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PubMed1996

The threshold for immune cell reactivity to milk antigens decreases in cow's milk allergy with intestinal symptoms.

BACKGROUND: In cow's milk allergy (CMA) with intestinal symptoms, peripheral blood mononuclear cells (PBMCs) secrete tumor necrosis factor-alpha (TNF-alpha), altering intestinal function. However, the type of cow's milk protein (CMP) that triggers symptoms (intact or intestinally processed) is not known, and neither is the minimal amount required. METHODS: PBMCs were isolated from infants with active CMA or cured infants just before a new challenge and stimulated with intact or intestinally processed CMP. Supernatants were tested for cytokine content and for their ability to perturb intestinal barrier capacity, measured in Using chambers in HT29-19A intestinal cells. RESULTS: PBMCs from infants with active CMA secreted more TNF-alpha, when they were stimulated with intact rather than intestinally processed CMPs, and more TNF-alpha than PBMCs from cured infants. Accordingly, supernatants from PBMCs stimulated with intact but not intestinally processed CMPs significantly increased intestinal permeability. The CMP concentration required to trigger TNF-alpha secretion capable of altering intestinal function was very small in infants with active CMA (approximately 2 micrograms/ml), but about 300 times higher in cured infants. CONCLUSION: Intact rather than intestinally processed proteins stimulate PBMCs to release TNF-alpha and alter intestinal barrier capacity. The threshold for PBMC reactivity to milk antigens drops considerably during active CMA with intestinal symptoms.

Animals↗
PubMed2006

Comparative study of the intestinal mucus barrier in normal and inflamed colon.

AIM: To study the role of mucus in the spatial separation of intestinal bacteria from mucosa. PATIENTS AND METHODS: Mucus barrier characteristics were evaluated using histological material obtained by biopsy from purged colon, colon prepared with enema and material from untreated appendices fixed with non-aqueous Carnoy solution. Bacteria were evaluated using fluorescence in situ hybridization, with bacterial 16S RNA probes and related to the periodic acid Schiff alcian blue stain. Biopsies from controls (n = 20), patients with self-limiting colitis (SLC; n = 20), ulcerative colitis (n = 20) and 60 randomly selected appendices were investigated. RESULTS: The mucosal surface beneath the mucus layer was free of bacteria in > or =80% of the normal appendices and biopsies from controls. The thickness of the mucus layer and its spread decreased with increasing severity of the inflammation; the epithelial surface showed bacterial adherence, epithelial tissue defects and deep mucosal infiltration with bacteria and leucocytes. Bacteria and leucocytes were found within mucus in all biopsy specimens from patients with ulcerative colitis, SLC, and acute appendicitis. The concentration of bacteria within mucus was inversely correlated to the numbers of leucocytes. CONCLUSIONS: The large bowel mucus layer effectively prevents contact between the highly concentrated luminal bacteria and the epithelial cells in all parts of the normal colon. Colonic inflammation is always accompanied by breaks in the mucus barrier. Although the inflammatory response gradually reduces the number of bacteria in mucus and faeces, the inflammation itself is not capable of preventing bacterial migration, adherence to and invasion of the mucosa.

Acute Disease↗
PubMed1996

Intestinal absorption barriers and transport mechanisms, including secretory transport, for a cyclic peptide, fibrinogen antagonist.

PURPOSE: The intestinal absorption of DMP 728, a cyclic peptide fibrinogen antagonist, was examined with the goals of identifying the cause(s) of its low oral bioavailability and understanding the mechanisms of its intestinal transport. METHODS: In vitro partitioning, metabolism, and permeation through rat intestinal segments were evaluated. RESULTS: DMP 728 had low lipophilicity and low intestinal permeation rates relative to model compounds. In addition, DMP 728 in vitro intestinal permeation in the secretory direction greatly exceeded transport in the absorptive direction. The secretory transport was saturable, glucose-dependent, and was inhibited by verapamil and by a monoclonal antibody to P-glycoprotein. DMP 728 likewise inhibited the secondary transport of verapamil. Mucosal-to-serosal permeation rates increased in going from the proximal to distal intestinal sites, but were lower than serosal-to-mucosal permeation rates for each site. CONCLUSIONS: Net secretory transport and low lipophilicity are the major barriers to absorption of DMP 728.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Impairment of intestinal intraepithelial lymphocytes in Id2 deficient mice.

BACKGROUND: Id2, an inhibitor of basic helix-loop-helix transcription factors, regulates cell differentiation. Id2-/- mice exhibit a variety of phenotypes in the immune system. AIMS: In this study we investigated whether Id2 plays a role in intestinal intraepithelial lymphocytes (IELs), which constitute the main defence against pathogens in the intestinal tract. METHODS: Flow cytometry and bone marrow transplantation were used to analyse and characterise subsets of IELs of Id2-/- mice. Gene expression was analysed by real-time polymerase chain reaction. Intestinal barrier function was evaluated by treating mice with 5-fluorouracil (5-FU). RESULTS: Among the four members of the Id gene family, Id2 was selectively expressed in all T cell subsets in the small intestinal IELs. Id2-/- mice showed alteration in the proportions of T cell subsets and a substantial reduction in the number of IELs, especially those of the CD4+ and CD8 alpha beta+ T cell subsets, indicating a more pronounced effect on thymus derived IELs. Expression of alphaE integrin was reduced in CD4+ and CD8 alpha beta+ T cell subsets in IELs of Id2-/- mice. IELs isolated from C57BL/6 mice reconstituted with Id2-/- bone marrow cells showed a similar phenotype to that of Id2-/- mice, indicating that the defects are intrinsic to bone marrow derived cells. Expression of genes encoding intestinal epithelial cell derived cytokines was reduced in Id2-/- mice. The 5-FU treatment revealed impaired intestinal barrier function of Id2-/- mice. CONCLUSIONS: The Id2 gene is essential for constituting the intestinal mucosal barrier, particularly with respect to IELs. Id2 null mutant mice may provide a good experimental model for studying the ontogeny of IELs and intestinal inflammation and infection.

Animals↗
PubMed2006

Evidence for intestinal oxidative stress in patients with obstructive jaundice.

BACKGROUND: Obstructive jaundice results in failure of the intestinal barrier with consequent systemic endotoxemia associated with septic complications. We have recently shown that gut barrier failure in experimental obstructive jaundice is associated with high intestinal oxidative stress. This study was undertaken to investigate whether oxidative alterations occur in the intestinal mucosa of patients with obstructive jaundice. PATIENTS AND METHODS: Fifteen patients with malignant biliary obstruction and no signs of cholangitis and 15 control patients were subjected to duodenal biopsy to assess intestinal oxidative stress, estimated by lipid peroxidation (malondialdehyde - MDA) and glutathione redox state [reduced glutathione (GSH), glutathione disulphide (GSSG) and GSH/GSSG ratio]. In addition, mucosal biopsies were examined histologically and intestinal mucosal protein content was determined biochemically as an index of intestinal trophic state. RESULTS: Patients with obstructive jaundice presented high levels of intestinal oxidative stress, with significantly increased lipid peroxidation (P < 0.001). Glutathione redox state was also suggestive of high intestinal oxidative stress in jaundiced patients, indicated by significantly decreased GSH (P = 0.001) and GSH/GSSG ratio (P = 0.006) and increased GSSG (P = 0.026). Histological examination showed a mild infiltration of the lamina propria by chronic inflammatory cells in obstructive jaundice, whereas duodenal architecture remained intact and epithelial continuity was retained. Duodenal mucosa was atrophic in jaundiced patients as indicated by a significant reduction of mucosal protein content compared with controls (P = 0.001). Among oxidative stress parameters, intestinal GSH exhibited a significant positive correlation with mucosal protein content (r = 0.588, P = 0.021). CONCLUSIONS: Obstructive jaundice in humans induces intestinal oxidative stress, which may be a key factor contributing to intestinal barrier failure and the development of septic complications in this patient population.

Aged↗
PubMed2005

Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?

BACKGROUND AND AIMS: A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn's disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. METHODS: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. RESULTS: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. CONCLUSIONS: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.

Adolescent↗
PubMed1980

Rate-limiting barriers to intestinal drug absorption: a review.

The intestinal epithelium is composed of several structures that could serve as barriers to the transfer of drugs from the GI lumen to the systemic circulation. An aqueous stagnant layer that overlies the apical membrane and the subepithelial blood flow are potential barriers to the absorption of drugs that readily penetrate the absorbing cell of the epithelium. The apical, basal, and basement membranes are potential barriers to the absorption of less permeable drugs. The cytoplasm of the absorbing cell is a relatively, thick barrier that must also be traversed. While the location and structure of these potential barriers are well known, those barriers that are operative and the kinds of molecules for which they are operative are not known. The structure and permeability properties of the potential barriers are considered, along with the roles of the paracellular pathway and countercurrent exchange in the villus circulation.

Animals↗
PubMed2005

Innate defenses of the intestinal epithelial barrier.

The innate immune system plays a crucial role in maintaining the integrity of the intestine and protecting the host against a vast number of potential microbial pathogens from resident and transient gut microflora. Mucosal epithelial cells and Paneth cells produce a variety of antimicrobial peptides (defensins, cathelicidins, crytdinrelated sequence peptides, bactericidal/permeabilityincreasing protein, chemokine CCL20) and bacteriolytic enzymes (lysozyme, group IIA phospholipase A2) that protect mucosal surfaces and crypts containing intestinal stem cells against invading microbes. Many of the intestinal antimicrobial molecules have additional roles of attracting leukocytes, alarming the adaptive immune system or neutralizing proinflammatory bacterial molecules. Dysfunction of components of the innate immune system has recently been implicated in chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, illustrating the pivotal role of innate immunity in maintaining the delicate balance between immune tolerance and immune response in the gut.

Animals↗
PubMed1994

Regulation of intestinal epithelial barrier function by TGF-beta 1. Evidence for its role in abrogating the effect of a T cell cytokine.

Maintenance of the integrity of the single-cell-thick intestinal epithelium as an in vivo barrier between environmental Ags and mucosal immunocytes is pivotal for health. The T cell cytokine IFN-gamma consistently disrupts this epithelial barrier in vitro, but the substances in mucosa that may be responsible for sustaining or enhancing barrier function have not been clearly identified. Therefore, we characterized the effect on the epithelial barrier of TGF-beta 1 and three prominent neuropeptides (VIP, substance P, somatostatin) by using a model system in which barrier function of a mature polar human colonic epithelial (T84) cell monolayer is reflected in 1) the electrical potential difference across the apical to basolateral surface of each cell, 2) the transmonolayer permeability to macromolecules such as horseradish peroxidase, and 3) lactate dehydrogenase release into the medium indicating epithelial cell cytolysis. Whereas T84 monolayers exposed to TGF-beta 1 alone demonstrated a modest increase in electrical resistance and barrier integrity, TGF-beta 1 showed a striking ability to reduce the capacity of IFN-gamma to disrupt epithelial barrier function. Characterization studies demonstrated that this TGF-beta 1 effect was prolonged (e.g., days) after a single exposure, progressive over the dose range 0.1 to 2.5 ng/ml, reversible with increased concentrations of IFN-gamma, and more pronounced when TGF-beta 1 exposure was to basolateral rather than to apical epithelial membranes. Macromolecular (horseradish peroxidase) penetration of epithelium was not simultaneously altered by TGF-beta 1 and epithelial cellular injury was minimal as gauged by lactate dehydrogenase release. Additional studies using a human pathogen demonstrated that TGF-beta 1 delayed and decreased the barrier disruption caused by exposure to Cryptosporidium parvum. TGF-beta 1 may be the first of a new class of cytokines that maintains and/or enhances barrier function of human enterocytes, in part by countering the effect of a T cell cytokine.

Animals↗
PubMed2006

Probiotics and the immune response.

Beneficial effects exerted by probiotic bacteria in the treatment of human disease may be broadly classified as those effects which arise due to activity in the large intestine and are related to colonization or inhibition of pathogen growth; and those effects which arise in both the small and large intestine, and are related to enhancement of the host immune response and intestinal barrier function. In a strain dependent fashion, probiotic bacteria can enhance intestinal barrier function and modulate signal transduction pathways and gene expression in epithelial and immune cells. Oral administration of live probiotics and bacterial structural components can also differentially modulate dendritic cells resulting in an increased production of IL-10 and regulatory T cells. Both innate and adaptive immune responses can be modulated by probiotic bacteria.

Administration, Oral↗
PubMed2003

Association of vitamin A and zinc status with altered intestinal permeability: analyses of cohort data from northeastern Brazil.

To examine the association of intestinal barrier function with vitamin A deficiency and whether supplementation of micronutrients improves intestinal function and/or linear growth, height-for-age z-score (HAZ), concentrations of serum retinol and zinc, and intestinal permeability were determined in a cross-sectional sample of 75 children in northeastern Brazil. Effects of vitamin A and supplementation of zinc on intestinal permeability and growth were also determined comparing results before and after treatment in 20 children and age-matched controls. Lactulose:mannitol (L/M) permeability ratios inversely correlated with serum retinol concentrations (r = -0.55, p < 0.0005). Increased L/M permeability ratios with reduced concentrations of serum retinol were predominantly attributable to lower absorption of mannitol (r = 0.28, p = 0.02). L/M permeability ratios (p = 0.001) and HAZ scores (p = 0.007) improved with supplementation. It is concluded that impaired intestinal barrier function and linear growth shortfalls improve following supplementation of vitamin A and zinc in this setting.

Brazil↗
PubMed2004

Experimental obstructive jaundice disrupts intestinal mucosal barrier by altering occludin expression: beneficial effect of bombesin and neurotensin.

BACKGROUND: Little is known of the molecular events leading to increased intestinal permeability in obstructive jaundice. This study was undertaken to investigate the influence of experimental obstructive jaundice on the expression of the tight junction-associated protein occludin in the intestinal epithelium. STUDY DESIGN: Seventy male Wistar rats were randomly divided into five groups: I, controls; II, sham-operated; III, bile duct ligation (BDL); IV, BDL+Bombesin (BBS) (30 microg/kg/d); and V, BDL+Neurotensin (NT) (300 microg/kg/d). At the end of the experiment, on day 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and immunohistochemically for evaluation of occludin expression in the intestinal epithelium. Lipid peroxidation and protein oxidation were determined on tissue homogenates from terminal ileum and microbiologic analysis was performed in cecal contents. RESULTS: Obstructive jaundice resulted in portal and aortic endotoxemia, which was significantly reduced after BBS or NT administration. In the BDL group, there was total loss of occludin expression in numerous enterocytes mainly at the upper third of the villi, while a gradient of positivity existed from crypt to tip. Occludin expression was restored to control state after treatment with BBS or NT. In addition, both peptides reduced intestinal lipid peroxidation, while BBS reduced protein oxidation as well. CONCLUSIONS: Experimental obstructive jaundice induces regional loss of occludin expression in the intestinal epithelium, which may be a key factor contributing to the disruption of the mucosal barrier. Gut regulatory peptides BBS and NT prevent this alteration, leading to lower portal and systemic endotoxemia.

Animals↗
PubMed2003

The delta-isoform of protein kinase C causes inducible nitric-oxide synthase and nitric oxide up-regulation: key mechanism for oxidant-induced carbonylation, nitration, and disassembly of the microtubule cytoskeleton and hyperpermeability of barrier of intestinal epithelia.

Using intestinal (Caco-2) cells, we found that oxidant-induced disruption of barrier integrity requires microtubule disassembly. Protein kinase C (PKC)-delta isoform seems to be essential for disruption, but the mechanism is unknown. Because inducible nitric-oxide synthase (iNOS) is key to oxidant stress, we hypothesized that PKC-delta activation is essential in oxidant-induced iNOS up-regulation and the consequent cytoskeletal oxidation and disarray and monolayer barrier dysfunction. Cells were transfected with an inducible plasmid to overexpress native PKC-delta or with a dominant-negative to inhibit the activity of native PKC-delta. Clones were then incubated with oxidant (H(2)O(2)) +/- modulators. Parental cells were treated similarly. Exposure to oxidant-disrupted monolayers by increasing native PKC-delta activity, increasing six iNOS-related variables (iNOS activity and protein, nitric oxide, oxidative stress, tubulin oxidation and nitration), decreasing polymerized tubulin, disrupting the cytoarchitecture of microtubules, and causing monolayer dysfunction. Induction of PKC-delta overexpression by itself (3.5-fold) led to oxidant-like disruptive effects, including activation of the iNOS-driven pathway. Overexpression-induced up-regulation of iNOS was potentiated by oxidants. iNOS inhibitors or oxidant scavengers were protective. Dominant inhibition of native PKC-delta activity (99.5%) prevented all measures of oxidant-induced iNOS up-regulation and protected the monolayer barrier. The conclusions are as follows. 1) Oxidants induce loss of epithelial barrier integrity by oxidizing and disassembling the cytoskeleton, in part, through the activation of PKC-delta and up-regulation of iNOS. 2) Overexpression and activation of PKC-delta are by themselves key for cellular injury by oxidative stress of iNOS. 3) We thus report a pathophysiological mechanism, activation of iNOS pathway and its injurious consequences to the cytoskeleton, including oxidation and nitration, among the "novel" subfamily of PKC isoforms.

Blotting, Western↗
PubMed2003

Determining small bowel integrity following drug treatment.

Intestinal integrity is maintained by a delicate balance between mucosal defence and luminal aggressors that cause damage if exposed to the mucosa. The intestinal barrier function appears to be the gatekeeper for controlling this balance. It is becoming increasingly clear that if the intestinal barrier is disrupted the consequences are low grade intestinal inflammation which carry with it the risk of significant blood and protein loss both of which may cause clinical management problems. We review the strength and weaknesses of methods for assessing small bowel function that are useful for assessing drug-induced intestinal toxicity. There are a number of imaging methods for assessing intestinal integrity but these do not provide functional information. Intestinal permeability measurements have been optimized for specificity and there are now ways of measuring intestinal permeability regionally, but marker analyses continue to be cumbersome. Recent developments of faecal inflammatory markers make it a matter of routine to assess this in any routine chemical pathology laboratory. Bleeding, protein loss and other complications of inflammation can also be measured with good specificity, but again the methods are cumbersome. Using a combination of functional and imaging techniques it is now possible to characterize and define with precision, the small bowel side-effects of drugs, the best example being the small bowel side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease.

Crohn's disease is a chronic, inflammatory disease of the intestinal mucosa. Although intestinal bacteria are implicated in disease pathogenesis, the etiology is still unclear. The main location of disease is the small intestine (ileum) and the colon. Ileal disease has been linked to a mutation in the NOD2 gene. Defensins are antimicrobial peptides and in the ileum, are mainly expressed in Paneth cells, epithelial cells that also express NOD2. In the colon, defensins are expressed by enterocytes or metaplastic Paneth cells. Crohn's disease patients with ileal involvement, compared with controls or Crohn's patients without ileal involvement, have diminished expression of ileal Paneth cell defensins. This decrease is even more pronounced in Crohn's patients displaying a NOD2 mutation. In contrast, Crohn's disease of the colon is characterized by an impaired induction of beta-defensins in enterocytes. The colonic expression of the constitutive beta-defensin 1 is also decreased in the inflamed colonic mucosa, but this decrease is less specific to Crohn's disease, as it can also be found in ulcerative colitis patients. In conclusion, the regional localizations of Crohn's disease, ileal or colonic disease, can be linked to different defensin profiles. Crohn's disease of the ileum is associated with diminished defensin expression in Paneth cells. Crohn's disease of the colon is associated with diminished beta-defensin expression in enterocytes. Thus, it can be speculated that decreased defensin levels lead to a weakened intestinal barrier function to intestinal microbes and might be crucial in the pathophysiology of Crohn's disease.

Crohn Disease↗
PubMed1997

Bidirectional small intestinal permeability changes to different-sized molecules after HCl-induced injury in the rat.

A rat model was developed to assess bidirectional passage of macromolecules and low-molecular-weight markers across the intestinal barrier in intact and injured mucosa. Isolated in situ loops of distal small intestine were luminally perfused for 30 min with saline as control or HCI (pH 2.0) to induce an acute injury. The lumen-to-blood passage was followed during perfusion with bovine serum albumin, [14C]mannitol, and sodium fluorescein. Intravenously administered sodium fluorescein and endogenous serum albumin were used as blood-to-lumen markers. Acid exposure resulted in severe injury of the villi tips, with significantly increased lumen-to-blood passage of all markers compared with that of intact mucosa. Moreover, blood-to-lumen passage of rat serum albumin increased after the injury, while that of sodium fluorescein did not. The acid induced injury impaired the intestinal barrier function with an increased marker passage, where the macromolecules were more sensitive markers of the altered barrier function than low-molecular-weight markers.

Acute Disease↗