5-Hydroxytryptamine, enterotoxins, and intestinal fluid secretion.
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Cholera toxin stimulates secretion of immunoreactive intestinal mucin.
In vitro secretion of goblet cell mucin from rat small intestine was measured using a double-antibody radioimmunoassay for mucin. Cholera toxin (12.5-50 mg crude filtrate/ml) added to incubations of intestinal slices caused a dose-dependent increase in mucin secretion. By 90 min there was a four- to fivefold enhancement in secretion over noncholera-treated controls. Crude filtrate (dialyzed or nondialyzed) was a more effective mucin secretogogue than purified enterotoxin. Secretion was also assessed by administering [1-14C]glucosamine intraperitoneally to rats in vivo and 3 h later monitoring in vitro secretion of radioactive glycoprotein from intestinal slices. Cholera filtrate (12.5-50 mg/ml) caused a 1.5- to 2.0-fold enhancement in secretion after 90 min. The radioactivity data, however, underestimated total mucin secretion and the dependency of secretion on the dose of cholera filtrate. Cholera preparations also caused an enhancement (20-30% over controls) in the incorporation of [3H]glucosamine into tissue acid-precipitable glycoprotein, indicating a stimulation of glycoprotein synthesis. In the same experiments it was noted that the secretion of 3H-labeled (i.e., newly glycosylated) glycoprotein was increased 2.5- to 3.0-fold over untreated controls. Assuming that radioactivity partially reflects mucin synthetic and secretory events, it is possible, therefore, that cholera toxin promotes the release of both "old" mucin from storage granules as well as the synthesis and secretion of "new" mucin formed in goblet cells during incubation.
Animals↗
Effects of intestinal micro-organisms on fluid and electrolyte transport in the jejunum of the rat.
Culture filtrates of micro-organisms isolated from the upper intestinal secretions of malnourished children and grown in pure culture were shown to impair the intestinal absorption of water and electrolytes in live rats. Decreased net movement out of the intestinal lumen, or actual secretion of water, sodium or potassium into the intestinal lumen, was found with culture filtrates of single isolates of Staphylococcus epidermidis, Escherichia coli 055, Escherichia coli B7A, Shigella sonnei, Klebsiella pneumoniae, Candida albicans and Candida tropicalis. These organisms have been found to contaminate upper intestinal secretions in malnourished children and it is suggested that the effects observed in these experiments might be relevant to the production of the diarrhoea that is a dominant clinical feature of childhood malnutrition.
Animals↗
Asparagine stimulates piglet intestinal Cl- secretion by a mechanism requiring a submucosal glutamate receptor and nitric oxide.
Amino acids are potential components of oral rehydration solutions for infants, which could combine with glucose to further stimulate intestinal Na+ and water absorption. L-Glutamine, the principal fuel of the intestine, stimulates neutral NaCl absorption and enhances enterocyte DNA synthesis, but is unstable in solution. L-Asparagine (ASN), a more stable amino acid with similar structure to L-glutamine, also stimulates enterocyte proliferation. We determined the effects of ASN on electrolyte transport across piglet jejunum in Ussing chambers. Mucosal but not serosal ASN produced electrogenic Cl- secretion (delta JClnet = -1.8 +/- 0.3 microEq/cm2.hr-1). ASN, when added at 0.1 to 30 mM, increased short-circuit current in a dose-dependent manner with a K1/2 of approximately 5 mM and maximal effect at approximately 10 mM. The stimulation of Cl- secretion by ASN was blocked by pretreatment with serosal tetrodotoxin and bumetanide and was inhibited by preincubation with capsaicin (8-methyl-N-vanillyl-6-nonenamide) or substance P. Inhibition of nitric oxide synthesis with the structural analog of L-arginine, NG-monomethyl-L-arginine, reduced ASN-stimulated secretion by > 70%. Additionally, serosal 6-cyanonitro-quinoxaline 2-3-dione, which is a nonspecific blocker of neural non-N-methyl D-aspartate (NMDA) glutamate receptors, fully inhibited the ASN response (IC50 = 10(-6) M). Inhibition was specific for neurally mediated secretion. We found no inhibition of ASN-stimulated secretion by atropine, ketanserin, indomethacin or L-2-amino-5-phosphonovalerate (specific for NMDA receptors). When compared to ASN, L-glutamate was a weaker stimulator of jejunal Cl- secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Local intestinal immune response to Escherichia coli heat-labile (LT) enterotoxin: LT antitoxin levels in healthy, diseased and antigen-fed pigs.
With purified LT toxin and IgA, specific anti-LT enterotoxin activity was demonstrated in small intestinal contents of 27 pigs. After 60 days of age, rise in intestinal LT antitoxin titer was observed. Feeding LT containing E. coli antigen increased LT antibody levels in the intestinal secretions, but decreased antibody titers in sera. In post-weaning E. coli diarrhea LT antibody levels in intestinal secretions and sera decreased significantly. This phenomenon can be related to the occurrence of the frequently observed post-weaning E. coli diarrhea.
Animals↗
Studies on intestinal enzyme secretion; the action of cholecystokinin-pancreozymin, pentagastrin and bile.
Intravenous administration of 1 U cholecystokinin-pancreozymin (CCK-PZ) to rats caused the release of enteropeptidase, alkaline phosphatase (AP), and sucrase to the intestinal lumen in the absence of a concomitant increase in luminal DNA. Thus, the hormone elicited hydrolase secretion was not due to cell desquamation. Pentagastrin also stimulated hydrolase release. Following CCK-PZ administration enteropeptidase was released preferentially over sucrase and AP and showed a linear correlation with total protein output. The specific enteropeptidase activity was higher in the perfusate following secretion than in the mocosa. Enteropeptidase was found mainly in soluble form in both mucosa and perfusate; addition of bile following enteropeptidase release further increased its activity. In contrast, sucrase and AP were found mainly in insoluble form in both mucosa and perfusate and their specific activities were higher in the mucosa. The presence of bile rendered both sucrase and AP more soluble in the perfusate. The data indicate that enteropeptidase is released by a specific secretory process and that its subcellular site of origin is different from that of sucrase and AP. By eliciting the coordinated release of trypsinogen, enteropeptidase and bile, CCK-PZ plays a central role in the initiation of protein digestion.
Alkaline Phosphatase↗
STb enterotoxin of Escherichia coli: cyclic nucleotide-independent secretion.
Escherichia coli may produce a heat-labile enterotoxin (LT) or two heat-stable enterotoxins (STa, STb). Experimentally, STb is consistently active only in 5 h-weaned pig intestinal loops (WPIL), an effect that is largely removable by rinsing. At least three mechanisms initiate small intestinal secretion: cyclic AMP (LT), cyclic GMP (STa) and calcium (A23187). All three increase short-circuit current (SCC) in Ussing chambers by stimulating net Cl- secretion. STb significantly increases SCC within 2-5 minutes in Ussing chambers and is independent of cyclic AMP and cyclic GMP. When compared to crude culture filtrates of a non-toxigenic strain of E. coli, crude culture filtrates of STb did not alter Na+ or Cl- undirectional or net fluxes. However, the calculated residual ion flux (JRnet) increased significantly in STb-treated tissues and appeared to largely account for the STb-induced increase in SCC. Furosemide applied serosally (10(-3) M), the removal of extracellular calcium, and lanthanum chloride (10(-3) M) did not inhibit the effect of STb on SCC. Chlorpromazine (0.4 mM) completely inhibited STb-induced secretion in porcine loops. This inhibition was a non-specific reversal of the STb effect because in Ussing chambers, chlorpromazine simply induced an equal and opposite effect on SCC. These results indicate that STb initiates intestinal secretion in porcine jejunum in vitro by stimulating primarily non-chloride anion secretion in the absence of extracellular calcium. We postulate that STb causes bicarbonate secretion by a mechanism distinct from those of previously studied enterotoxins.
Animals↗
Cross-talk between enteric pathogens and the intestine.
Enteric pathogens finely regulate the expression of virulence genes in reply to stimuli generated by the intestinal environment. This minireview focuses on recently discovered strategies developed by enteric bacteria to cause intestinal secretion through the elaboration of factors that share structure and function with specific host counterparts. Such bacterial antigens appear to interfere largely with the epithelial cell signalling that physiologically regulates the numerous and, as yet not fully elucidated, mechanisms controlling both the transcellular and the paracellular secretion pathways. Heat-stable enterotoxins (STs) elaborated by enterotoxigenic Escherichia coli and the enteroaggregative E. coli enterotoxin (EAST1) are both typical examples of enteric toxins that activate the transcellular secretion pathway by mimicking guanylin, the endogenous modulator of cGMP signalling. Alternative strategies have been developed by Salmonella to induce intestinal secretion through the elaboration of a factor (SopB) that resembles at least two of the host cell 4-phosphatases, enzymes that activate the Ca-dependent transcellular secretion pathway. Finally, Vibrio cholerae has developed innovative tactics to activate the paracellular secretion pathway through the elaboration of Zonula occludens toxin (Zot), a factor that mimics a recently described physiological modulator of intercellular tight junctions.
Animals↗
The source of IgM and IgG in the dog intestine.
The source of IgM and IgG2a,b in the dog intestine was investigated, using labelled dog immunoglobulins and chronic Thiry-Vella loops of dog small intestine. Clearancess of IgM and IgG2a,b from serum into intestinal secretions were similar, reflecting transfer of a greater mass of IgG2a,b than of IgM. Only 20% of the intestinal IgM derived from serum, irrespective of the marker used. About one third of the total intestinal IgG, of all sub-classes and accrued from all sources, was serum-derived IgG2a,b. This indicates that serum is a major contributor to dog intestinal IgG2a,b.
Animals↗
Intake of monosaccharides or amino acids induces pituitary gland synthesis of proteins regulating intestinal fluid transport.
In cholera diarrhoea, the pituitary gland produces a 60-kDa protein known as antisecretory factor (ASF) which reverses intestinal secretion induced by the cholera toxin. We show here that ASF-like proteins are produced in the rat during intestinal secretion triggered by intake of a 500 mg dose of mannose, sorbitol, glycine or alanine. All the ASF-like proteins reversed cholera secretion, and all were of a similar size. However, they differed in charge: mannose and sorbitol induced a protein with an isoelectric point of 4.5; glycine induced two proteins, one with a pI of 6.3, the other of 7.7; and alanine induced two proteins, one with a pI of 6.3, the other of 9.4. Antibodies against naturally occurring ASF from porcine pituitary gland neutralized ASF induced by cholera toxin and two of the amino acid-induced proteins, while the sugar-induced protein(s) did not cross-react. All the proteins showed affinity to agarose and were dissociated again with methyl alpha-D-glucoside. A single peroral dose of cholera toxin or sorbitol induced antisecretory proteins which persisted in the pituitary gland for only 1-3 days. Seven treatments gave a sustained response, the protein induced by cholera toxin persisting for over 2 months, and that induced by sorbitol about 1 month.
Amino Acids↗
Cholera toxin as a mucosal adjuvant: effects of H-2 major histocompatibility complex and lps genes.
In previous studies we found that cholera toxin (CT) can act as a mucosal adjuvant; i.e., it can stimulate an intestinal secretory immunoglobulin A (S-IgA) response to an unrelated protein antigen when both are fed together to mice. The purpose of this study was to determine whether the mucosal adjuvanticity of CT is restricted by either H-2 major histocompatibility complex or lps genes by using congenic inbred strains that differ at only a single genetic locus. Groups of five mice each were fed saline, CT (10 micrograms), keyhole limpet hemocyanin (KLH) (5 mg), or both CT and KLH on four different days, and samples of intestinal secretions and plasma were obtained 1 week after the last feeding. In the mice fed both CT and KLH, the intestinal S-IgA anti-KLH response was higher in H-2b congenic strains than in H-2k congenic strains, and in addition there was a highly significant positive correlation between the intestinal S-IgA anti-KLH and S-IgA anti-CT responses in the intestinal secretions of individual mice. Similarly, in the lps congenic strains, mice of the endotoxin-responsive strain that were fed both CT and KLH had substantially higher S-IgA and plasma IgG responses to KLH than did mice of the endotoxin-unresponsive strain. The effect of CT on the induction of oral tolerance to KLH in the H-2 congenic strains was also examined. In contrast to the results above, the abrogation of oral tolerance to KLH by CT occurred in all strains regardless of H-2 haplotype. Similarly, the adjuvant effect of CT on plasma IgG anti-KLH responses after both were given together intraperitoneally was not restricted by H-2. I conclude that the mucosal adjuvanticity of CT is influenced by both the H-2 and lps genetic loci and that it appears to depend on a vigorous mucosal immune response to CT itself.
Adjuvants, Immunologic↗
Development of an irradiated vaccine that protects against enterotoxigenic Escherichia coli diarrhoea.
In the pathogenesis of diarrhoea in man bacteria adhesion to enterocytes is mediated by specific CFA/I or CFA/II antigens. A perorally administered vaccine was prepared from E. coli H10407 (078:H11) by irradiation with electrons with high energy (EHE). Two hours after cimetidine administration rats were immunized per os with 5 irradiated vaccine doses at 4-day intervals. Seven days after the last immunization animals were infected by inoculating 1 x 10(9) germs in the ligated intestinal loop. Reduction of the intestinal secretion by over 50% 18 hours after inoculation was considered an efficient protection marker. The obtained results have proved a significant reduction of the intestinal secretion in immunized animals infected with serotypes 078:H11(63 +/- 4%) and 078:H12(59 +/- 5%) as compared to non-immunized animals. Experimental induction of the intestinal protection against Escherichia coli enterotoxigenic (ETEC) strains points to the possibility of using this type of irradiated vaccine in the prophylaxis of diarrhoea in man.
Animals↗
Listeria monocytogenes-induced gamma interferon secretion by intestinal intraepithelial gamma/delta T lymphocytes.
gamma/delta T cells represent a major proportion of intestinal intraepithelial lymphocytes (IEL), and it has been suggested that these IEL serve as a first immune barrier against microbial invasion and that they do so by destroying infected epithelial cells. In the present study, we confirm that both alpha/beta and gamma/delta IEL from naive mice express potent cytotoxicity and produce gamma interferon (IFN-gamma) after T-cell receptor (TCR) engagement by specific monoclonal antibodies (MAb). Intraperitoneal administration of the anti-gamma/delta TCR MAb GL3 caused downregulation of the gamma/delta TCR in IEL, and IEL from gamma/delta TCR-modulated mice failed to express cytotoxic activity and to secrete IFN-gamma after gamma/delta TCR engagement. In contrast, alpha/beta IEL from such mice were still cytolytic and secreted IFN-gamma. Mice were infected orally with virulent Listeria monocytogenes at doses which caused bacterial invasion through the intestinal epithelia. Although alpha/beta and gamma/delta IEL from these mice expressed high cytolytic activities in antibody-redirected killer assays, target cells pulsed with listerial antigens were not lysed. In contrast, IFN-gamma secretion by IEL from L. monocytogenes-infected mice was induced not only by anti-TCR MAb but also by target cells pulsed with listerial antigens, whereas irrelevant antigens, including heat shock protein 60, did not induce IFN-gamma secretion. Furthermore, the number of IFN-gamma-secreting IEL, as assessed by the enzyme-linked immunospot technique, was increased during listeriosis. gamma/delta TCR modulation by GL3 administration abrogated antigen-induced IFN-gamma secretion by IEL from infected mice. These findings suggest that L. monocytogenes induced IFN-gamma secretion by gamma/delta IEL from mice suffering from intestinal L. monocytogenes infection and invasion. Thus, the data provide evidence for a role of IFN-gamma-secreting IEL in local resistance against listeriosis and perhaps other food-borne diseases.
Animals↗
Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique.
BACKGROUND AND AIMS: The contribution of the gastrointestinal tract in comparison with the liver for the low and variable bioavailability of orally administered drugs is still poorly understood. Here we report on a new intestinal perfusion technique for the direct assessment of absorption, metabolism, and transport of drugs by the intestinal wall. METHODS: In 6 healthy volunteers a multilumen perfusion catheter was used to generate a 20-cm isolated jejunal segment that was perfused with 80 mg verapamil. Simultaneously, 5 mg [(2)H(7)]verapamil was given intravenously. Blood, perfusate, and bile samples were analyzed for parent verapamil and its major metabolites. RESULTS: The mean fraction of the verapamil dose absorbed from the 20-cm segment was 0.76 but substantial interindividual variability (0.51-0.96) was shown. Bioavailability was low (19.3%). The intestinal wall contributed to the same extent as the liver to extensive first-pass metabolism (mean extraction ratio, 0.49 versus 0.48). Substantial transport of verapamil metabolites from the systemic circulation via the enterocytes into the intestinal lumen was observed. Compared with biliary excretion, intestinal secretion into a 20-cm jejunal segment contributed to drug elimination to a similar extent. CONCLUSION: First-pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites.
Adult↗
Neuronal influence on intestinal transport.
Reflex activation of the enteric nervous system (ENS) from the intestinal lumen and also from the serosa induces intestinal secretion. Thus mechanical distention, cholera toxin, heat-stable enterotoxin from E. coli, bile acids, mucosal inflammation and chemical peritonitis all induce an intestinal secretion that is inhibited by 60-100% by nerve-blocking agents. As a result of a large number of in vitro and in vivo studies, a picture of the organization of the secretory enteric nervous reflexes is now emerging. In secretory states with preserved intact intestinal epithelium, it is proposed that the reflex activation occurs via stimulation of receptor cells, i.e. epithelial endocrine cells such as EC and N-cells, which release peptides/amines into the interstitial space and thereby activate nerves close to the epithelium. The afferent neurones appear to transfer the reflex to the myenteric plexus, probably by using tachykinins as transmitters. This is in agreement with a superior and co-ordinating role for the myenteric plexus in the control of intestinal function by the ENS. Interneurones in turn mediate the transmission of the nerve signal to the submucosal plexus and the efferent neurones via cholinergic, nicotinic postganglionic receptors. The transmitters at the effector cells are acetylcholine and probably VIP.
Afferent Pathways↗
Involvement of 5-hydroxytryptamine and prostaglandin E2 in the intestinal secretory action of Escherichia coli heat-stable enterotoxin B.
The intestinal secretory action of Escherichia coli heat-stable enterotoxin B (STb) is poorly defined. Previous work indicates that STb causes loss of intestinal fluid and electrolytes by a mechanism independent of elevated levels of cyclic nucleotides, the hallmark of other E. coli cytotonic enterotoxins. In the work described in this report, we observed that treatment of ligated rat intestinal loops with purified STb of E. coli resulted in a dose-dependent rise in intestinal secretion concomitant with dose-related increases in levels of serotonin (5-hydroxytryptamine [5-HT]) and prostaglandin E2 (PGE2). Treatment of rats with the 5-HT2 receptor antagonist ketanserin prior to STb challenge resulted in significant (P < 0.05) reduction in intestinal secretion. Blockage of 5-HT2 receptors with ketanserin also reduced (P < 0.05) the level of PGE2 observed following STb treatment, indicating that at least a portion of the PGE2 was formed in response to 5-HT2 receptor stimulation. In a similar fashion, indomethacin, an inhibitor of cyclooxygenase activity, significantly reduced the level of secretion (P < 0.05) observed following STb treatment yet had no effect on 5-HT levels. Treatment of rats with both ketanserin and indomethacin further reduced STb-mediated secretion to a level not attained by either drug alone. Taken together, our data suggest that secretion due to STb involves both 5-HT and PGE2 as intestinal secretagogues. Furthermore, PGE2 formation appears to arise through both 5-HT-dependent and 5-HT-independent pathways.
Animals↗
Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT).
Multidrug resistance conferred to cancer cells is often mediated by the expression of efflux transporter "pumps". It is also believed that many of the same transporters are involved in drug efflux from numerous normal endothelial and epithelial cell types in the intestine, brain, kidney, and liver. Etoposide transport kinetics were characterized in Caco-2 cells and in well established Madin-Darby canine kidney (MDCKII) cell lines that were stably-transfected with a human cDNA encoding P-glycoprotein (Pgp), human multidrug resistance protein (MRP1), or the canalicular multispecific organic anion (cMOAT) transporters to determine the roles of these transporters in etoposide efflux. Etoposide transport kinetics were concentration-dependent in the MDCKII-MDR1 and MDCKII-cMOAT cells. The apparent secretory Michaelis constant (Km) and carrier-mediated permeability (Pc) values for Pgp and cMOAT were 254.96 +/- 94.39 microM and 5.96 +/- 0.41 x 10(-6) cm/s and 616.54 +/- 163.15 microM and 1.87 +/- 0.10 x 10(-5) cm/s, respectively. The secretory permeability of etoposide decreased significantly in the basal to apical (B to A) (i.e., efflux) direction, whereas the permeability increased 2.3-fold in the apical to basal (A to B) direction in MDCKII-MDR1 cells in the presence of elacridar (GF120918). Moderate inhibition of etoposide efflux by leukotriene C4 (LTC4) was observed in MDCKII-cMOAT cells. Furthermore, etoposide inhibited LTC4 efflux, confirming the involvement of cMOAT. The flux of etoposide in MDCKII-MRP1 cells was similar to that in MDCKII/wt control cells. The current results demonstrate that the secretory transport mechanism of etoposide involves multiple transporters, including Pgp and cMOAT but not MRP1. These results demonstrate that Pgp and cMOAT are involved in the intestinal secretory transport of etoposide. Since the intestinal secretion of etoposide was previously reported in the literature, it also suggests that they may be involved in the in vivo intestinal secretion of etoposide; however, mechanistic in vivo studies are required to confirm this.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Gluten sensitivity and latency: can patterns of intestinal antibody secretion define the great 'silent majority?'.
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Antibodies↗