Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins.

Clostridium difficile, the major etiologic factor of antibiotic-associated diarrhea and colitis, mediates its effects by releasing two large protein exotoxins, toxins A and B. A major toxin effect is related to the disassembly of actin microfilaments, leading to impairment of tight junctions in human colonocytes. The mechanism of actin disaggregation involves monoglucosylation of the signaling proteins Rho A, Rac, and Cdc 42, which control stress fiber formation directly by toxins A and B. An important aspect of C. difficile infection is the acute necroinflammatory changes seen in patients with pseudomembranous colitis. The early mechanism of toxin-mediated inflammation involves toxin effects on cellular mitochondria, release of reactive oxygen species, and activation of mitogen-activated protein kinases and the transcription factor nuclear factor-kappaB. Injection of toxin A into animal intestine triggers secretion of fluid and intestinal inflammation characterized by epithelial cell destruction and neutrophil activation. A critical feature of C. difficile enterotoxicity is communication between enterocytes and lamina propria nerves, macrophages, and mast cells mediated via release of neuropeptides and proinflammatory cytokines.