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PubMed2001

Transcytosis of pancreatic bile salt-dependent lipase through human Int407 intestinal cells.

In previous studies, we have shown that the bile-salt-dependent-lipase (BSDL), secreted by pancreatic acinar cells and secreted into the duodenal lumen, can be transcytosed through intestinal cells up to the lamina propria. In this study, we used an in vitro system to provide insights into the apical to basolateral transport of BSDL, across the intestinal barrier. The Int407 human epithelial cell line, grown under conditions that optimize polarity, was used as a tight epithelium model. We attempted to delineate uptake mechanisms and the transcytotic pathway followed by this pancreatic enzyme within the intestinal Int407 cells, which do not produce BSDL. When added to the apical reservoir of Transwell-grown Int407 cells, BSDL was shown to first interact with the apical membrane. Further, BSDL forms clusters that are internalized via clathrin-coated pits. Following endocytosis, BSDL is directed to a nocodazole- and colchicin-sensitive multivesicular compartment. Interestingly, this protein transits through the Golgi apparatus, where it was found to colocalize with the KDEL retrieval-receptor. Finally, enzymatically active intact BSDL was released at the basolateral membrane level. This is the first demonstration for an apical-to-basolateral transcytotic pathway of a secreted pancreatic digestive enzyme through polarized intestinal cells.

Animals↗
PubMed2002

Adherent-invasive Escherichia coli: a putative new E. coli pathotype associated with Crohn's disease.

Crohn's disease (CD) is an inflammatory bowel disease (IBD) of unknown aetiology. Genetically engineered rodent models showed that IBDs are immunologically mediated and that luminal bacteria play an essential role in the development of the inflammation. Various bacterial pathogens have been incriminated but results have been conflicting. A new pathovar of E. coli, designated adherent-invasive Escherichia coli (AIEC) may be associated with CD. AIEC strains colonize the intestinal mucosa by adhering to intestinal epithelial cells. They are also true invasive pathogens, able to invade intestinal epithelial cells via a macropinocytosis-like process, and to survive and replicate intracellularly after lysis of the endocytic vacuole. Within macrophages, AIEC strains survive and replicate extensively without inducing host cell death and induce the release of high amounts of TNFalpha. All these virulence properties designate AIEC as a possible pathogen potentially able to induce persistent intestinal inflammation, by crossing and breaching the intestinal barrier, moving to deep tissues, and continuously activating macrophages.

Bacterial Adhesion↗
PubMed1988

Intestinal absorption of oyster shell electrolysate.

High voltage electric current was passed through oyster shell powder for electrolysis. The crystalline shape of oyster shell electrolysate appeared to be quite different from that of CaO or CaCO3. Higher serum calcium values were achieved by oral administration of the same amount of as oyster shell electrolysate than as calcium carbonate in vitamin D-deficient rats, suggesting a better intestinal absorption of the former than the latter. In four patients with postoperative hypoparathyroidism with reduced intestinal calcium absorption, the same amount of elementary calcium as oyster shell electrolysate was more effective than calcium carbonate in raising serum calcium in the absence of vitamin D supplement. Oyster shell electrolysate was also more effective in suppressing serum parathyroid hormone concentration than calcium carbonate in two patients with secondary hyperparathyroidism with renal failure. Calcium thus appears to be more readily absorbed from oyster shell electrolysate than from calcium carbonate through intestinal barriers produced by insufficient vitamin D action.

Adult↗
PubMed1984

Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred rat.

Experiments were performed to investigate the immunological consequences associated with the persorption of poorly degradable carregeenans from the diet. Using an inbred strain of rat it was demonstrated histochemically, by the carrageenan-specific Alcian blue staining technique, that small quantities of food-grade carrageenans given at 0.5% in drinking-water for 90 days could penetrate the intestinal barrier of adult animals. This apparently occurred via an intact mucosa in the absence of inflammatory or pathological lesions. The carrageenan was demonstrated in macrophage-like cells present within the villi and lamina propria of the small intestine. The oral administration of kappa, lambda or iota food-grade carrageenans did not affect local (biliary) or systemic antibody responses to gut commensal microorganisms, or to orally-administered sheep erythrocytes. However, when sheep red blood cells were administered parenterally the ensuing anti-sheep red blood cell haemagglutinating antibody response was temporarily suppressed in carrageenan-fed rats. lambda-Carrageenan and iota-carrageenan both significantly (P less than or equal to 0.01 and P less than or equal to 0.05, respectively) reduced the mid-phase (14-28 days) haemagglutinin response; kappa-carrageenan (L100) was less effective but caused significant depression at day 21 (P less than or equal to 0.01). Individual responses were, however, within the control range 35 days after sheep erythrocyte administration, thus indicating the temporary nature of this effect. Although carrageenan administration depressed the anti-sheep erythrocyte antibody response, it did not affect T-cell immune competence as measured by the popliteal lymph node assay for graft-versus-host reactivity.

Administration, Oral↗
PubMed2004

Targeting and crossing of the human maternofetal barrier by Listeria monocytogenes: role of internalin interaction with trophoblast E-cadherin.

Listeria monocytogenes produces severe fetoplacental infections in humans. How it targets and crosses the maternofetal barrier is unknown. We used immunohistochemistry to examine the location of L. monocytogenes in placental and amniotic tissue samples obtained from women with fetoplacental listeriosis. The results raised the possibility that L. monocytogenes crosses the maternofetal barrier through the villous syncytiotrophoblast, with secondary infection occurring via the amniotic epithelium. Because epidemiological studies indicate that the bacterial surface protein, internalin (InlA), may play a role in human fetoplacental listeriosis, we investigated the cellular patterns of expression of its host receptor, E-cadherin, at the maternofetal interface. E-cadherin was found on the basal and apical plasma membranes of syncytiotrophoblasts and in villous cytotrophoblasts. Established trophoblastic cell lines, primary trophoblast cultures, and placental villous explants were each exposed to isogenic InlA+ or InlA- strains of L. monocytogenes, and to L. innocua expressing or not InlA. Quantitative assays of cellular invasion demonstrated that bacterial entry into syncytiotrophoblasts occurs via the apical membrane in an InlA-E-cadherin dependent manner. In human placental villous explants, bacterial invasion of the syncytiotrophoblast barrier and underlying villous tissue and subsequent replication produces histopathological lesions that mimic those seen in placentas of women with listeriosis. Thus, the InlA-E-cadherin interaction that plays a key role in the crossing of the intestinal barrier in humans is also exploited by L. monocytogenes to target and cross the placental barrier. Such a ligand-receptor interaction allowing a pathogen to specifically cross the placental villous trophoblast barrier has not been reported previously.

Bacterial Proteins↗
PubMed2005

Inhibition of IL-18 reduces myeloperoxidase activity and prevents edema in intestine following alcohol and burn injury.

Previous studies have shown that alcohol (EtOH) ingestion before burn injury impaired intestinal barrier and immune function. This study determined whether EtOH and burn injury up-regulate interleukin (IL)-18 and whether IL-18 up-regulation following EtOH and burn injury is a cause for neutrophil recruitment and increased intestinal edema. Rats (250 g) were gavaged with EtOH to achieve a blood EtOH level in the range of 100 mg/dL prior to burn or sham injury (25% total body surface area). A group of rats was treated with Ac-YVAD-CHO (5 mg/kg), an inhibitor of caspase-1 (an enzyme that converts pro-IL-18, an inactive form of IL-18, to mature IL-18), at the time of injury. One day after injury, rats were killed. IL-18 production was determined in circulation and in the supernatants harvested from spleen, mesenteric lymph nodes, and Peyer's patch cell cultures as well as in intestinal tissue homogenates. Neutrophil accumulation in intestine was determined by measuring myeloperoxidase (MPO) activity. We found a significant increase in IL-18 levels in the lymphoid cell supernatants and intestinal tissue homogenates obtained from EtOH and burn-injured rats compared with the rats receiving burn or sham injury. This was accompanied by an increase in intestinal MPO and edema. No demonstrable change in intestinal morphology was observed in any group. Treatment of rats with caspase-1 inhibitor significantly attenuated the increase in IL-18 levels and intestinal MPO activity in EtOH and burn-injured rats. Inhibition of IL-18 also prevented an increase in intestinal tissue water content. As MPO is considered an index of neutrophil infiltration, results presented in this manuscript collectively suggest that IL-18 up-regulation is likely to contribute to the increased neutrophil infiltration and edema in intestinal tissue observed following EtOH and burn injury.

Animals↗
PubMedDate not supplied

Pharmacokinetic examination of antipyrine passage through the placenta and the small intestine in rats.

The placental and small intestinal barriers, though obviously different, show many functional as well as morphological similarities. When the surface area of both barriers in man was recalculated to a unit of body weight, nearly identical values (2.71 and 2.86 m2/kg of body mass, respectively) were obtained. The aims of the present study were (1) to compare mutual permeability of these two barriers to antipyrine (AP), and (2) to describe pharmacokinetics of AP in pregnant and non-pregnant rats. In placental studies AP showed that its rapid transfer through the placenta (k(tr) = 0.046 min(-1)) was governed by the mechanism of passive diffusion. In the closed circuit, FMCR(eq) was 1.085, t(eq) was 112.10 min and k(eq) was 0.020 min(-1). Absorptive studies performed on the rat small intestine indicated an identical mechanism of drug transport. The apparent first-order absorption rate constant of AP was 0.479 min(-1), and Tmax was 8.95 minutes. Differences in AP pharmacokinetics between pregnant and non-pregnant rats were significant during the distribution phase (t(1/2) = 3.78 and 5.87 min, respectively), whereas the elimination phase was unaffected. AP has been demonstrated, as expected, to be an excellent marker for drug transport studies through different body barriers.

Animals↗
PubMed2006

Efficacy and mechanism of action of chitosan nanocapsules for oral peptide delivery.

PURPOSE: We have previously shown that high molecular weight (MW > 100 kDa) chitosan nanocapsules are efficient vehicles for improving the oral absorption of salmon calcitonin (sCT). In the present work, our objectives were, first, to investigate the influence of some formulation parameters on the efficacy of chitosan nanocapsules as carriers for the oral administration of sCT and, second, to elucidate the mechanism of interaction of chitosan nanocapsules with intestinal model cell lines. METHODS: sCT-loaded chitosan nanocapsules were prepared by the solvent displacement technique. They were characterized for their size, zeta potential, and sCT loading. The ability of chitosan nanocapsules to enhance the oral absorption of sCT was investigated in rats by monitoring the serum calcium levels. Finally, the mechanism of interaction of chitosan nanocapsules with the Caco-2 cell model or in the coculture of Caco-2 with HT29-M6 cells was investigated by confocal fluorescence microscopy. RESULTS: Chitosan nanocapsules presented a particle size in nanometer range, a positive surface charge, and an efficient encapsulation of sCT. Following oral administration to rats, all formulations of nanocapsules exhibited the ability to reduce calcemia levels; however, the intensity of the response varied depending on the formulation conditions. With regard to the mechanism of interaction of chitosan nanocapsules with cell culture, the xz images evidenced that chitosan nanocapsules interact and remain associated to the apical side of both model cell cultures. In addition, chitosan nanocapsules showed a preferable association to the mucus-secreting cells (HT29-M6). CONCLUSIONS: Chitosan nanocapsules are able to enhance and prolong the intestinal absorption of sCT and this effect could be mainly ascribed to their mucoadhesive character and intimate interaction with the intestinal barrier.

Administration, Oral↗
PubMed2003

Differential alterations in intestinal permeability after trauma-hemorrhage.

BACKGROUND: Recent studies have shown that the intestinal barrier function is altered and macromolecules can translocate after trauma and hemorrhagic shock. The translocated molecules are absorbed from the lymphatic tissue or directly enter the circulation in the gut. However, it remains unknown to what degree these compartments contribute to the clearance of the macromolecules. METHODS: Male Sprague-Dawley rats (350-400 g) underwent a 5-cm midline laparotomy (i.e., soft tissue injury), were bled to a mean arterial pressure of 35 mmHg and maintained for approximately 90 min, and then resuscitated with Ringer's lactate (4x the shed blood volume) over 60 min. At 2 h after resuscitation, a solution containing 51Cr-EDTA, FITC-dextran-4 kDa, and rhodamine B-dextran-40 kDa was instilled into a jejunal blind loop and their concentrations were determined in mesenteric lymph and blood samples harvested between 2 h and 4 h after resuscitation. RESULTS: Trauma-hemorrhage and crystalloid resuscitation significantly increased mesenteric lymph flow and the mucosal permeability for the three marker molecules. There was no difference in the concentrations of 51Cr-EDTA between the blood and lymph compartment after trauma-hemorrhage. However, the high molecular weight marker (rhodamine-B-dextran-40 kDa) accumulated in significantly higher concentrations in the mesenteric lymph than in the plasma under such conditions. CONCLUSIONS: The accumulation of macromolecules in the mesenteric lymph suggests that this compartment plays an important role in the altered gut barrier function after trauma-hemorrhage.

Animals↗
PubMedDate not supplied

[Increased intestinal permeability to 51 Cr-EDTA among children with persistent diarrhea].

Persistent diarrhea, a condition highly prevalent in developing countries, causes different morphological and functional alterations of the mucosa of the small intestine, including increased permeability to different test molecules. In the present study we investigate for the first time the intestinal permeability to 51Cr-EDTA of Brazilian children with persistent diarrhea. The test of 51Cr-EDTA absorption was performed in 13 control children and in 14 children with persistent diarrhea by offering 50 microCi of the test substance by the oral route, with later detection of radioactivity excreted in 24-hour urine. There was a statistically significant difference between the control group (median = 1.26; range = 0.20-3.31%) and the group with persistent diarrhea (median = 4.68; range = 1.40-10.29%). Using the minimum and maximum values detected in the control group as the normal reference standard for the test of urinary 51Cr-EDTA absorption, we observed that 61.5% of the patients with persistent diarrhea showed altered results. Among the patients with persistent diarrhea, 51Cr-EDTA excretion was significantly higher in the group fed a protein hydrolysate diet and/or total parenteral nutrition than in the group that did not receive this diet. In four patients with persistent diarrhea, the test was performed after clinical recovery, with a fall in the excretion levels in all cases. On the basis of these data, we may conclude that: 1) in persistent diarrhea there must be alteration of intestinal permeability that might permit an increased entry of local alimentary antigens, with subsequent sensitization and allergic enteropathy, contributing to the perpetuation of the diarrhea, malabsorption and malnutrition cycle; 2) the 51Cr-EDTA test may be useful as an indicator of severity in persistent diarrhea; 3) alteration of intestinal permeability is a secondary phenomenon in persistent diarrhea, with normalization occurring after reconstruction of the intestinal barrier.

Absorption↗
PubMed2006

Wound-induced p38MAPK-dependent histone H3 phosphorylation correlates with increased COX-2 expression in enterocytes.

Gastrointestinal epithelial cell damage triggers an important biological response called restitution, a process aimed at re-epithelializing the wounded areas. Unfortunately, little is known about the intrinsic molecular signaling events implicated in this host response. We hypothesized that wounding intestinal epithelial cells activates signaling pathways leading to chromatin modification and COX-2 upregulation during restitution. Confluent rat IEC18 cells were mechanically wounded by multiple parallel scratches using a pipet tip. NF-kappaB(Ser536), p38, and histone H3(Ser10) (H3S10) phosphorylation were determined by Western blot using specific phospho-antibodies. COX-2 gene expression was evaluated by RT-PCR, Western Blot, and ELISA. Association of phosphorylated H3, RelA (NF-kappaB), and RNA polymerase II to the COX-2 gene promoter was evaluated by chromatin immunoprecipitation (ChIP). The specific inhibitors Bay11-7082 and SB239063 as well as Ad5IkappaB-superrepressor (Ad5IkappaBAA) and Ad5dnp38 were used to block NF-kappaB- and p38-signaling pathways, respectively. Wounding induced a rapid and sustained (24 h) phosphorylation of RelAS536, H3S10, and p38MAPK in enterocytes. ChIP analysis of the COX-2 gene promoter demonstrated the presence of phospho-H3S10 and recruitment of RelA and RNA polymerase II, a process blocked by SB239063. Finally, molecular blockade of NF-kappaB (Ad5IkappaBAA) or p38MAPK (Ad5dnp38) signaling strongly inhibited enterocyte restitution. p38MAPK-dependent histone 3 phosphorylation is an important component of the intestinal wound-healing response. Targeting-signaling pathways selectively involved in healing/restitution may provide a novel means to maintain or re-establish host intestinal barrier integrity.

Animals↗
PubMed1994

Translocation of bacteria due to direct mucosal damage caused by Gastrografin. An experimental study in newborn rats.

A study was carried out on 40 newborn rats to determine the effect of Gastrografin (a hyperosmolar solution, 1700 mosm/liter) on the gastrointestinal tract. All the newborns received an inoculum of Klebsiella bacteria to the gastrointestinal tract. Thirty received, in addition to maternal milk, a feeding of Gastrografin twice daily. The Gastrografin was found to cause severe and irreversible damage to the mucosa of the small intestine, causing the death of 24 rats less than a week after start of the experiment. The 10 rats who received no Gastrografin and served as controls showed no signs of disease or damage to the intestinal tract. Cultures taken from the peritoneal cavity after sacrifice were all positive for Klebsiella in the Gastrografin group (30 rats) and negative in the controls (10 rats). This study has therefore demonstrated that severe damage to the small intestine mucosa will lower the intestinal barrier and lead to transmural translocation of bacteria into the peritoneal cavity.

Animals↗
PubMed2001

Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis.

Neonatal necrotizing enterocolitis (NEC) is a major cause of morbidity in preterm infants. We hypothesize that the intestinal injury in this disease is a consequence of synergy among three of the major risk factors for NEC: prematurity, enteral feeding, and bacterial colonization. Together these factors result in an exaggerated inflammatory response, leading to ischemic bowel necrosis. Human milk may decrease the incidence of NEC by decreasing pathogenic bacterial colonization, promoting growth of nonpathogenic flora, promoting maturation of the intestinal barrier, and ameliorating the proinflammatory response.

Digestive System↗
PubMed1984

Intestinal transmission of macromolecules (BSA and FITC-labelled dextrans) in the neonatal pig. Influence of age of piglet and molecular weight of markers.

The intestinal transmission of two macromolecular markers, of similar molecular weight but different susceptibility to proteolytic digestion, was investigated in the neonatal pig. Piglets of varying age (0 h-7 days old) were given a mixture of bovine serum albumin (BSA) and fluorescein-isothiocyanate labelled dextran 70,000 (FITC-D 70) by stomach tube, and the serum concentrations were determined 2 h after feeding. A high correlation between the patterns of transmission were obtained for the two marker substances (r=0.91, n=39). Furthermore, a rapid decrease in the transmission of the markers was observed during the first day of life in suckled piglets, and intestinal macromolecular closure was well developed in the piglets after 18-36 h of life. These findings indicate that 'closure' is unrelated to changes in intestinal proteolytic activity. After closure, only small amounts of the markers were transmitted to the serum. During the first day of life, great individual differences in the transmission were found between piglets. As shown by feeding different-sized FITC-D (MW = 3,000-70,000 dalton) and unconjugated FITC (MW = 389 dalton), molecules having a molecular weight greater than 3,000 daltons were excluded upon macromolecular closure. On the other hand, smaller molecules like FITC were transmitted across the intestinal barriers independent of closure.

Aging↗
PubMed1993

Thermal injury-induced changes in the rat intestine brush border cytoskeleton.

BACKGROUND: The brush border cytoskeleton maintains the selective absorptive surface of the intestine epithelium. Increased intestinal permeability caused by cutaneous thermal injury may be the result of changes in the organization of the brush border cytoskeleton. METHODS: In this study we used electron and laser confocal microscopy to examine the temporal and spatial organization of the rat brush border cytoskeleton after thermal injury. RESULTS: Vesiculation of microvilli and disruption of core actin filament bundles were observed in rats with burns covering 20% total body surface area (TBSA). In rats with 40% TBSA burns changes in the brush border cytoskeleton were more pronounced, resulting in increased vesiculation of microvilli and disruption of terminal web actin filaments. Confocal microscopy of corresponding areas of the gut epithelium after staining with rhodamine-phalloidin showed rearrangement of brush border actin filaments. Although tight junctions were intact, the apical region of the gut epithelium in rats with 40% TBSA burns was constricted, possibly because of contraction of brush border actin filaments. Changes in brush border structure and cytoskeletal organization were most pronounced in the ileum of rats 18 hours after injury. CONCLUSIONS: These findings suggest that disruption of the brush border cytoskeleton may, in part, be responsible for the loss of intestinal barrier function after thermal injury in animal models.

Actins↗
PubMedDate not supplied

Bioadhesive properties of poly(alkylcyanoacrylate) nanoparticles coated with polysaccharide.

Development of bioadhesive nanoparticles is of great interest to improve drug absorption through the intestinal barrier. Various Polysaccharide-coated poly(alkylcyanoacrylate) nanoparticles were prepared. The bioadhesive properties of the nanoparticles coated with dextran or chitosan in end-on or side-on conformation were evaluated with an ex-vivo adsorption experiment on rat intestine. Results show that diffusion of nanoparticles in mucus layer was governed by the nanoparticle diameter and isotherms of adsorption were influenced by the nature of polysaccharide used. High amount of nanoparticles coated with chitosan can be entrapped in the mucus layer even at low nanoparticle concentration in suspension. When nanoparticle concentration increased, a pseudo-plateau was reached. In the case of dextran-coated nanoparticles, linear increase of adsorption was observed and no saturation phenomenon was highlighted over the range of nanoparticle concentration used in this study. These results suggested that interactions involved in bioadhesion mechanism depended on the nature of polysaccharide. Electrostatic interactions are enhanced between chitosan-coated nanoparticles and glycoproteins of mucus leading to a saturated adsorption phenomenon whereas dextran-coated nanoparticles interacted by non-electrostatic interactions with mucus resulting in a non-saturated phenomenon. Polysaccharides grafted at the nanoparticle surface in the brush conformation appeared more favorable to promote interactions of nanoparticles with glycoproteins of mucus in comparison with the more compact loop conformation of polysaccharide chains.

Adhesiveness↗
PubMed1981

Distribution of radioactivity following oral administration of carcinogenic 14CH3-labelled nitrosocarbaryl in the rat.

After a single intragastric administration of 14C-labelled carcinogenic nitrosocarbaryl, a nitrosated pesticide, the distribution of radioactivity was investigated in the blood and a number of organs in male rats. The animals received 0.25 mg/kg of labelled nitrosamine and were killed following administration at timed intervals between 0.5 h and 24 h. Our results show that the greatest amount of the 14CH3--group was associated with the forestomach, tumor-susceptible tissue; the level of radioactivity is noteworthy but less important in the glandular stomach. There are also sites of radioactivity accumulation mainly in the liver. Moreover, [14C]nitrosocarbaryl was revealed in the blood suggesting that nitrosamine itself rapidly (0.5 h) crosses the intestinal barrier and in a significant quantity (13%). These facts constitute a potential carcinogenic risk.

Animals↗
PubMed2000

[The significance of the expression of the HSP70 and HSP90 in the intestinal mucosa in scalded rats during early postburn stage].

OBJECTIVE: To investigate the changes in the expression, the tissue contents and the distribution of heat shock protein (HSP) 70 and HSP90 in the intestinal mucosa in scalded rats during early postburn stage and to elucidate the effects of heat shock response of intestinal mucosal cell on burn victim's systemic pathophysiology. METHODS: The scalded rats were taken as the model. ELISA, immunoblotting analysis and immunohistochemical methods were employed to analyze and study the expression, the tissue contents and the distribution and their functional status of HSP70 and HSP90 in the intestinal mucosa. RESULTS: (1) The free HSP70 content in the intestinal mucosa exhibited significantly transient decrease in the early postburn stage. (2) The total contents of HSP70 and HSP90 in the intestinal mucosa increased obviously postburn. (3) There exhibited remarkable heterogeneity of the molecular structure of HSP70 in the intestinal mucosa in the early postburn stage. CONCLUSION: The expression and the changes in the contents and the tissue distribution of the two HSPs in the intestinal mucosal cell might play important roles in the cellular stress reaction of the intestinal mucosa and even in the intestinal barrier functional mechanism.

Animals↗