Alternative treatment for secretory diarrhea revealed in a new class of CFTR inhibitors

Diarrhea remains the number one killer of children less than 5 years of age throughout the world. A large number of organisms are responsible including viruses (rotaviruses), bacteria (Escherichia coli and cholera vibrios) and parasites. It may not be obvious to most people but we are living during the sixth pandemic of cholera in modern memory. This pandemic started in the Celebes Islands in the late 1950’s, marched around the globe in less than two decades and now every continent has had reported cases. Unlike previous pandemics, the causative organism is Vibrio El Tor not the classical V. cholerae. Studies prompted by this most recent pandemic have contributed an immense increase in our understanding of the mechanism underlying diarrhea. Robert Koch, in his original description of cholera seen among pilgrims in the Egyptian city of El Tor, found ulceration of the intestinal mucosa and postulated that the cause of diarrhea was an increased leak of plasma into the lumen. More recent research has now shown that the Vibrio exotoxin induces intestinal secretion, a process that was previously unknown (1). Cholera exotoxin binds to ganglioside GM1 on the apical surface and after internalization causes an increase in cellular cyclic AMP levels (2). The toxin ADP-ribosylates adenylyl cyclase resulting in a permanent activation of the enzyme (3). The increased level of cyclic […]