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PubMed1991

Biliary excretion of the vasopressin analogue DDAVP after intraduodenal, intrajugular and intraportal administration in the conscious pig.

The biliary excretion of the vasopressin analogue 1-deamino-8-D-arginine vasopressin (dDAVP) was determined in the pig after three administration routes, intrajugular venous, intraportal venous and intraduodenal. In all cases the biliary excretion was less than 1% of the administered dose. The plasma/bile concentration ratio was less than 1:1. A significant first-pass effect was found when the liver was exposed to a high intraportal dose of dDAVP. Possible uptake and degradation/biotransformation was evaluated by incubating [3H]dDAVP with liver tissue slices showing that [3H]dDAVP was rapidly removed from the incubation medium. The following conclusions can be drawn from these experiments: 1) The intestinal mucosa constitutes the major barrier to intestinal absorption of dDAVP. 2) dDAVP is excreted in bile in small amounts. 3) Indirect evidence suggests that the dDAVP molecule is degraded/biotransformed in the liver at its C-terminus.

Animals↗

PubMed1996

Endogenous endotoxemia after massive hepatectomy and portal vein stenosis: beneficial effect of a prostaglandin I2 analogue on intestinal permeability.

Portal vein (PV) stenosis may contribute to operative death after extended hepatectomy combined with PV reconstruction leading to impairment of the intestinal mucosal barrier. This study was designed to investigate whether rats undergoing such surgery developed endogenous endotoxemia and increased intestinal permeability. The effect of a prostaglandin I2 (PGI2) analogue on mucosal barrier function was also studied. The rats were divided into the following five groups: sham operation, massive hepatectomy (Ht), PV stenosis (PS), combined Ht and PS (Ht+PS), and Ht+PS with subcutaneous injection of PGI2 preoperatively (PG). The 10-day survival rate, portal endotoxin level and intestinal permeability (two-sugar test) were evaluated in each group. The Ht+PS group showed a significant increase in both the portal endotoxin level and intestinal permeability (p < 0.05) and a significant worse 10-day survival (p < 0.01) than the other four groups. PGI2 pretreatment did not influence splanchnic blood flow, but decreased the endotoxin level and reduced intestinal permeability. In conclusion, the synergistic effect of massive hepatectomy and PV stenosis induced an increased intestinal permeability and consequently endotoxemia. PGI2 pretreatment significantly improved both intestinal barrier function and survival.

Animals↗

PubMed2004

Effects of tributyltin on barrier functions in human intestinal Caco-2 cells.

The effect of tributyltin (TBT) on human intestinal epithelial cell functions was investigated by using human intestinal Caco-2 cell monolayers. We paid particular attention to the effect of TBT on two barrier functions: the tight junction as a physical barrier and MDR1/P-glycoprotein as a biological barrier. A loss of monolayer integrity was apparent from the TBT treatment and the paracellular permeability was increased by TBT. On the other hand, the activity of P-glycoprotein, which was examined by measuring the accumulation of Rhodamine-123 and daunomycin, was increased by prolonged TBT treatment in a concentration-dependent manner (1-100 nM). Furthermore, it was clarified by Western and Northern blots that this increase was accompanied by the increased expression of MDR1 mRNA and protein. The activation of a multidrug resistance transporter P-glycoprotein by TBT would cause a disorder of the human intestines by changing the drug pharmacokinetics.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Tumor necrosis factor-alpha (TNFalpha) regulates the epithelial barrier in the human intestinal cell line HT-29/B6.

Cytokines are supposed to be mediators in diarrhoeal diseases. The aim of this study is to characterize the effect of tumor necrosis factor-alpha (TNFalpha) on epithelial barrier function in the colonic epithelial cell line HT-29/B6. Active ion transport and barrier function were measured as short-circuit current and transepithelial electrical resistance (Rt), respectively. In parallel, freeze-fracture electron microscopy (EM) of tight junctions (TJ) and immunofluorescence microscopy of the zonula occludens protein-1 (ZO-1) were performed. Serosal addition of TNF(alpha) (100 ng/ml) decreased Rt by 81%. This effect was dose-dependent and could be mimicked by antibodies against the p55 form of the TNF receptor. Cytotoxic effects were excluded by a negative lactate dehydrogenase (LDH) assay. Immunofluorescence localization with anti-ZO-1 antibodies revealed no evidence for disruption of the monolayer after TNFalpha treatment. In freeze-fracture EM, TJ complexity was decreased by TNFalpha, as indicated by a decrease in the number of strands from 4.7 to 3.4. The tyrosine kinase blocker genistein and the protein kinase A inhibitor H-8 reduced the effect of TNFalpha. A combination of TNFalpha with interferon-gamma acted synergistically on the epithelial barrier. In conclusion, TNFalpha impairs epithelial barrier function by altering structure and function of the tight junction, which could be of pathogenic relevance in intestinal inflammation.

Apoptosis↗

PubMed2000

Cytokine-induced alteration of the epithelial barrier to food antigens in disease.

The alteration of the intestinal epithelial barrier is often a consequence of various intestinal diseases but may also be the starting point of these diseases. Undigested food antigens are transported across the intestinal epithelium by a transcytotic mechanism, including a processing within the enterocytes, and leading to the passage of intact proteins, peptides, and amino acids to the underlying mucosa. Inflammation and infection lead to the upregulation of the transport and processing of food proteins; for example, IFN gamma increases the rate of transcytosis and alters, like TNF alpha, the tight junction permeability. Infection of gastric digestive epithelia with Helicobacter pylori also increases the antigenic load transmitted to the underlying immune system by inhibiting the enterocytic lysosomal degradation of proteins. In allergic diseases, such as cow's milk allergy, TNF alpha may be involved in the intestinal dysfunction and the associated enteropathy.

Animals↗

PubMed1999

Ethanol-induced barrier dysfunction and its prevention by growth factors in human intestinal monolayers: evidence for oxidative and cytoskeletal mechanisms.

Exposure of intestinal mucosa to ethanol (EtOH) disrupts barrier function and growth factors [epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha)] are protective, but the mechanisms remain obscure. Accordingly, we sought to determine whether the molecular mechanism of EtOH-induced intestinal barrier dysfunction involves oxidative stress and disassembly of microtubules and whether the mechanism of protection by EGF or TGF-alpha involves prevention of these alterations. To this end, human colonic (Caco-2) monolayers were exposed to 0 to 15% EtOH with or without pretreatment with EGF or TGF-alpha (10 ng/ml) or with oxidative or cytoskeletal modulators. Effects on cell viability, barrier function, tubulin (microtubules), and oxidative stress were then determined. Cells were also processed for immunoblots of polymerized tubulin (S2; index of stability) and the monomeric tubulin (S1; index of disruption). EtOH dose-dependently decreased the stable S2 polymerized tubulin and concomitantly increased measures of oxidative stress, including oxidation and nitration of tubulin, fluorescence of dichlorofluorescein, and inducible nitric oxide synthase activity. EtOH also dose-dependently disrupted barrier function and extensively damaged microtubules, and these effects were prevented by pretreatment with antioxidant scavengers: L-cysteine, superoxide dismutase, and L-N(6)-1-iminoethyl-lysine (an inducible nitric oxide synthase inhibitor). In monolayers exposed to EtOH, pretreatment with EGF or TGF-alpha prevented the oxidation and nitration of tubulin, increases in the levels of the unstable S1 tubulin, disruption of microtubules, and barrier dysfunction. A microtubule stabilizer (paclitaxel,Taxol) mimicked, in part, the effects of EGF and TGF-alpha, whereas a microtubule disruptive drug (colchicine) prevented the protective effects of these growth factors. We concluded that mucosal barrier dysfunction induced by EtOH involves oxidative stress, which causes the disassembly of the microtubule cytoskeleton. Protection by EGF and TGF-alpha involves the prevention of these EtOH-induced alterations in microtubules.

Antioxidants↗

PubMed2006

Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection.

BACKGROUND & AIMS: Intestinal epithelial integrity and permeability is dependent on intercellular tight junction (TJ) complexes. How TJ integrity is regulated remains unclear, although phosphorylation and dephosphorylation of the integral membrane protein occludin is an important determinant of TJ formation and epithelial permeability. We have investigated the role intestinal intraepithelial lymphocytes (iIELs) play in regulating epithelial permeability in response to infection. METHODS: Recombinant strains of Toxoplasma gondii were used to assess intestinal epithelial barrier function and TJ integrity in mice with intact or depleted populations of iIELs. Alterations in epithelial permeability were correlated with TJ structure and the state of phosphorylation of occludin. iIEL in vivo reconstitution experiments were used to identify the iIELs required to maintain epithelial permeability and TJ integrity. RESULTS: In the absence of gammadelta+ iIELs, intestinal epithelial barrier function and the ability to restrict epithelial transmigration of Toxoplasma and the unrelated intracellular bacterial pathogen Salmonella typhimurium was severely compromised. Leaky epithelium in gammadelta+ iIEL-deficient mice was associated with the absence of phosphorylation of serine residues of occludin and lack of claudin 3 and zona occludens-1 proteins in TJ complexes. These deficiencies were attributable to the absence of a single subset of gammadelta T-cell receptor (TCR-Vgamma7+) iIELs that, after reconstituting gammadelta iIEL-deficient mice, restored epithelial barrier function and TJ complexes, resulting in increased resistance to infection. CONCLUSIONS: These findings identify a novel role for gammadelta+ iIELs in maintaining TJ integrity and epithelial barrier function that have implications for understanding the pathogenesis of intestinal inflammatory diseases associated with disruption of TJ complexes.

Animals↗

PubMed2026

Effects of Acalypha australis L. Extract on Growth Performance, Antioxidant Capacity and Intestinal Microbial Composition in Weaned Piglets.

The objective of this study was to investigate the effects of Acalypha australis L. extract (ALE) on the growth performance and intestinal health in piglets. A total of 24 weaned piglets were randomly allocated to three groups: the control group (CON), which was fed a basal diet, and the ALE0.5 and ALE1.0 groups, which were fed the basal diet supplemented with 0.5 and 1.0 g/kg of ALE, respectively. The measured variables included growth performance, digestive enzyme activity, intestinal morphology, antioxidant capacity, and intestinal microbiota and metabolites. The results showed that, compared to the CON group, supplementation of 1.0 g/kg ALE in the diets of weaned piglets significantly increased the ratio of gain to feed from 15 to 21 days (p < 0.05), decreased the diarrhea rate from Days 15 to 21 and Days 0 to 21 (p < 0.05), and increased the activities of pancreatic α-amylase, lipase, trypsin, and chymotrypsin, as well as duodenal α-amylase, lipase, and trypsin, and jejunal maltase and sucrase (p < 0.05). Additionally, supplementation of 1.0 g/kg ALE in the diet significantly improved the intestinal morphology of the duodenum and jejunum, as well as the expression of intestinal barrier-related genes in the small intestine (p < 0.05). Moreover, it significantly increased serum glutathione peroxidase activity and jejunal and ileal superoxide dismutase activities (p < 0.05), and also significantly increased the colonic propionic acid concentration of piglets (p < 0.05). The ALE supplementation increased the abundance of the colonic marker bacteria Collinsella in the piglets and influenced pathways related to amino acid metabolism, carbohydrate metabolism, and lipid metabolism. ALE can serve as a potential natural feed additive to regulate the structure of intestinal microbiota and metabolic pathways, enhance antioxidant capacity, improve intestinal health, reduce diarrhea incidence, and ultimately promote the growth performance of piglets.

Acalypha australis L. extract↗

PubMed2005

Effects of recombinant human growth hormone on intestinal translocation of bacteria and endotoxin in rats with obstructive jaundice.

BACKGROUND: Extrahepatic biliary obstruction promotes intestinal translocation of bacteria and endotoxin and this process is an important cause of morbidity and mortality in patients with jaundice. This study was undertaken to investigate the effect and mechanism of recombinant human growth hormone(rhGH) and to alleviate intestinal translocation of bacteria and endotoxin in murine obstructive jaundice. METHODS: A group of 42 Wistar rats were divided into 3 groups:sham operation(SO), bile duct ligation (BDL), and BDL and rhGH treatment(rhGH). By the end of the experiment, on day 7, the animals were killed, and their liver function and serum endotoxin were measured, bacterial cultures of the liver, kidney and mesenchymal lymph were made. Terminal ileum mucosa was observed under an electron microscope. RESULTS: Liver function was improved more significantly in the rhGH group than in the BDL group. The value of endotoxin in the rhGH group was 0.38+/-0.03 EU/ml, significantly lower than that in the BDL group(0.65+/-0.04 EU/ml, P < 0.01), and similar to that in the SO group (0.30+/-0.02 EU/ml, P > 0.05). The rate of bacteria translocation in the liver, kidney and mesenteric lymph was much higher in the BDL group than in other two groups. The rate of bacteria translocation in mesenteric lymph was 64.29%, significantly higher than that in the SO group and the rhGH group (P < 0.05). There was no significant difference in bacteria translocation rate between the SO group and the rhGH group (P > 0.05). Under an electron microscope, ileum mucosa epithelial cells in the BDL group were necrotic, and organelle were markedly metamorphic. In the rhGH group, ultrastructural changes were less evident or similar to those in the SO group. CONCLUSION: rhGH has significant protective effects on intestinal mucosa barrier in obstructive jaundice, and reduces intestinal translocation of bacteria and endotoxin.

Animals↗

PubMed2005

Understanding how Listeria monocytogenes targets and crosses host barriers.

Human listeriosis is caused by the Gram-positive bacterium Listeria monocytogenes. In humans, this pathogen has the ability to cross the intestinal, placental and blood-brain barriers, leading to gastroenteritis, maternofetal infections and meningoencephalitis, respectively. The entry of L. monocytogenes into cultured human epithelial cells is mediated by the interaction of an L. monocytogenes surface protein, internalin, with its human receptor, E-cadherin. The internalin-E-cadherin interaction is species-specific, and relies on the nature of a single amino-acid in the E-cadherin molecule, which is proline in permissive species such as humans, and glutamic acid in non-permissive species such as the mouse. In a transgenic mouse model that expresses human E-cadherin in enterocytes, internalin allows L. monocytogenes to cross the intestinal barrier. Epidemiological evidence also supports a role for internalin in human listeriosis, not only for crossing the intestinal barrier, but also for targeting and crossing the placental and blood-brain barriers. Consistent with these epidemiological data, infection with L. monocytogenes of trophoblastic cell lines, primary trophoblast cultures and human placental villous explants demonstrates that bacterial invasion of the syncytiotrophoblast barrier is mediated by the internalin-E-cadherin interaction, leading to histopathological lesions that mimic those seen in the placentas of women with listeriosis. Thus, the internalin-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. Further investigations are currently focusing on the molecular mechanisms by which L. monocytogenes targets and crosses the blood-brain barrier.

Animals↗

PubMed2002

Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period.

Immaturity of intestinal epithelial barrier function and absorptive capacity may play a role in the pathophysiology of intestinal complications in preterm neonates during the early postnatal period. We determined the intestinal permeability and carrier-mediated absorption of monosaccharides in preterm neonates during the first 2 wk after birth. Fifty-nine preterm neonates born between 25 and 32 wk gestation were included within 24 h of birth. Neonates received exclusively parenteral nutrition during the first 7 d after birth; enteral feeding was initiated at d 8. An intestinal permeability-absorption test was performed at 1, 4, 7, and 14 d after birth. The lactulose-to-rhamnose ratio was determined as a marker of intestinal permeability. Urinary excretion percentages of D-xylose and 3-O-methyl-D-glucose were determined as markers of passive and active carrier-mediated monosaccharide absorption, respectively. Intestinal permeability transiently increased between d 1 and 7 in all neonates (p < 0.05). Carrier-mediated monosaccharide absorption increased between d 1 and 14 in neonates of 28-30 wk (p < 0.05) to the level observed in the neonates of 30-32 wk gestation. In neonates <28 wk, intestinal permeability at d 7 was higher (p < 0.05) and carrier-mediated monosaccharide absorption at d 14 was lower (p < 0.01) as compared with neonates >or=28 wk. The barrier function of the intestinal epithelium transiently decreases during the first week after birth in preterm neonates who are not enterally fed. Diminished barrier function and low monosaccharide absorptive capacity, particularly in neonates <28 wk, may predispose these patients to the development of intestinal complications during the early postnatal period.

Female↗

PubMed2006

Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: tight junction dynamics exposed.

Like all mucosal surfaces, the intestine forms a barrier that separates the external environment, i.e., the gut lumen, from the protected internal milieu. The intestinal barrier is formed by the epithelial cells that line the luminal surface. Plasma membranes of these cells prevent free passage of hydrophilic molecules across this barrier but do not seal the space between cells. This function is provided by the tight junction. Each cell is encircled at the apicolateral boundary by the tight junction, which seals the paracellular space. The tight junction does not form a completely impermeant seal, however, because that would prevent paracellular absorption of essential nutrients and ions; intestinal tight junctions are "leaky" and allow solutes to be transported paracellularly according to size and charge. Abundant data are available to demonstrate that barrier properties of tight junctions can be modulated in response to physiological, pharmacological, and pathophysiological stimuli, but the structural modifications responsible for these responses are poorly defined. Recent advances in understanding the role of tight junction dynamics in response to such stimuli are the focus of this review.

Animals↗

PubMed2004

The effect of N-acetylcysteine on oxidative stress in intestine and bacterial translocation after thermal injury.

Ischemia due to transient splanchnic vasoconstriction following major burns causes oxidative and/or nitrosative damage in intestinal tissue followed by reperfusion injury. Thus, burn injury leads to breakdown in the intestinal mucosal barrier which can induce bacterial translocation (BT). As an antioxidant and anti-inflammatory agent the protective effects of N-acetylcysteine (NAC) are documented in several studies. This study was designed to determine the effect of NAC treatment on the oxidative stress in the intestine and BT after burn injury. To evaluate this, 32 Wistar rats were randomly divided into four groups as sham (n = 8), burn (n = 8), pre-burn, NAC injection (150 mgkg(-1), intraperitoneally) 15 min before thermal injury (n = 8), post-burn, NAC injection (150 mgkg(-1), intraperitoneally) 2h after thermal injury. Under anesthesia, the shaved dorsal skin of rats was exposed to boiling water for 12s to induce burn injury in a standardized manner. Twenty-four hours later, tissue samples from mesenteric lymph nodes (MLN), spleen, and liver were obtained under sterile conditions for microbiological analysis and ileum samples were harvested for biochemical analysis. In the burn group, the incidence of isolating bacteria in MLN, spleen, and liver specimens was significantly higher than other groups. NAC treatment prevented burn-induced BT in both pre- and post-burn groups. Thermal injury caused a significant decrease in glutathione (GSH) level, significant increases in malondialdehyde (MDA) and myeloperoxidase (MPO) activity at post-burn 24th hour. Treatment of rats with NAC significantly elevated the reduced GSH levels while decreasing MDA levels and MPO activity. These data suggested that NAC has a crucial cytoprotective role in intestinal mucosal barrier and preventive effects against burn injury-induced BT.

Acetylcysteine↗

PubMed2001

Expression of clusterin in Crohn's disease of the terminal ileum.

Crohn's disease (CD) is a chronic inflammatory intestinal disorder with disturbance and injury of the intestinal mucosal barrier, in which various proinflammatory molecules as well as molecules with antiinflammatory activity and cytoprotective function are found to be expressed. We investigated whether clusterin, a multifunctional cytoprotective protein, is upregulated in Crohn's disease, because augmented expression of clusterin is seen in many organs following various forms of tissue injury. Human actively and inactively inflamed ileal tissues from CD patients as well as normal intestinal specimens from control patients (normal ileum) were investigated by Western blot analysis, immunohistochemisty and in situ hybridization. As compared with controls, a strongly enhanced expression of clusterin was found in CD tissues, correlating with disease activity. Immunohistochemistry and in situ hybridization analysis revealed foci of crypts almost completely lined by clusterin expressing enterocytes in CD, a feature that was never seen in controls. Such crypts appeared especially within the morphologically intact mucosa apart from erosive or ulcerative lesions. Besides epithelia, clusterin was also expressed by inflammatory mononuclear cells. Enhanced expression of clusterin by crypt epithelia might reflect a cytoprotective function of the protein in order to prevent further injury of the intestinal mucosal barrier in CD.

Adult↗

PubMed1991

A model of human small intestinal absorptive cells. 1. Transport barrier.

The Caco-2 cell culture model of human small intestinal absorptive cells was used to investigate transepithelial transport. Transport of permeability markers such as mannitol demonstrated that Caco-2 monolayers became less permeable with increasing age in culture. Cells were routinely used for transport studies between day 18 and day 32. A transport index was determined for each compound by calculating the ratio of transport of the molecules under investigation to transport of an internal standard such as the permeability marker mannitol. Comparison of transport rates at 4 and 37 degrees C was a simple approach for differentiating primary transport mechanisms (passive paracellular, passive transcellular, or transporter-mediated) but must be coupled with additional experimental manipulations for definitive determination of transport pathways. Compounds predicted to undergo predominantly paracellular transport (mannitol, FITC, PEG-900, and PEG-4000), transporter-mediated transcellular transport (glucose, biotin, spermidine, or alanine), or lipophilic transcellular transport (alprenolol, propranolol, clonidine, or diazepam) showed differential effects of temperature on rates of transport as well as the transport index.

Biological Transport↗

PubMed2003

The effect of lower limb ischaemia-reperfusion on intestinal permeability and the systemic inflammatory response.

OBJECTIVES: a relationship has been demonstrated between increased intestinal permeability, endotoxaemia and the development of the systemic inflammatory response syndrome (SIRS) after aortic surgery. The aim of this study was to evaluate whether isolated lower limb ischaemia-reperfusion (I/R) injury affects intestinal mucosal barrier function and cytokine release. PATIENTS AND METHODS: four groups of patients were investigated, group I, patients with critical limb ischaemia (CLI) undergoing infra-inguinal bypass surgery (n=18); group II, patients with intermittent claudication (IC) undergoing infra-inguinal bypass surgery (n=14); group III, patients with CLI unsuitable for arterial reconstruction, undergoing major amputation (n=12); and group IV, patients undergoing carotid endarterectomy for symptomatic carotid stenosis (n=13). Intestinal permeability, endotoxaemia and urinary soluble tumour necrosis factor receptors were assessed (p55TNF-R). RESULTS: an increase in intestinal permeability was observed on the 3rd postoperative day only in CLI group. This was found to correlate with arterial clamp time. Patients who had a femoro-distal bypass had significantly higher intestinal permeability compared to those who had femoro-popliteal bypass. Endotoxaemia was not detected in any of the groups. Postoperative urinary p55TNF-R concentrations were significantly higher in CLI group compared to the other groups. These did not correlate with the increased intestinal permeability. CONCLUSIONS: our results support the hypothesis that revascularisation of critically ischaemia limbs leads to intestinal mucosal barrier dysfunction and cytokine release. They also suggest that the magnitude of the inflammatory response following I/R injury is related to the degree of initial ischaemia.

Aged↗

PubMed1993

Systemic mediators released from the gut in critical illness.

OBJECTIVE: To discuss the mediators released from the gut in critical states, with emphasis on the intestinal mucosal barrier function, mediators of bacterial origin, and myocardial depressant factors. DATA SOURCES: Relevant articles that have been published in the English language literature. STUDY SELECTION: No special study has been carried out for the present discussion. DATA EXTRACTION: Information from the literature has been used to illustrate important points in the discussion. DATA SYNTHESIS: Due to decreased mucosal blood flow, increased short-circuiting of oxygen in the mucosal countercurrent exchanger, and increased oxygen demand in sepsis mucosal injury develops rapidly in the gut after various forms of shock and splanchnic ischemia. In addition, due to increased generation of oxygen-derived radicals, injury may also occur with reperfusion. As a consequence of increased permeability of the intestinal mucosal barrier between the luminal content and the sterile interior milieu, increased translocation of bacteria and bacterial endotoxin occurs. In addition, cardiodepressant factors are released, as is evident from in vivo and in vitro studies. No such factor has been fully identified chemically. CONCLUSIONS: Intestinal mucosal injury, as seen in critical illness, may induce increased translocation of bacteria and endotoxin and release of myocardial depressant factors into the circulation.

Animals↗

PubMed2004

Glutamine regulates Caco-2 cell tight junction proteins.

Intestinal epithelial tight junction (TJ) barrier dysfunction may lead to inflammation and mucosal injury. Glutamine (GLN) plays a role in maintenance of intestinal barrier function in various animal models and critically ill humans. Recent evidence from intestinal cell monolayers indicates that GLN maintains transepithelial resistance and decreases permeability. The mechanisms of these effects remain undefined. We hypothesized that GLN affects proteins involved in the intercellular junctional complex. GLN availability was controlled in Caco-2 monolayers by addition to the medium and treatment with methionine sulfoximine (MSO) to inhibit glutamine synthetase (GS). Expression of TJ proteins, claudin-1, occludin, and zonula occluden (ZO)-1 was measured by immunoblotting. Localization of TJ proteins was evaluated by immunofluorescence light microscopy. Structure of TJ was determined by transmission electron microscopy (TEM). Deprivation of GLN decreased claudin-1, occludin, and ZO-1 protein expression and caused a disappearance of perijunctional claudin-1 and a reduction of occludin but had no effect on ZO-1. TEM revealed that MSO-treated cells in the absence of GLN formed irregular junctional complexes between the apical lateral margins of adjoining cells. These findings indicate that TJ protein expression and cellular localization in Caco-2 cell monolayers rely on GLN. This mechanism may similarly relate to GLN-mediated modulation of intestinal barrier function in stressed animals and humans.

Blotting, Western↗