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Results for “Intestinal Barrier Function”

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PubMed1979

GI absorption of beta-lactam antibiotics. III: Kinetic evidence for in situ absorption of ionized species of monobasic penicillins and cefazolin from the rat small intestine and structure-absorption rate relationships.

Absorption rates of monobasic beta-lactam antibiotics were measured as a function of lumen solution pH between 4 and 9 by utilizing the rat intestinal recirculating method in situ. Between pH 6.5 and 9, the absorption rate constants of ionized antibiotics were almost identical; but, at pH 4, the unionized species were highly absorbed, depending on their lipophilicity through the GI membrane lipoidal barrier. The structure-absorption rate relationship was established with the unstirred layer model.

Animals↗

PubMed2003

The cellular prion protein PrPc is expressed in human enterocytes in cell-cell junctional domains.

The physiological function of PrPc, the cellular isoform of prion protein, still remains unclear, although it has been established, in vitro or by using nerve cells, that it can homodimerize, bind copper, or interact with other proteins. Expression of PrPc was demonstrated as necessary for prion infection propagation. Considering the importance of the intestinal barrier in the process of oral prion infectivity, we have analyzed the expression of PrPc in enterocytes, which represent the major cell population of the intestinal epithelium. Our study, conducted both on normal human intestinal tissues and on the enterocytic cell line Caco-2/TC7, shows for the first time that PrPc is present in enterocytes. Interestingly, we found that this glycosylphosphatidylinositol-anchored glycoprotein was localized in cholesterol-dependent raft domains of the upper lateral membranes of enterocytes, beneath tight junctions, in cell-cell junctional domains. We observed that PrPc, E-cadherin, and Src co-localized in adherens junctions and that PrPc was co-immunoprecipitated with Src kinase but not with E-cadherin. Alteration of cell polarity after cholesterol depletion or loosening of the cell-cell junctions after EGTA treatment rapidly impaired membrane targeting of PrPc. Overall, our results point out the signaling of cell-cell contacts as a putative role for PrPc in epithelial cells.

Adherens Junctions↗

PubMedDate not supplied

Probiotics, prebiotics and child health: where are we going?

Changes in gastrointestinal (GI) bacteria caused by diet, antibiotics or other factors could alter enteric and systemic immune functions; changing the gut microflora composition by diet supplementation with specific live microbiota (probiotics) may be beneficial. The 'natural' target of ingested probiotics is the intestine, its microflora and associated immune system. Most published data concern use of probiotics to prevent and treat GI infections. Evidence for possible beneficial effects on mucosal barrier dysfunctions, including food allergy, inflammatory bowel disease, and respiratory and urinary tract infections, is emerging. The role of prebiotics (non-digestible oligosaccharides that reduce the growth or virulence of pathogens and induce systemic effects) is being investigated. Preliminary studies indicate that prebiotics may be useful dietary adjuncts for managing GI infections. Prebiotic and probiotic use in infants is attempting to modify a complex microbial ecosystem. Better understanding of the long-term effects of these interventions on infant gut microflora is an important goal.

Child↗

PubMed2004

Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice.

We tested the hypothesis that increased production of nitric oxide (NO.) associated with lipopolysaccharide (LPS)-induced systemic inflammation leads to functionally significant alterations in the expression and/or targeting of key tight junction (TJ) proteins in ileal and colonic epithelium. Wild-type or inducible NO. synthase (iNOS) knockout male C57B1/6J mice were injected intraperitoneally with 2 mg/kg Escherichia coli O111:B4 LPS. iNOS was inhibited using intraperitoneal L-N(6)-(1-iminoethyl)lysine (L-NIL; 5 mg/kg). Immunoblotting of total protein and NP-40 insoluble proteins revealed decreased expression and decreased TJ localization, respectively, of the TJ proteins, zonula occludens (ZO)-1, ZO-2, ZO-3, and/or occludin in ileal mucosa and colonic mucosa (total protein only) after injection of C57B1/6J mice with LPS. Immunohistochemistry showed deranged distribution of ZO-1 and occludin in both tissues from endotoxemic mice. Endotoxemia was associated with evidence of gut epithelial barrier dysfunction evidenced by increased ileal mucosal permeability to fluorescein isothiocyanate-dextran (Mr=4 kDa) and increased bacterial translocation to mesenteric lymph nodes. Pharmacologic inhibition of iNOS activity using L-NIL or genetic ablation of the iNOS gene ameliorated LPS-induced changes in TJ protein expression and gut mucosal barrier function. These results support the view that at least one mechanism contributing to the pathogenesis of gastrointestinal epithelial dysfunction secondary to systemic inflammation is increased iNOS-dependent NO. production leading to altered expression and localization of key TJ proteins.

Animals↗

PubMed2006

Evaluation of intestinal mucosal permeability function in patients with acute pancreatitis.

This study aims to evaluate the intestinal mucosal permeability in patients with acute pancreatitis. The lactulose:mannitol (L:M) ratio was used to assess permeability. It is an inexpensive and quite reliable method. The intestinal permeability was increased in patients with acute pancreatitis compared with the controls. In addition, patients with severe pancreatitis had higher intestinal barrier dysfunction compared with patients with mild pancreatitis, the L:M ratio being .2 and .029, respectively. It was also concluded that the permeability increased gradually over the course of pancreatitis and was maximum at day 7 (P < .01). This provides a window of opportunity for therapeutic intervention to prevent the late observed increase in intestinal permeability.

Adolescent↗

PubMed2000

Radiation induced cytochrome c release causes loss of rat colonic fluid absorption by damage to crypts and pericryptal myofibroblasts.

BACKGROUND: Therapeutic or accidental exposure to radiation commonly causes gastrointestinal disturbances, including diarrhoea. Rats subjected to whole body ionising radiation at a dose of 8 Gy lose their capacity to absorb fluid via the descending colon after four days. After seven days, fluid absorption recovers to control levels. AIMS: To investigate the effect of ionising radiation on colonic permeability together with its effect on mitochondria dependent apoptotic signals and intercellular adhesion molecules. METHODS: Rats were irradiated with doses of 0-12 Gy. Colonic permeability was measured by accumulation of fluorescein isothiocyanate (FITC) dextran in crypt lumens. Changes in levels of cytochrome c, caspase 3, E and OB cadherin, beta-catenin smooth muscle actin, and collagen IV were assessed using immunocytochemistry with confocal microscopy. RESULTS: Cytosolic cytochrome c increased after 8 Gy (t(1/2) 1.4 (0.6) hours) and peaked at approximately six hours. Caspase 3 increased more slowly, particularly in crypt epithelial cells (t(1/2) 57 (14.5) hours). Pericryptal myofibroblasts disintegrated within 24 hours as was evident from loss of OB cadherin and smooth muscle actin. This coincided with increased crypt permeability to dextran. Intercellular adhesion between crypt luminal cells was not lost until day 4 when both beta-catenin and E-cadherin were minimal. The half maximal dose-response for these effects was in the range 2-4 Gy. Recovery of colonic transport was concurrent with recovery of pericryptal smooth muscle actin and OB cadherin. The pan caspase inhibitor Z-Val-Ala-Asp.fluoromethylketone (1 mg/kg per day) had a small effect in conserving the pericryptal sheath myofibroblasts and sheath permeability but had no systemic therapeutic effects. CONCLUSIONS: These data suggest that radiation damage to the colon may be initiated by mitochondrial events. Loss of crypt fluid absorption and increased permeability coincided with decreased intercellular adhesion between crypt epithelial cells and loss of pericryptal sheath barrier function.

Animals↗

PubMed1977

Evidence of aluminum absorption from the gastrointestinal tract and bone deposition by aluminum carbonate ingestion with normal renal function.

The question of whether aluminum is toxic in patients ingesting large oral loads, either for phosphate binding in renal dialysis or as an antacid for peptic ulcer, has been raised. The permeability of the gut barrier for aluminum has not been established because of the lack of precise analytical techniques. Urine aluminum was measured in this study before and during oral aluminum carbonate loading in six subjects with normal renal function, one of which had peptic ulcer disease and a 25-year history of high oral aluminum ingestion. The analytical procedure involved destructive neutron activation analysis. Aluminum was present in the urine in all instances before loading and rose in every case from 4-fold to 10-fold. Bone aluminum was measured in six autopsy specimens, three dialysis patients, three nondialysis patients, and in an iliac crest biopsy from the peptic ulcer patient who had osteoporosis. The bone biopsy aluminum level in the ulcer patient was intermediate between those of "normal subjects" and patients on dialysis. These results show that the gut barrier is permeable to heavy aluminum load and suggest that bone aluminum deposition occurs in humans with normal renal function.

Adult↗

PubMed1996

Intestinal epithelial cytoskeleton selectively constrains lumen-to-tissue migration of neutrophils.

Migration of neutrophils (polymorphonuclear leukocytes; PMN) across polarized epithelia is asymmetrical: basolateral-to-apical (physiologically directed) migration is far more efficient than migration in the reverse direction, suggesting the presence of luminal retention signal(s). Following pilot observations, we used polarized intestinal epithelial monolayers (T84) to examine whether asymmetrical constraint of migration afforded by the epithelial cytoskeleton might underlie such retention signals. Rearrangement of epithelial cortical F-actin accompanied PMN transepithelial migration (in either direction) and was prevented by preloading monolayers with the F-actin stabilizing agent phallacidin. Although phallacidin preloading did not influence physiologically directed PMN transepithelial migration, such treatment greatly enhanced migration in the reverse direction (i.e., effective loss of luminal retention signal). 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) preloading also prevented epithelial cortical actin rearrangements and selectively resulted in loss of luminal retention signal(s). BAPTA preloading did not influence resistance or forskolin-induced Cl- secretion, and phallacidin preloading did not influence resistance or carbachol-induced Cl- secretion, suggesting that barrier function and surface polarity were maintained under these conditions. These and supplementary data suggest that epithelial actin (but not microtubule) cytoskeletal reordering asymmetrically influences PMN migration and underlies, at least in part, the observed signal that biases for retention of PMN in the luminal space.

Actins↗

PubMed1994

Salicylates for inflammatory bowel disease.

Targeted delivery of 5-aminosalicylic acid to the small intestine and colon by controlled-release or azo-bonded compounds potentially offers treatment for ileal Crohn's disease as well as ulcerative colitis. The pharmacokinetics of sulphasalazine and aminosalicylate derivatives have been discussed and potential modes of action reviewed. These include actions on epithelial cell-surface receptors, cellular events and barrier function. Evidence for an influence of salicylates on circulating and tissue inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides, eicosanoids, cytokines and reactive oxygen metabolites. The precise mechanism remains unknown, but a pluripotential mode of action is an advantage when influencing the network of events that constitutes chronic inflammation. Controlled clinical trials of salicylates in ulcerative colitis and Crohn's disease have been reviewed. Their main role remains as maintenance therapy for ulcerative colitis, but relatively high doses of controlled-release preparations benefit patients with ileal Crohn's disease, following resection, or those who have recently relapsed. Finally, issues of clinical relevance have been addressed, including the choice of salicylate and safety, indications for initiating therapy, dose and duration of treatment, role in managing refractory colitis and future developments.

Aminosalicylic Acids↗

PubMed1996

Carrier-mediated intestinal transport of drugs.

Recent advances in the field of carrier-mediated intestinal absorption of of amino acids, oligopeptides, monosaccharides, monocarboxylic acids, phosphate, bile acids and several water-soluble vitamins across brush-border and basolateral membranes are summarized. An understanding of the molecular and functional characteristics of the intestinal membrane transporters will be helpful in the utilization of these transporters for the enhanced oral delivery of poorly absorbed drugs. Some successful examples of the synthesis of prodrugs recognized by the targeted transporters are described. Functional expression of the multidrug resistance gene product, P-glycoprotein, as a primary active transporter in the intestinal brush-border membrane leads to net secretion of some drugs such as anticancer agents in the blood-to-luminal direction, serving as a secretory detoxifying mechanism and as a part of the absorption barrier in the intestine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Skin bioavailability of dietary vitamin E, carotenoids, polyphenols, vitamin C, zinc and selenium.

Dietary bioactive compounds (vitamin E, carotenoids, polyphenols, vitamin C, Se and Zn) have beneficial effects on skin health. The classical route of administration of active compounds is by topical application direct to the skin, and manufacturers have substantial experience of formulating ingredients in this field. However, the use of functional foods and oral supplements for improving skin condition is increasing. For oral consumption, some dietary components could have an indirect effect on the skin via, for example, secondary messengers. However, in the case of the dietary bioactive compounds considered here, we assume that they must pass down the gastrointestinal tract, cross the intestinal barrier, reach the blood circulation, and then be distributed to the different tissues of the body including the skin. The advantages of this route of administration are that the dietary bioactive compounds are metabolized and then presented to the entire tissue, potentially in an active form. Also, the blood continuously replenishes the skin with these bioactive compounds, which can then be distributed to all skin compartments (i.e. epidermis, dermis, subcutaneous fat and also to sebum). Where known, the distribution and mechanisms of transport of dietary bioactive compounds in skin are presented. Even for compounds that have been studied well in other organs, information on skin is relatively sparse. Gaps in knowledge are identified and suggestions made for future research.

Administration, Oral↗

PubMed2005

Involvement of innate immunity in the development of inflammatory and autoimmune diseases.

Initial events and effector mechanisms of most inflammatory and autoimmune diseases remain largely unknown. Dysfunction of the innate and adaptive immune systems associated with mucosae (the major interface between the organism and its environment, e.g., microbiota, food) can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Animal models help in elucidating the etiology and pathogenetic mechanisms of human diseases, such as the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, severe chronic diseases affecting the gut. To study the role of innate immunity and gut microbiota in intestinal inflammation, colitis was induced by dextran sulfate sodium (DSS) in mice with severe combined immunodeficiency (SCID). Conventionally reared (microflora-colonized) SCID mice displayed severe inflammation like that seen in immunocompetent Balb/c mice, whereas only minor changes appeared in the intestinal mucosa of DSS-fed gnotobiotic germ-free SCID mice. The presence of microflora facilitates the inflammation in DSS-induced colitis that develops in immunodeficient SCID mice, that is, in the absence of T and B lymphocytes. Celiac disease, a chronic autoimmune small bowel disorder, afflicts genetically susceptible individuals with wheat gluten intolerance. We showed that, in contrast with any other food proteins, wheat gliadin and its peptic fragments activate mouse macrophages and human monocytes to produce proinflammatory cytokines through the nuclear factor-kappaB signaling pathway. Activation of innate immunity cells by food proteins or components from gut microbiota thus could participate in the impairment of intestinal mucosa and the development of intestinal and/or systemic inflammation.

Animals↗

PubMed1996

Quantitative evaluation of the gastrointestinal absorption of protein into the blood and lymph circulation.

In order to investigate the fate of orally administered proteins, the absorption of ovalbumin (OVA) from the gastrointestinal tract into both the blood and lymph circulation was quantitatively evaluated. After oral administration, a significant amount of intact OVA was detected in both the plasma and the lymph fluid by means of a two-site enzyme immunoassay. The extent of absorption into the plasma, calculated from the area under the plasma concentration versus time curve of OVA after oral and intravenous administration, was only 0.007-0.008% of the dose. This value is extremely low compared to that after nasal administration, showing the stronger barrier function of the gastrointestinal tract against the invasion of macromolecular proteins into the body. The extent of absorption into the lymph was dose-dependent (0.0007-0.002% of dose), and a higher dose leads to a higher fraction of OVA absorbed into the lymph. Moreover, it was demonstrated that not only the small intestine but also the stomach can absorb OVA. OVA absorbed from the stomach was transferred almost exclusively to the blood circulation, which suggests different mechanisms and/or routes of absorption between the stomach and the small intestine. In order to improve the low oral absorption, OVA was incorporated in liposomes and administered orally. Although the effect of liposomes was not significant, it increased OVA absorption into both the plasma and lymph by about 2 to 3-fold. It was considered that the liposomes suppressed the enzymatic degradation of OVA and released it slowly in the gastrointestinal tract.

Administration, Intranasal↗

PubMed2004

Colonic expression of MUC2, MUC5AC, and TFF1 in inflammatory bowel disease in children.

BACKGROUND: The quantity and quality of mucins are affected in inflammatory bowel disease (IBD) both because of a reduction in the number of goblet cells and a decrease in the number of sugar residues per oligosaccharide side chain. Alteration in the types of mucins and aberrant location may contribute to the underlying pathology by affecting the mucus barrier function or may instead be a response to inflammation. The authors used the periodic acid-Schiff/Alcian blue stain to distinguish neutral and acidic mucins, and used specific antibodies to the mature goblet cell mucin MUC2, MUC2 core antigen, foveolar cell mucin MUC5AC, and gastric trefoil factor (TFF1), to characterize their presence and distribution in colonic tissue sections from patients with IBD. RESULTS: Both core and mature MUC2 were expressed in all colonic goblet cells from patients with ulcerative colitis (UC) and Crohn disease and from healthy controls. MUC5AC and TFF1, which are not normally expressed by colonic tissue, also were expressed in scattered goblet cells, coexpressing with MUC2. In areas of goblet cell depletion, MUC2 was present in cytoplasmic granules of flattened, cuboidal, nongoblet-cell-like surface cells. The staining was more intense and homogenous with the MUC2 core antibody, suggesting expression of relatively immature mucin. Some of these cells also coexpressed MUC5AC but to a lesser extent. These findings are not unique to IBD but were also found in other types of intestinal inflammation. CONCLUSION: The study confirms earlier observations that MUC2 is the major colonic mucin in IBD. It appears in two forms: mature MUC2 in goblet cells and immature MUC2 especially in secretory granules of cells that are not phenotypically goblet cells. MUC5AC and TFF1 expression in goblet cells is common in IBD and other inflammatory conditions of the colon. These changes may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.

Adolescent↗

PubMed2006

Assessment and prevention of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesic, anti-inflammatory and, in the case of aspirin, for anti-thrombotic actions. The serious gastrointestinal side-effects associated with these drugs are of concern and pose a significant obstacle to their use. This review discusses the pathogenic mechanisms by which the conventional acidic NSAIDs induce gastrointestinal toxicity, with particular emphasis on non-prostaglandin effects. Methods of assessment of NSAID-induced enteropathy are reviewed, with particular emphasis on the use of functional measurement of NSAID-induced changes in the gastrointestinal tract. The advances in our knowledge of the pathogenesis of these effects have resulted in the development of a range of novel NSAIDs. Where functional assessment of the effects of NSAIDs has been employed, it appears to be more useful as an indicator of early-stage changes rather than a predictor of the effects of long-term NSAID exposure. Successful pharmaceutical strategies now offer considerable promise for reducing the severity of NSAID damage to the gastrointestinal tract. The utility of intestinal permeability measurements for selection and assessment of these strategies is discussed.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

Influence of colostomy on in vivo and in vitro permeability of the rat colon.

PURPOSE: Barrier properties of an isolated colon loop and the remnant colon in continuity with the gastrointestinal tract after colostomy were studied in the rat. METHODS: The in vivo absorption after colonic loop administration of the marker fluorescein sodium was measured as the urinary recovery. The in vitro permeability was measured in Ussing diffusion chambers as the transmucosal passage of [14C]mannitol and of human serum albumin in the isolated and the nonexcluded colonic segments and was compared with the corresponding colonic regions from sham-operated rats at 1 to 14 days after operation. RESULTS: Body weight gain of the rats decreased and diarrhea appeared from day 2 after colostomy. Histologic examination showed mucosal atrophy with decreased villus height in the isolated colonic loop and an increased villus height in the nonexcluded colon segment. Absorption of fluorescein sodium in the isolated loop was increased at 8 and 14 days. Moreover, permeability in the isolated loop was increased for both mannitol and human serum albumin from four days after colostomy compared with the corresponding colonic segments after the sham operation, whereas a decrease in the passage of mannitol was noted in the nonexcluded colon. CONCLUSIONS: Experimentally performed colostomy diversion in the rat induced alterations of the barrier function in both the isolated colonic loop and the nonexcluded colon in continuity with the fecal stream.

Animals↗

PubMed2000

The role of up-regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis.

Proteinases are important at several phases of physiological and pathological inflammation, mediating cellular infiltration, cytokine activation, tissue damage, remodeling, and repair. However, little is known of their role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess the role of tissue proteases in a mouse model of colitis. Proteolytic activity was analyzed, using gel and in situ zymography, in colonic tissues from severe combined immunodeficient mice with colitis induced by transfer of CD4(+) T lymphocytes. Serine proteinase levels increased in colitic tissue, with major species of 23 kd, 30 kd, and 45 kd. Co-migration and inhibition studies indicated that the 23-kd proteinase was pancreatic trypsin and that the 30-kd species was neutrophil elastase. Matrix metalloproteinase (MMP)-9 expression, and MMP-2 and MMP-9 activation, was elevated in colitic tissues. Proteinase levels followed a decreasing concentration gradient from proximal to distal colon. Proteolysis was localized to infiltrating leukocytes in diseased severe combined immunodeficient mice. Transmural inflammation was associated with serine proteinase and MMP activity in overlying epithelium and with marked subepithelial proteolytic activity. The results demonstrate a clear elevation in the levels and activation of proteases in colitis, potentially contributing to disease progression through loss of epithelial barrier function.

Animals↗

PubMed2006

Phosphatidylinositol 3'-kinase is a critical mediator of interferon-gamma-induced increases in enteric epithelial permeability.

The epithelial lining of mucosal surfaces acts as a barrier to regulate the entry of antigen and pathogens. Nowhere is this function of the contiguous epithelium more important than in the gut, which is continually exposed to a huge antigenic load and, in the colon, an immense commensal microbiota. We assessed the intracellular signaling events that underlie interferon (IFN) gamma-induced increases in epithelial permeability using monolayers of the human colonic T84 epithelial cell line. Confluent epithelial monolayers on semipermeable supports were treated with IFNgamma (20 ng/ml), and barrier function was assessed 48 h later by measuring transepithelial electrical resistance (TER: reflects passive ion flux), fluxes of (51)Cr-EDTA and horseradish peroxidase (HRP), and transcytosis of noninvasive, nonpathogenic Escherichia coli (strain HB101). Exposure to IFNgamma decreased barrier function as assessed by all four markers. The phosphatidylinositol 3'-kinase (PI-3K) inhibitors, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] and wortmannin, did not affect baseline permeability characteristics but completely blocked the drop in TER, increased fluxes of (51)Cr-EDTA and HRP, and significantly reduced E. coli transcytosis evoked by IFNgamma. In addition, use of the pan-protein kinase C (PKC) inhibitor, bisindolylmaleimide I (5 muM), but not rottlerin (blocks PKCdelta), partially ameliorated the drop in TER and inhibited increased E. coli transcytosis. Addition of the PI-3K and PKC inhibitors to epithelia 6 h after IFNgamma exposure still prevented the increase in paracellular permeability but not E. coli transcytosis. Thus, IFNgamma-induced increases in epithelial paracellular and transcellular permeability are critically dependent on PI-3K activity, which may represent an epithelial-specific target to treat immune-mediated loss of barrier function.

Bacterial Translocation↗