Antibiotic therapy attenuates colitis in interleukin 10 gene–deficient mice

doi:10.1016/S0016-5085(00)70362-3

Gastroenterology

Volume 118, Issue 6, June 2000, Pages 1094-1105

https://doi.org/10.1016/S0016-5085(00)70362-3 Get rights and content

Abstract

Background & Aims: Interleukin (IL)-10 gene–deficient mice, raised under germfree conditions, do not develop colitis, implying a role for bacteria. This study mapped the appearance of luminal colonic bacteria and, using antibiotic treatment, determined their association with colitis in IL-10 gene–deficient mice. Methods: Mice were treated with ciprofloxacin or with neomycin and metronidazole. The intestine was harvested for histological scoring and bacterial assessment. Results: At 2 weeks of age, before the development of colitis, IL-10 gene–deficient mice demonstrated an earlier appearance of Streptococcus and Clostridium sp., and had a greater proportion (P < 0.01) of bacteria adherent to the colonic mucosa. This pattern of increased adherent bacteria persisted for the 12 weeks of study. Treatment of mice before the onset of colonic inflammation, with either antibiotic regime, reduced mucosal adherent bacteria and prevented colitis (P < 0.01). In contrast, treatment of established colitis with neomycin and metronidazole did not reduce adherent bacterial levels, yet was more efficacious (P < 0.05) in treating established colitis than ciprofloxacin, which did reduce adherent colonic bacteria. Conclusions: In the IL-10 gene–deficient mouse model, the appearance and number of mucosal adherent colonic bacteria are altered before the onset of colitis. Antibiotics both prevent and treat the colitis through correction of this primary bacterial alteration.

GASTROENTEROLOGY 2000;118:1094-1105

Section snippets

Animals

Homozygous IL-10 gene–deficient mice, generated on a 129 Sv/Ev background, and 129 Sv/Ev controls were housed behind a barrier under specific pathogen–free conditions. All provisions for the facility were autoclaved. Nonautoclavable supplies were sprayed with disinfectant and introduced through an HEPA-filtered air lock. Mice were housed in micro-isolator cages with tight-fitting lids containing a spun-polyester fiber filter. In sentinel Balb/c mice, bacterial cultures, parasitological

Animal profile

There was no difference in the average number of pups born to control and IL-10 gene–deficient mothers (data not shown). At 2 weeks of age, IL-10 gene–deficient pups had body weights similar to those of controls (control,10.4 ± 0.3 g; IL-10 gene–deficient, 8.5 ± 0.6 g). However, by 4 weeks of age, IL-10 gene–deficient mice had significantly lower body weights than their age-matched controls (control, 20.7 ± 1.9 g; IL-10 gene–deficient, 15.0 ± 0.4 g; P < 0.05); this difference persisted

Discussion

There is increasing evidence from both clinical studies and animal models to incriminate luminal bacteria or bacterial products in Crohn's disease initiation and progression. The spontaneous colitis that develops in transgenic HLA-B27/β₂-microglobulin rats,¹³ IL-2,¹⁶ IL-10,⁴ and T-cell receptor–deficient mice¹⁷ requires the presence of luminal bacteria; animals raised under germfree conditions generally do not develop colitis in these genetically engineered rodent models. Furthermore, in

Acknowledgements

The authors thank the University of Alberta Hospital Microbiology Laboratory for assistance in bacterial culture and Schering Canada Inc. for support of the interleukin 10 gene–deficient mouse colony.

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^☆: Address requests for reprints to: Richard N. Fedorak, M.D., Division of Gastroenterology, University of Alberta, 519 Newton Building, Edmonton, Alberta, Canada T6G 2C2. e-mail: [email protected]; fax: (780) 407-3744.

^☆☆: Supported by Crohn's and Colitis Foundation of Canada and the Alberta Heritage Foundation for Medical Research.

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Alimentary TractAntibiotic therapy attenuates colitis in interleukin 10 gene–deficient mice☆,☆☆

Abstract

Section snippets

Animals

Animal profile

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

Gastroenterology

Cell

Gastroenterology

Gastroenterology

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Trends Microbiol

Microbial factors in the pathogenesis of Crohn's disease, ulcerative colitis, and experimental intestinal inflammation

Interleukin-10

Annu Rev Immunol

Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4+ TH1-like responses

J Clin Invest

Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice

Infect Immun

Helicobacter hepaticus does not potentiate colitis in interleukin-10 deficient mice (abstr)

Gastroenterology

Metronidazole excretion in human milk and its effect on the suckling neonate

Br J Clin Pharmacol

High-voltage electrophoretic identification of residual antibiotics in milk

Veterinarni Medicina

Pharmacokinetics of three newer quinolones in pregnant and lactating women

Am J Med

Alimentary Tract
Antibiotic therapy attenuates colitis in interleukin 10 gene–deficient mice☆,☆☆

Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4⁺ TH1-like responses