A new principle for resistance to cholera: desensitization to cyclic AMP-mediated diarrhea induced by cholera toxin in the mouse intestine.

The mechanisms behind the intestinal resistance to cholera toxin was studied in a mouse model. Repeated peroral treatments with cholera toxin (CT) led to a long-lasting inhibition of the toxin-induced activation of intestinal adenylate cyclase (AC). A corresponding inhibition of the intestinal fluid secretion induced not only by CT but also by prostaglandin E1 was observed. This unspecific desensitization was followed by a CT-specific inhibition of secretion and AC after 8 to 16 days. The desensitization to CT was totally reversed by a 4 hour-treatment with cycloheximide, an inhibitor of protein synthesis. Neither the secretory response to dibutyryl-cyclic AMP nor the activity of soluble phosphodiesterase differed between the CT-treated mice and the control group. Nor was the average turn-over rate of intestinal cells changed as judged from the mucosal incorporation of [3H]-thymidine. It is postulated that intestinal resistance to CT is mainly a function of AC-desensitization mediated by an inducible protein.