Small Intestinal Permeability Research Articles

Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism

Altered intestinal barrier function is postulated to be a central predisposing factor to intestinal diseases, including inflammatory bowel diseases and food allergies. However, the mechanisms involved in maintaining homeostatic intestinal barrier integrity remain undefined. In this study, we demonstrate that mice deficient in mast cells (Kit(W-sh/W-sh) [Wsh]) or mast cell chymase (Mcpt4(-/-)) have significantly decreased basal small intestinal permeability compared with wild-type (WT) mice. Altered intestinal barrier function was linked to decreased intestinal epithelial cell migration along the villus/crypt axis, altered intestinal morphology, and dysregulated claudin-3 crypt expression. Remarkably, engraftment of Wsh mice with WT but not Mcpt4(-/-) mast cells restored intestinal epithelial cell migration, morphology, and intestinal epithelial barrier function. Collectively, these findings identify a mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function.

Small bowel epithelial gaps and intestinal permeability in Crohnʼs disease

Small bowel epithelial gaps and intestinal permeability in Crohnʼs disease

The Relationship between Small-Intestinal Bacterial Overgrowth and Intestinal Permeability in Patients with Irritable Bowel Syndrome

Background/AimsSmall-intestinal bacterial overgrowth (SIBO) is a frequent finding in patients with irritable bowel syndrome (IBS). Many patients with IBS also have abnormal intestinal permeability, which is probably due to low-grade inflammation in the intestinal mucosa. Our aim was to verify the relationship between SIBO and small-intestinal permeability in IBS patients.MethodsA cohort of 38 IBS patients (20 women and 18 men; age range 16-70 years; mean age 40.2 years) with symptoms that fulfilled Rome-II criteria, and 12 healthy controls (5 women and 7 men; age range 25-52 years; mean age: 37.8 years) were recruited. All subjects underwent lactulose breath tests (LBTs) and intestinal permeability tests using the polyethylene glycol (PEG) 3350/400 retrieval ratio.ResultsA positive LBT was found in 18.4% (7/38) of patients with IBS and 8.3% (1/12) of control subjects. Intestinal permeability was significantly increased in patients with IBS compared with the normal controls (0.82±0.09 vs 0.41±0.05 [mean±SD], respectively; p<0.05). However, the intestinal permeability did not differ significantly between IBS patients with a positive LBT and those with a negative LBT (0.90±0.13 and 0.80±0.11, respectively; p>0.05).ConclusionsIntestinal permeability was increased in patients with IBS, but this finding did not correlated with the occurrence of SIBO.

Clostridium perfringens Epsilon Toxin Increases the Small Intestinal Permeability in Mice and Rats

Epsilon toxin is a potent neurotoxin produced by Clostridium perfringens types B and D, an anaerobic bacterium that causes enterotoxaemia in ruminants. In the affected animal, it causes oedema of the lungs and brain by damaging the endothelial cells, inducing physiological and morphological changes. Although it is believed to compromise the intestinal barrier, thus entering the gut vasculature, little is known about the mechanism underlying this process. This study characterizes the effects of epsilon toxin on fluid transport and bioelectrical parameters in the small intestine of mice and rats. The enteropooling and the intestinal loop tests, together with the single-pass perfusion assay and in vitro and ex vivo analysis in Ussing's chamber, were all used in combination with histological and ultrastructural analysis of mice and rat small intestine, challenged with or without C. perfringens epsilon toxin. Luminal epsilon toxin induced a time and concentration dependent intestinal fluid accumulation and fall of the transepithelial resistance. Although no evident histological changes were observed, opening of the mucosa tight junction in combination with apoptotic changes in the lamina propria were seen with transmission electron microscopy. These results indicate that C. perfringens epsilon toxin alters the intestinal permeability, predominantly by opening the mucosa tight junction, increasing its permeability to macromolecules, and inducing further degenerative changes in the lamina propria of the bowel.

Bone Marrow Mesenchymal Stem Cells Reduce Intestinal Ischemia/Reperfusion Injuries in Rats

Adult stem cells are promising novel therapies in regenerative medicine. We investigated effects of bone marrow-derived mesenchymal stem cells (MSCs) on intestinal mucosal permeability impaired by ischemia/reperfusion (I/R). We used a common I/R model in rats to induce intestinal injury by clamping and unclamping the superior mesenteric artery (SMA) in female Sprague-Dawley rats. MSCs were directly injected into the small intestinal submucosa of the syngenic female rats. Control group were injected with the same volume of 0.9% sodium chloride. Small intestine samples were examined for the engraftment of donor-derived mesenchymal stem cells (MSCs) by Y chromosome in situ hybridization analysis. The small intestinal permeability and histomorphologic alternations were measured to evaluate the therapeutic effect of MSCs transplantation. Small intestinal permeability and villi injuries were significantly reduced in the MSCs administrated group compared with control group. MSCs administration accelerated the recovery of the intestinal barrier dysfunction. We concluded that submucosal infusion of MSCs might exert protective effects on the integrity of intestinal barrier.

Intestinal barrier function is modulated by short-term exposure to fumonisin B1 in Ussing chambers

Fumonisin B₁ (FB1) alters intestinal epithelial cell cycle, absorptive, secretory and barrier properties of intestinal epithelial cells in vitro but data with intestinal mucosa are lacking. Therefore, we tested the hypothesis that acute exposure to FB1 alters indices of intestinal absorptive and secretory physiology and barrier function ex vivo. Eighteen non-littermates pigs (n=18) weaned at 28 d were slaughtered 7 d post-weaning. Jejunal tissue was collected immediately, the mucosa was mounted in Ussing chambers (UC) and short-term (2 h) effects of pure FB1 were investigated. Increased transepithelial resistance (TER) (P=0.05) and macromolecular passage (P=0.06) were observed after 60-90 min of incubation of jejunal mucosa with FB1. FB1 did not alter the jejunal absorptive and secretory physiology. In conclusion, 2h-exposure to FB1 tended to increase the trans- cellular permeability and increased para-cellular permeability of pig small intestine.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

W2006 Beneficial Effects of Fermented Milk Containing Lactobacillus GG and L. Gasseri Tmc0356 On Regulating Intestinal Microflora and Immune Responses for Patients with Allergic Disease

Background & Aims: TNF DARE/B6 mice develop a chronic and severe intestinal inflammation, primarily localized to the terminal ileum, that is dependent on the global overproduction of TNFα due to a targeted deletion in the 3' untranslated region (UTR) of the TNF gene. The use of probiotics has shown great potential as an effective therapy for the treatment and maintenance of remission in both patients with IBD as well experimental models of colitis. However, the specific mechanism(s) of probiotic efficacy in the treatment of IBD remains to be elucidated. The aim of the present study was to determine whether administration of VSL#3, a probiotic mixture of Streptococcus thermophilus, 3 strains of Bifidobacterium, and 4 strains of lactobacillus, had the ability to decrease the severity of TNF-dependent chronic intestinal inflammation and evaluate potential mechanism(s) for its efficacy. Methods: TNF DARE/B6 and control mice with active and severe ileitis (16 wks of age) were fed a diet supplemented with VSL#3 for a period of 6 wks. In Vivo permeability along the gut axis was evaluated at t=0, 2, 4, and 6 wks and measured by the fractional excretion (FE) of specific sugars in the urine of experimental mice following oral gavage of a sugar probe cocktail administered 18 hrs before collection. Disease activity was assessed by histologic evaluation of ilea after the 6 wk treatment period using an established scoring system, and circulating TNFα protein levels measured by ELISA in the serum of experimental mice. Results: Treatment of TNF DARE/B6 mice with VSL#3 significantly decreased total ileal inflammation compared to untreated control mice (7.75±1.64 vs. 22.8±1.88, p<0.001). Administration of VSL#3 also resulted in a dramatic and significant decrease of serum TNFα protein levels in treated versus untreated TNF DARE/B6 mice (25.86±7.95 vs. 184.68±58.14 pg/ml, p=0.01). Finally, small intestinal permeability was significantly lower in VSL#3treated TNF DARE/B6 mice compared to mice with established ileitis (0.358±0.0096 vs. 0.779±0.031 lactulose/mannitol FE, p<0.001). Conclusion: Our results demonstrate that administration of the probiotic mixture, VSL#3, had the ability to ameliorate the severity of TNF-dependent experimental ileitis by potentially decreasing circulating TNF levels and improving overall epithelial barrier function in the gut. These data underscore the critical role in regulating TNFα expression for the treatment of chronic intestinal inflammation, such as that observed in IBD.

W2002 Regulation of TNF By the Probiotic Mixture, VSL#3, and Its Efficacy to Ameliorate TNF-Dependent Chronic Intestinal Inflammation in the TNF Dare Model of Crohn's Disease

Background & Aims: TNF DARE/B6 mice develop a chronic and severe intestinal inflammation, primarily localized to the terminal ileum, that is dependent on the global overproduction of TNFα due to a targeted deletion in the 3' untranslated region (UTR) of the TNF gene. The use of probiotics has shown great potential as an effective therapy for the treatment and maintenance of remission in both patients with IBD as well experimental models of colitis. However, the specific mechanism(s) of probiotic efficacy in the treatment of IBD remains to be elucidated. The aim of the present study was to determine whether administration of VSL#3, a probiotic mixture of Streptococcus thermophilus, 3 strains of Bifidobacterium, and 4 strains of lactobacillus, had the ability to decrease the severity of TNF-dependent chronic intestinal inflammation and evaluate potential mechanism(s) for its efficacy. Methods: TNF DARE/B6 and control mice with active and severe ileitis (16 wks of age) were fed a diet supplemented with VSL#3 for a period of 6 wks. In Vivo permeability along the gut axis was evaluated at t=0, 2, 4, and 6 wks and measured by the fractional excretion (FE) of specific sugars in the urine of experimental mice following oral gavage of a sugar probe cocktail administered 18 hrs before collection. Disease activity was assessed by histologic evaluation of ilea after the 6 wk treatment period using an established scoring system, and circulating TNFα protein levels measured by ELISA in the serum of experimental mice. Results: Treatment of TNF DARE/B6 mice with VSL#3 significantly decreased total ileal inflammation compared to untreated control mice (7.75±1.64 vs. 22.8±1.88, p<0.001). Administration of VSL#3 also resulted in a dramatic and significant decrease of serum TNFα protein levels in treated versus untreated TNF DARE/B6 mice (25.86±7.95 vs. 184.68±58.14 pg/ml, p=0.01). Finally, small intestinal permeability was significantly lower in VSL#3treated TNF DARE/B6 mice compared to mice with established ileitis (0.358±0.0096 vs. 0.779±0.031 lactulose/mannitol FE, p<0.001). Conclusion: Our results demonstrate that administration of the probiotic mixture, VSL#3, had the ability to ameliorate the severity of TNF-dependent experimental ileitis by potentially decreasing circulating TNF levels and improving overall epithelial barrier function in the gut. These data underscore the critical role in regulating TNFα expression for the treatment of chronic intestinal inflammation, such as that observed in IBD.

W2003 Differential Effects of Two Probiotic Strains On Pain Perception of Gastric and Colonic Distension in Sprague Dawley Rats

Background & Aims: TNF DARE/B6 mice develop a chronic and severe intestinal inflammation, primarily localized to the terminal ileum, that is dependent on the global overproduction of TNFα due to a targeted deletion in the 3' untranslated region (UTR) of the TNF gene. The use of probiotics has shown great potential as an effective therapy for the treatment and maintenance of remission in both patients with IBD as well experimental models of colitis. However, the specific mechanism(s) of probiotic efficacy in the treatment of IBD remains to be elucidated. The aim of the present study was to determine whether administration of VSL#3, a probiotic mixture of Streptococcus thermophilus, 3 strains of Bifidobacterium, and 4 strains of lactobacillus, had the ability to decrease the severity of TNF-dependent chronic intestinal inflammation and evaluate potential mechanism(s) for its efficacy. Methods: TNF DARE/B6 and control mice with active and severe ileitis (16 wks of age) were fed a diet supplemented with VSL#3 for a period of 6 wks. In Vivo permeability along the gut axis was evaluated at t=0, 2, 4, and 6 wks and measured by the fractional excretion (FE) of specific sugars in the urine of experimental mice following oral gavage of a sugar probe cocktail administered 18 hrs before collection. Disease activity was assessed by histologic evaluation of ilea after the 6 wk treatment period using an established scoring system, and circulating TNFα protein levels measured by ELISA in the serum of experimental mice. Results: Treatment of TNF DARE/B6 mice with VSL#3 significantly decreased total ileal inflammation compared to untreated control mice (7.75±1.64 vs. 22.8±1.88, p<0.001). Administration of VSL#3 also resulted in a dramatic and significant decrease of serum TNFα protein levels in treated versus untreated TNF DARE/B6 mice (25.86±7.95 vs. 184.68±58.14 pg/ml, p=0.01). Finally, small intestinal permeability was significantly lower in VSL#3treated TNF DARE/B6 mice compared to mice with established ileitis (0.358±0.0096 vs. 0.779±0.031 lactulose/mannitol FE, p<0.001). Conclusion: Our results demonstrate that administration of the probiotic mixture, VSL#3, had the ability to ameliorate the severity of TNF-dependent experimental ileitis by potentially decreasing circulating TNF levels and improving overall epithelial barrier function in the gut. These data underscore the critical role in regulating TNFα expression for the treatment of chronic intestinal inflammation, such as that observed in IBD.

W2004 IBD Prevention Using An Oligosaccharide Synthesize Enzyme via Improvement of Bowel Flora, TLR-2 and Claudin-4

Background & Aims: TNF DARE/B6 mice develop a chronic and severe intestinal inflammation, primarily localized to the terminal ileum, that is dependent on the global overproduction of TNFα due to a targeted deletion in the 3' untranslated region (UTR) of the TNF gene. The use of probiotics has shown great potential as an effective therapy for the treatment and maintenance of remission in both patients with IBD as well experimental models of colitis. However, the specific mechanism(s) of probiotic efficacy in the treatment of IBD remains to be elucidated. The aim of the present study was to determine whether administration of VSL#3, a probiotic mixture of Streptococcus thermophilus, 3 strains of Bifidobacterium, and 4 strains of lactobacillus, had the ability to decrease the severity of TNF-dependent chronic intestinal inflammation and evaluate potential mechanism(s) for its efficacy. Methods: TNF DARE/B6 and control mice with active and severe ileitis (16 wks of age) were fed a diet supplemented with VSL#3 for a period of 6 wks. In Vivo permeability along the gut axis was evaluated at t=0, 2, 4, and 6 wks and measured by the fractional excretion (FE) of specific sugars in the urine of experimental mice following oral gavage of a sugar probe cocktail administered 18 hrs before collection. Disease activity was assessed by histologic evaluation of ilea after the 6 wk treatment period using an established scoring system, and circulating TNFα protein levels measured by ELISA in the serum of experimental mice. Results: Treatment of TNF DARE/B6 mice with VSL#3 significantly decreased total ileal inflammation compared to untreated control mice (7.75±1.64 vs. 22.8±1.88, p<0.001). Administration of VSL#3 also resulted in a dramatic and significant decrease of serum TNFα protein levels in treated versus untreated TNF DARE/B6 mice (25.86±7.95 vs. 184.68±58.14 pg/ml, p=0.01). Finally, small intestinal permeability was significantly lower in VSL#3treated TNF DARE/B6 mice compared to mice with established ileitis (0.358±0.0096 vs. 0.779±0.031 lactulose/mannitol FE, p<0.001). Conclusion: Our results demonstrate that administration of the probiotic mixture, VSL#3, had the ability to ameliorate the severity of TNF-dependent experimental ileitis by potentially decreasing circulating TNF levels and improving overall epithelial barrier function in the gut. These data underscore the critical role in regulating TNFα expression for the treatment of chronic intestinal inflammation, such as that observed in IBD.

Clinical relevance of measuring colonic permeability

Gastroduodenal and small intestinal permeability are increased in patients with Crohn's disease (CD) and intensive care patients. The relevance of colonic permeability has not yet been adequately investigated. The aim of this study was to investigate the clinical value of sucralose excretion as indicator for colonic permeability in these patient groups. After oral administration of four sugars and subsequent analysis of urinary excretion, gastroduodenal and intestinal permeability were calculated from saccharose excretion and lactulose/mannitol (L/M) ratio over 5 h, and sucralose excretion from 5 to 26 h in 100 healthy controls, 29 CD and 35 patients after coronary surgery (CABG). In controls, sucralose excretion was highly variable (0.67+/-0.92%) and not related to small intestinal permeability. In CD and CABG, L/M ratio was increased (0.054+/-0.060; 0.323+/-0.253 vs. 0.018+/-0.001 in controls). Sucralose excretion was increased in 77% of CABG but only in 7% of CD. There was an association between gastroduodenal and intestinal permeability in CD and CABG (r=0.72, and r=0.51), but sucralose excretion was not related to either one of these two parameters. Other than a weak association between sucralose and length of stay in intensive care in CABG patients (P=0.099), sucralose excretion was not related to clinical outcome. The proposed cut-off for normal sucralose excretion is 2.11%, but its high variability and lack of association to gastrointestinal permeability or clinical outcome leave it open, if it can provide information beyond established permeability tests.

Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse

Background:Defects in the small intestinal epithelial barrier have been associated with inflammatory bowel disease but their role in the causation of disease is still a matter of debate. In some...

Increased Gastrointestinal Permeability and Gut Inflammation in Children with Functional Abdominal Pain and Irritable Bowel Syndrome

To determine gastrointestinal (GI) permeability and fecal calprotectin concentration in children 7 to 10 years of age with functional abdominal pain and irritable bowel syndrome (FAP/IBS) versus control subjects and ascertain potential relationships with pain symptoms and stooling. GI permeability and fecal calprotectin concentration were measured. Children kept a 2-week diary of pain episodes and stooling pattern. Proximal GI permeability was greater in the FAP/IBS group (n = 93) compared with control subjects (n = 52) (0.59 +/- 0.50 vs 0.36 +/- 0.26, respectively; mean +/- SD; P < .001) as was colonic permeability (1.01 +/- 0.67 vs 0.81 +/- 0.43, respectively; P < .05). Gastric and small intestinal permeability were similar. Fecal calprotectin concentration was greater in children with FAP/IBS compared with control children (65.5 +/- 75.4 microg/g stool vs 43.2 +/- 39.4, respectively; P < .01). Fecal calprotectin concentration correlated with pain interference with activities (P = .01, r(2) = 0.36). There was no correlation between GI permeability and pain related symptoms. Neither permeability nor fecal calprotectin correlated with stool form. Children with FAP/IBS have evidence of increased GI permeability and low-grade GI inflammation, with the latter relating to the degree to which pain interferes with activities.

Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome

The pain intensity of patients with FM has recently been reported to be correlated with the degree of small intestinal bacterial overgrowth (SIBO). SIBO is often associated with an increased intestinal permeability (IP). Increased IP, if shown in FM, may have pathogenetic relevance because it leads to the exposure of immune cells to luminal antigens and consequent immune modulation. It is currently unknown whether IP is altered in FM. We therefore examined the IP in a group of patients with primary FM and in two control groups, healthy volunteers and patients with an unrelated chronic pain syndrome, complex regional pain syndrome (CRPS). We hypothesized that patients with FM, but not volunteers or those patients with CRPS, would have altered IP. Both gastroduodenal and small IP were assessed using an established three-sugar test, where urinary disaccharide excretion reflecting intestinal uptake was measured using HPLC. Forty patients with primary FM, 57 age- and sex-matched volunteers and 17 patients with CRPS were enrolled in this study. In the FM group, 13 patients had raised gastroduodenal permeability and 15 patients had raised small intestinal permeability, but only one volunteer had increased gastroduodenal permeability (P < 0.0001, chi-square test for the three groups). The IP values were significantly increased in the patient groups (P < 0.0003 for all comparisons, one-way analysis of variance). The IPs in primary FM and, unexpectedly, CRPS are increased. This study should stimulate further research to determine the implication of altered IP in the disease pathophysiology of FM and CRPS.

Yoghurts Containing Probiotics Reduce Disruption of the Small Intestinal Barrier in Methotrexate-Treated Rats

Small intestinal permeability was employed to assess the efficacy of commercially available yoghurts containing probiotics in a rat model of methotrexate (MTX)-induced mucositis. Male Sprague-Dawley rats were allocated to four groups (n = 8): MTX + water, MTX + cow's milk yoghurt (CY; fermented with Lactobacillus johnsonii), MTX + sheep's milk yoghurt (SY; containing Lactobacillus bulgaricus and Streptococcus thermophilus), and saline. Treatment gavage occurred twice daily for 7 days pre-MTX and 5 days post-MTX. Intestinal permeability was assessed on days -7, -1, 2, and 5 of the trial. Intestinal sections were collected at sacrifice for histological and biochemical analyses. Histology revealed that rats receiving CY and SY did not have a significantly damaged duodenum compared to controls. However, an improved small intestinal barrier function was evident, determined by a decreased lactulose/mannitol ratio. Probiotics containing SY and CY may be useful in preventing disruption to intestinal barrier function in MTX-induced mucositis.

Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study

We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls and children without developmental disabilities. We enrolled 14 children with autism, 7 developmentally normal siblings of these children and 8 healthy, developmentally normal, unrelated children. Our study did not detect differences in these measures of gastrointestinal function in a group of children with autism.

Concept of Crohn's disease being conditioned by four main components, and irritable bowel syndrome being an incomplete Crohn's disease

Several mechanisms have been proposed for the development of Crohn's disease. Evidence in favour of a unifying 4-component concept to explain the development of Crohn's disease is presented. The four components are a genetic predisposition to an increased intestinal permeability, the key and initial triggering factor being an oral-pharyngeal bacterium that increases the mucosal permeability of the small intestine with only a minimal inflammatory reaction, an adherent-invasive strain of Escherichia coli that penetrates the mucosa and causes an acute inflammatory reaction in the intestinal wall, and finally a secondary invasion of bacteria causing the chronic inflammatory characteristics. Irritable bowel syndrome (IBS) is a functional bowel disorder with intermittent symptoms of varying intensity. Clinically, there is evidence to suggest a link between IBS patients with diarrhoea and patients with Crohn's disease. The common denominator and initial trigger for IBS with diarrhoea and Crohn's disease seems to be an increased small intestinal permeability, probably caused by an oral-pharyngeal bacterial strain. The important missing factor in IBS patients seems to be the adherent-invasive strain of E. coli in the proximal colon, causing the acute inflammatory process in patients with Crohn's disease. IBS with diarrhoea can then be looked upon as an incomplete Crohn's disease.

Altered Intestinal Function in Patients With Chronic Heart Failure

We evaluated morphology and function of the gut in patients with chronic heart failure (CHF). Intestinal translocation of bacterial endotoxin may contribute to the inflammatory state observed in patients with CHF. The morphology and function of the gut may be abnormal. We studied 22 patients with CHF (age 67 +/- 2 years, left ventricular ejection fraction [LVEF] 31 +/- 1%, New York Heart Association functional class 2.3 +/- 0.1, peak VO2 15.0 +/- 1.0 ml/kg/min) and 22 control subjects (62 +/- 1 years, LVEF 68 +/- 2%, peak VO2 24.7 +/- 1.3 ml/kg/min). Bowel wall thickness was assessed by transcutaneous sonography, small intestinal permeability by the lactulose-mannitol test, passive carrier-mediated transport by D-xylose test, large intestinal permeability by sucralose test (5- and 26-h urine collection, high-performance liquid chromatography), and mucosal bacterial biofilm by fluorescence in situ hybridization in biopsies taken during sigmoidoscopy. Chronic heart failure patients, compared with control patients, showed increased bowel wall thickness in the terminal ileum (1.48 +/- 0.16 mm vs. 1.04 +/- 0.08 mm), ascending colon (2.32 +/- 0.18 mm vs. 1.31 +/- 0.14 mm), transverse colon (2.19 +/- 0.20 vs. 1.27 +/- 0.08 mm), descending colon (2.59 +/- 0.18 mm vs. 1.43 +/- 0.13 mm), and sigmoid (2.97 +/- 0.27 mm vs. 1.64 +/- 0.14 mm) (all p < 0.01). Chronic heart failure patients had a 35% increase of small intestinal permeability (lactulose/mannitol ratio: 0.023 +/- 0.001 vs. 0.017 +/- 0.001, p = 0.006), a 210% increase of large intestinal permeability (sucralose excretion: 0.62 +/- 0.17% vs. 0.20 +/- 0.06%, p = 0.03), and a 29% decrease of D-xylose absorption, indicating bowel ischemia (26.7 +/- 3.0% vs. 37.4 +/- 1.4%, p = 0.003). Higher concentrations of adherent bacteria were found within mucus of CHF patients compared with control subjects (p = 0.007). Chronic heart failure is a multisystem disorder in which intestinal morphology, permeability, and absorption are modified. Increased intestinal permeability and an augmented bacterial biofilm may contribute to the origin of both chronic inflammation and malnutrition.

ABSENCE OF FUNCTIONAL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-α ENHANCED ILEUM PERMEABILITY DURING EXPERIMENTAL COLITIS

The aim of the present study was to examine the role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligand on the permeability and structure of small intestine tight junctions (TJs) in an animal model of experimental colitis, induced by dinitrobenzene sulfuric acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin, zonula occludens 1, and claudin 2. Administration of DNBS to wild-type mice induced colon injury associated with a significant increase of plasma and colon tumor necrosis factor-alpha levels and with a significant increase of ileal permeability. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. Small intestinal permeability was associated with the presence of apoptosis (evaluated by FAS ligand expression and terminal deoxynucleotidyltransferase-mediated UTP nick end labeling coloration), which was associated with a significantly increased expression of proapoptotic Bax and decreased ileum content of antiapoptotic Bcl-2. Absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of all the above-described parameters. Taken together, our results clearly demonstrate that endogenous PPAR-alpha ligands reduced small intestinal permeability in experimental colitis through the regulation of apoptosis and TJ protein.