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PubMed1997

An in vitro model to assess mucosal immune function and bacterial translocation.

The importance of secretory immunoglobulin A (IgA) on intestinal barrier function has gained increasing acceptance. However, due to the complexity of the intestinal microenvironment, the relative role of secretory IgA (sIgA) in mucosal defense has been difficult to study in vivo. Polarized Madin-Darby canine kidney (MDCK) epithelial cells expressing the complementary DNA (cDNA) for the polymeric Ig receptor were grown as monolayers in an in vitro two-chamber cell culture system to study the impact of sIgA on bacterial translocation (BT). Polymeric sIgA or media alone was added to the apical chambers of cell monolayers followed by apical inoculation with bacteria. The basal compartment was sampled at timed intervals thereafter to determine BT. Bacterial passage across the MDCK epithelial cell monolayers occurred in a time and bacterial inoculum concentration gradient. Addition of sIgA led to significant reductions in BT across the epithelial cell monolayers. This is a useful model for further investigation on the role of sIgA in intestinal barrier function.

Animals↗
PubMedDate not supplied

Intestinal permeability is increased in patients with advanced cirrhosis.

BACKGROUND/AIMS: The dysfunction of the intestinal barrier is a factor that has been related to bacterial translocation from lumen to extra-intestinal sites and consequently to the development of spontaneous bacterial peritonitis. The aim of this study was to investigate if the alterations of the intestinal barrier in cirrhosis are related with the degree of liver failure and associated with other clinical complications. METHODOLOGY: Intestinal permeability was assessed by means of the lactulose/mannitol test in 79 cirrhotic and 25 controls subjects. They received 10 g of lactulose and 5 g of mannitol. Lactulose and mannitol were measured in a five-hour urinary volume. RESULTS: Lactulose/mannitol ratio was significantly higher in cirrhotic patients than in controls (p = 0.03). This was more evident in end-stage cirrhosis. Patients with ascites, or encephalopathy showed a statistically significant increase in lactulose/mannitol ratio when compared to patients without these complications. CONCLUSIONS: The increased intestinal permeability is related to the progression of the liver disease and is more relevant with overt clinical complications. This is due to an increased absorption of lactulose. However, as liver disease progresses, mannitol absorption is progressively reduced, probably due to a reduced surface of absorption, and these events are more relevant in patients with overt clinical complications.

Disease Progression↗
PubMed2000

Carbonylation and disassembly of the F-actin cytoskeleton in oxidant induced barrier dysfunction and its prevention by epidermal growth factor and transforming growth factor alpha in a human colonic cell line.

BACKGROUND: Intestinal barrier dysfunction concomitant with high levels of reactive oxygen metabolites (ROM) in the inflamed mucosa have been observed in inflammatory bowel disease (IBD). The cytoskeletal network has been suggested to be involved in the regulation of barrier function. Growth factors (epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha)) protect gastrointestinal barrier integrity against a variety of noxious agents. However, the underlying mechanisms of oxidant induced disruption and growth factor mediated protection remain elusive. AIMS: To determine: (1) if oxidation and disassembly of actin (a key cytoskeletal component) plays a major role in ROM induced epithelial monolayer barrier dysfunction; and (2) if growth factor mediated protection involves prevention of theses alterations. METHODS: Caco-2 monolayers were preincubated with EGF, TGF-alpha, or vehicle before incubation with ROM (H(2)O(2) or HOCl). Effects on cell integrity, barrier function, and G- and F-actin (oxidation, disassembly, and assembly) were determined. RESULTS: ROM dose dependently and significantly increased F- and G-actin oxidation (carbonylation), decreased the stable F-actin fraction (index of stability), and increased the monomeric G-actin fraction (index of disassembly). Concomitant with these changes were disruption of the actin cytoskeleton and loss of the monolayer barrier function. In contrast, growth factor pretreatment decreased actin oxidation and enhanced the stable F-actin, while in concert prevented actin disruption and restored normal barrier function of monolayers exposed to ROM. Cytochalasin-D, an inhibitor of actin assembly, not only caused actin disassembly and barrier dysfunction but also abolished the protective action of growth factors. Moreover, an actin stabilising agent, phalloidin, mimicked the protective actions of the growth factors. CONCLUSIONS: Oxidation, disassembly, and instability of the actin cytoskeleton appears to play a key role in the mechanism of oxidant induced loss of intestinal barrier integrity. In contrast, organisation and stabilisation of actin through promotion of its assembly plays a critical role in the mechanism of growth factor mediated protection.

Actins↗
PubMed2006

Intestinal permeability in rats with CCl4-induced portal hypertension.

AIM: To investigate the intestinal barrier changes in rats with CCl4-induced portal hypertension. METHODS: The permeability of intestinal barrier detected by Lanthanum as a tracer was evaluated in rats. Bacterial translocation and plasma endotoxin were also determined. RESULTS: The incidence of bacterial translocation was 85% in rats with CCl4-induced portal hypertension, which was significantly higher than that in control rats (20%, P<0.01). Plasma endotoxin level was significantly higher in experimental group than in control group. Permeability of the epithelial mucosa and pathological alteration were increased in the ileum and the microvilli became shorter and thinner in rats with portal hypertension. CONCLUSION: Bacterial translocation occurs in rats with CCl4-induced portal hypertension and increased permeability between epithelial cells contributes to the translocation.

Animals↗
PubMed2002

In-vitro transfer of nitazoxanide across the intestinal epithelial barrier.

Nitazoxanide is a thiazolide compound that exhibits antimicrobial properties against helminths, protozoa, anaerobic bacteria and also Helicobacter pylori. The mucosal diffusion of this new drug has not been studied. The aim of this study was to examine the transport of radiolabelled nitazoxanide across the epithelial barrier according to the mode (mucosal or serosal) of drug administration. HT29-19A intestinal epithelial cells, grown as monolayers on microporous filters, were used as an epithelial model. In a short-term (100 min) transport study, the apical to basal and the basal to apical transport of nitazoxanide across the monolayers was studied in an Ussing chamber. In a long-term (24 h) study, the transport of the drug and its intracellular accumulation were studied in filter-grown epithelial monolayers kept in culture plates. In the short-term transport study, both the apical and basal fluxes achieved a steady state after 70 min and there was no significant difference between the apical to basal (3991+/-1001 ng h(-1) cm(-2)) and the basal to apical (4246+/-856 ng h(-1) cm(-2)) nitazoxanide fluxes. In the long-term transport study, after apical or basal drug application, a gradual increase in the drug concentration in the opposite compartment was noted, which reached similar values for apical and basal fluxes (2497+/-125 and 2309+/-81 ng mL(-1), respectively) after 24 h. Moreover, a rapid, although transitory, intracellular accumulation of nitazoxanide was observed at 10 min after apical (299+/-25 ng/10(6) cells) and basal (124+/-10 ng/10(6) cells) drug application, but decreased thereafter. There is an important transepithelial transport of nitazoxanide across the digestive epithelial monolayer with a rapid intracellular accumulation of the drug. No difference between the apical to basal and basal to apical fluxes of the drug was observed, suggesting that both topical and systemic modes of action of this antibiotic are successful.

Anti-Bacterial Agents↗
PubMed2004

[Intestinal permeability of patients with advanced digestive tract malignant tumors].

OBJECTIVE: To assess the intestinal barrier function of patients with advanced digestive tract malignant tumors by measuring the changes in intestinal permeability. METHODS: Sixteen patients with digestive tract tumors and 16 healthy volunteers were enrolled. After oral administration of mannitol and lactulose in deionized water, the 6-hour urine samples were collected for analyzing mannitol and lactulose concentrations using gas-liquid chromatography. RESULTS: Urine lactulose concentration and lactulose/mannitol (L/M) ratio of the tumor patients were increased in comparison with those of the healthy subjects (P<0.05). CONCLUSION: he intestinal permeability increased in these tumor patients, indicating intestinal barrier dysfunction.

Aged↗
PubMed2006

Regulation of the intestinal epithelial barrier by the apical junctional complex.

PURPOSE OF REVIEW: Epithelial intercellular junctions are important components of the epithelial barrier and are compromised in disorders such as Crohn's disease. We will highlight recent progress in understanding the role of an intercellular junction referred to as the apical junctional complex in regulating small intestinal epithelial permeability in health and disease. RECENT FINDINGS: Recent studies have implicated aberrant regulation of the AJC as an underlying factor contributing to a leaky epithelial barrier in Crohn's patients. Consequences of increased epithelial permeability include exposure of intestinal tissue to luminal antigens/pathogens which in turn influence disease activity. Furthermore, proinflammatory cytokines released into the milieu of the epithelium in patients with Crohn's disease influence apical junctional complex and epithelial barrier function. Such cytokines induce disassembly of the apical junctional complex by promoting differential endocytosis of component proteins. Additionally, apical junctional complex proteins are targeted by pathogens that use the epithelium as a portal of entry to establish disease in the host. SUMMARY: The epithelial apical junctional complex is important in determining epithelial barrier properties. Recent studies have highlighted contribution of proinflammatory cytokines and endocytosis of apical junctional complex proteins to the epithelial barrier defect. Continued advances in understanding of this field will yield new therapeutic targets for intestinal disorders.

Adherens Junctions↗
PubMed2004

The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity, and microflora.

OBJECTIVE: To investigate the effect of bile replacement following percutaneous transhepatic biliary drainage, ie, external drainage, on intestinal permeability, integrity, and microflora in a clinical setting. SUMMARY BACKGROUND DATA: Several authors have reported that internal biliary drainage is superior to external drainage. However, it is unclear whether bile replacement following external drainage is beneficial. METHODS: Twenty-five patients with biliary cancer underwent percutaneous transhepatic biliary drainage (PTBD) as a part of presurgical management. All externally drained bile was replaced either per os or by administration through a nasoduodenal tube. The interval between PTBD and the beginning of bile replacement was 21.3 +/- 19.7 days, and the length of bile replacement was 20.7 +/- 9.6 days. The lactulose-mannitol test, measurement of serum diamine oxidase (DAO) activity, and analyses of fecal microflora and organic acids were performed before and after bile replacement. RESULTS: The volume of externally drained bile varied widely from patient to patient, ranging from 220 +/- 106 mL/d to 1616 +/- 394 mL/d (mean, 714 +/- 346 mL/d). Biliary concentrations of bile acids, cholesterol, and phospholipids increased significantly after bile replacement. The lactulose-mannitol (L/M) ratio decreased from 0.063 +/- 0.060 before bile replacement to 0.038 +/- 0.032 after bile replacement (P < 0.05). Serum DAO activity increased from 3.9 +/- 1.4 U/L before bile replacement to 5.1 +/- 1.6 U/L after bile replacement (P < 0.005), and the magnitude of change in serum DAO activity correlated with the length of bile replacement (r = 0.483, P < 0.05). Neither the L/M ratios nor serum DAO activities before bile replacement correlated with the interval between PTBD and the beginning of bile replacement. Fecal microflora and organic acids were unchanged. CONCLUSION: Impaired intestinal barrier function does not recover by PTBD without bile replacement. Bile replacement during external biliary drainage can restore the intestinal barrier function in patients with biliary obstruction, primarily due to repair of physical damage to the intestinal mucosa. Our results support the hypothesis that bile replacement during external drainage is beneficial.

Adult↗
PubMed2001

PKC-beta1 mediates EGF protection of microtubules and barrier of intestinal monolayers against oxidants.

Using monolayers of human intestinal (Caco-2) cells, we found that oxidants and ethanol damage the cytoskeleton and disrupt barrier integrity; epidermal growth factor (EGF) prevents damage by enhancement of protein kinase C (PKC) activity and translocation of the PKC-beta1 isoform. To see if PKC-beta1 mediates EGF protection, cells were transfected to stably over- or underexpress PKC-beta1. Transfected monolayers were preincubated with low or high doses of EGF (1 or 10 ng/ml) or 1-oleoyl-2-acetyl-sn-glycerol [OAG; a PKC activator (0.01 or 50 microM)] before treatment with oxidant (0.5 mM H(2)O(2)). Only in monolayers overexpressing PKC-beta1 (3.1-fold) did low doses of EGF or OAG initiate protection, increase tubulin polymerization (assessed by quantitative immunoblotting) and microtubule architectural integrity (laser scanning confocal microscopy), maintain normal barrier permeability (fluorescein sulfonic acid clearance), and cause redistribution of PKC-beta1 from cytosolic pools into membrane and/or cytoskeletal fractions (assessed by immunoblotting), thus indicating PKC-beta1 activation. Antisense inhibition of PKC-beta1 expression (-90%) prevented these changes and abolished EGF protection. We conclude that EGF protection against oxidants requires PKC-beta1 isoform activation. This mechanism may be useful for development of novel therapies for the treatment of inflammatory gastrointestinal disorders including inflammatory bowel disease.

Caco-2 Cells↗
PubMed2005

Inhibition of p38 mitogen-activated protein kinase may decrease intestinal epithelial cell apoptosis and improve intestinal epithelial barrier function after ischemia- reperfusion injury.

AIM: To investigate the role of p38 mitogen-activated protein kinase in rat small intestine after ischemia-reperfusion (I/R) insult and the relationship between activation of p38 MAPK and apoptotic cell death of intestine. METHODS: Ninety Wistar rats were divided randomly into three groups, namely sham-operated group (C), I/R vehicle group (R) and SB203580 pre-treated group (S). In groups R and S, the superior mesenteric artery (SMA) was separated and occluded for 45 min, then released for reperfusion for 0.25, 0.5, 1, 2, 6, 12 and 24 h. In group C, SMA was separated without occlusion. Plasma D-lactate levels were examined and histological changes were observed under a light microscope. The activity of p38 MAPK was determined by Western immunoblotting and apoptotic cells were detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUDP-biotin nick end labeling (TUNEL). RESULTS: Intestinal ischemia followed by reperfusion activated p38 MAPK, and the maximal level of activation (7.3-fold vs sham-operated group) was reached 30 min after I/R. Treatment with SB 203580, a p38 MAPK inhibitor, reduced intestinal apoptosis (26.72+/-3.39% vs 62.50+/-3.08% in I/R vehicle, P<0.01) and decreased plasma D-lactate level (0.78+/-0.15 mmol/L in I/R vehicle vs 0.42+/-0.17 mmol/L in SB-treated group) and improved post-ischemic intestinal histological damage. CONCLUSION: p38 MAPK plays a crucial role in the signal transduction pathway mediating post-ischemic intestinal apoptosis, and inhibition of p38 MAPK may attenuate ischemia-reperfusion injury.

Animals↗
PubMed2001

Disturbance of purine nucleotide metabolism: a possible early key event in development of intestinal damage induced by chemotherapy.

Protective strategies to minimize the hematological toxicity in connection with bone marrow transplantation (BMT) have been successful, but toxicity to the gastrointestinal tract prevents further dose escalation and therefore limits the application of the treatment. As it is known that chemotherapy leads to disruption of the intestinal barrier and morphological changes of mitochondria in enterocytes, this study was conducted in order to investigate intestinal energy metabolism and permeability after intensive cytotoxic therapy in rats. Intestinal damage was produced by intraperitoneal administration of the cytostatic etoposide. Intestinal permeability was assessed by a [51Cr]EDTA absorption test and intestinal purine nucleotide content by a high-performance liquid chromatography (HPLC) technique. Four hours after the administration of etoposide, and the next 48 hr, there was a significant increase in the intestinal permeability (P < 0.05) and a significant reduction of the purine nucleotide content in the intestinal epithelial cells (P < 0.01) as compared to control animals. This early disturbance in enterocyte energy metabolism may be a key event in the development of the intestinal damage, induced by chemotherapy, and an explanation for the early disruption of the intestinal barrier demonstrable before morphological changes are evident.

Animals↗
PubMed1994

Mechanisms and sites of mannitol permeability of small and large intestine in the rat.

Mannitol is commonly used as an intestinal permeability probe, yet the mechanisms of its penetration of the intestinal barrier are not entirely clear. Therefore, we studied mannitol's permeability of different segments of the intestine and studied the kinetics and influence of intraluminal factors on mannitol permeability in vivo in perfused intestinal segments of rats. There was linear relationship between permeability rate of mannitol and its luminal concentration (y = 7.2x + 1.7; r = 0.98), indicating that passive diffusion is involved in mannitol's permeability. Increased luminal fluid osmolarity from 0.3 to 0.6 osmol/liter resulted in decreased net water flux with a corresponding decrease in mannitol permeability in both jejunum and colon (P < 0.01), indicating the prominent influence of solvent drag on net mannitol permeability. The relationship between mannitol permeability and water absorption at different osmolarities was linear in the jejunum and colon. At luminal osmolarity of 0.3 osmol/liter, 34.6% of mannitol permeability was mediated by passive diffusion and 65.4% was mediated by solvent drag in the jejunum. Mannitol permeability was much more dependent on solvent drag in the colon (88.9%) than in the small intestine (65.4%). The net permeability rate of mannitol was similar in the jejunum and ileum but was much higher in the colon (P < 0.01). Addition of chenodeoxycholate (5 mM) to the perfusate resulted in a significant decrease in absorption of water (P < 0.01) with a corresponding decrease in mannitol permeability (P < 0.01). These studies indicate that mannitol permeability of the intestinal barrier is mediated by passive diffusion and solvent drag, with the latter accounting for a greater fraction of the total permeability.

Animals↗
PubMed2002

[Immunonutritive enteral feeding in the critically ill].

Since imbalances in the immune system of the critically ill patient have been demonstrated, the role of the gastrointestinal tract for the pathogenesis of multiple organ failure has been a focus of research in intensive care medicine. Particularly, the integrity of the intestinal barrier function has been studied experimentally and clinically. The enormous number of gram-negative bacteria up to 10(11)/ml intestinal liquid inducing the release of significant amounts of endotoxin, is considered to be a vital threat to the intensive care unit (ICU) patient. Acute failure of the intestinal barrier following various types of severe shock or following parenteral nutrition inducing atrophy of intestinal mucosa may lead to multiple organ dysfunction. Maintenance of hemodynamic stability is a mainstay of therapy of the critically ill. In addition, the intestinal integrity can be preserved by the early onset of enteral nutrition. Moreover, recent concepts of enteral nutrition using immunomodulating nutrients like omega-3-fatty acids, glutamine, arginine, and nucleotides are under clinical evaluation.

Critical Illness↗
PubMed2006

Citrobacter rodentium infection causes both mitochondrial dysfunction and intestinal epithelial barrier disruption in vivo: role of mitochondrial associated protein (Map).

Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli are non-invasive attaching/effacing (A/E) bacterial pathogens that infect their host's intestinal epithelium, causing severe diarrhoeal disease. These bacteria utilize a type III secretion apparatus to deliver effector molecules into host cells, subverting cellular function. Mitochondrial associated protein (Map) is a multifunctional effector protein that targets host cell mitochondria and contributes to infection-induced epithelial barrier dysfunction in vitro. Unfortunately, the relevance of these actions to the pathogenesis of EPEC-induced disease is uncertain. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that Map colocalized with host cell mitochondria, and that in vivo infection led to a disruption of mitochondrial morphology in infected colonocytes as assessed by electron microscopy. Histochemical staining for the mitochondrial enzyme succinate dehydrogenase also revealed a significant loss of mitochondrial respiratory function in the infected intestinal epithelium; however, both pathologies were attenuated in mice infected with a Deltamap strain. C. rodentium Map was also implicated in the disruption of epithelial barrier function both in vitro and in vivo. These studies thus advance our understanding of how A/E pathogens subvert host cell functions and cause disease, demonstrating that Map contributes to the functional disruption of the intestinal epithelium during enteric infection by C. rodentium.

Animals↗
PubMed1993

Influence of prenatal corticosteroids on bacterial colonization in the newborn rat.

The interactions between bacteria and the host's intestinal barrier appear to be important regulators of bacterial colonization. In this study we investigated the effect of prenatal corticosteroids, known to accelerate the intestinal maturation of newborn rats, on bacterial colonization in the rat pup. Pregnant rats were treated with either cortisone acetate or normal saline on days 18-21 of gestation and were allowed to deliver spontaneously. The pups, after normal delivery, were sacrificed at different times during the first 10 days of life. The entire small intestine was removed, and each lumen was flushed to exclude nonadherent, transient organisms and homogenized. Tenfold dilutions were plated on horse-blood agar (total bacteria) and MacConkey's medium (gram-negatives). Quantitation and bacterial typification was determined after 24 h of incubation at 37 degrees C. Total bacteria and gram-negatives found in association with the mucosa were significantly lower in pups prenatally treated with steroids. These changes were not related to any changes in motility or intraluminal digestion. This suggests that the developmental condition of the host's intestinal barrier may be an important regulator of the bacterial microenvironment of the newborn small intestinal mucosa.

Animals↗
PubMed1995

Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein.

BACKGROUND & AIMS: Goblet cells secrete a combination of trefoil peptides and mucin glycoproteins to form a continuous gel on the mucosal surface. The functional effects of these products remain uncertain. METHODS: Trefoil peptides and/or mucin glycoproteins were added to Transwell monolayers of the human colonic cancer-derived T84 cell line. Intact monolayers permitted penetration of < 4% of the inert marker [3H]mannitol at 4 hours. Exposure to the toxic lectin phytohemagglutinin (1 mg/mL), oleic acid (8 mmol/L) and taurocholic acid (12 mmol/L), or Clostridium difficile toxin A (0.7 microgram/mL) resulted in loss of barrier function with 36%, 62%, and 45% of [3H]mannitol penetration, respectively. RESULTS: Addition of recombinant human intestinal trefoil factor in physiological concentrations (1-5 micrograms/microL) resulted in attenuation of the damage to monolayer integrity by up to 52%. Protection was enhanced (up to 95%) by the copresence of human colonic mucin glycoproteins. Similar effects were observed when rat intestinal trefoil factor or human spasmolysin, another human trefoil peptide, were added alone or in the presence of human mucin glycoproteins. Conversely, mucin glycoproteins isolated from the rat colon or stomach facilitated protection when added with human spasmolysin or human intestinal trefoil factor. CONCLUSIONS: Trefoil peptides and mucin glycoproteins protect gastrointestinal mucosa from a variety of insults.

Bacterial Toxins↗