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Intestinal permeability and the effect of NSAIDs on permeability were investigated in 14 irritable bowel syndrome (IBS) patients and 15 healthy subjects. In the study, 24-h urinary recoveries of orally administered polyethylene glycols (PEGs 400, 1500, and 4000) were not significantly different in healthy subjects and IBS patients before or after NSAID ingestion. Lactulose mannitol ratios in healthy subjects and IBS patients were not significantly different. Only time-dependent monitoring of PEG excretion showed that NSAIDs enhanced intestinal permeability for PEG 4000 in healthy subjects (P = 0.050) and for PEGs 400, 1500, and 4000 in IBS patients (P = 0.012, P = 0.041, and P = 0.012, respectively). These results show that intestinal permeability in IBS patients is not different from that in healthy subjects; NSAIDs compromise intestinal permeability in IBS patients to a greater extent than in healthy subjects, which suggests that IBS is associated with an altered response of the intestinal barrier to noxious agents. [ABSTRACT FROM AUTHOR]

Investigates the effects of the inflammatory mediator prostaglandin E2 (PGE2) on myenteric neurons, by intracellular recordings in a conventional plexus preparation. Concept of neuroinmmunomodulation in the gastro-intestinal tract; Important role played by prostaglandins; Details on the study.

Colorectal visceral hypersensitivity has been demonstrated in a subset of irritable bowel syndrome (IBS) patients. Serine protease and serotonergic signaling modulate gastrointestinal visceral sensitivity. We evaluated whether altered mucosal serine protease and serotonergic pathway components are related to rectal visceral hypersensitivity in IBS patients. Colorectal mucosal biopsies of 23 IBS patients and 15 controls were collected. Gene transcripts of protease-activated receptor (PAR)-2, trypsinogen IV, tryptophan hydroxylase (TPH)-1, and serotonin reuptake transporter (SERT) were quantified using real-time polymerase chain reaction. Substance P and 5-HT contents were measured by ELISA. The number of enterochromaffin cells, mast cells, and intraepithelial lymphocytes was determined using immunohistochemistry. Rectal visceral sensitivity was determined in IBS patients using barostat programmed for phasic ascending distension. Rectal hypersensitivity (+) and (-) IBS patients showed lower TPH-1 and SERT mRNA levels in the rectum compared with controls (P≦0.05). Rectal hypersensitivity (+) IBS patients (n = 12) showed lower TPH-1 mRNA level in the sigmoid compared with controls (P = 0.015). No significant differences were observed in PAR-2 and trypsinogen IV expression between controls and IBS patients. Rectal substance P content was increased in IBS patients compared with controls (P = 0.045). No significant differences were found in transcript levels, cell counts, and substance P and 5-HT contents between rectal hypersensitivity (+) and (-) IBS patients. In conclusion, regardless of visceral hypersensitivity state, several serotonergic signaling components are altered in IBS patients. [ABSTRACT FROM AUTHOR]

The cardiovascular response to a meal is modulated by gastric distension and the interaction of nutrients, particularly carbohydrate, within the small intestine. We tested the hypothesis that the depressor effect of small intestinal glucose is greater in older than in young subjects, because the reflex increase in muscle sympathetic nerve activity (MSNA) is blunted by age. The effects of intraduodenal glucose infusion (IDGI) on blood pressure, heart rate and MSNA were evaluated in eight healthy young subjects (4 women; mean age ± SEM: 28.8 ± 3.4 years), eight healthy elderly (4 women; 75.3 ± 1.6 years) and in two patients with symptomatic postprandial hypotension (PPH), one young (21 years), and one old (90 years). In both young and elderly healthy subjects, IDGI decreased blood pressure ( P < 0.05), but the fall in systolic blood pressure was greater in the older subjects (−17.0 ± 4.1 vs. −6.5 ± 1.6 mmHg, P < 0.03). MSNA increased similarly, after infusion in both young (9.0 ± 3.4 bursts/min) and elderly (7.8 ± 1.0 bursts/min) subjects. Baroreflex sensitivity for number of sympathetic bursts was attenuated in the elderly ( P < 0.03). The increase in burst area in the young patient with PPH was attenuated (18 vs. 63% in the healthy young group). The fall in BP induced by IDGI was greater in healthy elderly compared to healthy young subjects. The reason for this is unclear, as they have similar increases in MSNA. [ABSTRACT FROM AUTHOR]

Background: Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis. Methods: Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs. Results: In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology. Conclusion: We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon. [ABSTRACT FROM AUTHOR]

Prophylactic probiotic therapy has shown beneficial effects in an experimental rat model for acute pancreatitis on the health status of the animals. Mechanisms by which probiotic therapy interferes with severity of acute pancreatitis and associated sepsis, however, are poorly understood. The aims of this study were to identify the probiotic-induced changes in the gut microbiota and to correlate these changes to disease outcome. Duodenum and ileum samples were obtained from healthy and diseased rats subjected to pancreatitis for 7 days and prophylactically treated with either a multispecies probiotic mixture or a placebo. Intestinal microbiota was characterized by terminal-restriction fragment length polymorphism (T-RFLP) analyses of PCRamplified 16S rRNA gene fragments. These analyses showed that during acute pancreatitis the host-specific Heal microbiota was replaced by an "acute pancreatitis-associated microbiota." This replacement was not reversed by administration of the probiotic mixture. An increase, however, was observed in the relative abundance of a novel bacterial phylotype most closely related to Clostridiu,n lituseburense and referred to as commensal rat ileum bacterium (CRIB). Specific primers targeting the CRIB 16S rRNA gene sequence were developed to detect this phylotype by quantitative PCR. An ileal abundance of CRIB 16S rRNA genes of more than 7.5% of the total bacterial 16S rRNA gene pool was correlated with reduced duodenal bacterial overgrowth, reduced bacterial translocation to remote organs, improved pancreas pathology, and reduced promflaminatory cytokine levels in plasma. Our current findings and future studies involving this uncharacterized bacterial phylotype will contribute to unraveling one of the potential mechanisms of probiotic therapy. [ABSTRACT FROM AUTHOR]

Background: During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. Methodology/Principal Findings: Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP= 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and 51Cr- EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r=0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4±33.5 vs. placebo 223.7±93.7 a.u.; P=0.001), 51Cr-EDTA flux (16.7±10.1 vs. 32.1±10.0 cm/s10-6; P=0.005), apoptosis, lipid peroxidation (0.42±0.13 vs. 1.62±0.53 pmol MDA/mg protein; P,0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33±1.47 vs. 8.82±1.30 nmol/mg protein, P,0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33±1.47 vs. 10.70±1.74 nmol/ mg protein, P=0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88±1.21 vs. placebo 1.94±0.55 nmol/min/mg protein; P<0.05) coinciding with an increase in mRNA expression of glutamate-cysteine-ligase catalytic (GCLc) and modifier (GCLm) subunits. Conclusions: Probiotic pre-treatment diminished AP-induced intestinal barrier dysfunction and prevented oxidative stress via mechanisms mainly involving mucosal glutathione biosynthesis. [ABSTRACT FROM AUTHOR]

Factors determining severity of acute pancreatitis (AP) are poorly understood. Oxidative stress causes acinar cell injury and contributes to the severity, whereas prophylactic probiotics ameliorate experimental pancreatitis. Our objective was to study how probiotics affect oxidative stress, inflammation, and acinar cell injury during the early phase of AP. Fifty-three male Sprague-Dawley rats were randomly allocated into groups: 1) control, 2) sham procedure, 3) AP with no treatment, 4) AP with probiotics, and 5) AP with placebo. AP was induced under general anesthesia by intraductal glycodeoxycholate infusion (15 mM) and intravenous cerulein (5 μg·kg[sup-1]·h[sup-1], for 6 h). Daily probiotics or placebo were administered intragastrically, starting 5 days prior to AP. After cerulein infusion, pancreas samples were collected for analysis including lipid peroxidation, glutathione, glutamate-cysteine-ligase activity, histological grading of pancreatic in- jury, and NF-κB activation. The severity of pancreatic injury conelated to oxidative damage (r = 0.9) and was ameliorated by probiotics (1.5 vs. placebo 5.5; P = 0.014). AP-induced NF-κB activation was reduced by probiotics (0.20 vs. placebo 0.53 OD[sub450nm]/mg nuclear protein; P < 0.001). Probiotics attenuated AP-induced lipid peroxidation (0.25 vs. placebo 0.51 pmol malondialdehyde/mg protein; P < 0.001). Not only was AP-induced glutathione depletion prevented (8.81 vs. placebo 4.1 p.mol/mg protein, P < 0.001), probiotic pre-treatment even increased glutathione compared with sham rats (8.81 vs. sham 6.18 μ.mol/mg protein, P < 0.001). Biosynthesis of gluta-thione (glutamate-cysteine-ligase activity) was enhanced in probiotic-pretreated animals. Probiotics enhanced the biosynthesis of glutathione, which may have reduced activation of inflammation and acinar cell injury and ameliorated experimental AP, via a reduction in oxidative stress. [ABSTRACT FROM AUTHOR]

The article focuses on research which examined probiotic prophylaxis in predicted severe acute pancreatitis. In the research 298 patients with predicted severe acute pancreatitis were studied. researchers found that in patients with predicted severe acute pancreatitis, probiotic prophylaxis with a combination of probiotic strains did not reduce the risk of infectious complications and was also associated with an increased risk of mortality. Researchers suggested that probiotic prophylaxis should not be administered in patients with predicted severe acute pancreatitis.

This study comprises assessment of autonomic function in irritable bowel syndrome (IBS) patients, focusing on meal-related changes. In 18 IBS patients (4 males, mean age 45±3.0 [SEM] years) and 19 healthy volunteers (6 males, mean age 41±3.5 years) blood pressure, heart rate, heart rate variability and muscle sympathetic nerve activity (MSNA) were assessed before, during and after consumption of a standardized meal. In pre- and postprandial phase Valsalva maneuver, cold pressor test (CPT) and deep breathing test were carried out and Visual Analog Scale (VAS) scores for nausea, bloating and pain were obtained. In the IBS group, the meal induced significantly higher VAS scores for pain (P=0.002) and bloating (P=0.02). During food intake, the increase in blood pressure, heart rate and MSNA was equal in patients and controls, but the increase of LF/HF ratio of heart rate variability was significantly higher in the IBS group (median [quartiles] 2.29 [1.14–3.00] versus 0.77 [0.25–1.81]; P=0.03). IBS patients scored lower on pre- and postprandial RRmax/RRmin ratio during deep breathing (DB ratio, P=0.03). The increase in MSNA (burst frequency) in response to CPT tended to be higher in the IBS patients (P=0.07). We conclude that reactivity to food intake, measured as muscle sympathetic nerve activity, is normal in IBS patients. The lower DB ratio and higher LF/HF ratio during food intake in IBS patients is an indication of a reduced parasympathetic reactivity. These results suggest that reduced baseline activity as well as responsiveness of the parasympathetic system could play a role in the pathogenesis of IBS. [ABSTRACT FROM AUTHOR]

Infectious complications in surgical patients often originate from the intestinal microflora. In the critically ill patient, small bowel motility is disturbed, leading to bacterial overgrowth and subsequent bacterial translocation due to dysfunction of the gut mucosal barrier. The optimal prophylactic strategy should act on all these factors, but such a strategy is not yet available. For several decades, antibiotic prophylaxis to prevent translocation of pathogenic bacteria has been studied with conflicting results. Selective decontamination of the digestive tract has shown good results, but fear for bacterial multiresistance has prevented worldwide implementation. In recent years, probiotics, living bacteria with a potential beneficial effect to their host, have shown promising results in several randomized placebo-controlled trials. Currently, in vitro and experimental research focuses on the effects of probiotics on the microflora responsible for gut-derived infections, structural mucosal barrier function and the immune system. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective. It is not well known whether physical activity (PA) is useful in the management of patients complaining of constipation. The aim of this study was to test the influence of regular PA on colonic transit time and defecation in middle-aged inactive patients suffering from chronic idiopathic constipation. Material and methods. Forty-three subjects (>45 years) were randomly divided into group A (n=18, 16 F, 2 M) and group B (n=25, 20 F, 5 M). Group A subjects maintained their normal lifestyle during 12 weeks, followed by a 12-week PA programme. Group B performed a 12-week PA programme after randomization. PA comprised 30 min of brisk walking and a daily 11-min home-based programme. Both groups received dietary advice. Colonic transit time was measured using a radiographic multiple marker single film technique. Results. Despite dietary advice, mean fibre and fluid intake did not change. In group B a significant reduction in 3 out of 4 of the Rome I criteria for constipation was observed, i.e. percentage of incomplete defecations, percentage of defecations requiring straining and percentage of hard stools (p<0.05). As a consequence, the number of fulfilled Rome criteria for constipation decreased (2.7 to 1.7; p<0.05). Furthermore, the rectosigmoid and total colonic transit time decreased (17.5 to 9.6 h and 79.2 to 58.4 h, respectively; p<0.05). After PA the number of fulfilled Rome criteria also decreased in group A (2.6 to 1.7; p<0.05). Conclusions. In middle-aged inactive subjects with symptoms of chronic constipation, it is advisable to promote regular physical activity since it improves both the defecation pattern and rectosigmoid or total colonic transit time. [ABSTRACT FROM AUTHOR]

Objective: To develop a standardised and reproducible model of intra-abdominal infection and abscess formation in rats. Design: Experimental study. Setting: University hospital, The Netherlands. Subjects: 36 adult male Wistar rats. Interventions: In 32 rats, peritonitis was produced using two different concentrations of Escherichia coli (E. coli) and Bacteroides fragilis (B. fragilis) incorporated in fibrin clots (E. coli: 1 x 105 colony forming units (CFU) /ml or 1 x 108 CFU/ml, B. fragilis: 1 x 108 CFU/ml). Four rats with fibrin clots without bacteria served as uninfected controls. Main outcome measurements: Macroscopy and bacterial counts in peritoneal fluid, blood, and fibrin clots after 24 hours, 4 days, 7 days, and 4 weeks. Results: Macroscopically, there were signs of intra-abdominal infection and abscesses. With the higher starting concentration of E. coli, macroscopic signs were more pronounced and in nearly all rats bacterial counts in peritoneal fluid and fibrin clots showed persistently high numbers of E. coli and B. fragilis for at least 7 days (E. coli = 2 x 103 to 1 x 106 CFU/ml and 5 x 107 to 9 x 108 CFU/clot; B. fragilis = 1 x 103 to 1 x 106 CFU/ml and 5 x 107 to 6 x 108 CFU/clot). Conclusion: This standardised and reproducible model of intra-abdominal infection and abscess formation seems well suited for further use and development in experiments on the pathophysiology of intra-abdominal infection and abscesses. [ABSTRACT FROM AUTHOR]

Background/Aims: Translocation of gut bacteria occurs in obstructive jaundice, the underlying mechanisms are unclear. We designed this experimental study to investigate the association between interdigestive motility and the pathogenesis of bacterial translocation during biliary obstruction. Methods: Rats were fitted with jejunal myoelectrodes for the measurement of the interdigestive migrating motor complex (MMC) and with two cannulas in the proximal common bile duct (CBD) for exteriorization of biliary flow. This allowed measurement of MMCs under control conditions with an intact enterohepatic circulation and during 3 days of CBD obstruction without surgical intervention. Mesenteric lymph nodes, liver, spleen and segments of the duodenum, the jejunum and the caecum were removed for microbial culturing. Results: The MMC cycle length increased from 17.3 min before CBD obstruction to 31.9, 34.1, and 25.3 min on days 1, 2 and 3, respectively, after CBD obstruction (p < 0.05 for all days). Bacterial levels in the jejunum were significantly higher in CBD-obstructed rats than in control rats. The translocation incidence was significantly higher in rats with CBD obstruction (6/8) than in control rats (1/8). The bacterial levels in the jejunum correlated significantly with the MMC cycle length (r = 0.60, p <0.05). Conclusion: Experimental biliary obstruction is associated with disturbance of MMCs, small-bowel bacterial overgrowth and increased bacterial translocation.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: The gastric fundus affects afferent control of lower oesophageal sphincter function. Nitric oxide is an important relaxant of the fundus. We postulated that gastric distensibility, compliance and nitric oxide sensitivity may be altered in patients with gastro-oesophageal reflux disease (GERD). Methods: 9 patients with erosive oesophagitis (6 males; median age 55 years) and 16 healthy controls (9 males; median age 36 years) were studied fasting with a gastric barostat. Minimal distending pressure (MDP) and gastric compliance (Δv/Δp) were determined by increasing intrabag pressure in 2-mm Hg increments. The pressures required to produce initial sensation and maximum tolerated sensation were recorded. With the intrabag pressure set at MDP +2 mm Hg, 500 μg sublingual glyceryl trinitrate was administered and the percentage change in intrabag volume from initial volume recorded. Results: The MDP was significantly greater in patients than controls (7.5 vs. 6.7 mm Hg median; p = 0.02). Gastric compliance was similar in both groups (57.8 vs. 67.2 ml/mm Hg; p = 0.4). There was no difference between groups in the pressure at first intragastric sensation (11.2 vs. 10.3 mm Hg above MDP; p = 0.5) or in the maximal tolerated pressure (15.8 vs. 14.3 mm Hg above MDP; p = 0.2). The proportional change in gastric volume from baseline in response to glyceryl trinitrate was smaller in patients than controls (66 (3–200) vs. 120 (26–1,053)%; p = 0.02). Conclusions: Gastric MDP may be altered in GERD, but gastric compliance and sensitivity to distension are normal. Major gastric relaxation occurs in response to a nitric oxide donor, but this appears to be diminished in patients with GERD. Upper gut nitrinergic mechanisms may be altered in oesophageal reflux disease. [ABSTRACT FROM AUTHOR]

Introduction:Impairment of the mucosal barrier plays an important role in the pathophysiology of acute pancreatitis. The myosin IXB (MYO9B) gene and the two tight-junction adaptor genes, PARD3 and MAGI2, have been linked to gastrointestinal permeability. Common variants of these genes are associated with celiac disease and inflammatory bowel disease, two other conditions in which intestinal permeability plays a role. We investigated genetic variation in MYO9B, PARD3 and MAGI2 for association with acute pancreatitis. Methods:Five single nucleotide polymorphisms (SNPs) in MYO9B, two SNPs in PARD3, and three SNPs in MAGI2 were studied in a Dutch cohort of 387 patients with acute pancreatitis and over 800 controls, and in a German cohort of 235 patients and 250 controls. Results:Association to MYO9B and PARD3 was observed in the Dutch cohort, but only one SNP in MYO9B and one in MAGI2 showed association in the German cohort (p < 0.05). Joint analysis of the combined cohorts showed that, after correcting for multiple testing, only two SNPs in MYO9B remained associated (rs7259292, p = 0.0031, odds ratio (OR) 1.94, 95% confidence interval (95% CI) 1.35-2.78; rs1545620, p = 0.0006, OR 1.33, 95% CI 1.16-1.53). SNP rs1545620 is a non-synonymous SNP previously suspected to impact on ulcerative colitis. None of the SNPs showed association to disease severity or etiology. Conclusion:Variants in MYO9B may be involved in acute pancreatitis, but we found no evidence for involvement of PARD3 or MAGI2. [ABSTRACT FROM AUTHOR]

In this letter Marc G. Besselink responds to criticism of the article "Probiotic Prophylaxis in Predicted Severe Acute Pancreatitis: A Randomised Double-Blind Placebo Controlled Trial" published in volume 371 of this journal in 2008.