Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice.
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.
Rhee
Ki-Jong
KJ
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, USA. kjrhee@uic.edu
Wu
Shaoguang
S
Wu
Xinqun
X
Huso
David L
DL
Karim
Baktiar
B
Franco
Augusto A
AA
Rabizadeh
Shervin
S
Golub
Jonathan E
JE
Mathews
Lauren E
LE
Shin
Jai
J
Sartor
R Balfour
RB
Golenbock
Douglas
D
Hamad
Abdel R
AR
Gan
Christine M
CM
Housseau
Franck
F
Sears
Cynthia L
CL
D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism* / Q000633:toxicity; D001442:Bacteroides Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D001441:Bacteroides fragilis / Q000378:metabolism / Q000472:pathogenicity*; D002460:Cell Line; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003713:Dendritic Cells / Q000166:cytology; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000378:metabolism* / Q000633:toxicity; D005856:Germ-Free Life; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D013047:Specific Pathogen-Free Organisms
D001427:Bacterial Toxins; D004768:Enterotoxins; C405031:Bacteroides fragilis toxin; D008666:Metalloendopeptidases