The chemotactic response of human granulocytes to Clostridium difficile toxin A is age dependent

Elderly patients are at high risk for developing diarrhea and colitis as a complication of antimicrobial therapy. Clostridium difficile, the causative agent of antibiotic-associated diarrhea and colitis produces an enterotoxin (toxin A) and a cytotoxin (toxin B). Of these two exotoxins, toxin A appears to be largely responsible for the inflammatory phenomena of C. difficile colitis, because it produces secretion, pronounced granulocytic infiltration, and epithelial cell necrosis and ulceration in ligated ileal loops of experimental animals. We have recently demonstrated that the inflammatory effects of C. difficile toxin A in the intestine may be related to its ability to mobilize intracellular calcium and elicit a chemotactic response by human granulocytes. In this study, in order to explain why the elderly are at greater risk for developing antibiotic-associated colitis, we investigated the effects of toxin A on activation of granulocytes from healthy elderly and young subjects. Highly purified toxin A and the chemotactic factor N-formyl-Met-Leu-Phe (FMLP) at concentrations of 10(-7) M both elicited a significant (p less than 0.001) and comparable chemotactic and chemokinetic response in human granulocytes from both age groups. A significantly (p less than 0.001) increased chemotactic effect in elderly subjects compared with young subjects was elicited by toxin A and not by FMLP. These findings suggest that the enhanced intestinal inflammatory effects of C. difficile in the elderly, compared with the young, may be related to the ability of its enterotoxin to elicit a more pronounced chemotactic response by granulocytes.