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Institut für Mikrobiologie und Hygiene, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin and Campus Mitte, Berlin, Germany
Oral infection of susceptible mice with Toxoplasma gondii results in Th1-type immunopathology in the ileum. We investigated gut flora changes during ileitis and determined contributions of gut bacteria to intestinal inflammation. Analysis of the intestinal microflora revealed that ileitis was accompanied by increasing bacterial load, decreasing species diversity, and bacterial translocation. Gram-negative bacteria identified as Escherichia coli and Bacteroides/Prevotella spp. accumulated in inflamed ileum at high concentrations. Prophylactic or therapeutic administration of ciprofloxacin and/or metronidazole ameliorated ileal immunopathology and reduced intestinal NO and IFN-
levels. Most strikingly, gnotobiotic mice in which cultivable gut bacteria were removed by quintuple antibiotic treatment did not develop ileitis after Toxoplasma gondii infection. A reduction in total numbers of lymphocytes was observed in the lamina propria of specific pathogen-free (SPF), but not gnotobiotic, mice upon development of ileitis. Relative numbers of CD4+ T cells did not differ in naive vs infected gnotobiotic or SPF mice, but infected SPF mice showed a significant increase in the frequencies of activated CD4+ T cells compared with gnotobiotic mice. Furthermore, recolonization with total gut flora, E. coli, or Bacteroides/Prevotella spp., but not Lactobacillus johnsonii, induced immunopathology in gnotobiotic mice. Animals recolonized with E. coli and/or total gut flora, but not L. johnsonii, showed elevated ileal NO and/or IFN- levels. In conclusion, Gram-negative bacteria, i.e., E. coli, aggravate pathogen-induced intestinal Th1-type immunopathology. Thus, pathogen-induced acute ileitis may prove useful to study bacteria-host interactions in small intestinal inflammation and to test novel therapies based on modulation of gut flora.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft to R.R.S. (SFB633/Project A7), U.B.G. (SFB633/Project A7; KFO104/Project 6), and O.L. (SFB633/Project B6). A.F. received a scholarship from the Sonnenfeld-Stiftung Berlin.
2 M.M.H., S.B., and A.F. contributed equally.
3 Address correspondence and reprint requests to Dr. Oliver Liesenfeld, Institut für Mikrobiologie und Hygiene, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany. E-mail address: oliver.liesenfeld{at}charite.de
4 Abbreviations used in this paper: IBD, inflammatory bowel disease; GvHD, graft-vs-host disease; SPF, specific pathogen free; DGGE, denaturing gradient gel electrophoresis; ddH2O, double-distilled H2O; FISH, fluorescence in situ hybridization; LPL, lamina propria lymphocyte; IEL, intraepithelial lymphocyte; p.i., postinfection; Cf, ciprofloxacin; Mtz, metronidazole; DAPI, 4',6'-diamidino-2-phenylindole.
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  M M Heimesaat, A Fischer, H-K Jahn, J Niebergall, M Freudenberg, M Blaut, O Liesenfeld, R R Schumann, U B Gobel, and S Bereswill Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli Gut, July 1, 2007; 56(7): 941 - 948. [Abstract] [Full Text] [PDF]
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