Background & aims: Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis, diseases afflicting millions of people each year. Although C. difficile releases 2 structurally similar exotoxins, toxin A and toxin B, animal experiments suggest that only toxin A mediates diarrhea and enterocolitis. However, toxin A-negative/toxin B-positive strains of C. difficile recently were isolated from patients with antibiotic-associated diarrhea and colitis, indicating that toxin B also may be pathogenic in humans.
Methods: Here we used subcutaneously transplanted human intestinal xenografts in immunodeficient mice to generate a chimeric animal model for C. difficile toxin-induced pathology of human intestine.
Results: We found that intraluminal toxin B, like equivalent concentrations of toxin A, induced intestinal epithelial cell damage, increased mucosal permeability, stimulated interleukin (IL)-8 synthesis, and caused an acute inflammatory response characterized by neutrophil recruitment and tissue damage. Laser capture microdissection and real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) showed that intestinal epithelial cell-specific IL-8 gene expression also was increased significantly after luminal exposure to C. difficile toxins in vivo.
Conclusions: We conclude that C. difficile toxin B, like toxin A, is a potent inflammatory enterotoxin for human intestine. Future therapeutic or vaccine strategies for C. difficile infection therefore need to target both toxins.