Clostridium difficile is a Gram-positive sporeforming anaerobic bacillus, which is found in the stool flora of 25-80% of healthy infants but rarely in the stool of healthy adults and children over the age of 12 months. Ingested spores of C. difficile survive the gastric acid barrier and germinate in the colon. Colonization of the adult intestinal tract occurs when antibiotics alter normal intestinal flora, which otherwise facilitates resistance to colonization. Between one third and two thirds of patients colonized develop clinical symptoms. Some strains of C. difficile are non-toxinogenic, but the majority make two protein exotoxins, toxin A, a 308 kDa protein and toxin B, a 275 kDa protein. Toxin A binds to a specific receptor on the brush border of the intestinal epithelium, a glycoprotein with an α-linked galactose; the intestinal receptor in humans for toxin B is less well-characterized. Both toxins modify Rho proteins at a specific threonine residue by addition of a glucose molecule, leading to inactivation of the protein. This is followed by disaggregation of polymerized actin, opening of tight junctions between cells, cell rounding and subsequent cell death. The toxins also induce the release by various cells of pro-inflammatory mediators and cytokines (such as IL-8), as well as activation of the enteric nervous system, leading to neutrophil chemotaxis and fluid secretion. Toxin B is not enterotoxic in animals (as is toxin A), but it is a much more potent cytotoxin in tissue culture than toxin A. Occasional toxinogenic strains of C. difficile associated with clinical illness make toxin B but contain an internal deletion in the gene for toxin A and do not make an active form of this toxin. Strains of C. difficile that produce neither toxin A nor B do not cause clinical illness.
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