Endogenous corticosteroids modulate Clostridium difficile toxin A-induced enteritis in rats

We examined the role of glucocorticoids in acute inflammatory diarrhea medi ated by Clostridium difficile toxin A. Toxin A (5 mug) or buffer was inject ed in rat ileal loops, and intestinal responses were measured after 30 min to 4 h. Ileal toxin A administration increased plasma glucocorticoids after 1 h, at which time the toxin-stimulated secretion was not significant. Adm inistration of the glucocorticoid analog dexamethasone inhibited toxin A-in duced intestinal secretion and inflammation and downregulated toxin A-media ted increase of macrophage inflammatory protein-2. Adrenalectomy followed b y replacement with glucocorticoids at various doses suggested that intestin al responses to toxin A were related to circulating levels of glucocorticoi ds. Administration of the glucocorticoid receptor antagonist RU-486 enhance d toxin A-mediated intestinal secretion and inflammation. We conclude that C. difficile toxin A causes increased secretion of endogenous glucocorticoi ds, which diminish the intestinal secretory and inflammatory effects of tox in A.