The effect of nutrition on intestinal epithelial barrier function.
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Animals↗
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[Comparison of effects of two kinds of fluid for resuscitation on bacterial translocation and inflammation of small intestine in rats with hemorrhagic shock].
OBJECTIVE: To investigate the effects of Ringer's solution (RS) or 6% hydroxyethyl saline (HES) on bacterial translocation and inflammation of the small intestine in rats with hemorrhagic shock. METHODS: Fifty healthy male SD rats were randomly divided into the sham group (SHA group, n=10), the Ringer's solution group (RS group, n=20) and 6% hydroxyethyl saline group (HES group, n=20). Controlled hemorrhagic shock model was reproduced in RS and HES groups. Bacterial translocation to the liver, the content of tumor necrosis factor-alpha (TNF-alpha) in intestinal tissue, and the myeloperoxidase (MPO) activity in the intestinal tissue were determined and compared among the groups, and the pathologic changes in the small intestine were observed. RESULTS: The mortality rate, bleeding volume and Chiu's scores were same in HES and RS groups (all P>0.05). Compared to SHA group, bacterial count and TNF-alpha level were increased significantly in HES and RS groups, and they were higher at 1 hour and lower at 24 hours in HES group than those in RS group. Compared to the SHA group, MPO activity increased at 1 hour in RS and HES groups, but no significant difference between the groups was found at 24 hours. CONCLUSION: RS prevents compromise of the intestinal barrier function better than the HES at 1 hour after fluid resuscitation. However, HES seems to be better in protecting the intestinal barrier function compared with RS at 24 hours after fluid resuscitation.
Animals↗
Effect of hemorrhagic shock on bacterial translocation, intestinal morphology, and intestinal permeability in conventional and antibiotic-decontaminated rats.
Bacterial translocation and ileal and cecal injury have been shown to occur 24 h after limited periods of hemorrhagic shock. The present studies were performed to determine the temporal sequence of mucosal injury, permeability, and bacterial translocation after hemorrhagic shock. The results indicated that bacterial translocation and mucosal injury have occurred by 2 h after a 30-min episode of shock (mean arterial pressure 30 mm Hg). Although the histologic extent of the intestinal mucosal injury was less at 2 h postshock than at 24 h postshock, at both times intestinal barrier function was lost as measured by permeability to horseradish peroxidase. Since the role of translocating bacteria in potentiating the loss of intestinal barrier function after shock is unclear, the second goal was to determine whether the extent of shock-induced mucosal injury and permeability could be reduced or abrogated by antibiotic decontamination of the gut. The extent of shock-induced mucosal injury and intestinal permeability was similar between rats with a normal gut flora (greater than 10(6) bacteria/g cecum) and antibiotic-decontaminated rats (less than 10(3) bacteria/g cecum) 2 h postshock, although the incidences of bacterial translocation were 67% and 0, respectively. Thus, shock-induced mucosal permeability and injury appear not to be directly related to the presence of translocating bacteria.
Animals↗
Gut barrier dysfunction in food allergy.
Intestinal permeability tests used in the diagnosis of allergic diseases in response to oral food challenge have led to the conclusion that constitutive defects of the intestinal barrier are not the primary cause of allergic diseases. However, perturbation of environmental factors (infection, stress), by increasing intestinal permeability and enhancing danger signals, may favour food allergy in susceptible individuals. The mechanisms of enhanced permeability to specific and bystander antigens have been delineated as well as the molecular events involved in the sequential phases of allergic reactions. Intestinal absorption of food antigens and immune responses are mutually dependent, and luminal (environmental) and serosal (intrinsic) factors synergize to maintain a self-perpetuating cycle in which antigens penetrate the mucosa and induce allergic inflammation.
Antigens↗
Absence of Fer protein tyrosine kinase exacerbates endotoxin induced intestinal epithelial barrier dysfunction in vivo.
BACKGROUND AND AIMS: Fer kinase is activated by a number of growth factors and cytokines, and phosphorylates cortactin during cell shape change induced cortical actin reorganisation. In addition, Fer participates in cytoskeletal interactions mediated by cadherins, platelet endothelial cell adhesion molecule 1 (PECAM-1), and integrins, and has recently been implicated in limiting the innate immune response. Here we examined the role of Fer in modulating leucocyte recruitment and epithelial barrier function in the gut in response to lipopolysaccharide (LPS). METHODS: Mice targeted with a kinase inactivating mutation (FerDR) or strain matched wild-type (129Sv/J) mice were studied after intraperitoneal injection of LPS. Intravital microscopy was used to examine intestinal leucocyte kinetics, and leucocyte infiltration was assessed by fluorescence activated cell sorting. Systemic inflammation was assessed by measuring lung myeloperoxidase activity. Epithelial barrier function was assessed in vivo using blood to lumen 51Cr-EDTA clearance, with or without antibody based depletion of circulating neutrophils. RESULTS: LPS induced a significant increase in leucocyte adhesion and neutrophil infiltration into the intestinal tissue, and increased blood to lumen 51Cr-EDTA clearance. Pretreatment with neutrophil depleting antibody completely abrogated this response in wild-type mice. In FerDR mice, LPS induced leucocyte adhesion within the intestinal venules was exacerbated and associated with a trend towards increased neutrophil transmigration relative to wild-type mice. Surprisingly, LPS induced epithelial barrier permeability was increased 2.5-fold in FerDR mice relative to wild-type mice, and this barrier defect was only partly attenuated by depleting circulating neutrophils by >93 %. CONCLUSIONS: Fer plays a role in regulating LPS induced epithelial barrier dysfunction in vivo through both neutrophil dependent and neutrophil independent mechanisms.
Animals↗
[Damage of intestinal mucosal barrier function after fluid resuscitation during hemorrhagic shock].
The aim of this study is to evaluate the effects of fluid resuscitation during hemorrhagic shock on bacterial overgrowth, bacterial translocation and intestinal pathology. Thirty male Sprague-Dawley rats were divided into three groups as follows: sham shock (anesthesia and femoral artery catheterization, control) was performed on group C, on group B, blood was withdrawn and maintained at a mean blood pressure of 25 mmHg for 30 min, followed by resuscitation with whole shed blood; and on group L, shock was induced by the same method, followed by resuscitation with the same shed blood volume of lactated Ringer's solution. Rats were sacrificed at 24h postshock, and bacterial cultures of blood, liver, mesenteric lymph node and cecum were obtained for standard bacteriological examinations. Furthermore, histologic examination of the end of the ileum was performed. The results indicate the pathologic mucosal injury, bacterial overgrowth and the high magnitudes of translocation occurred more frequently in group L than in groups C and B. Thus, resuscitation with lactated Ringer's solution alone for hemorrhagic shock induces intestinal histologic damage and bacterial overgrowth and leads to increase bacterial translocation.
Animals↗
Clostridium difficile toxins may augment bacterial penetration of intestinal epithelium.
BACKGROUND: Clostridium difficile can be recovered from many high-risk hospitalized patients receiving broad-spectrum antibiotic therapy. Clostridium difficile toxins A and B have been associated with increased intestinal permeability in vitro and there is growing evidence that increased intestinal permeability may be a common mechanism whereby enteric bacteria penetrate the intestinal epithelium. HYPOTHESIS: Clostridium difficile-induced alterations in the intestinal barrier facilitate microbial penetration of the intestinal epithelium, which in turn facilitates the translocation of intestinal bacteria. DESIGN: Mature Caco-2 enterocytes were pretreated with varying concentrations of toxin A or toxin B followed by 1 hour of incubation with pure cultures of either Salmonella typhimurium, Escherichia coli, or Proteus mirabilis. The effects of toxins A and B on enterocyte viability, cytoskeletal actin, and ultrastructural topography were assessed using vital dyes, fluorescein-labeled phalloidin, and scanning electron microscopy, respectively. The toxins' effects on bacterial adherence and bacterial internalization by cultured enterocytes were assessed using enzyme-linked immunosorbent assay and quantitative culture, respectively. Epithelial permeability was assessed by changes in transepithelial electrical resistance and by quantifying paracellular bacterial movement through Caco-2 enterocytes cultivated on permeable supports. RESULTS: Neither toxin A nor toxin B had a measurable effect on the numbers of enteric bacteria internalized by Caco-2 enterocytes; however, both toxins were associated with alterations in enterocyte actin, decreased transepithelial electrical resistance, and increased bacterial adherence and paracellular transmigration. CONCLUSION: Clostridium difficile toxins A or B may facilitate bacterial adherence and penetration of the intestinal epithelial barrier.
Bacterial Adhesion↗
The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn's disease.
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Crohn Disease↗
Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia.
Intestinal barrier function was prospectively examined in the course of a clinical trial evaluating the efficacy and safety of lisofylline for reducing cytotoxic therapy-induced intestinal epithelial damage-related infectious morbidity in patients receiving standard remission-induction therapy for acute myeloid leukaemia. The absorption and permeation of oral D-Xylose, lactulose and mannitol were measured weekly from baseline until marrow recovery in adult recipients of idarubicin plus cytarabine for untreated acute myeloid leukaemia. These studies were correlated with non-haematologic chemotherapy-related toxicities reflecting mucosal damage, including nausea, vomiting, stomatitis, diarrhoea, abdominal pain and systemic infection. D-xylose absorption decreased and lactulose:mannitol ratio reflecting intestinal permeability increased from baseline until the second and third week after the beginning of the treatment followed by recovery. These measures correlated with infection rates, nausea, vomiting, diarrhoea and increased blood product utilization. Lisofylline was associated with increased intestinal permeability, nausea, vomiting and infection-related morbidity despite a reduction in the duration of neutropaenia. These surrogates of intestinal barrier function correlated well with clinically important outcomes despite the failure to demonstrate reduced morbidity with lisofylline and represent useful objective outcome measurements for future clinical trials of products for the amelioration of the effects of cytotoxic therapy on the intestinal mucosa.
Adult↗
Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients.
BACKGROUND: Increased intestinal permeability was described in several intestinal auto-immune conditions. There are very few and contradictory reports about type I diabetes mellitus, an auto-immune condition sometimes associated with celiac disease. AIMS: To investigate intestinal permeability in type I diabetes mellitus patients with no concomitant celiac disease, with a comparison to ultra-structural aspects of duodenal mucosa. PATIENTS: 46 insulin dependent diabetes mellitus, non-celiac, patients (18 females and 28 males, mean age 15.8 +/- 5.3 [S.D.] years) were enrolled. The mean duration of the disease was 5.7 years. METHODS: The morphological aspect of the small bowel mucosa, at standard light microscopy and electron transmission microscopy, along with intestinal permeability (by lactulose/mannitol test) were studied. Lactulose and mannitol urinary excretion were determined by means of high performance anion exchange chromatography-pulsed amperometric detection. RESULTS: The lactulose/mannitol ratio was 0.038 [0.005-0.176] (median and range) in 46 patients compared to 0.014 [0.004-0.027] in 23 controls: insulin dependent diabetes mellitus group values being significantly higher than those of the controls (P < 0.0001, Mann-Whitney test). Eight insulin dependent diabetes mellitus patients underwent endoscopy and biopsies were analysed by means of light microscopy and transmission electron microscopy. At the light microscopy level, none of the biopsy samples showed any sign of atrophy nor inflammation, whereas transmission electron microscopy analysis showed remarkable ultra-structural changes in six out of the eight patients. Four parameters were evaluated: height and thickness of microvilli, space between microvilli and thickness of tight junctions. CONCLUSIONS: This alteration of intestinal barrier function in non-celiac type I diabetes mellitus, frequently associated with mucosal ultra-structural alterations, could suggest that a loss of intestinal barrier function can be a pathogenetic factor in a subset of insulin dependent diabetes mellitus patients.
Adolescent↗
Understanding iron absorption and metabolism, aided by studies of hemochromatosis.
Duodenal iron absorption from food is selectively blocked to prevent iron intoxication. The prime example of pathologic increase in intestinal iron absorption is seen in patients with hemochromatosis. They suffer iron damage to the heart, liver, and other tissues resulting in premature death if the iron is not removed by vigorous phlebotomy. Examples of overcoming the intestinal barrier to iron are alcohol consumption, vitamin preparations with vitamin C, and iron consumed by individuals without anemia. Endogenous generation of excess iron by hemolysis, owing to abnormal hemoglobin or many transfusions, are not controlled by the intestinal barrier.
Ferritins↗
Development of intestinal mucosal barrier function to antigens and bacterial toxins.
In this paper, we have tried to provide evidence for the association between the microvillus membrane immaturity of young infants/animals and the enhanced attachment and uptake of intestinal antigens and toxins. Finally, we have reviewed observations that growth factors that alter the newborn MVM composition towards maturity may also affect the handling of antigens by the intestinal surface.
Age Factors↗
Microbes and microbial Toxins: paradigms for microbial-mucosal toxins. V. Cholera: invasion of the intestinal epithelial barrier by a stably folded protein toxin.
Cholera toxin (CT) produced by Vibrio cholerae is the virulence factor responsible for the massive secretory diarrhea seen in Asiatic cholera. To cause disease, CT enters the intestinal epithelial cell as a stably folded protein by co-opting a lipid-based membrane receptor, ganglioside G(M1). G(M1) sorts the toxin into lipid rafts and a retrograde trafficking pathway to the endoplasmic reticulum, where the toxin unfolds and transfers its enzymatic subunit to the cytosol, probably by dislocation through the translocon sec61p. The molecular determinants that drive entry of CT into this pathway are encoded entirely within the structure of the protein toxin itself.
Animals↗
Proceedings: Mechanism of intestinal mucosal barrier absorption. 3. Property of aggregation by divalent cations of separated lipoprotein from microvillus membrane.
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Animals↗
[Goblet cells in spontaneous colibacteriosis in pigs].
This work is a part of the studies on the intestinal barrier undertaken to cast some more light on the pathogenesis of colibacteriosis in pigs. The objective of the work was to investigate the goblet cells in the intestines of pigs ill with spontaneous colibacteriosis in the form of oedema disease and gastrointestinal form. The investigations were carried out on 26 pigs segregated into 3 groups: I group -- typical oedema disease (12 pigs), II group -- colibacteriosis in the gastrointestinal form (8 pigs), III group -- healthy controls (6 pigs). The segregation into the first two groups was based on the clinical, pathological and bacteriological criteria. In all the animals, the number of the goblet cells was counted in the duodenum, jejunum, ileum, cecum and colon. The results, analysed statistically, showed that in spontaneous colibacteriosis (oedema disease as well as the gastrointestinal form) a slight decrease of the number of the goblet cells was observed. In oedema disease, this decrease is significant only in the epithelium of the jejunal villi and in that of the colon, in the gastrointestinal form -- in the duodenal and jejunal villi. It results from the present investigations that the goblet cells, as one of the factors of the intestinal barrier, are not liable to such changes in spontaneous colibacteriosis as to explain or cast light on the pathogenesis of this disease.
Animals↗
Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia.
Peroxynitrite-mediated DNA strand breaks trigger poly (ADP-ribose) synthetase (PARS) activation, resulting in intracellular energetic failure and organ dysfunction. We investigated the role of PARS activation on the inflammatory and functional response of the intestine to mesenteric ischemia-reperfusion injury. Anesthetized rats exposed to 15 min occlusion of the superior mesenteric artery showed an increased mucosal PARS activity (ex vivo incorporation of radiolabelled NAD+ in gut mucosal scrapings) as soon as 10 min after reperfusion. During the first 30 min of reperfusion, significant mucosal damage developed, as well as mucosal hyperpermeability to a 4000 MW fluorescent dextran (FD4). These alterations were significantly reduced by treatment with the NO synthase inhibitor L-NMA, which blocks the production of peroxynitrite, as well as with the PARS inhibitors 3-aminobenzamide and nicotinamide, whereas they were markedly enhanced by the glutathione depletor L-buthionine-(S,R)-sulfoximine. Also, PARS inhibition significantly reduced ileal neutrophil infiltration (myeloperoxidase activity) at 3 h reperfusion. In a second set of experiments, the effects of 15 or 30 min ischemia followed by 3 h reperfusion were evaluated in PARS knockout and wild-type mice. Significant protection against histological damage, neutrophil infiltration, and mucosal barrier failure (evaluated by the mucosal-to-serosal FD4 clearance of everted ileal sacs incubated ex vivo) was noted in PARS knockout mice, who also showed reduced alterations in remote organs, as shown by lesser lipid peroxidation (malondialdehyde formation) and neutrophil infiltration in the lung and liver. In conclusion, PARS plays a crucial role in mediating intestinal injury and dysfunction in the early and late phases of mesenteric reperfusion. Pharmacological inhibition of PARS may be a novel approach to protect tissues from reperfusion-related damage.
Animals↗
Enteric glia inhibit intestinal epithelial cell proliferation partly through a TGF-beta1-dependent pathway.
Although recent studies have shown that enteric neurons control intestinal barrier function, the role of enteric glial cells (EGCs) in this control remains unknown. Therefore, our goal was to characterize the role of EGCs in the control of intestinal epithelial cell proliferation using an in vivo transgenic and an in vitro coculture model. Assessment of intestinal epithelial cell proliferation after ablation of EGCs in transgenic mice demonstrated a significant increase in crypt cell hyperplasia. Furthermore, mucosal glial network (assessed by immunohistochemical detection of S-100beta) is altered in colon adenocarcinoma compared with control tissue. In an in vitro coculture model of subconfluent Caco-2 cells seeded onto Transwell filters with EGCs, Caco-2 cell density and [3H]thymidine incorporation were significantly lower than in control (Caco-2 cultured alone). Flow cytometry analysis showed that EGCs had no effect on Caco-2 cell viability. EGCs induced a significant increase in Caco-2 cell surface area without any sign of cellular hypertrophy. These effects by EGCs were also seen in various transformed or nontransformed intestinal epithelial cell lines. Furthermore, TGF-beta1 mRNA was expressed, and TGF-beta1 was secreted by EGCs. Exogenously added TGF-beta1 reproduced partly the EGC-mediated effects on cell density and surface area. In addition, EGC effects on Caco-2 cell density were significantly reduced by a neutralizing TGF-beta antibody. In conclusion, EGCs have profound antiproliferative effects on intestinal epithelial cells. Functional alterations in EGCs may therefore modify intestinal barrier functions and be involved in pathologies such as cancer or inflammatory bowel diseases.
Adenocarcinoma↗
Abrogation of IFN-gamma mediated epithelial barrier disruption by serine protease inhibition.
The intestinal barrier function is often impaired in a variety of diseases including chronic inflammatory bowel disease. Increased intestinal permeability during episodes of active disease correlates with destruction or rearrangement of the tight junction protein complex. IFN-gamma has been widely studied for its effect on barrier function and tight junction structures but its mode of action remains unclear. Since the claudin family of tight junction proteins is proposed to be involved in barrier maintenance we studied the effect of IFN-gamma on claudin expression in relation to epithelial barrier function. Cycloheximide and protease inhibitors were used to study mechanisms of IFN-gamma mediated barrier disruption. Intestinal epithelial cells were exposed to IFN-gamma and permeability was evaluated by horse radish peroxidase (HRP) and 4 kD FITC-dextran fluxes. Occludin and claudin-1, -2, -3, and -4 tight junction protein expression was determined by Western blotting. Occludin and claudin-2 protein expression was dramatically reduced after IFN-gamma exposure, which correlated with increased permeability for HRP and FITC-dextran. Interestingly, cleavage of claudin-2 was observed after incubation with IFN-gamma. Serine protease inhibitor AEBSF completely abrogated IFN-gamma mediated barrier disruption which was associated with preservation of claudin-2 expression. Moreover, IFN-gamma induced loss of barrier integrity was found to affect claudin-2 and occludin expression through different mechanisms. Since inhibition of serine protease activity abrogates IFN-gamma mediated barrier disruption this may be an important target for therapeutic intervention.
Blotting, Western↗