Proton-Pump Inhibitor Exposure Aggravates Clostridium difficile-Associated Colitis: Evidence From a Mouse Model

J Infect Dis. 2015 Aug 15;212(4):654-63. doi: 10.1093/infdis/jiv184. Epub 2015 Mar 24.

Abstract

Background: Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients. In addition to the infection due to toxigenic C. difficile in the gastrointestinal tract of susceptible hosts, other predisposing factors for C. difficile infection (CDI) are identified, including advanced age, a prolonged hospital stay, and use of acid-suppressive drugs. Of note, exposure to gastric acid-reducing agents, such as H2 blockers and proton pump inhibitors (PPIs), remains a controversial risk factor, and has been associated with CDI in some studies but not in others. A mouse model of antibiotic-associated clostridial colitis was established to examine the role of PPIs for CDI.

Materials and methods: A mouse model of antibiotic-associated clostridial colitis was set up. NF-κB reporter mice were used to address the in vivo spatial and temporal inflammatory patterns of C. difficile-associated colitis. Serum levels of lipopolysaccharide and dextran-FITC were measured to reflect the barrier permeability of affected intestines.

Results: Mice with CDI that were exposed to PPI exhibited greater losses of stool consistency and body and cecal weights than those that were not exposed to PPI. Further, more neutrophilic infiltrations, epithelial damage, and inflammatory cytokine expression were noted in colon specimens of the mice with PPI exposure. More-evident inflammatory responses were detected by in vivo imaging of NF-κB reporter mice with CDI that were exposed to PPI. Gut barrier permeability was increased to a greater extent, as reflected by higher serum levels of lipopolysaccharide and dextran-FITC in mice with CDI that were exposed to PPI.

Conclusions: Our mouse model demonstrates that PPI exposure increases the severity of intestinal inflammation in mice with C. difficile-associated colitis.

Keywords: C. difficile infection; NF-κB reporter mice; gut barrier permeability; mouse model; proton-pump inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / adverse effects
  • Clostridium difficile* / drug effects
  • Clostridium difficile* / growth & development
  • Colon / pathology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Enterocolitis, Pseudomembranous / chemically induced*
  • Enterocolitis, Pseudomembranous / pathology
  • Esomeprazole / adverse effects*
  • Feces / microbiology
  • Gene Expression Regulation, Bacterial
  • Genes, Reporter
  • Goblet Cells
  • Mice
  • NF-kappa B / metabolism
  • Proton Pump Inhibitors / adverse effects*
  • Up-Regulation

Substances

  • Anti-Bacterial Agents
  • Cytokines
  • NF-kappa B
  • Proton Pump Inhibitors
  • Esomeprazole