被引：226

作者：

Rhee, Ki-Jong ^{[1
]}

Wu, Shaoguang ^{[1
]}

Wu, XinQun ^{[1
]}

Huso, David L. ^{[2
,6
]}

Karim, Baktiar ^{[2
]}

Franco, Augusto A. ^{[1
]}

Rabizadeh, Shervin ^{[4
]}

Golub, Jonathan E. ^{[1
]}

Mathews, Lauren E. ^{[1
]}

Shin, Jai ^{[1
]}

Sartor, R. Balfour ^{[7
,8
]}

Golenbock, Douglas ^{[9
]}

Hamad, Abdel R. ^{[3
]}

Gan, Christine M. ^{[5
]}

Housseau, Franck ^{[5
,6
]}

Sears, Cynthia L. ^{[1
,5
,6
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA

[4] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21231 USA

[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA

[6] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[7] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA

[8] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

[9] Univ Massachusetts, Dept Med, Dept Med, Worcester, MA USA

来源：

INFECTION AND IMMUNITY | 2009年 / 77卷 / 04期

关键词：

INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; DIARRHEAL DISEASE; FLUID SECRETION; CROHNS-DISEASE; TOXIN GENE; E-CADHERIN; C-MYC; EXPRESSION;

D O I：

10.1128/IAI.00814-08

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1708 / 1718

页数：11

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