Abstract
Heat-stable toxins (STs) produced by enterotoxigenic bacteria cause endemic and traveler’s diarrhea by binding to and activating the intestinal receptor guanylyl cyclase C (GC-C). Advances in understanding the biology of GC-C have extended ST from a diarrheagenic peptide to a novel therapeutic agent. Here, we summarize the physiological and pathophysiological role of GC-C in fluid-electrolyte regulation and intestinal crypt-villus homeostasis, as well as describe translational opportunities offered by STs, reflecting the unique characteristics of GC-C, in treating irritable bowel syndrome and chronic constipation, and in preventing and treating colorectal cancer.
Highlights
Activation of guanylyl cyclase C (GC-C) stimulates a rise in intracellular Cyclic guanosine monophosphate (cGMP), which binds and activates its three downstream effectors [17]: cGMP-dependent protein kinases (PKGs), phosphodiesterases (PDEs) and cyclic nucleotide-gated (CNG) channels
Multi-center trial of 310 patients with chronic constipation treated with linaclotide (75–600 μg daily) for four weeks, all doses improved the weekly rate of spontaneous bowel movements (SBM) and complete spontaneous bowel movements (CSBM) in addition to improving stool consistency, straining, abdominal discomfort, bloating, and quality of life [81]
This study suggests that induction of GC-C signaling prevents tumor initiation and progression by promoting apoptosis, rather than restricting cell proliferation
Summary
Bacterial heat-stable enterotoxins (STs) first came to attention in the 1970s after heat-inactivation of cultures of bacteria isolated from patients suffering from diarrhea failed to eliminate enterotoxigenic activity [1,2]. Investigation of the pathogenesis underlying diarrhea produced by ST revealed two intestinal paracrine hormones, guanylin and uroguanylin, and the receptor for these homologous peptides, guanylyl cyclase C (GC-C), encoded by the gene GUCY2C [14]. Guanylin and uroguanylin are synthesized as pro-peptides [23], but unlike ST, these endogenous peptides undergo proteolytic processing following secretion [22,24,25]. These considerations suggest that ST and enterotoxigenic diarrhea are prime examples of molecular mimicry and convergent evolution. Cysteines linked by the extra-disulfide bond, providing ST greater potency than guanylin and uroguanylin, are colored in blue
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