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Infection and Immunity, October 2004, p. 6040-6049, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.6040-6049.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bacterial Overgrowth in the Cystic Fibrosis Transmembrane Conductance Regulator Null Mouse Small Intestine

Oxana Norkina,1 Tim G. Burnett,2 and Robert C. De Lisle1*

Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City,1 Division of Biological Sciences, Emporia State University, Emporia, Kansas2

Received 24 May 2004/ Returned for modification 1 July 2004/ Accepted 9 July 2004

We recently reported the inflammation of the cystic fibrosis (CF) mouse small intestine, and we hypothesized bacterial overgrowth as a possible cause. Quantitative PCR of bacterial 16S genomic DNA in the CF mouse small intestine revealed an increase of greater than 40-fold compared to controls. Sequencing of 16S PCR products and Gram staining showed that the majority of bacteria in the CF mouse intestine were gram negative. Bacteria were observed to colonize the mucus that accumulates in the intestinal lumen of mice with CF. Impaired Paneth cell defenses were suggested by observation of partially dispersed Paneth granules in the mucus plugs of CF mouse intestinal crypts, and this mucus was strongly immunoreactive for Paneth cell bactericidal products. The role of bacterial overgrowth in intestinal inflammation in CF was tested by treating mice with oral antibiotics (ciprofloxacin and metronidazole) for 3 weeks, which reduced bacterial load in the CF mouse small intestine over 400-fold. Antibiotic treatment decreased the expression of the inflammation-related genes mast cell protease 2, leucine-rich {alpha}2 glycoprotein/leucine-rich high endothelial venule glycoprotein, suppressor of cytokine signaling 3, hematopoietic cell transcript 1, and resistin-like molecule ß/found in inflammatory zone 2, all of which were no longer expressed at levels significantly different from control levels. The reduction of intestinal bacteria also significantly improved the growth of CF mice but had no effect on the growth of wild-type mice. These data suggest that bacterial overgrowth in the CF mouse small intestine has a role in inflammation and contributes to the failure to thrive in this mouse model of CF.

* Corresponding author. Mailing address: Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160. Phone: (913) 588-2742. Fax: (913) 588-2742. E-mail: rdelisle{at}kumc.edu.

Editor: J. D. Clements

Infection and Immunity, October 2004, p. 6040-6049, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.6040-6049.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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