Effect of Purified Escherichia coli Heat-Stable Enterotoxin on Intestinal Cyclic Nucleotide Metabolism and Fluid Secretion

Enterotoxigenic Escherichia coli cause diarrhea by elaborating two enterotoxins. The large-molecular-weight, heat-labile toxin causes intestinal secretion by stimulating cyclic adenosine 5'-monophosphate production. The mechanism by which the small-molecular-weight, heat-stable enterotoxin induces secretion is unclear. The present study tested the hypothesis that heat-stable enterotoxin induces secretion by altering intestinal cyclic nucleotide concentrations. This was studied in suckling mice by using highly purified E. coli heat-stable enterotoxin obtained from a strain pathogenic for humans. At 3 min after administration of this toxin, intestinal cyclic guanosine 5'-monophosphate (GMP) levels were increased 10-fold. Cyclic GMP levels decreased thereafter, but still were greater than control levels at 120 min. Cyclic adenosine 5'-monophosphate levels fell to one-half of control levels at 3 min and remained below control levels for 120 min. When the time course of enterotoxin-induced secretion was compared with changes in cyclic GMP levels, fluid secretion was not evident until 15 to 30 min after enterotoxin administration. Thus, the increase in intestinal cyclic GMP concentration preceded measurable fluid secretion. And finally, administration of the 8-bromo analog of cyclic GMP evoked fluid secretion, the time course of which was similar to that induced by enterotoxin. These, and other data, strongly suggest that E. coli heat-stable enterotoxin induces intestinal secretion by increasing intestinal cyclic GMP levels.