Changes In Intestinal Permeability Research Articles

Early Changes of Small Intestine Function in Rats After Liver Transplantation

Objective The aims of this study were to explore the concomitant changes of the barrier function, bacterial translocation, absorption, and small intestinal motility in rats after liver transplantation and to correlate these changes with levels of plasma endotoxin. Methods Thirty Wistar rats were divided randomly between a sham operation group ( n = 10) and a liver transplantation group ( n = 10 pairs). The intestinal transit function, intestinal permeability, bacterial translocation, absorption function, levels of plasma endotoxin, and nitrogen monoxide (NO) changes in plasma and small intestinal mucosa were monitored in the two groups. The expression of iNOS mRNA in the intestine was investigated by reverse transcriptase-polymerase chain reactions. Results Significant differences were observed between the liver transplantation group and the sham operation group for aspects of intestinal transit function, intestinal permeability, bacterial translocation, absorption function, and NO changes in both plasma and small intestine. Compared with the sham operation group, the expression of iNOS mRNA was significantly increased ( P < .05) in the small intestine of rats that had undergone liver transplantation. Conclusion The functions of motility, barrier, and absorption in the intestine were decreased among rats that had undergone liver transplantation. Reduced motility in the small intestine of the rats following liver transplantation may be related to the enhanced expression of iNOS in the intestine with a negative correlation to plasma levels of endotoxin.

Antidepressants Attenuate Increased Susceptibility to Colitis in a Murine Model of Depression

Psychiatric factors may determine gastrointestinal health outcomes. Here, we used a model of depression based on neonatal maternal separation (MS) to identify alterations in gut physiology and to assess its association with increased sensitivity to experimental colitis in adulthood. We also examined whether antidepressant therapy attenuates the increased susceptibility to colitis. C57BL/6 mouse pups were separated from mothers for 3 hours per day at 1-21 days of age. Maternally unseparated (US) litters served as controls. At 8 weeks of age mice were examined for changes in behavior, intestinal permeability, and sensitivity to colitis. Separate sets of MS and US mice were given either saline or the antidepressant desipramine 15 mg/kg once daily at 23-36 days of age. Testing of mice occurred at 8 weeks of age. Adult MS mice showed evidence of depressive-like behavior and enhanced intestinal permeability but showed no evidence of spontaneous inflammation. A more severe colitis was seen in MS compared with US mice. Antidepressant therapy improved parameters of depressive-like behavior and reduced the vulnerability to dextran sulphate sodium colitis in MS mice but had no effect on colitis in US mice. MS may lead to depression and increased responsiveness to stress, to impaired intestinal barrier function, and to enhanced vulnerability to colitis in adulthood. This vulnerability is reversed by antidepressant therapy. Depression increases vulnerability to intestinal inflammation. We speculate that pre-existing depression may facilitate the expression of inflammatory bowel diseases.

Comparative assessment of two indices of drug induced permeability changes in the perfused rat intestine

In the present study, two indices of acute intestinal permeability changes were investigated as measurements of drug induced intestinal damage. The first method was based on 14C-polyethylene glycol (PEG) 4000 permeability assessment and the second was based on histological evaluation of the intestine. The test compounds were ibuprofen, ketoprofen and naproxen and the alanine, glycine and phenylalanine amide derivatives of ibuprofen. Perfusion studies were carried out using a rat model. Post-perfusion, the gut was fixed and tissue changes were assessed and scored. Ibuprofen, ketoprofen and naproxen altered the barrier properties of the intestine to PEG 4000 with significantly higher scores ( p < 0.05) for gastrointestinal toxicity relative to blank buffer. For ketoprofen, PEG 4000 permeability and intestinal damage scores increased with increasing ketoprofen concentration. Ibuprofen amide derivatives did not induce significant histological damage or PEG 4000 permeability when compared with ibuprofen. A correlation coefficient of 0.91 is obtained when intestinal damage scores are plotted against PEG 4000 permeability for all compounds. Both indices are proposed as rapid and useful measures of drug induced acute intestinal damage.

A pilot study of the use of epidermal growth factor in pediatric short bowel syndrome

Background This study examined the effects of enterally administered epidermal growth factor (EGF) on nutrient absorption and tolerance of enteral feeds in pediatric patients with short bowel syndrome (SBS). Methods Patients identified with severe SBS (<25% bowel length predicted for age) were prospectively enrolled in treatment using human recombinant EGF (1-53); 100 μg/kg per day given mixed with enteral feeds and patients were treated for 6 weeks. End points followed were patient weight, tolerance of enteral feeds, nutrient absorption, and intestinal permeability as determined using carbohydrate probes and hematologic values for liver function parameters. Results Five patients were treated with EGF; all showed a significant improvement in carbohydrate absorption (3-0 methylglucose): absorption 24.7% ± 9.7% pretreatment vs 34.1% ± 13.8% posttreatment and improved tolerance of enteral feeds (enteral energy as % of total energy, 25% ± 28% pretreatment vs 36% ± 24% posttreatment; mean ± SD; P < .05 by Wilcoxon's signed rank test). Epidermal growth factor treatment was not associated with significant changes in intestinal permeability, the rate of weight gain, or liver function tests. During the treatment phase, no patients developed episodes of sepsis; however, within 2 weeks of discontinuation of EGF treatment, 3 patients developed septic episodes. No adverse effects of EGF administration were noted. Conclusions These results suggest that enteral treatment with EGF in pediatric SBS improves nutrient absorption, increases tolerance with enteral feeds, and may improve the infection rate. Further studies exploring treatment strategies including the timing and duration of EGF administration are indicated.

Changes in Intestinal Morphology and Permeability in the BioBreeding Rat Before the Onset of Type 1 Diabetes

Type 1 diabetes is an autoimmune disorder that occurs in genetically susceptible individuals. It has been hypothesized that the disease could be triggered by environmental agents that gain entry into the body through small intestinal absorption. Increased intestinal permeability has been reported both in spontaneous animal models of type 1 diabetes and human type 1 diabetes. In these studies, we examined both the physical and functional permeability characteristics of the small intestine in diabetes-prone and control rats. In a series of studies, BioBreeding diabetes-prone(n = 31), BioBreeding diabetes-resistant (n = 20) and control Wistar (n = 25) rats were examined at intervals from 21 to 125 days of age. The percentage of goblet cells and the mucosal crypt depth were significantly greater in BioBreeding diabetes-prone than BioBreeding diabetes-resistant rats (P < 0.001 and P = 0.01, respectively). BioBreeding diabetes-prone and BioBreeding diabetes-resistant rats expressed less of the tight junction protein claudin (P < 0.05) and exhibited greater intestinal permeability (P < 0.001) than did Wistar rats. Intestinal permeability measured both in vivo and ex vivo decreased in all rat strains as age increased (P < 0.001). In a genetically susceptible rodent model of diabetes, early increased intestinal permeability might allow unregulated passage of environmental antigens that could potentially trigger the autoimmune response leading to type 1 diabetes.

Everted Intestinal Sacs As In vitro Model For Assessing Absorptivity Of L- Histidine Under The Effect Of Aspirine And Gum Acacia In Male Rats

The purpose of this study was to characterize intestinal permeability changes over a range of physiologically relevant intestinal injury. The experiments were performed in 80 rats subdivided into four groups as aspirin (400 mg/kg b.w.), gum Acacia ( 1g./day) and aspirin with gum Acacia groups for 21 days compared with control group. Relative reabsorption of L- Histidine was greater(p<0.001) in the aspirin in 10 min of incubation compared with that of the control rats. In aspirin in combination with gum Acacia, the relative reabsorption were significantly (p<0.001) decrease in 10, 20 and 30 min. of incubation compared with that of the control rats. Moreover, the relative reabsorption of L-histidine was significantly (p<0.01) reduced by the aspirin at 45 min of time of the incubation buffer compared with that of the control. However, gum acacia treatment was increased at 10 min (p<0.01) ,30 min (p<0.01) and 45 min (p<0.001) respectively compared with that of the control rats. Relative reabsorption of L-histidine record a nonsignificant increase of aspirin at 20 min and 30 min of incubation compared with that of the control. Gum and aspirin with gum at 20min and 45min of incubation resulted an increase and decrease in relative reabsorption of L-histidine respectively compared with that of the control. Aspirin and aspirin in combination with gum acacia treatment increased body, intestinal weights and mucosal total protein significantly with percent changes ranged from 8% to 40% compared with that of the control. On the other hand, gum treatment decreased body, intestinal weights and mucosal total protein significantly with percent changes ranged from 8% to 35% compared with that of the control. These results demonstrated that L-histidine is actively taken up by a gum Acacia system in intestinal everted sac mechanism of rat with energy supplied by glucose and Na + in incubation buffer. Moreover, aspirin system had an inhibitory effect on L-histidine uptake in 45 min of incubation , indicating the saturation by L-histidine in first ten minuts of incubation. Also, these results provide evidence the uptake of L-histidine into rat intestine was not reduced at all by the treatment of aspirin. These results suggest that the uptake of L-histidine by intestinal everted sac of rat has different characteristics of aspirin with gum compared with that of the control in respect to relative reabsorption of L- histidine.

Everted Intestinal Sacs As In vitro Model For Assessing Absorptivity Of L- Histidine Under The Effect Of Aspirine And Gum Acacia In Male Rats

The purpose of this study was to characterize intestinal permeability changes over a range of physiologically relevant intestinal injury. The experiments were performed in 80 rats subdivided into four groups as aspirin (400 mg/kg b.w.), gum Acacia ( 1g./day) and aspirin with gum Acacia groups for 21 days compared with control group. Relative reabsorption of L- Histidine was greater(p<0.001) in the aspirin in 10 min of incubation compared with that of the control rats. In aspirin in combination with gum Acacia, the relative reabsorption were significantly (p<0.001) decrease in 10, 20 and 30 min. of incubation compared with that of the control rats. Moreover, the relative reabsorption of L-histidine was significantly (p<0.01) reduced by the aspirin at 45 min of time of the incubation buffer compared with that of the control. However, gum acacia treatment was increased at 10 min (p<0.01) ,30 min (p<0.01) and 45 min (p<0.001) respectively compared with that of the control rats. Relative reabsorption of L-histidine record a nonsignificant increase of aspirin at 20 min and 30 min of incubation compared with that of the control. Gum and aspirin with gum at 20min and 45min of incubation resulted an increase and decrease in relative reabsorption of L-histidine respectively compared with that of the control. Aspirin and aspirin in combination with gum acacia treatment increased body, intestinal weights and mucosal total protein significantly with percent changes ranged from 8% to 40% compared with that of the control. On the other hand, gum treatment decreased body, intestinal weights and mucosal total protein significantly with percent changes ranged from 8% to 35% compared with that of the control. These results demonstrated that L-histidine is actively taken up by a gum Acacia system in intestinal everted sac mechanism of rat with energy supplied by glucose and Na + in incubation buffer. Moreover, aspirin system had an inhibitory effect on L-histidine uptake in 45 min of incubation , indicating the saturation by L-histidine in first ten minuts of incubation. Also, these results provide evidence the uptake of L-histidine into rat intestine was not reduced at all by the treatment of aspirin. These results suggest that the uptake of L-histidine by intestinal everted sac of rat has different characteristics of aspirin with gum compared with that of the control in respect to relative reabsorption of L- histidine.

INFLUENCE OF MICROBIAL FERMENT ON PLASMA D-LACTIC INDUCED BY METHYLPREDNISOLONE

A260 Aims: . To investigate the changes of intestinal barrier permeability from methylprednisolone, and the influence of microbial ferment on such changes, so as to provide new testimony for further prevent early bacterial infection after transplantation. Methods: 70 healthy male Wistar rats were divided into three groups: control (N)? immunosupressant(MeP) and microbial ferment(MiF) groups, each group was further divided into four subgroups :0, 3, 5, 7day, at each time point the rats were killed to get blood and some tissue by sterile, and to assay plasma D-lactic and gut microbial ecology. Results: Compared with N groups plasma D-lactic in Mep groups increased significantly at 3, 5, 7day subgroups(0N 0.30±0.03, 3N 0.31±0.03 vs 3MeP 0.89±0.30, p<0.01; 0N 0.30±0.03, 5N 0.32±0.02 vs 5MeP 0.96±0.40, p<0.01; 0N 0.30±0.03, 7N 0.31±0.03 vs 7MeP 0.86±0.40, p<0.05); Gut microbial ecology did not change any. Compared with Mep groups, D-lactic in 7 day MiF sugroup decreased obviously(7MeP0.86±0.40 vs 7MiF0.27±0.10, p<0.01), yet there were no difference at 3, 5day between MeP and MiF groups; Bifidobacterium(TPY) and yeast(MRS) in MiF groups increased obviously at 5, 7day than that in MeP groups(5MiF MRS 8.69±0.28 vs 5MeP MRS8.27±0.35, p<0.05; 7Mif TPY 9.23±0.66 vs 7MeP TPY 8.31±0.49, p<0.05; 7MiF MRS 9.29±0.55 vs 7MeP MRS8.23±0.54, p<0.01), yet there was no difference between the 3 day groups. Conclusions: Methylprednisolone can result in intestinal barrier permeability increase, and microbial ferment can decrease the permeability from methylprednisolone.

Does glutamine-enriched parenteral nutrition really affect intestinal morphology and gut permeability?

Background: Nutritional depletion has been related to low glutamine levels in plasma and gut mucosa. This study was set up to investigate the effects of glutamine-enriched total parenteral nutrition on intestinal morphology and permeability. Methods: Twenty-three depleted patients were randomized and after stabilization baseline measurements were performed. Plasma glutamine concentrations, gut morphology (including proliferation and lymphocyte markers) and intestinal permeability were measured. After administration during 8–10 days of a glutamine enriched total parenteral nutrition or an isonitrogenous control solution the measurements were repeated. Results: No significant changes in glutamine concentrations, intestinal permeability, mucosal morphology or gut mucosal inflammation were observed between groups. Conclusions: Glutamine enriched total parenteral nutrition in a depleted patient population does not result in improvements in gut morphology and gut barrier function.

Enteric nematodes induce stereotypic STAT6-dependent alterations in intestinal epithelial cell function.

Infection with gastrointestinal nematodes exerts profound effects on both the immune and physiological responses of the host. We showed previously that the Th2 cytokines, IL-4 and IL-13, induce STAT6-dependent changes in intestinal epithelial cell permeability, absorption, and secretion that are similar to those observed in a secondary infection with Heligmosomoides polygyrus. In the current study we investigated whether nematode-induced effects on epithelial cell function were 1) generic, 2) dependent upon STAT6, and 3) attributable to direct effects on the epithelial cells themselves or mediated by effects on enteric nerves. Our results demonstrate that infection of BALB/c mice with three different gastrointestinal nematodes (H. polygyrus, Nippostrongylus brasiliensis, and Trichinella spiralis) alters intestinal epithelial cell function by decreasing resistance, glucose absorption, and secretory responses to 5-hydroxytryptamine and acetylcholine, two critical mediators in the submucosal reflex pathway. These modified responses are dependent on STAT6 and are the result of both direct effects and indirect effects mediated through enteric nerves.

In situ intestinal absorption studies on low molecular weight heparin in rats using Labrasol as absorption enhancer

Oral absorption of low molecular weight heparin (LMWH) is limited by its molecular size and negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and decrease the hospital expenses. Studies were aimed at evaluating Labrasol for improving intestinal absorption of LMWH. Formulations containing LMWH and Labrasol were administered to duodenum, jejunum, and ileum of the fasted rats. The doses of LMWH and Labrasol were 200 IU/kg and 50 mg/kg, respectively. Reversibility of absorption enhancing effect of Labrasol was assessed by administering LMWH to jejunum after 0.5 and 1 h of administration of Labrasol. The effect of different doses of Labrasol on LMWH absorption was studied by administering Labrasol at 50, 100, and 200 mg/kg doses. Administration of LMWH formulation to jejunum resulted in the highest plasma anti-Xa activity (0.50±0.03 IU/ml) compared to duodenum (0.19±0.03 IU/ml), and ileum (0.29±0.06 IU/ml) and the anti-Xa levels were maintained above the therapeutic level for about 160 min. The absorption of LMWH was negligible when LMWH was administered at 0.5 and 1 h post-Labrasol administration. Increasing the dose of Labrasol has decreased the absorption of LMWH from jejunum. Labrasol increased the intestinal absorption of LMWH, and jejunum was found to be the best site of absorption. Intestinal membrane permeability changes induced by Labrasol were transient and reversible. Maintaining high drug concentration gradient across intestinal wall is important to obtain increased intestinal LMWH absorption.

The mechanisms of prednisone inhibition of inflammation in Crohn's disease involve changes in intestinal permeability, mucosal TNFalpha production and nuclear factor kappa B expression.

The clinical course of Crohn's disease after the induction of remission with medical therapy is characterized by unpredictable relapse. To evaluate three surrogate markers, intestinal permeability, mucosal TNFalpha and nuclear factor (NF)-kappaB/IkappaBalpha expression, in order to determine the relationship of these parameters to clinical relapse. Thirty patients with active Crohn's disease were treated with a 10 week course of prednisone using a tapering dosing regimen. Intestinal permeability (lactulose/mannitol [L/M ratio]) was determined at baseline and at the end of prednisone tapering. TNFalpha production and the levels of expression of NF-kappaB/IkappaBalpha were measured in colonic mucosal biopsies obtained after the induction of remission. Twenty-two patients (73%) achieved remission and 50% of patients experienced a clinical relapse during the ensuing 12 months. Treatment with prednisone resulted in a significant decrease in the L/M ratio. Of the patients that relapsed, 75% had a raised L/M ratio at the time of remission compared with 20% of patients with a normal L/M ratio (P < 0.008; hazard ratio = 6.094; CI 1.55, 17.43). Mucosal TNFalpha production was greater in relapsers compared with those who remained in remission. The levels of NF-kappaB in relapsers were significantly greater and levels of cytosolic IkappaBalpha were significantly lower compared with those measured in patients who remained in remission. These findings underscore the importance of incorporating biological parameters of inflammation in determining the clinical course of Crohn's disease.

Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice.

Acute ethanol exposure causes liver injury in experimental animals, and accumulating evidence suggests that a major responsible factor for the pathogenesis is endotoxemia, which results from bacterial endotoxin leakage from the small intestine due to increased intestinal permeability under alcohol challenge. The purpose of this study was to examine whether zinc pretreatment would inhibit acute ethanol-induced liver injury through prevention of intestinal permeability changes. Male 129 SvPCJ mice were treated with three intragastric doses of ZnSO4 at 5 mg of zinc ion per kg each dosing prior to acute ethanol challenge with a single oral dose of 6 g/kg ethanol. The zinc treatment did not alter the elevation of serum concentrations of alcohol. The acute ethanol exposure caused an elevation in serum alanine aminotransferase levels as well as fatty liver and hepatic degenerative necrotic foci as determined by biochemical assay and histochemical analysis, respectively. A significant increase in liver tumor necrosis factor-alpha (TNF-alpha) levels was detected by enzyme-linked immunosorbent assay. These pathological effects correlated well with increases in serum endotoxin levels. Importantly, acute ethanol treatment caused significant damage to the small intestine as determined by morphological analysis of intestinal sections and permeability assay. These alcohol-induced hepatic pathological changes and TNF-alpha elevation were significantly inhibited in the zinc-pretreated animals. The inhibitory action of zinc on alcohol-induced liver damage and activation of inflammation was associated with zinc suppression of alcohol-induced intestinal permeability changes. These results thus demonstrate that zinc prevention of increased intestinal permeability is importantly involved in the inhibition of acute ethanol-induced liver damage in mice.

The early increase in intestinal permeability and systemic endotoxin exposure in patients with severe acute pancreatitis is not associated with systemic bacterial translocation: molecular investigation of microbial DNA in the blood.

Sepsis is the main cause of late mortality in patients with severe acute pancreatitis and is largely attributed to secondary infection of pancreatic necrosis with gram-negative enteric organisms. This is commonly preceded by a significant increase in intestinal colonization with such microbes and with early increases in intestinal permeability, thus suggesting a mechanism of bacterial translocation. Whilst cultures of blood specimens from these patients often remain sterile, it is conceivable that bacteria might translocate in small volumes with detrimental effects but elude detection by standard microbial culture techniques. To investigate the incidence and frequency with which bacterial DNA may exist in the systemic circulation of patients with acute pancreatitis and to relate that to disease severity, changes in intestinal permeability, and systemic endotoxin exposure. Blood samples were obtained at admission and on days 3 and 7 from 26 patients with acute pancreatitis (seven with severe cases) and from 10 healthy controls for DNA extraction and standard microbial cultures. Polymerase chain reaction techniques were used to amplify a gene region (16S ribosomal RNA) found in all bacteria. Levels of serum endotoxin and antibodies to endotoxin core (EndoCAb) were measured at admission, and intestinal permeability to the macromolecule polyethylene glycol 3350 was determined within 72 hours of the onset of symptoms. Blood cultures yielded and enterococci for one patient with a severe attack and coagulase-negative staphylococci for another patient with a mild attack. No bacterial DNA was found in any of the samples. Endotoxemia was detected in 20 patients (five with severe cases), and levels of serum IgM EndoCAb were depleted in patients with severe attacks but remained relatively unchanged during mild attacks (p = 0.033). Intestinal permeability was significantly increased in patients with severe attacks of acute pancreatitis but remained unchanged during mild attacks (p < 0.05). Whilst severe attacks of acute pancreatitis are associated with early derangement in gut barrier function and systemic endotoxin translocation, there is no molecular evidence for associated bacterial "translocation."

Epidermal growth factor reduces ischemia-reperfusion injury in rat small intestine.

To measure the effect of pre-ischemic administration of intraluminal epidermal growth factor on the changes in intestinal permeability induced by 30 mins of superior mesenteric artery occlusion, followed by 2 hrs of reperfusion. Prospective, randomized, placebo-controlled experimental study. University basic science research laboratory. Healthy, young, adult, male Sprague-Dawley rats. A 10-cm segment of small intestine was isolated and studied in situ in rats that were anesthetized with fentanyl and mechanically ventilated. Intestinal ischemia-reperfusion injury was induced by temporary occlusion of the superior mesenteric artery for 30 mins, followed by 2 hrs of reperfusion. Three groups were studied: time controls with a sham operation, saline-treated ischemia-reperfusion, and epidermal growth factor-treated ischemia-reperfusion. Epidermal growth factor, 100 ng/min, was infused intraluminally, beginning 30 mins before and continued until 40 mins after ischemia. Intestinal permeability was measured for each 10-min time period by using chromium-labeled EDTA. Histopathologic injury was assessed by light microscopy. After superior mesenteric artery occlusion, intestinal permeability increased approximately ten-fold and was sustained for 2 hrs of reperfusion in saline-treated rats. Pretreatment with epidermal growth factor significantly reduced the permeability changes during reperfusion by >60% compared with saline-treated animals (p <.05). Histopathologic sections revealed apparently more extensive loss of epithelial cells and mucosal disruption in saline-treated intestine compared with epidermal growth factor-treated intestine. Pre-ischemic administration of intraluminal epidermal growth factor significantly protects against intestinal ischemia-reperfusion injury.

Proteinases and proteinase-activated receptor 2: A possible role to promote visceral hyperalgesia in rats

PAR-2s are highly expressed throughout the gastrointestinal tract. These receptors are cleaved by trypsin and mast cell tryptase and can be activated by peptides corresponding to the tethered ligand of the receptor (SLIGRL-NH2 for rat). The aim of this study was to determine whether colonic administration of PAR-2 agonists affects visceral sensitivity to rectal distention in conscious rats. Abdominal contractions (a criteria of visceral pain) were recorded in rats equipped with intramuscular electrodes. Rectal distention was performed at various times after intracolonic infusion of SLIGRL-NH2 and trypsin. Inflammation parameters and permeability were followed in the colon after the intracolonic injections. Fos expression at a spinal level (L4-L6) was also studied 2 hours after intracolonic injection of SLIGRL-NH2. Rectal distention significantly increased abdominal contractions starting at the RD volume of 0.8 mL. Intracolonic injection of SLIGRL-NH2 (200 microg/rat) and trypsin (200 U/rat), but not vehicle, LRGILS-NH2 (control peptide), boiled trypsin, or SLIGRL-NH2 injected IP, significantly increased (P < 0.05) abdominal contractions for high volumes of distention, 10- and 24-hour postinfusion. SLIGRL-NH2-induced hyperalgesia was inhibited by a NK1 receptor antagonist (SR 140333) but not by indomethacin. Intracolonic injection of SLIGRL-NH2 elevated spinal Fos expression and caused increased intestinal permeability but did not cause detectable inflammation. Intracolonic infusion of subinflammatory doses of PAR-2 agonists activated spinal afferent neurons and produced a delayed rectal hyperalgesia that involves changes in intestinal permeability and the activation of NK1 receptors. These results identify a possible role for proteinases and PAR-2 in the genesis of visceral hyperalgesia.

Selected Contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress

The purpose of this study was to characterize intestinal permeability changes over a range of physiologically relevant body temperatures in vivo and in vitro. Initially, FITC-dextran (4,000 Da), a large fluorescent molecule, was loaded into the small intestine of anesthetized rats. The rats were then maintained at approximately 37 degrees C or heated over 90 min to a core body temperature of approximately 41, approximately 41.5, or approximately 42.5 degrees C. Permeability was greater in the 42.5 degrees C group compared with the 37, 41, or 41.5 degrees C groups. Histological analysis revealed intestinal epithelial damage in heated groups. Everted intestinal sacs were then used to further characterize hyperthermia-induced intestinal permeability and to study the potential role of oxidative and nitrosative stress. Increased permeability to 4,000-Da FITC-dextran in both small intestinal and colonic sacs was observed at a temperature of 41.5-42 degrees C compared with 37 degrees C, along with widespread intestinal epithelial damage. Administration of antioxidant enzyme mimics or a nitric oxide synthase inhibitor did not reduce permeability due to heat stress, and tissue concentrations of a lipid peroxidation product were not altered by heat stress, suggesting that oxidative and nitrosative stress were not likely mediators of this phenomenon in vitro. In conclusion, hyperthermia produced increased permeability and marked intestinal epithelial damage both in vivo and in vitro, suggesting that thermal disruption of epithelial membranes contributes to the intestinal barrier dysfunction manifested with heat stress.

Six of the Best, Upper GI 15

Aims: The aim of this study was to investigate whether these early changes in intestinal permeability predict outcome of the attack, and to compare that with C-reactive protein (CRP) and the APACHE II scoring system. Methods: Intestinal permeability to macromolecules (polyethylene glycol 3350) was determined within 72 h of onset of symptoms in 85 patients with acute pancreatitis. Serum CRP was measured daily, and a peak within 120 h was identified. APACHE II scores were determined at 24 h. Attacks were classified as mild (n = 57) or severe (n = 21) according to the Atlanta criteria. Results: Patients with severe attacks had significantly greater peak serum CRP levels (median: 260 mg L−1versus 93 mg L−1; P < 0.0001), intestinal permeability index (0.06 versus 0.008; P < 0.0001), and APACHE II scores (10 versus 5; P < 0.001) compared to mild attacks. The areas under the ROC curve for the prediction of severe attacks, the development of sepsis, organ failure or death, and a prolonged hospital stay were comparable between the three prognostic variables. Conclusions: Early changes in intestinal permeability to macromolecules in patients with acute pancreatitis are highly predictive of severity and outcome of the attacks, and have a predictive power that is comparable to that of the APACHE II scoring system and serum CRP. Early therapeutic interventions aimed at restoration of the gut barrier function might have a favourable impact on the course of the disease.

Morphological and functional adaptation of the small intestine after colectomy and ileal pouch-anal anastomosis in rats

This study investigated morphological and functional changes in the small bowel after colectomy and ileal pouch-anal anastomosis (IPAA). In 15 rats electrolyte, glucose, and water absorption was determined by in vivo single-pass perfusion of the proximal and distal small intestine 15 weeks after IPAA. Afterwards the small intestine was resected for morphometric evaluation. Controls were 15 identically treated rats without operation. IPAA led to a significant increase in the small intestinal diameter and a significant increase in villus length and density, which was more apparent in ileum than in jejunum. Therefore the mucosal surface per unit serosa increased significantly by 59% in the jejunum and by 76% in the ileum. In the pouch there was a significant increase in goblet cell density, crypt depth, and diameter of the muscularis which was not detectable in the segments proximal from the pouch. Due to the increase in mucosal surface there was a significant increase in total glucose and electrolyte and sorption in the ileum while absorption rates per unit mucosa were unchanged, with the exception of an increase in mucosal sodium absorption. Jejunal absorption and ileal absorption of water remained unchanged. Adaptation of the small intestine after IPAA leads to colonic metaplasia in the pouch and intestinal hyperplasia proximal from the pouch. The loss of colonic absorption is compensated by the increase in ileal mucosal surface with subsequently elevated electrolyte and glucose absorption. Changes in intestinal permeability may be responsible for additional water depletion, which is compensated by the upregulation of enteric water and sodium absorption.

Effects of anti-tumour necrosis factor, interleukin-10 and antibiotic therapy in the indometacin-induced bowel inflammation rat model.

The administration of indometacin to rats increases intestinal permeability and induces inflammatory pathology of the small bowel. This represents a potential model for Crohn's disease. To analyse the pathogenic role of T cells, tumour necrosis factor and bacterial flora in indometacin-induced changes in small bowel permeability and inflammation. Rats were given indometacin, 13 mg/kg, on day 1 and day 2. The effects of antibiotic (metronidazole, aztreonam and amoxicillin/clavulanic acid), anti- tumour necrosis factor and interleukin-10 therapy were evaluated. The parameters used were weight change, serum haemoglobin, chromium-51 ethylenediaminetetra-acetate permeability and macro-and microscopic score on day 5. Results in conventionally harboured rats were compared with those in T-cell-free rats. Additional in vitro experiments were carried out to test the effect of metronidazole on tumour necrosis factor production. Indometacin administration resulted in small bowel ulcers and inflammation, independently of T cells. Metronidazole was more potent than amoxicillin/clavulanic acid and anti-tumour necrosis factor in improving the indometacin-induced small bowel inflammation. Only part of the efficacy was through improvement of increased intestinal permeability. Aztreonam and interleukin-10 had no effect. Metronidazole also suppressed in vitro lipopolysaccharide-induced tumour necrosis factor production, suggesting a therapeutic effect of this drug through the inhibition of tumour necrosis factor. These data implicate anaerobic bacteria and tumour necrosis factor production, but not T cells, as essential elements of the pathogenesis of indometacin-induced small bowel inflammation. Tumour necrosis factor is also involved in the change in intestinal permeability. Metronidazole was the most efficacious drug in this model, probably because it suppressed anaerobic bacteria and directly inhibited tumour necrosis factor production.