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PubMed2001

Glycoconjugate metabolism in a cystic fibrosis knockout mouse model.

Cystic fibrosis knockout mice (cftr(-/-)) die prematurely of obstruction of the intestine which may result from accumulation of dehydrated glycoconjugate-containing mucus. We noted an increase in the specific activity of [(14)C]glucosamine-labeled high-molecular weight glycoconjugates, probably mucin, in the lumen of the intestine of cftr(-/-) (homozygous) mice compared to cftr(+/+) (wild-type) and cftr(+/-) (heterozygous) mice and a decrease in the turnover of glycoconjugates of several organs of the cftr(-/-) mice. No difference in the anionic composition of secreted intestinal glycoconjugates was detected and no difference in the amount of mucin 1 (Muc1) was found in the small intestine, colon, pancreas, and lungs of the different genotypes. In addition, the spleen of the cftr(-/-) mice was significantly smaller than that of control mice and the small intestine and colon were, respectively, longer and shorter compared to control mice. These results indicate modified glycoconjugate metabolism in cystic fibrosis knockout mice and morphologic changes to the spleen and intestine where the latter modifications are possibly related to the intestinal malabsorption associated with cystic fibrosis.

Animals↗
PubMed1997

Zinc and intestinal anaphylaxis to cow's milk proteins in malnourished guinea pigs.

Zinc supplementation could favor recovery from diarrhea in malnourished children. As the recent experimental evidence suggests that oxidative stress and intestinal anaphylaxis may contribute to the intestinal dysfunction associated with malnutrition, we postulated that zinc could act through antioxidant or antianaphylactic properties. Control (C), malnourished (M), and malnourished zinc-treated (MZ) guinea pigs were, respectively, fed a normal 30% protein diet, a low 4% protein diet, and a low 4% protein diet plus 1800 ppm of zinc. Milk proteins were included in the diets to trigger intestinal anaphylaxis. Milk sensitization was assessed by passive cutaneous anaphylaxis (PCA) against beta-lactoglobulin and by intestinal anaphylaxis measured in Ussing chambers by the increase in short circuit-current after addition of beta-lactoglobulin (deltaIsc(betaLg)). Oxidative stress was assessed by intestinal lipid peroxidation. The intestinal secretion was assessed by deltaIsc induced by inflammatory mediators. Malnutrition increased the level of anti-betaLg reaginic antibodies [PCA = 1.19 +/- 0.79 and 0.69 +/- 0.67 log(l/titer) in M versus C guinea pigs, p = 0.07] and enhanced intestinal anaphylaxis (deltaIsc(betaLg)) = 16.4 +/- 9.9 and 9.1 +/- 5.8 microA/cm2 in M versus C guinea pigs, p = 0.07), without inducing intestinal lipid peroxidation. Moreover, malnutrition enhanced significantly the intestinal secretory response to histamine and 5-hydroxytryptamine. Administration of pharmacologic doses of zinc during malnutrition inhibited the increase in milk sensitization induced by malnutrition, both at the systemic [PCA = 0.35 +/- 0.55 log(l/titer) in MZ guinea pigs, p = 0.03 versus M] and intestinal (deltaIsc(betaLg)) = 2.8 +/- 2.5 microA/cm2 in MZ guinea pigs; p = 0.001 versus M) level, and prevented the hypersecretion in response to histamine and 5-hydroxytryptamine. These data suggest that zinc has antianaphylactic and antisecretory properties that may contribute to its capacity to prevent intestinal dysfunction during malnutrition.

Anaphylaxis↗
PubMed1989

Gastric inhibitory polypeptide: a gut hormone with anabolic functions.

The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), has been isolated and characterized because of its enterogastrone-type effects. It is also named glucose-dependent insulinotropic polypeptide and is actually considered to be the main incretin factor of the entero-insular axis. Besides these well-described effects on gastric secretion and pancreatic beta cells, it also has direct metabolic effects on other tissues and organs, such as adipose tissue, liver, muscle, gastrointestinal tract and brain. In adipose tissue it is involved in the activation and regulation of lipoprotein lipase (LPL); it also inhibits glucagon-induced lipolysis and potentiates the effect of insulin on incorporation of fatty acids into triglycerides. It may play a role in the development of obesity because of the hypersensitivity of adipose tissue of obese animals to some of these actions. In the liver it does not modify insulin extraction, and its incretin effects are due only to the stimulation of insulin secretion and synthesis. It reduces hepatic glucose output and inhibits glucagon-stimulated glycogenolysis. It might increase glucose utilization in peripheral tissues such as muscle. GIP also has an effect on the volume and/or electrolyte composition of intestinal secretion and saliva. The functional importance of its effect on the hormones of the anterior pituitary lobe remains to be established, as it has never been detected in the brain. Its links with insulin are very close and the presence of insulin is sometimes necessary for the greater efficiency of both hormones. GIP can be considered as a true metabolic hormone, with most of its functions tending to increase anabolism.

Adipose Tissue↗
PubMed1982

Regulation of intestinal goblet cell secretion. I. Role of parasympathetic stimulation.

The in vivo effects of the parasympathomimetic drug pilocarpine on rat intestinal goblet cells were analyzed by autoradiography, light microscopy (LM), and electron microscopy (EM). Pilocarpine accelerated the release of mucus by compound exocytosis from crypt (but not surface) goblet cells throughout the small and large intestine. Pilocarpine-induced mucus secretion was blocked by atropine alone in ileum and colon, but total inhibition in proximal small intestine required a combination of atropine and tubocurarine. The sensitivity of morphological-autoradiographic methods for detection of goblet cell secretion was compared with that of a biochemical detection method, separation of labeled high-molecular-weight glycoproteins by Sepharose 4B gel filtration of luminal washings. Even when secretion of labeled mucus by compound exocytosis was clearly demonstrated by LM, EM, and autoradiography, gel filtration assay of luminal washings from pilocarpine-injected rats failed to reveal an increase in labeled high-molecular-weight glycoproteins. Autoradiographs of mucosal tissue after luminal washing showed that newly secreted, labeled mucus was retained in the crypts and was thus unavailable to the biochemical assay. Thus, direct observation of exocytosis in individual goblet cells provides a qualitative, but sensitive, assay for short-term acceleration of intestinal mucus secretion.

Animals↗
PubMed1986

Eicosanoids and their role in the pathogenesis of diarrhoeal diseases.

Eicosanoids are unsaturated fatty acid compounds derived from 20-carbon 'essential' fatty acids, the most important being arachidonate. Both cyclooxygenase and lipoxygenase products of arachidonate are abundant in the human gut and their biological effects include modulation of fluid and electrolyte secretion, motor activity, mucosal blood flow, and cytoprotection, in addition to chemotaxis and immune response in inflammation. In health, these lipid mediators reinforce or synergize normal homeostatic mechanisms that could proceed in their absence. Receptors for control of intestinal secretion can be divided into two major classes, one of which triggers the production of cyclic AMP and another, which initiates phospholipid breakdown and arachidonate release. An intimate connection appears to exist between phospholipid metabolism, cytosolic Ca2+ levels, electrogenic anion secretion, Na+ pump rate, electroneutral Na+/H+ exchange activity, and intracellular pH. Ca2+-dependent secretagogues affect fluid and electrolyte transport in the small and the large bowel by increasing Ca2+ entry and Ca2+ mobilization through stimulation of eicosanoid formation, prostaglandins of the E type being the most important. Secretory diarrhoea may be thought of, therefore, as cellular Ca2+ intoxication. Uncontrolled formation of eicosanoids, perhaps with a changed spectrum of arachidonate metabolites, may not only be the source of diarrhoea associated with mucosal inflammation, but may also be critical for cell proliferation resulting in abnormal cell differentiation, which seems to be the link between long-standing inflammatory bowel disease and the increased risk of colonic neoplasia. A better understanding of the pathophysiological role of eicosanoids in diarrhoeal disease has allowed reinterpretation of the rationale behind current therapy.

Animals↗
PubMed2000

Supernatants from macrophages stimulated with microcystin-LR induce electrogenic intestinal response in rabbit ileum.

Microcystin-LR is a cyclic heptapeptide hepatotoxin produced by the cyanobacterium Microcystis aeruginosa. This microorganism often forms toxic blooms in freshwater lakes and reservoirs for drinking water supply, producing serious disorders in humans and animals. Some have suggested that certain biological activities of microcystin may depend upon the stimulation of immune cells. Therefore, the aims of this research were to examine electrogenic intestinal secretion, in vitro, caused by the supernatants from macrophages stimulated with microcystin-LR, as well as to investigate the presence of interleukin-1beta and tumour necrosis factor-alpha in these supernatants. We found that the supernatants of macrophages stimulated with microcystin-LR (0.1, 0.3 and 1.0 microg/ml) caused electrogenic intestinal effects (change in short circuit currents (delta SCC)=57.6, 50.8 and 73.3, respectively, versus control=19.6 microA.cm(-2)) in a time-dependent way (microcystin-LR (1.0 microg/ml)=63.2, 108.8, 120.4 and 132.3 microA.cm(-2) at time 0, 40, 50 and 60 min., respectively). In addition, the intestinal secretory activity present in these supernatants was blocked (57%) by the prior treatment of macrophages with dexamethasone. We also demonstrated that microcystin-LR (0.1, 0.3 and 1.0 ,microg/ml) is capable of stimulating the synthesis of tumour necrosis factor-alpha (375.4, 369.0 and 610.8 pg/ml, respectively, versus control=165.0 pg/ml) and interleukin-1beta (198.9, 189.3 and 522.1 pg/ml, respectively, versus control=39.7 pg/ml). These findings demonstrate that microcystin-LR induces the release of interleukin-1beta and tumour necrosis factor-alpha by peritoneal macrophages in vitro, and that the supernatants from these macrophages induce electrogenic secretion in rabbit ileal mucosa.

Animals↗
PubMed1973

Thyrocalcitonin and the jejunal absorption of calcium, water, and electrolytes in normal subjects.

Jejunal absorption of calcium, water, and electrolytes was measured in 10 normal subjects by the triple-lumen perfusion method. During the control period, water and electrolyte movements were minimal when a bicarbonate-free test solution was infused. By contrast, bicarbonate-containing solutions were readily absorbed in the control period. Intravenous infusion of synthetic salmon calcitonin (SCT) (1 Medical Research Council U/kg wt/h) over 110-120 min resulted in a marked jejunal secretion of water, sodium, potassium, and chloride in 8 of the 10 subjects. This jejunal secretion occurred with both the bicarbonate-free and the bicarbonate-containing test solutions. Calcium absorption was not affected by SCT, and the serum calcium concentration did not fall during SCT infusion. These results suggest that diarrhea in patients with medullary carcinoma of the thyroid may be due to intestinal secretion secondary to high blood concentrations of thyrocalcitonin.

Adult↗
PubMed1987

Ir gene control of the murine secretory IgA response to cholera toxin.

In these experiments we examined the genetic control of the secretory IgA (sIgA) response to cholera toxin (CT) after CT feeding. Inbred, congenic and intra-H-2I region recombinant mouse strains were immunized with intragastric application of 10 micrograms CT on days 0 and 14. Samples of intestinal secretions and plasma were collected 1 week after the second dose and antibodies to CT measured in them by antigen- and isotype-specific enzyme-linked immunosorbent assay. In three different sets of H-2-congenic strains the intestinal IgA anti-CT response clearly depended on the H-2 haplotype rather than on background or IgH genes. H-2b (B10, A.BY/SnJ, C3H.SW) and H-2q (B10.T(6R), DBA/1J) strains were high responders, H-2k (B10.BR, C3H/He), H-2s (A.SW/SnJ) and H-2d (B10.D2) strains were low responders. Within the H-2 complex the intestinal IgA anti-CT response was mapped to the I-A subregion with the use of congenic intra-H-2I region recombinant strains: B10.A(3R) and B10.A(5R) were high responders and B10.A(4R), B10.MBR and B10.GD were low responders. Plasma IgG anti-CT after CT feeding paralleled the sIgA results. Surprisingly, the sIgA and plasma IgG anti-CT responses in individual mice of the various strains tested showed a highly significant positive correlation. We conclude that both the sIgA response and plasma IgG anti-CT response after CT feeding is controlled by the I-A subregion of H-2.

Animals↗
PubMed1991

Amplification of the secretory IgA response to Toxoplasma gondii using cholera toxin.

Our study demonstrates that cholera toxin (CT) markedly enhances the intestinal anti-T. gondii antibody response following oral immunisation of mice with a T. gondii sonicate (TSo) and CT. The antibodies induced were mostly IgA and secretory IgA but a small quantity of IgG was also produced. In contrast, no intestinal anti-T. gondii IgM antibodies were detected. Anti-CT IgA antibodies were also present in intestinal secretions but in much lower quantities than the T. gondii-specific IgA. No anti-CT IgG nor IgM antibodies were detected. Western blot analysis showed that CT induced not only an increase of the intensity of the intestinal IgA antibody response to the 30-kDa band but also induced intestinal IgA antibodies against other major T. gondii proteins (p22, and the 28-kDa antigen) as recognised by specific monoclonal antibodies. The amplification of the anti-T. gondii secretory IgA response by means of an appropriate adjuvant may be one major step leading towards an orally induced immune protection against toxoplasmosis.

Adjuvants, Immunologic↗
PubMed1991

Smoking, humoral immunity, and ulcerative colitis.

Since ulcerative colitis predominantly affects non-smokers and ex-smokers we have examined the possibility that smoking modifies the humoral immune response to an antigenic challenge from the gut lumen. Gut lavage was used in healthy subjects and patients with ulcerative colitis, including both smokers and non-smokers. Antibodies in the intestinal fluid to Escherichia coli (five pooled serotypes), Candida albicans, gliadin, ovalbumin, and beta lactoglobulin were measured by ELISA to determine specific antibody concentrations of IgG, IgA, and IgM classes. Total IgG, IgA, and IgM were also measured in intestinal secretions and serum. In addition, circulating antibody concentrations of IgG, IgA, and IgM to three gut commensals - E coli (five pooled serotypes) C albicans, and Poroteus mirabilis were measured. There was a significant reduction in the IgA concentration in intestinal fluid of smokers with ulcerative colitis compared with healthy non-smoking controls. No other significant differences were found between the groups. Overall, these data are not consistent with the idea that smoking suppresses immune responses in the gut and suggest that the effect of smoking in colitis is mediated by another mechanism.

Adult↗
PubMed1982

Lanthanum chloride inhibition of the secretory response to Escherichia coli heat-stable enterotoxin.

Escherichia coli heat-stable enterotoxin (ST) appears to cause intestinal fluid secretion by activating intestinal particulate guanylate cyclase. Recent studies suggest that chlorpromazine and quinacrine reduce the intestinal secretory response to ST and activation of guanylate cyclase by ST. We have examined the effects of lanthanum chloride, another agent that has been shown to inhibit calcium-dependent cellular processes, on the intestinal secretory response to ST and on the inhibition of ST by chlorpromazine and quinacrine. Lanthanum (2.5 to 10 mumol per mouse) reduced ST-mediated intestinal fluid secretion in the suckling mouse assay by 40 to 56%, respectively, but did not reduce basal fluid accumulation or ST activation of particulate guanylate cyclase. Intestinal fluid secretion in suckling mice induced by 8-bromocyclic GMP was also reduced by lanthanum. When subeffective doses of lanthanum and chlorpromazine were combined, they blocked both ST- and 8-bromocyclic GMP-mediated gut secretion in suckling mice. Likewise, the combination of subeffective doses of lanthanum and quinacrine reduced ST-mediated gut secretion in suckling mice. However, 8-bromocyclic GMP-induced secretion was not synergistically inhibited by lanthanum and quinacrine. These results suggest that lanthanum blocks ST-induced secretion after ST activation of guanylate cyclase. Additionally, lanthanum potentiates the inhibitory effects of quinacrine and chlorpromazine on ST and suggests that combination antisecretory therapy deserves further exploration.

Animals↗
PubMed1994

Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding.

The purpose of this study was to investigate whether oral tolerance, defined as Ag-specific immunologic unresponsiveness after Ag feeding, could be induced in humans after prolonged Ag ingestion. Eight adult volunteers ingested a total dose of 0.5 g of keyhole limpet hemocyanin (KLH) followed by subcutaneous immunization with KLH. Eight controls received only the subcutaneous immunization. In the group fed KLH, there was a significant reduction in KLH-specific T cell proliferation (p = 0.04) and delayed skin test responses (p = 0.07) to KLH. KLH ingestion alone did not induce significant levels of Abs in either serum or secretions. However, after the subsequent subcutaneous immunization, the number of circulating IgG and IgM anti-KLH-producing cells, the titers of serum IgG, IgA, and IgM anti-KLH Abs, and the titers of IgA anti-KLH Abs in saliva and intestinal secretions were significantly greater in the KLH-fed group than in the nonfed group. We conclude that KLH feeding induced systemic T cell tolerance, but B cell priming, at both systemic and mucosal sites. These studies support the concept of using Ag feeding as a treatment for certain immune-mediated diseases.

Administration, Oral↗
PubMed1987

Hepatic bile formation in the rat. Addition of vasoactive intestinal peptide to the equation.

While changes in gastric, pancreatic, and intestinal secretion in response to more recently identified gastrointestinal peptides have been characterized, there has been less investigation into effects of these hormones on hepatic bile production. The isolated perfused rat liver model has been used to examine effects of vasoactive intestinal peptide (VIP), somatostatin, bombesin, and thyrotropin-releasing hormone (TRH) on bile flow and bile acid transport. No changes were seen following bolus administration of bombesin (3 X 10(-8)-1.5 X 10(-6) M) or TRH (3 X 10(-7)-3 X 10(-6) M), while somatostatin (6 X 10(-6) M) produced a small decrease in bile flow without any change in bile acid output. VIP (3 X 10(-7) M) caused a highly significant increase in both volume of bile flow (0.85 +/- 0.8 to 1.11 +/- 0.09 microliter/min/g liver, P less than 0.001) and bile acid output (31.6 +/- 1.5 to 43.2 +/- 1.7 nmol/min/g liver, P less than 0.001). Elimination of Ca2+ from liver perfusate did not prevent VIP-induced increases in bile flow and bile acid output, and no synergistic effect of concomitant theophylline administration was observed. While effects of VIP on bile flow appear to be due to alterations in hepatic transport of bile acids, the exact mechanism(s) producing these changes remains to be elucidated.

Animals↗
PubMed1978

Normal jejunal cyclic nucleotide content in a patient with secretory diarrhea.

A case of chronic secretory diarrhea with elevated plasma vasoactive intestinal peptide (VIP) and serum gastrin levels is described. Plasma secretin, glucagon, insulin, and cyclic adenosine and guanine monophosphate (cAMP and (CGMP) concentrations were normal. Administration of a prostaglandin synthetase inhibitor failed to decrease the volume of diarrhea. There was no evidence of laxative abuse, antral cell hyperplasia, gastric hypersecretion, or pancreatic hypersecretion. The pancreatic histology was interpreted as islet cell hyperplasia. Jejunal tissue cAMP and cGMP concentrations were in the same range as those obtained from three control subjects. This report suggests that cyclic nucleotides may not mediate intestinal secretion in hormone-induced diarrhea.

Aged↗
PubMed1984

Multicompartmental analysis of the effects of dietary fat saturation and cholesterol on absorptive lipoprotein metabolism in the rat.

The potential contribution of the metabolism of absorptive lipoproteins to effects of dietary cholesterol and saturated (versus polyunsaturated) fat on plasma lipids and lipoproteins was studied in rats. Recipients were fed either a commercial stock diet, a low fat/cholesterol-free semipurified diet with a neutral P/S ratio, or one of two high fat/cholesterol-containing diets that had a high (4.6) or low (0.2) P/S ratio. Chylomicrons and intestinal very low-density lipoproteins labeled with 3H-oleic acid and/or 14C-cholesterol were isolated from donor rats receiving the high or low P/S ratio oil and were injected into recipients. Data on plasma disappearance and hepatic recovery of labels were analyzed by compartmental analysis. A multicompartmental model was required to fit these data and included steps interpreted to correspond to activation of newly secreted intestinal lipoproteins; delipidation on capillary endothelia by lipoprotein lipase, with transfer of cholesterol to other lipoproteins and tissue uptake of cholesterol and fatty acids; hepatic clearance of remnants; and secretion of lipoproteins by the liver. Metabolic state of the recipients (especially plasma triglyceride concentrations) had a greater influence on the rate of chylomicron turnover than did the source of donor chylomicrons, although saturated chylomicrons tended to be metabolized more slowly than polyunsaturated ones. For recipients fed the commercial stock diet and injected with saturated (versus polyunsaturated) chylomicrons, the mechanistic model predicted an increased retention of triglycerides during remnant formation, and thus an increased delivery of triglyceride to the liver. A consequent elevation in hepatic production of very low-density lipoprotein triglycerides may be related to the observed slower clearance of chylomicrons and increased plasma lipid levels in rats fed saturated fat and cholesterol.

Absorption↗
PubMed1995

Contribution of individual disulfide bonds to biological action of Escherichia coli heat-stable enterotoxin B.

Heat-stable enterotoxins (STs) of Escherichia coli are peptides which alter normal gut physiology by stimulating the loss of water and electrolytes. The action of heat-stable toxin B (STb) is associated with an increase in levels of lumenal 5-hydroxytryptamine and prostaglandin E2, known mediators of intestinal secretion. In addition, the toxin is responsible for elevation of cytosolic calcium ion levels in cultured cells. STb is a 48-amino-acid basic peptide containing four cysteine residues and two disulfide bonds. Previous work indicates that disulfide bonds are required for intestinal secretory activity, and yet the relative contribution of the two bonds to toxin stability and action is presently unclear. Site-directed mutagenesis was used to alter the cysteine residues of STb to assess the role of the individual disulfide bonds in toxin activity. Our results indicate that loss of a single disulfide bond was sufficient to abolish the intestinal secretory and G protein-coupled calcium ion influx activities associated with STb toxicity. Loss of toxin action was not a function of increased sensitivity of STb mutants to proteolysis, since mutant toxins displayed proteolytic decay rates equivalent to that of wild-type STb. Circular dichroism spectroscopy of mutant STb toxins indicated that single-disulfide-bond elimination did not apparently affect the toxin secondary structure of one mutant, STbC33S,C71S. In contrast, the alpha-helical content of the other disulfide bond mutant, STbC44S,C59G, was significantly altered, as was that of reduced and alkylated authentic STb. Since both Cys-Cys mutant STbs were completely nontoxic, the absence of biological activity cannot be explained by dramatic secondary structural changes alone; keys to the conformational requirements for STb toxicity undoubtedly reside in the three-dimensional structure of this peptide.

Alkylation↗
PubMed1997

Signal transduction pathways via guanylin and uroguanylin in stomach and intestine.

Guanylin and uroguanylin are peptides that activate receptor guanylate cyclases (GCs) and elicit increased intestinal secretion. Bacteria that cause traveler's diarrhea produce heat-stable toxins (STs) that mimic this action. Investigation of the distribution and identity of receptor GCs in the gastrointestinal tract of rats revealed that receptors were localized to epithelial cells in stomach and intestine. Clusters of cells in gastric mucosa and enterocytes lining the intestine exhibited specific binding of 125I-labeled ST. Ligated loops of stomach and intestine treated with intraluminal ST had significant increases in guanosine 3',5'-cyclic monophosphate (cGMP), with duodenum exhibiting the greatest response. Expression of guanylate cyclase C (GCC) mRNA and a truncated, GCC-like mRNA was found in both stomach and intestine. Both mRNAs were isolated as cDNAs encoding the GC catalytic domain. The 0.9-kilobase (kb) cDNA is 99.8% identical to GCC, whereas the truncated, 0.75-kb GCC-like cDNA has a 159-nucleotide deletion and is 96.6% identical to GCC at the protein level. Uroguanylin and guanylin mRNAs were detected in stomach and intestine. Uroguanylin mRNA was most abundant in small intestine, whereas guanylin mRNA was highest in large intestine. Thus the stomach and intestine are targets for regulation of transport by guanylin and uroguanylin via cGMP.

Amino Acid Sequence↗
PubMed2002

Novel targets for the control of secretory diarrhoea.

Secretory diarrhoea continues to be a major clinical problem worldwide. It is now recognised that the enteric nervous system plays an important role in the pathogenesis of enterotoxin mediated intestinal secretion, which has resulted in the identification of novel therapeutic targets for the treatment of acute watery diarrhoea.

Diarrhea↗