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Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
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-
B. 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.
intestinal inflammation; neuropeptides; Rho proteins; mast cells; neutrophils
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