Impaired Mucosal Barrier Function in the Small Intestine of the Cystic Fibrosis Mouse

De Lisle, Robert C.; Mueller, Racquel; Boyd, Megan

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e318219c397
Original Articles: Gastroenterology
Abstract

Objectives: The intestinal mucosal barrier protects the body from the large numbers of microbes that inhabit the intestines and the molecules they release. Intestinal barrier function is impaired in humans with cystic fibrosis (CF), including reduced activity of the lipopolysaccharide-detoxifying enzyme intestinal alkaline phosphatase (IAP) and increased permeability. The objective of this study was to determine the suitability of using the CF mouse to investigate intestinal barrier function, and whether interventions that are beneficial for the CF mouse intestinal phenotype (antibiotics or laxative), would improve barrier function. Also tested were the effects of exogenous IAP administration.

Materials and Methods: The Cftrtm1UNC mouse was used. IAP expression (encoded by the murine Akp3 gene) was measured by quantitative reverse transcription-polymerase chain reaction and enzyme activity. Intestinal permeability was assessed by measuring rhodamine-dextran plasma levels following gavage.

Results: CF mice had 40% Akp3 mRNA expression and 30% IAP enzyme activity, as compared with wild-type mice. Oral antibiotics and laxative treatments normalized Akp3 expression and IAP enzyme activity in the CF intestine. CF mice had a 5-fold greater transfer of rhodamine-dextran from gut lumen to blood. Antibiotic and laxative treatments reduced intestinal permeability in CF mice. Administration of exogenous purified IAP to CF mice reduced intestinal permeability to wild-type levels and reduced small intestinal bacterial overgrowth by >80%.

Conclusions: The CF mouse intestine has impaired mucosal barrier function, similar to human CF. Interventions that improve other aspects of the CF intestinal phenotype (antibiotics and laxative) also increase IAP activity and decrease intestinal permeability in CF mice. Exogenous IAP improve permeability and strongly reduce bacterial overgrowth in CF mice, suggesting this may be a useful therapy for CF.

Author Information

Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS.

Address correspondence and reprint requests to Robert C. De Lisle, PhD, Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160 (e-mail: rdelisle@kumc.edu).

Received 11 October, 2010

Accepted 10 March, 2011

This work was supported by National Institutes of Health grant R21 AI083479 and a pilot project as part of P20 RR024214, COBRE on Molecular Regulation of Cell Development and Differentiation, from the National Center for Research Resources.

The authors report no conflicts of interest.

Copyright 2011 by ESPGHAN and NASPGHAN