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 e xotoxins, toxins A and B. A major toxin effect is related to the disassembl y of actin microfilaments, leading to impairment of tight junctions in huma n colonocytes. The mechanism of actin disaggregation involves monoglucosyla tion 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. diff icile infection is the acute necroinflammatory changes seen in patients wit h pseudomembranous colitis. The early mechanism of toxin-mediated inflammat ion involves toxin effects on cellular mitochondria, release of reactive ox ygen species, and activation of mitogen-activated protein kinases and the t ranscription factor nuclear factor-kappaB. Injection of toxin A into animal intestine triggers secretion of fluid and intestinal inflammation characte rized 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 releas e of neuropeptides and proinflammatory cytokines.