Dual-association of gnotobiotic Il-10−/− mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis
Article first published online: 30 AUG 2007
Copyright © 2007 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 13, Issue 12, pages 1457–1466, December 2007
How to Cite
Kim, S. C., Tonkonogy, S. L., Karrasch, T., Jobin, C. and Sartor, R. B. (2007), Dual-association of gnotobiotic Il-10−/− mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis. Inflamm Bowel Dis, 13: 1457–1466. doi: 10.1002/ibd.20246
- Issue published online: 5 NOV 2007
- Article first published online: 30 AUG 2007
- Manuscript Accepted: 9 JUL 2007
- Manuscript Received: 6 JUL 2007
- NIH. Grant Numbers: R01 DK53347, T32 DK07634, K08 DK063111-01
- Crohn's and Colitis Foundation of America (CCFA)
- Career Development Award in honor of Melissa Ann Miller and Amanda Bash. Grant Number: NIH R0I DK 47700
- American Gastroenterological Association Fiterman Basic Research grant
- Center for Gastrointestinal Biology and Disease. Grant Numbers: CGIBD, NIH P30 DK34987
- Core Laboratories
- National Gnotobiotic Rodent Resource Center. Grant Number: NIH P40 R018603
- gnotobiotic IL-10-/- mice;
- commensal bacteria
Background: Monoassociating gnotobiotic IL-10-deficient (−/−) mice with either nonpathogenic Enterococcus faecalis or a nonpathogenic Escherichia coli strain induces T-cell-mediated colitis with different kinetics and anatomical location (E. faecalis: late onset, distal colonic; E. coli: early onset, cecal). Hypothesis: E. faecalis and E. coli act in an additive manner to induce more aggressive colitis than disease induced by each bacterial species independently.
Methods: Germ-free (GF) inbred 129S6/SvEv IL-10−/− and wildtype (WT) mice inoculated with nonpathogenic E. faecalis and/or E. coli were killed 3–7 weeks later. Colonic segments were scored histologically for inflammation (0 to 4) or incubated in media overnight to measure spontaneous IL-12/IL-23p40 secretion. Bacterial species were quantified by serial dilution and plated on culture media. Mesenteric lymph node (MLN) CD4+ cells were stimulated with antigen-presenting cells pulsed with bacterial lysate (E. faecalis, E. coli, Bacteroides vulgatus) or KLH (unrelated antigen control). IFN-γ and IL-17 levels were measured in the supernatants.
Results: Dual-associated IL-10−/− (but not WT) mice developed mild-to-moderate pancolitis by 3 weeks that progressed to severe distal colonic-predominant pancolitis with reactive atypia and duodenal inflammation by 7 weeks. NF-κB was activated in the duodenum and colon in dual-associated IL-10−/− × NF-κBEGFP mice. The aggressiveness of intestinal inflammation and the degree of antigen-specific CD4+ cell activation were greater in dual- versus monoassociated IL-10−/− mice.
Conclusion: Two commensal bacteria that individually induce phenotypically distinct colitis in gnotobiotic IL-10−/− mice act additively to induce aggressive pancolitis and duodenal inflammation.
(Inflamm Bowel Dis 2007)