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Intestinal Permeability (intestinal + permeability)
Kinds of Intestinal Permeability Selected AbstractsPhosphatidylcholine Reverses Ethanol-Induced Increase in Transepithelial Endotoxin Permeability and Abolishes Transepithelial Leukocyte ActivationALCOHOLISM, Issue 3 2009Katja Mitzscherling Background:, Chronic alcohol abuse increases both intestinal bacterial overgrowth and intestinal permeability to macromolecules. Intestinal permeability of endotoxin, a component of the outer cell membrane of Gram-negative bacteria, plays a crucial role in the development of alcohol-induced liver disease (ALD). As impaired bile flow leads to endotoxemia and the bile component phosphatidylcholine (PC) is therapeutically active in ALD, we tested the hypothesis that conjugated primary bile salts (CPBS) and PC inhibit ethanol-enhanced transepithelial permeability of endotoxin and the subsequent transepithelial activation of human leukocytes. Methods:, For this purpose, we used a model in which intestinal epithelial cells (Caco-2) were basolaterally cocultivated with mononuclear leukocytes. Cells were challenged apically with endotoxin from Escherichia coli K12 and were incubated with or without the addition of CPBS (1.5 mM), PC (0.38 mM), pooled human bile (2%) in combination with ethanol (0 to 66 mM). Results:, Ethanol decreased integrity of intestinal epithelial cell monolayer and enhanced transepithelial permeability of endotoxin. Both the transepithelial permeability of endotoxin and the transepithelial stimulation of leukocytes were nearly completely abolished after the apical supplementation of PC with CPBS, but not by CPBS alone. Ethanol up to 66 mM was not able to reverse this effect. Conclusions:, A considerable part of the therapeutic and preventive effect of PC supplementation in ALD might result from a reduction of ethanol-enhanced permeability of endotoxin through the intestinal barrier. [source] Indications of ,atopic bowel' in patients with self-reported food hypersensitivityALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2010K. LILLESTØL Aliment Pharmacol Ther,31, 1112,1122 Summary Background, An association between atopic disease and gastrointestinal complaints has been suggested. Aim, To explore the association between atopic disease, gastrointestinal symptoms, and possible gastrointestinal manifestations of atopic disease in patients with self-reported food hypersensitivity. Methods, Symptoms, skin prick tests, serum markers of allergy and intestinal permeability were recorded in 71 adult patients. Eosinophils, tryptase- and IgE-positive cells were counted in duodenal biopsies. Results, Sixty-six (93%) patients had irritable bowel syndrome (IBS) and 43 (61%) had atopic disease, predominantly rhinoconjunctivitis. All 43 were sensitized to inhalant allergens, 29 (41%) to food allergens, but food challenges were negative. Serum total IgE and duodenal IgE-positive cell counts were significantly correlated (P < 0.0001) and both were significantly higher in atopic than in non-atopic patients (P < 0.0001 and P = 0.003 respectively). IgE-positive cells appeared to be ,armed' mast cells. Intestinal permeability was significantly elevated in atopic compared with non-atopic patients (P = 0.02). Gastrointestinal symptoms and numbers of tryptase-positive mast cells and eosinophils did not differ between groups. Conclusions, Patients with self-reported food hypersensitivity had a high prevalence of IBS and atopic disease. Atopic patients had increased intestinal permeability and density of IgE-bearing cells compared with non-atopic patients, but gastrointestinal symptoms did not differ between groups. [source] Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2006R. D'INCÀ Summary Background Abnormal barrier function may be genetically determined in Crohn's disease. Aim To examine the role of abnormal intestinal permeability in genetic predisposition in multiplex vs. sporadic Crohn's disease families. Methods Intestinal permeability was measured in patients, relatives and partners by means of lactulose/mannitol test. Healthy subjects from the hospital staff served as controls. CARD15 mutations were investigated in sporadic and familial Crohn's disease patients and in a group of blood donors. Results The median lactulose/mannitol ratio was increased significantly in Crohn's disease patients vs. their relatives [0.03 (0.01,0.24) vs. 0.01 (0.003,0.19), P = 0.005]. The percentage of abnormal tests was significantly higher in familial vs. sporadic first-degree relatives of Crohn's disease patients (29% vs. 11%, P = 0.0281). Abnormal permeability occurred significantly more frequent in patients with familial Crohn's disease carrying the frameshift mutation. The frameshift mutation 3020insC was associated with increased permeability in 75% in the multiplex and in 61% of the sporadic CD patients. One partner had abnormal lactulose/mannitol ratio. Conclusion Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease. [source] Intestinal permeability and irritable bowel syndromeNEUROGASTROENTEROLOGY & MOTILITY, Issue 7 2007M. Camilleri Abstract, Based on a systematic PubMed search, this short review addresses why intestinal permeability may be important in the pathobiology of irritable bowel syndrome (IBS), the evidence of abnormal permeability in patients with IBS, and the pros and cons of the different probe molecules available to assess intestinal permeability. While a subgroup of patients with IBS appears to have evidence of increased intestinal permeability, improvements in the methods and validation are key to further research in this field in order to better understand intestinal barrier functions in IBS. [source] Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease,HEPATOLOGY, Issue 6 2009Luca Miele The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of 51Cr-ethylene diamine tetraacetate (51Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. Conclusions: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition. (HEPATOLOGY 2009.) [source] What role does intestinal permeability have in ibd pathogenesis?INFLAMMATORY BOWEL DISEASES, Issue S2 2008Jon Meddings MD No abstract is available for this article. [source] Do changes in intestinal permeability predict disease relapse in Crohn's disease?INFLAMMATORY BOWEL DISEASES, Issue S2 2008H. Vogelsang MD No abstract is available for this article. [source] Anti- Saccharomyces Cerevisiae antibodies (ASCA), phenotypes of IBD, and intestinal permeability: A study in IBD familiesINFLAMMATORY BOWEL DISEASES, Issue 1 2001Severine Vermeire Abstract Background Serologic markers anti- Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies with perinuclear staining (pANCA) have been proposed to study the immunopathogenesis of IBD. Their measurement may allow better phenotyping of the disease and the detection of subclinical disease. Aims To test the hypothesis that serological markers identify an immunologic trait related to disease susceptibility. We also wanted to test the hypothesis that ASCA is a marker related to abnormal tissue permeation by common antigens. Methods We studied the prevalence of pANCA and ASCA in a large cohort of sporadic and familial inflammatory bowel diseases and their unaffected relatives and spouses. Kinetics of ASCA was studied and the relationship between ASCA and 51Cr-EDTA intestinal permeation was investigated. Results ASCA was associated with sporadic Crohn's disease (CD) (63%), with Crohn's patients belonging to pure CD families (62%) and also with their unaffected family members (21%). pANCA was associated with UC (58%). The prevalence of ASCA in CD patients belonging to mixed families was strikingly low (33%). ASCA was a stable marker throughout the disease and was not related to an increased small intestinal permeability. Conclusion ASCA is strongly associated with familial CD in Belgium, and 21% of healthy family members also display the marker. The association is much weaker in patients belonging to mixed families. ASCA is a stable marker and is not a secondary phenomenon due to increased intestinal permeability. [source] Milk formulas in acute gastroenteritis and malnutrition: A randomized trialJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 6 2002RH Kukuruzovic Objective: To compare three low-lactose milk formulas differing in osmolality and degree of protein hydrolysis in the treatment of diarrhoea and malnutrition in subjects with high rates of lactose intolerance, osmotic diarrhoea and a tropical/environmental enteropathy. Methods: A randomized double-blind trial of 180 Aboriginal children under 3 years of age admitted with acute diarrhoea and/or malnutrition was carried out. The intervention milk formulas were: (i) De-Lact, a low-osmolality lactose-free formula; (ii) O-Lac, a lactose-free formula; and (iii) Alfaré, a partially hydrolysed formula. Outcome measures were diarrhoeal severity, weight gain, formula palatability and changes in intestinal permeability (L/R ratios). Results: The duration of diarrhoea in days (mean; 95% confidence interval) was significantly longer on Alfaré (8.5; 7.0,10.0) compared to De-Lact (6.1; 5.0,7.2) and O-Lac (6.9; 5.6,8.1; P = 0.04). There were no differences in mean intake between formulas, but palatability of Alfaré was significantly worse (P < 0.01) than the other formulas. Over the trial 5 days, improvement in L/R ratios was significantly greater (P = 0.05) for De-Lact (18.6; 10.6,26.6) than for Alfaré (8.5; 2.1,14.9). Weight gain was not significantly different between the three formulas, except in a malnourished subgroup who had better weight gain on De-Lact (P = 0.05). Conclusions: In these Aboriginal children with diarrhoea and growth failure, a low osmolality milk was associated with better outcomes and a partially hydrolysed formula with less improvement in mucosal recovery, suggesting that cow's milk protein intolerance is not contributing to greater diarrhoeal severity or enteropathy in Aboriginal children. [source] Environmental triggers of type 1 diabetesJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 3 2001JJ Couper Abstract: High risk HLA class II alleles account for 40% of the genetic susceptibility to type 1 diabetes in Caucasians, but the majority of the genetically predisposed do not develop the disease. This supports some environmental modification of the autoimmune destruction of , cells that precedes type 1 diabetes. Identical twin studies and geographical variation in incidence also argue for a critical role of environmental factors. Attention has been directed to the possible harmful effect of cow's milk protein (or protective effect of breast-feeding) and enteric infections in early life. Natural history studies that follow children at increased risk of type 1 diabetes provide the best opportunity to study environmental triggers. The Australian Baby Diab Study has followed approximately 500 babies from birth who have a first-degree relative with type 1 diabetes. No prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity was found. The same Australian cohort demonstrated a relationship between rotavirus infection and the first appearance or increase in islet antibodies. Enteroviral infection is seen more frequently in prediabetic children and prior to the onset of islet autoimmunity in Finnish cohorts. Environmental factors may interact. Breast milk protects against enteric infections; enteric infections in turn could increase immunity to dietary antigens by increasing intestinal permeability. It is also possible that an alteration in gut mucosal immune function in genetically susceptible individuals underlies any effect of dietary or viral proteins on the development of islet autoimmunity in early life. [source] Tacrolimus is a class II low-solubility high-permeability drug: The effect of P-glycoprotein efflux on regional permeability of tacrolimus in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Shigeki Tamura Abstract The objective of this study is to investigate the role of P-glycoprotein (P-gp), a membrane efflux pump associated with multidrug resistance (MDR) and a known substrate for tacrolimus, in determining the regional intestinal permeability of tacrolimus in rats. Thus, isolated segments of rat jejunum, ileum, or colon were perfused with tacrolimus solutions containing polyethoxylated hydrogenated castor oil 60 surfactant, and with or without verapamil, a P-gp substrate used to reverse the MDR phenotype. The results indicated that the intrinsic permeability of tacrolimus in the jejunum, calculated on the basis of the concentration of non-micellized free tacrolimus, was quite high (,,1.4,×,10,4 cm/s). The apparent permeability (Papp) in the jejunum was unaffected by the presence of verapamil; however, the Papp in the ileum and the colon increased significantly in the presence of verapamil and were similar to the values observed in the jejunum. The results suggest that systemic absorption of tacrolimus from the gastrointestinal tract could be significantly affected by P-gp efflux mechanisms. It is also possible that differences in P-gp function at various intestinal sites in a subject or at a given intestinal site in various subjects could lead to large intra- and interindividual variability in bioavailability of tacrolimus following oral administration. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:719,729, 2002 [source] Effects of continuous exposure to digoxin on MDR1 function and expression in Caco-2 cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2003Kohji Takara The Caco-2 cell line has been used widely for studying intestinal permeability and several transport functions, and express the multidrug resistance transporter MDR1/P-glycoprotein. Previously, the transient exposure to digoxin for 24h was found to induce MDR1 mRNA in Caco-2 cells. Here, a digoxin-tolerant Caco-2 subline (Caco/DX) was newly established by the continuous exposure of Caco-2 cells to digoxin, and the effects of continuous exposure to digoxin on MDR1 were examined. The 50% growth inhibitory concentration (IC50) values for digoxin in Caco-2 and Caco/DX cells were 17.2 and 81.4 nm, respectively. The IC50 values for paclitaxel, an MDR1 substrate, were 1.0 and 547 nm, respectively, whereas the cytotoxicity of 5-fluorouracil was comparable in both cells. The uptake and efflux of Rhodamine123, an MDR1 substrate, in Caco/DX cells were significantly less and greater, respectively, than those in Caco-2 cells, and these transports were affected by the addition of ciclosporin. The expression of MDR1 mRNA in Caco/DX cells was approximately 2- and 1.7-fold compared with Caco-2 cells and Caco-2 cells treated with 100 nm digoxin for 24 h, respectively. On the other hand, MRP1 mRNA in Caco/DX cells was unchanged. These observations confirmed that the continuous exposure to digoxin, as well as the transient exposure, induced MDR1 in Caco-2 cells. [source] Nitric Oxide-Mediated Intestinal Injury Is Required for Alcohol-Induced Gut Leakiness and Liver DamageALCOHOLISM, Issue 7 2009Yueming Tang Background:, Alcoholic liver disease (ALD) requires endotoxemia and is commonly associated with intestinal barrier leakiness. Using monolayers of intestinal epithelial cells as an in vitro barrier model, we showed that ethanol-induced intestinal barrier disruption is mediated by inducible nitric oxide synthase (iNOS) upregulation, nitric oxide (NO) overproduction, and oxidation/nitration of cytoskeletal proteins. We hypothesized that iNOS inhibitors [NG-nitro- l -arginine methyl ester (l -NAME), l -N6 -(1-iminoethyl)-lysine (l -NIL)] in vivo will inhibit the above cascade and liver injury in an animal model of alcoholic steatohepatitis (ASH). Methods:, Male Sprague,Dawley rats were gavaged daily with alcohol (6 g/kg/d) or dextrose for 10 weeks ± l -NAME, l -NIL, or vehicle. Systemic and intestinal NO levels were measured by nitrites and nitrates in urine and tissue samples, oxidative damage to the intestinal mucosa by protein carbonyl and nitrotyrosine, intestinal permeability by urinary sugar tests, and liver injury by histological inflammation scores, liver fat, and myeloperoxidase activity. Results:, Alcohol caused tissue oxidation, gut leakiness, endotoxemia, and ASH. l -NIL and l -NAME, but not the d -enantiomers, attenuated all steps in the alcohol-induced cascade including NO overproduction, oxidative tissue damage, gut leakiness, endotoxemia, hepatic inflammation, and liver injury. Conclusions:, The mechanism we reported for alcohol-induced intestinal barrier disruption in vitro , NO overproduction, oxidative tissue damage, leaky gut, endotoxemia, and liver injury , appears to be relevant in vivo in an animal model of alcohol-induced liver injury. That iNOS inhibitors attenuated all steps of this cascade suggests that prevention of this cascade in alcoholics will protect the liver against the injurious effects of chronic alcohol and that iNOS may be a useful target for prevention of ALD. [source] Phosphatidylcholine Reverses Ethanol-Induced Increase in Transepithelial Endotoxin Permeability and Abolishes Transepithelial Leukocyte ActivationALCOHOLISM, Issue 3 2009Katja Mitzscherling Background:, Chronic alcohol abuse increases both intestinal bacterial overgrowth and intestinal permeability to macromolecules. Intestinal permeability of endotoxin, a component of the outer cell membrane of Gram-negative bacteria, plays a crucial role in the development of alcohol-induced liver disease (ALD). As impaired bile flow leads to endotoxemia and the bile component phosphatidylcholine (PC) is therapeutically active in ALD, we tested the hypothesis that conjugated primary bile salts (CPBS) and PC inhibit ethanol-enhanced transepithelial permeability of endotoxin and the subsequent transepithelial activation of human leukocytes. Methods:, For this purpose, we used a model in which intestinal epithelial cells (Caco-2) were basolaterally cocultivated with mononuclear leukocytes. Cells were challenged apically with endotoxin from Escherichia coli K12 and were incubated with or without the addition of CPBS (1.5 mM), PC (0.38 mM), pooled human bile (2%) in combination with ethanol (0 to 66 mM). Results:, Ethanol decreased integrity of intestinal epithelial cell monolayer and enhanced transepithelial permeability of endotoxin. Both the transepithelial permeability of endotoxin and the transepithelial stimulation of leukocytes were nearly completely abolished after the apical supplementation of PC with CPBS, but not by CPBS alone. Ethanol up to 66 mM was not able to reverse this effect. Conclusions:, A considerable part of the therapeutic and preventive effect of PC supplementation in ALD might result from a reduction of ethanol-enhanced permeability of endotoxin through the intestinal barrier. [source] Activation of the Innate Immune System and Alcoholic Liver Disease: Effects of Ethanol per se or Enhanced Intestinal Translocation of Bacterial Toxins Induced by Ethanol?ALCOHOLISM, Issue 2005Christiane Bode The mechanisms involved in the ethanol-induced activation of monocytes/macrophages (including Kupffer cells) are however, still a matter of debate. The brief review will summarize the published data from the literature on the two main pathomechanisms discussed until now: I) Gut-derived bacterial toxins, specially endotoxin; and II) metabolic changes induced by alcohol oxidation (independent of mechanism I). For pathomechanism I, clear evidence has been published from numerous groups: Alcohol induces mucosal injury in the upper gastrointestinal tract and leads to marked increase in the permeability of the gut mucosa to macromolecules such as endotoxin. The resulting endotoxemia then leads to activation of Kupffer cells and other macrophages. The increased release of pro-inflammatory mediators (e.g., TNF-,, Il-1, reacting oxygen species) and infiltration of other inflammatory cells (e.g., neutrophils) finally causes liver damage. Regarding the second pathomechanism it has repeatedly been argued that the metabolic alterations which are induced by chronic administration of ethanol to rats or mice might increase the sensitivity of monocytes/macrophages to secrete TNF-, and other pro-inflammatory mediators thereby increasing the susceptibility to ethanol-induced liver injury. However, in all feeding experiments the effect of ethanol on intestinal permeability and enhanced translocation of bacterial toxins (endotoxin) is likely to occur (or at least cannot be excluded). The latter holds true also for experiments using isolated macrophages/Kupffer cells from ethanol fed animals. Therefore, to clarify whether or not alterations related to ethanol metabolism ("direct" effects of ethanol) contribute to the activation of the innate immune system studies using germ-free animals are needed to exclude the "indirect" effect of ethanol via gut-derived bacterial toxins. [source] Effect of Acute Ethanol Administration on the Intestinal Absorption of Endotoxin in RatsALCOHOLISM, Issue 3 2000Hironao Tamai Background: Endotoxin has been implicated in the pathogenesis and progression of alcoholic liver disease. Not only inactivation of reticuloendothelial function, which reduces clearance of endotoxin, but also an increase in absorption of endotoxin from the intestine may be involved in mechanisms of ethanol-induced endotoxemia. However, it is unclear how ethanol affects absorption of endotoxin from the intestine in vivo. Methods: We gave 10 mg/kg of lipopolysaccharides to rats with water (group 1), 5% ethanol (group 2), or 20% ethanol (group 3) using an intubation tube to the stomach. Blood samples were collected and plasma endotoxin levels were measured. We used fluorescence spectrophotometer to examine permeability of the gut to macromolecules (fluorescein isothiocyanate-dextran; 4,000 Da [FD4] or 20,000 Da [FD20]). Results: Plasma endotoxin levels were not different between group 1 (9 ± 2 pg/ml) and group 2 (14 ± 3 pg/ml), whereas they significantly increased in group 3 with a peak at 60 min (87 ± 35 pg/ml). Acute ethanol administration did not affect clearance of endotoxin in rats. Hemorrhagic erosions of the proximal small intestine with epithelial cell loss were observed in group 3 at 4 hr, but no significant histological change was observed at 30 min by light microscopy. Acute ethanol administration (20%) increased the permeability of the small intestine to FD4 and FD20 in 30 min when no hemorrhagic erosions of the proximal small intestine with epithelial cell loss were observed. Conclusions: Acute ethanol administration increases intestinal permeability before pathological changes are revealed by light microscopy. Acute ethanol ingestion, especially at high concentrations, facilitates the absorption of endotoxin from rats' small intestine via an increase in intestinal permeability, which may play an important role in endotoxemia observed in alcoholic liver injury. [source] Indications of ,atopic bowel' in patients with self-reported food hypersensitivityALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2010K. LILLESTØL Aliment Pharmacol Ther,31, 1112,1122 Summary Background, An association between atopic disease and gastrointestinal complaints has been suggested. Aim, To explore the association between atopic disease, gastrointestinal symptoms, and possible gastrointestinal manifestations of atopic disease in patients with self-reported food hypersensitivity. Methods, Symptoms, skin prick tests, serum markers of allergy and intestinal permeability were recorded in 71 adult patients. Eosinophils, tryptase- and IgE-positive cells were counted in duodenal biopsies. Results, Sixty-six (93%) patients had irritable bowel syndrome (IBS) and 43 (61%) had atopic disease, predominantly rhinoconjunctivitis. All 43 were sensitized to inhalant allergens, 29 (41%) to food allergens, but food challenges were negative. Serum total IgE and duodenal IgE-positive cell counts were significantly correlated (P < 0.0001) and both were significantly higher in atopic than in non-atopic patients (P < 0.0001 and P = 0.003 respectively). IgE-positive cells appeared to be ,armed' mast cells. Intestinal permeability was significantly elevated in atopic compared with non-atopic patients (P = 0.02). Gastrointestinal symptoms and numbers of tryptase-positive mast cells and eosinophils did not differ between groups. Conclusions, Patients with self-reported food hypersensitivity had a high prevalence of IBS and atopic disease. Atopic patients had increased intestinal permeability and density of IgE-bearing cells compared with non-atopic patients, but gastrointestinal symptoms did not differ between groups. [source] Clinical trial: prophylactic intravenous alanyl-glutamine reduces the severity of gastrointestinal toxicity induced by chemotherapy , a randomized crossover studyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009Y. LI Summary Background, Glutamine has been shown in numerous studies to reduce intestinal permeability which can be increased by chemotherapy. However, there have been few reports that conduct on its clinical effect on gastrointestinal toxicity. Aim, To examine whether prophylactic intravenous alanyl-glutamine dipeptide can ameliorate clinical manifestations of gastrointestinal toxicity induced by chemotherapy. Methods, Forty-four patients with gastric or colorectal cancer developing WHO side-effect grading system of grade 2 or higher were randomized to either control group (n = 22) or Gln group (n = 22) during next cycle of chemotherapy. Patients were crossed over to the alternate treatment during chemotherapy cycle 2. In the control group, the patients received the same chemotherapy regimens as screening cycle and in the Gln group, the patients received chemotherapy and alanyl-glutamine. Prophylactic intravenous 20 g of alanyl-glutamine dipeptide was given for 5 days. Results, Compared with the control group, the plasma glutamine level in the Gln group was significantly higher and the plasma endotoxin level was significantly lower. The scores of nausea/vomiting and diarrhoea decreased significantly. Conclusion, Prophylactic intravenous alanyl-glutamine is effective in preventing intestinal permeability disruption induced by chemotherapy and clinical manifestations of gastrointestinal toxicity. [source] Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2009J. N. KING This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t1/2 << 1 min), whilst COX-2 binding was slowly reversible (t1/2 = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2,30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40,0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall,Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF1, concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs. [source] Altered intestinal permeability is predictive of early relapse in children with steroid-responsive ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2007E. MIELE SUMMARY Aim To determine if small bowel involvement at diagnosis could predict early relapse in children with ulcerative colitis. Methods Children with newly diagnosed ulcerative colitis were evaluated prospectively at three time points: within 1 month, 6 months and 1 year after diagnosis. Clinical activity indices were used to measure disease activity. Laboratory studies were performed at each visit and/or at the time of relapse. At diagnosis, all patients underwent colonoscopy and a cellobiose/mannitol small intestinal permeability study. Some children were further investigated with an upper gastrointestinal endoscopy. Results Thirty-three patients completed the 1-year study. Overall, nine patients (27.3%) relapsed within 6 months of diagnosis, one patient (3%) within 1 year, whereas 23 patients (69.7%) did not relapse. The mean clinical activity indices, laboratory parameters, extent of colonic involvement, upper and lower gastrointestinal histological features were not predictive of early relapse. Results of the cellobiose/mannitol small intestinal permeability study were significantly higher in children who relapsed within 6 months compared with children who did not relapse (P < 0.013). The cellobiose/mannitol small intestinal permeability study was abnormal in 77.8% of early relapsers compared with only 8.3% of non-relapsers. Conclusion Abnormal small intestinal permeability in children with ulcerative colitis could predict a more relapsing disease. [source] Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2006R. D'INCÀ Summary Background Abnormal barrier function may be genetically determined in Crohn's disease. Aim To examine the role of abnormal intestinal permeability in genetic predisposition in multiplex vs. sporadic Crohn's disease families. Methods Intestinal permeability was measured in patients, relatives and partners by means of lactulose/mannitol test. Healthy subjects from the hospital staff served as controls. CARD15 mutations were investigated in sporadic and familial Crohn's disease patients and in a group of blood donors. Results The median lactulose/mannitol ratio was increased significantly in Crohn's disease patients vs. their relatives [0.03 (0.01,0.24) vs. 0.01 (0.003,0.19), P = 0.005]. The percentage of abnormal tests was significantly higher in familial vs. sporadic first-degree relatives of Crohn's disease patients (29% vs. 11%, P = 0.0281). Abnormal permeability occurred significantly more frequent in patients with familial Crohn's disease carrying the frameshift mutation. The frameshift mutation 3020insC was associated with increased permeability in 75% in the multiplex and in 61% of the sporadic CD patients. One partner had abnormal lactulose/mannitol ratio. Conclusion Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease. [source] Personal view: food for thought , western lifestyle and susceptibility to Crohn's disease.ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 12 2005The FODMAP hypothesis Summary Susceptibility to the development of Crohn's disease involves a combination of genetic and environmental factors. The association of Crohn's disease with westernization has implicated lifestyle factors in pathogenesis. While diet is a likely candidate, evidence for specific changes in dietary habits and/or intake has been lacking. A new hypothesis is proposed, by which excessive delivery of highly fermentable but poorly absorbed short-chain carbohydrates and polyols (designated FODMAPs , Fermentable Oligo-, Di- and Mono-saccharides And Polyols) to the distal small intestinal and colonic lumen is a dietary factor underlying susceptibility to Crohn's disease. The subsequent rapid fermentation of FODMAPs in the distal small and proximal large intestine induces conditions in the bowel that lead to increased intestinal permeability, a predisposing factor to the development of Crohn's disease. Evidence supporting this hypothesis includes the increasing intake of FODMAPs in western societies, the association of increased intake of sugars in the development of Crohn's disease, and the previously documented effects of the ingestion of excessive FODMAPs on the bowel. This hypothesis provides potential for the design of preventive strategies and raises concern about current enthusiasm for putative health-promoting effects of FODMAPs. One of the greatest challenges in defining the pathogenesis of Crohn's disease is to identify predisposing environmental factors. Such an achievement might lead to the development of preventive strategies for, and the definition of, possible target for changing the natural history of this serious disease. The present paper describes a new hypothesis for one such environmental factor. [source] Effects of probiotic therapy on portal pressure in patients with cirrhosis: a pilot studyLIVER INTERNATIONAL, Issue 7 2009Puneeta Tandon Abstract Background: Recent literature has supported the role of bacterial translocation as a mediator of splanchnic vasodilatation and portal hypertension. The objective of this study was to determine whether the probiotic VSL#3 would reduce portal pressure in patients with cirrhosis. Methods: Eight patients with compensated or very early decompensated cirrhosis and hepatic venous pressure gradient (HVPG) >10 mmHg, received 2 months of VSL#3 (3600 billion bacteria daily). The HVPG, intestinal permeability, endotoxin, tumour necrosis factor (TNF)-,, interleukin (IL)-6, IL-8, renin and aldosterone were measured at baseline and study end. Results: There was no change in the HVPG or intestinal permeability from baseline to study end but there was a trend to reduction in plasma endotoxin (P=0.09), a mild but significant increase in serum TNF-, (P=0.02) and a significant reduction in plasma aldosterone (P=0.03). Conclusions: Within the limitations of small sample size, there does not appear to be a benefit of probiotic therapy for portal pressure reduction in patients with compensated or early decompensated cirrhosis. The reductions in endotoxin and aldosterone suggest possible beneficial effects of probiotics for this patient population. The clinical significance of the small but unexpected increase in TNF-, is unclear. Future studies are planned in patients with decompensated cirrhosis. [source] The gastrointestinal safety profile of rofecoxib, a highly selective inhibitor of cyclooxygenase-2, in humansALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2001C. J. Hawkey Highly selective inhibitors of cyclooxygenase-2, such as rofecoxib, are hypothesized to have an improved gastrointestinal tolerability and safety profile compared with non-selective NSAIDs, which inhibit cyclooxygenase-1 and cyclooxygenase-2 non-selectively. This paper reviews data from randomized, double-blind, placebo-controlled studies which investigated the effects of rofecoxib and NSAIDs on the human gastrointestinal tract. In healthy subjects, rofecoxib 25 mg and 50 mg daily had no effect on gastric mucosal prostaglandin synthesis, whilst naproxen 1000 mg daily caused a 70% reduction. Therapeutic doses of rofecoxib 25 mg and 50 mg daily did not increase intestinal permeability or faecal blood loss in healthy subjects, whereas increases in both measures were seen with indometacin 150 mg or ibuprofen 2400 mg. A supra-therapeutic dose of rofecoxib (250 mg) given daily for 7 days did not induce an increase in gastroduodenal erosions in healthy subjects, whilst increased numbers of erosions were found in subjects given ibuprofen 2400 mg or aspirin 2600 mg. The endoscopic findings in healthy subjects were confirmed in two 6-month clinical studies involving 1516 patients with osteoarthritis; the incidences of ulcers following rofecoxib 25 mg or 50 mg daily were similar to placebo and less than ibuprofen 2400 mg. The advantage of rofecoxib over NSAIDs in these studies appears to translate into clinically relevant benefits; an analysis of 5435 patients with osteoarthritis found a significantly lower incidence of gastrointestinal perforations, ulcers and bleeds in patients taking rofecoxib compared with patients taking NSAIDs. Overall, the findings from these studies suggest that, as a result of cyclooxygenase-1 sparing, rofecoxib is significantly less gastrotoxic than non-selective NSAIDs, and may not differ from placebo. [source] The effects of smoking and indomethacin on small intestinal permeabilityALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2000Suenaert Background: Smoking modulates inflammatory bowel disease, protecting from ulcerative colitis on the one hand and worsening the course of Crohn's disease on the other. This influence might occur through changes in intestinal permeability, because permeability is increased in most patients with Crohn's disease. Aim: To study the influence of smoking on small intestinal permeability and its increase induced by indomethacin. Methods: 50 smokers and 50 nonsmokers underwent a 51Cr-EDTA basal permeability test and the same test after challenge with indomethacin 125 mg p.o. Results: Small intestinal permeability was the same in smokers (median 1.22%; IQR 1.00,1.58) and nonsmokers (1.24%; 0.94,1.66). Basal small intestinal permeability was lower in females (1.09%; 0.87,1.33) than in males (1.48%; 1.18,1.88). Indomethacin challenge increased permeability by 110% (71,141) in smokers, vs. 156% (78,220) in the nonsmokers (P=0.04). Conclusion: Smoking reduces the effect of NSAID on small intestinal permeability. It is therefore unlikely that the adverse effect of smoking on Crohn's disease is related to its influence on intestinal permeability. [source] Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the ratALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2000Somasundaram Background: The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation. Aims: To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat. Methods: We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a ,topical' effect and (iii) the two together, using (iv) indomethacin as a positive control. Results: Dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin. Conclusions: These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers. [source] Linaclotide , a secretagogue and antihyperalgesic agent , what next?NEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2010A. E. Bharucha Abstract Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose,effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors. [source] Intestinal permeability and irritable bowel syndromeNEUROGASTROENTEROLOGY & MOTILITY, Issue 7 2007M. Camilleri Abstract, Based on a systematic PubMed search, this short review addresses why intestinal permeability may be important in the pathobiology of irritable bowel syndrome (IBS), the evidence of abnormal permeability in patients with IBS, and the pros and cons of the different probe molecules available to assess intestinal permeability. While a subgroup of patients with IBS appears to have evidence of increased intestinal permeability, improvements in the methods and validation are key to further research in this field in order to better understand intestinal barrier functions in IBS. [source] Allergen-specific antibody and cytokine responses, mast cell reactivity and intestinal permeability upon oral challenge of sensitized and tolerized miceCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2010C. Perrier Summary Background Food allergy has reached an epidemic level in westernized countries and although central mechanisms have been described, the variability associated with genetic diversity underscores the still unresolved complexity of these disorders. Objective To develop models of food allergy and oral tolerance, both strictly induced by the intestinal route, and to compare antigen-specific responses. Methods BALB/c mice were mucosally sensitized to ovalbumin (OVA) in the presence of the mucosal adjuvant cholera toxin, or tolerized by intra-gastric administrations of OVA alone. Antibody titres and cytokines were determined by ELISA, and allergic status was determined through several physiologic parameters including decline in temperature, diarrhoea, mast cell degranulation and intestinal permeability. Results OVA-specific antibodies (IgE, IgGs and IgA in serum and feces) were produced in sensitized mice exclusively. Upon intra-gastric challenge with OVA, sensitized mice developed anaphylactic reactions associated with a decline of temperature, diarrhoea, degranulation of mast cells, which were only moderately recruited in the small intestine, and increased intestinal permeability. Cytokines produced by immune cells from sensitized mice included T-helper type 2 cytokines (IL-5, IL-13), but also IL-10, IFN-, and IL-17. In contrast, all markers of allergy were totally absent in tolerized animals, and yet the latter were protected from subsequent sensitization, demonstrating that oral tolerance took place efficiently. Conclusion This work allows for the first time an appropriate comparison between sensitized and tolerized BALB/c mice towards OVA. It highlights important differences from other models of allergy, and thus questions some of the generally accepted notions of allergic reactions, such as the protective role of IFN-,, the importance of antigen-specific secretory IgA and the role of mucosal mast cells in intestinal anaphylaxis. In addition, it suggests that IL-17 might be an effector cytokine in food allergy. Finally, it demonstrates that intestinal permeability towards the allergen is increased during challenge. Cite this as: C. Perrier, A.-C. Thierry, A. Mercenier and B. Corthésy, Clinical & Experimental Allergy, 2010 (40) 153,162. [source] Abrogation of IFN-, mediated epithelial barrier disruption by serine protease inhibitionCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2005L. E. M. Willemsen Summary The intestinal barrier function is often impaired in a variety of diseases including chronic inflammatory bowel disease. Increased intestinal permeability during episodes of active disease correlates with destruction or rearrangement of the tight junction protein complex. IFN-, has been widely studied for its effect on barrier function and tight junction structures but its mode of action remains unclear. Since the claudin family of tight junction proteins is proposed to be involved in barrier maintenance we studied the effect of IFN-, on claudin expression in relation to epithelial barrier function. Cycloheximide and protease inhibitors were used to study mechanisms of IFN-, mediated barrier disruption. Intestinal epithelial cells were exposed to IFN-, and permeability was evaluated by horse radish peroxidase (HRP) and 4 kD FITC-dextran fluxes. Occludin and claudin-1, -2, -3, and -4 tight junction protein expression was determined by Western blotting. Occludin and claudin-2 protein expression was dramatically reduced after IFN-, exposure, which correlated with increased permeability for HRP and FITC-dextran. Interestingly, cleavage of claudin-2 was observed after incubation with IFN-,. Serine protease inhibitor AEBSF completely abrogated IFN-, mediated barrier disruption which was associated with preservation of claudin-2 expression. Moreover, IFN-, induced loss of barrier integrity was found to affect claudin-2 and occludin expression through different mechanisms. Since inhibition of serine protease activity abrogates IFN-, mediated barrier disruption this may be an important target for therapeutic intervention. [source] | ||||||||||||||||||||||