Yuan-Pin Hung1, Wen-Chien Ko2, Po-Han Chou3, Yi-Hsuan Chen3, Hsiao-Ju Lin1, Ya-Hui Liu3, Hung-Wen Tsai4, Jen-Chieh Lee5, Pei-Jane Tsai6. 1. Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare Department of Internal Medicine Graduate Institute of Clinical Medicine, National Health Research Institutes, Tainan, Taiwan. 2. Department of Internal Medicine Center for Infection Control, National Cheng Kung University Hospital Department of Medicine, National Cheng Kung University Medical College. 3. Department of Medical Laboratory Science and Biotechnology. 4. Department of Pathology. 5. Department of Internal Medicine. 6. Department of Medical Laboratory Science and Biotechnology Center of Infectious Disease and Signaling Research, National Cheng Kung University.
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.
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. difficileinfection (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.
Authors: Sarah Tomkovich; Nicholas A Lesniak; Yuan Li; Lucas Bishop; Madison J Fitzgerald; Patrick D Schloss Journal: mSphere Date: 2019-11-20 Impact factor: 4.389