The enteric nervous system participates in the secretory response to the heat stable enterotoxins of Escherichia coli in rats and cats

doi:10.1016/0306-4522(85)90318-5

Neuroscience

Volume 14, Issue 2, February 1985, Pages 673-681

https://doi.org/10.1016/0306-4522(85)90318-5 Get rights and content

Abstract

Intestinal secretion was evoked in periarterially denervated jejunal segments of anesthetized rats and cats by exposing the intestines to the heat stable (ST) toxins from a strain of Escherichia coli producing both STa and STb toxins. The secretion was significantly inhibited and to about the same relative extent by the addition of each one of the three following drugs: hexamethonium (i.V., rats), lidocaine (applied on the serosal surface, rats) and tetrodotoxin (intra-arterial, cats). Atropine inhibited fluid secretion in some experiments.

It is proposed that a nervous mechanism is mediating part of the secretory response to Escherichia coli heat stable toxins, since three different drugs, which influence nervous activity in different ways, significantly diminished the secretory response. A model for the secretory nervous reflex(es) within the enteric nervous system is proposed; Escherichia coli heat stable toxins activate a “receptor cell” in the epithelium, which then stimulates surrounding dendritic nerve endings via the release of unknown substance(s). A nicotinic receptor is involved but further characteristics of the nervous reflex(es) remain to be elucidated.

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Cited by (79)

Deciphering ion transporters, kinases and PDZ-adaptor molecules that mediate guanylate cyclase C agonist-dependent intestinal fluid loss in vivo
2020, Biochemical Pharmacology
Citation Excerpt :
Studies in heterologous expression systems and isolated intestinal mucosa carefully delineated the STa-induced enterocyte signaling pathways, indicating that different PDZ-adaptor molecules from the NHERF family of PDZ-adaptors play a role in both CFTR activation and NHE3 inhibition [4,7,13,14]. In vivo studies in rats and cats, however, suggested that a major diarrheagenic effect of STa was mediated via neural transduction [22,43] as well. For decades, pharmacological strategies have been developed to target the key components of the STa-mediated secretory diarrhea, so far with insufficient efficacy and specificity [5,15,33,59,60].
The molecular basis for heat-stable Escherichia coli enterotoxin (STa) action and its synthetic analogue linaclotide is well understood at the enterocyte level. Pharmacologic strategies to prevent STa-induced intestinal fluid loss by inhibiting its effector molecules, however, have achieved insufficient inhibition in vivo.
To investigate whether the currently discussed effector molecules and signaling mechanisms of STa/linaclotide-induced diarrhea have similar relevance in vivo than at the enterocyte level, we studied the effect of 10⁻⁷M of the STa analogue linaclotide on short circuit current (Isc) of chambered isolated jejunal mucosa, and on the in vivo action on fluid transport in a perfused segment of proximal jejunum of anesthetized mice. The selected mice were deficient of transport (NHE3, CFTR, Slc26a3/a6), adaptor (NHERF1-3), or signal transduction molecules [cGMP-dependent kinase II (GKII)] considered to be downstream effectors after STa/linaclotide binding to guanylate cyclase C (GCC). Selective NHE3 inhibition by tenapanor was also employed.
The comparison allowed the separation of effectors for stimulation of electrogenic anion secretion and for inhibition of electrolyte/fluid absorption in response to STa/linaclotide. The cGKII-NHERF1-CFTR and cGKII-NHERF2-NHE3 interactions are indeed major effectors of small intestinal fluid loss downstream of GCC activation in vitro and in vivo, but 50% of the linaclotide-induced fluid loss in vivo, while dependent on CFTR activation and NHE3 inhibition, does not involve cGKII, and 30% does not depend on NHERF1 or NHERF2. A combined NHERF1 and NHERF2 inhibition appears nevertheless a good pharmacological strategy against STa-mediated fluid loss.
Escherichia coli heat-stable enterotoxins
2015, The Comprehensive Sourcebook of Bacterial Protein Toxins
Escherichia coli are normal inhabitants of the gastrointestinal tract of homeotherm animals. In humans, it is found in high numbers in the large intestine as a normal constituent of the microbiome. Within E. coli, many virulence groups are recognized, including enterotoxigenic E. coli (ETEC). ETEC are responsible for diarrhea in humans and animals through the production and release of heat-labile and heat-stable enterotoxins. This chapter will focus on ETEC heat-stable toxins, including STa, STb, and enteroaggregative heat-stable toxin 1 (EAST1). These molecules mainly affect chloride ion secretion through second messenger pathways. The relative importance of each toxin in disease will be discussed as well as the vaccine approach to control diarrhea.
Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology
2012, Physiology of the Gastrointestinal Tract, Two Volume Set
Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology
2012, Physiology of the Gastrointestinal Tract
Pathophysiology of Diarrhea in Calves
2009, Veterinary Clinics of North America - Food Animal Practice
Citation Excerpt :
STa-mediated secretion may also involve local reflex arcs in the enteric nervous system (ENS); however, it does not involve the autonomic nervous system.43 Most of the support for this idea comes from studies that inhibit the ENS and subsequently reduce the secretory effect of STa.44–46 The neurotransmitters critical in these responses are nitric oxide (NO) and VIP,40,46 whereas PGE2 and 5-HT are not involved.41 Furthermore, a well-defined example of the influence of the ENS in ETEC is its role in exacerbating STa-mediated secretory diarrhea in states of malnutrition,47–49 however the importance of these mechanisms in the calf is unknown because this was found in a rodent model of human disease.
Infectious diarrhea in calves is most commonly associated with enterotoxigenic Escherichia coli, Cryptosporidium parvum, rotavirus, coronavirus, or some combination of these pathogens. Each of these agents leads to diarrhea through either secretion or malabsorption/maldigestion, though the specific mechanisms and pathways may differ. Specific pharmacologic control and treatment are dependent on gaining a greater understanding of the pathophysiology of these organisms.
Morphological relationships between peptidergic nerve fibers and immunoglobulin A-producing lymphocytes in the mouse intestine
2008, Brain, Behavior, and Immunity
Citation Excerpt :
The enteric nervous system has various intrinsic reflex systems (Furness, 2006). The secretomotor reflexes are caused by the intraluminal administration of toxins such as cholera toxin (Cassuto et al., 1981a) and enterotoxins (Eklund et al., 1985), or infectious pathogens such as Salmonella (Brunsson, 1987),Cryptosporisium (Argenzio et al., 1996), and rotavirus (Lundgren et al., 2000). The secretion of VIP from the small intestine is increased by exposure to cholera toxin (Cassuto et al., 1981b) and VIP has an important role as the putative transmitter in intestinal secretion induced by toxins (Mourad and Nassar, 2000).
Immunoglobulin A (IgA) lymphocytes are present close to the nerve fibers in the lamina propria of the small intestine, and the administration of lipopolysaccharides (LPSs) increases the number of these cells and IgA secretion to the lumen. In the present study, we demonstrated that the nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) were close to the IgA lymphocytes in the mouse ileum lamina propria. Three hours after intraperitoneal administration of LPSs, IgA lymphocytes close to VIP nerve fibers, those close to basement membrane, and those close to both VIP nerve fibers and basement membrane were increased in number. Further, all IgA lymphocytes seen in the ileum lamina propria expressed the receptors for VIP, VIPR1, and VIPR2. Electron microscopy revealed that varicosities were in close apposition to the lymphocyte plasma membrane. The present study suggests that VIP/NPY/CGRP neurons in the submucosal plexus have a close anatomical relationship to IgA lymphocytes, playing a role in the secretion of IgA and intestinal fluid in response to stimulation by lipopolysaccharides, pathogens, or toxins.

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: The present research was supported by grants from the Swedish Medical Research Council (2855), from the Swedish Society of Medical Sciences, from the Faculty of Medicine, University of Göteborg, from Magnus Bergvall's Foundation and from the Astra Research Foundation.

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Neuroscience

Abstract

References (30)

Effect of propranolol on the secretory activity of Escherichia coli heat-stable enterotoxin in the suckling mouse assay

Zentbl. Bakt. Parasitkcle. Abt. I Orig. A.

Amino acid sequence of heatstable enterotoxin produced by Escherichia coli pathogenic for man

J. biol. Chem.

Failure of tetrodotoxin to affect sodium transport by frog skin and proximal tubule of rat kidney

Life Sci.

Effects of indomethacin, acetazolamide, ethacrynate sodium, and atropine on intestinal secretion mediated by Escherichia coli heat-stable enterotoxin in pig jejunum

Can. J. Physiol.

Pathogenesis and pathophysiology of diarrheal diseases caused by Vibrio cholera and enterotoxigenic Escherichia coli

Biological evaluation of a methanol-soluble, heat-stable Escherichia coli enterotoxin in infant mice, pigs, rabbits, and calves

Infection Immun.

Heat-stable enterotoxins from Escherichia coli P16

Infection Immun.

Release of vasoactive intestinal polypeptide from the cat small intestine exposed to cholera toxin

Gut

The effect of nicotinic and muscarinic receptor blockade on cholera toxin induced intestinal secretion in rats and cats

Acta physiol. scand.

On the role of intramural nerves in the pathogenesis of cholera toxin-induced intestinal secretion

Scand. J. Gastroenterol.

5-Hydroxytryptamine and cholera secretion: physiological and pharmacological studies in cats and rats

Scand. J. Gastroenterol.

The involvement of intramural nerves in cholera toxin induced intestinal secretion

Acta physiol. scand.

Nervous mechanisms in the pathophysiology of the secretion induced by the heat stable enterotoxin of Escherichia coli

Secretion of electrolytes and water by mammalian small intestine

Heat-stable enterotoxin of Escherichia coli: In vitro effects on guanylate cyclase activity, cyclic GMP concentration, and ion transport in small intestine

Cited by (79)

Deciphering ion transporters, kinases and PDZ-adaptor molecules that mediate guanylate cyclase C agonist-dependent intestinal fluid loss in vivo

Escherichia coli heat-stable enterotoxins

Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology

Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology

Pathophysiology of Diarrhea in Calves

Morphological relationships between peptidergic nerve fibers and immunoglobulin A-producing lymphocytes in the mouse intestine