Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice

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From: Gut(Vol. 52, Issue 12)
Publisher: BMJ Publishing Group Ltd.
Document Type: Article
Length: 5,585 words

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Gut 2003;52:1721-1727

Background and aims: Multiple rodent models implicate resident intestinal bacteria in the pathogenesis of chronic immune mediated intestinal inflammation. Specific pathogen free (SPF) interleukin 10 gene deficient (IL-[10.sup.-/-]) mice develop colitis, which does not occur in the germ free (GF) state. We investigated whether broad or narrow spectrum antibiotics affect onset and progression of disease in various regions of IL-[10.sup.-/-] mice.

Methods: Metronidazole, ciprofloxacin, vancomycin-imipenem (50 mg/kg/day), or water (control) was administered orally before (prevention) or two weeks after (treatment) colonisation of GF IL-[10.sup.-/-] mice with SPF bacteria. After four weeks, colonic histology scores and cytokine production by colonic explants were determined. Caecal and colonic contents were collected for quantitative bacterial analysis.

Results: In the prevention study, all antibiotics decreased inflammation in the caecum and colon. However, in the treatment study, ciprofloxacin and vancomycin-imipenem decreased caecal inflammation, and reduced Escherichia coli and Enterococcus faecalis concentrations, whereas only vancomycin-imipenem lowered direct microscopic bacterial counts. In contrast, metronidazole and vancomycin-imipenem reduced colonic injury and eliminated anaerobic bacteria, including Bacteroides spp.

Conclusions: Both narrow and broad spectrum antibiotics can prevent disease but treatment of established colitis is more selective. Ciprofloxacin is most effective in the treatment of caecal inflammation, metronidazole preferentially treats the colon, whereas vancomycin-imipenem definitively treats both regions. These results suggest that subsets of aerobic or anaerobic bacteria show regional differences in their capacity to mediate experimental colitis in IL-[10.sup.-/-] mice.

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In recent years, multiple studies have emphasised the role of commensal intestinal bacteria in the pathogenesis of inflammatory bowel diseases (IBD). (1 2) In several genetically engineered and induced rodent models of chronic immune mediated intestinal inflammation, susceptible hosts develop spontaneous colitis in the presence of non-pathogenic resident intestinal bacteria, which does not occur in the germ free (GF) state. (3)

In a well characterised murine model of T helper 1 (TH1) mediated colitis, interleukin 10 gene deficient (IL-[10.sup.-/-]) mice develop predominantly caecal inflammation shortly after weaning when susceptible strains (129 SvEv or mixed 129/C57Bl/6 background) are colonised with specific pathogen free (SPF) bacteria. (4 5). As disease progresses, inflammation also develops in the ascending and transverse colon, and finally in the remainder of the colon and rectum. (4 5). In contrast, GF conditions prevent development of inflammation in this model, emphasising the essential role of commensal intestinal organisms in the pathogenesis of chronic intestinal inflammation. (5) These observations are consistent with results in other models of chronic intestinal inflammation, such as in HLA-B27/[beta]2 microglobulin transgenic (TG) rats, IL-[2.sup.-/-], TCR[[alpha].sup.-/-], SAMP-1/Yit, and CD3[[epsilon].sub.26] TG mice in which the GF state prevents disease development and immune activation. (6-12) The role of intestinal bacteria in the pathogenesis of experimental colitis was further emphasised after showing that broad spectrum antibiotics can both prevent and treat colitis in HLA-B27 TG rats and dextran sulphate sodium (DSS) induced colitis in BALB/c mice, (13) as well as in IL-[10.sup.-/-] mice. (14)

However, it is relatively unknown how different subsets of aerobic or anaerobic bacteria influence the onset and perpetuation of experimental colitis. We describe...

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Gale Document Number: GALE|A111655823