Nerves and Intestinal Mast Cells Modulate Responses to Enterotoxins

Abstract

the pathophysiology of enterotoxin actions has evolved from a classic cell-oriented model to an integrated model incorporating neuronal and immune mediators in the lamina propria. According to the classic model, the pathogenesis of cholera toxin-mediated diarrhea requires binding of the toxin to a brush-border receptor and increases in enterocyte adenosine 39,59cyclic monophosphate (cAMP) levels, followed by intestinal chloride and water secretion via the paracellular pathway. An expanded model to explain cholera toxin diarrhea was advanced by Lundgren and associates (10) based on in vivo experiments. These workers showed that diarrhea caused by intraluminal instillation of cholera toxin or Escherichia coli heat-stable toxin in rats or cats could be completely inhibited by pretreating animals with the nerve blockers tetrodotoxin, hexamethonium, or lidocaine (reviewed in Ref. 10). Because these agents had no effect on intracellular levels of cAMP in villus enterocytes, the authors concluded that a ratelimiting step in cholera diarrhea was regulation by intestinal neurons. Recent studies from several laboratories indicate that a complex neural cascade is involved in the cholera response. The secretory effects of cholera toxin in vivo are mediated by release of 5-hydroxytryptamine and prostaglandins from enterochromaffin-like cells on the villus of small intestine, followed by activation of the enteric nervous system and release of vasoactive intestinal peptide (VIP). VIP then binds to crypt cell receptors, triggering secretion of NaCl and water (reviewed in Ref. 3) (Fig. 1). This new paradigm of toxin-mediated intestinal secretion maintains that the nervous system amplifies signals originating in the lumen when toxins or other noxious agents such as bile salts stimulate villus cell receptors. Our laboratory has incorporated this new model of toxin action into our studies of clostridial enterotoxins, which, like cholera toxin, are capable of stimulating massive intestinal secretion. As outlined below, cholera toxin and clostridial enterotoxins stimulate separate neuronal pathways involving distinct neuropeptides. Not surprisingly, the clinical manifestations of these two toxigenic diarrheas are also quite distinct.

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@inproceedings{Pothoulakis1999NervesAI, title={Nerves and Intestinal Mast Cells Modulate Responses to Enterotoxins}, author={Charalabos Pothoulakis and Ignazio Castagliuolo and John Thomas Lamont}, year={1999} }