title: Impaired mucosal barrier function in the small intestine of the cystic fibrosis mouse.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The Cftr(tm1UNC) 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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA. rdelisle@kumc.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: De Lisle
authors.forename: Racquel
authors.initials: R
authors.lastname: Mueller
authors.forename: Megan
authors.initials: M
authors.lastname: Boyd
mesh_terms: D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy; D058491:Bacterial Load / Q000187:drug effects; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism*; D054368:Laxatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger
chemical_list: D000900:Anti-Bacterial Agents; D054368:Laxatives; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C520837:Akp3 protein, mouse; D000469:Alkaline Phosphatase