B. Y. De Winter

Concurrent infection with Schistosoma mansoni attenuates inflammation induced changes in colonic morphology, cytokine levels, and smooth muscle contractility of trinitrobenzene sulphonic acid induced colitis in rats

Background and aims: Crohn’s disease, characterised by chronic T helper 1 (Th1) inflammation and dysmotility of the gut, is most prevalent in developed countries. Parasitic infections are most prevalent in developing countries and induce a T helper 2 (Th2) immune response. We hypothesised that this Th2 immune response protects against Th1 gut inflammation. Methods: The parasite Schistosoma mansoni induces a transient Th2 immune response in the semipermissive rat host. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis is an experimental model of Th1-like gut inflammation. The effect of concurrent infection with S mansoni on the course of TNBS induced colitis was assessed using macroscopic and microscopic damage scores, histology, myeloperoxidase (MPO) activity assay, cytokine production assay, and by studying in vitro contractility of longitudinal and circular colonic muscle strips. Results: TNBS induced colitis that spontaneously healed after four weeks. Concurrent infection with S mansoni significantly reduced the duration of TNBS induced colitis to two weeks, as shown by macroscopic and microscopic damage scores and by a faster decrease in colonic MPO activity. TNBS increased colonic interleukin 2 (IL-2) production whereas S mansoni increased splenic IL-4 and IL-2 levels. Contractility of longitudinal and circular muscle strips was maximally inhibited one week after TNBS and normalised after three weeks. After four weeks, longitudinal muscle strip contractility was significantly increased. Concurrent infection with S mansoni normalised longitudinal muscle contractility after one week whereas circular muscle contractility remained inhibited. Conclusions: Concurrent infection with S mansoni significantly attenuates TNBS induced colitis in the rat. Inflammation induced disturbances in contractility of longitudinal and circular colonic muscle strips may outlast the inflammatory reaction.

Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice

Abstract  Ghrelin is an orexigenic peptide with prokinetic effects in the rat. We investigated the effect of ghrelin and growth hormone‐releasing hormone 6 (GHRP‐6) on gastric emptying and transit in control and septic mice. Mice were injected i.p. with lipopolysaccharides (LPS) or saline (control). After 16–17 h mice were pretreated with saline, ghrelin or GHRP‐6 1 h before intragastric administration of Evans blue. Fifteen minutes later, after assessment of the behaviour scale, mice were killed and gastric emptying, transit and rectal temperature were measured. In control mice, ghrelin (100 μg kg−1) and GHRP‐6 (20–100 μg kg−1) accelerated gastric emptying, whereas ghrelin and GHRP‐6 failed to increase transit significantly. Septic mice developed a delay in gastric emptying and transit, hypothermia and a deterioration of the behaviour scale. In septic mice, ghrelin (20 μg kg−1) accelerated gastric emptying without effect on transit while GHRP‐6 significantly accelerated gastric emptying dose‐dependently and failed to increase transit significantly. Ghrelin and GHRP‐6 had no effect on the endotoxin‐induced hypothermia or deterioration of behaviour scale. Therefore, the beneficial prokinetic effect of ghrelin but mainly of GHRP‐6 offers potential therapeutic options in the treatment of septic gastric ileus.

Dyspeptic symptoms in the general population: a factor and cluster analysis of symptom groupings.

Abstract  Both dyspeptic and gastro‐oesophageal reflux‐like symptoms are frequent in the general population, but their degree of overlap is unknown. In severe functional dyspepsia (FD), symptoms are organized in factors associated with pathophysiological mechanisms. The aims of this study were: (i) to assess the prevalence of dyspeptic symptoms with and without overlapping reflux symptoms in the general population and their impact on daily life and on healthcare utilization; and (ii) to compare symptom groupings in the general population to FD patients. A total of 2025 subjects, representative of the Belgian general population, were used in this study. The subjects were submitted to a questionnaire with validated questions on their dyspeptic and reflux symptoms and with evaluators of impact on daily life and use of healthcare resources. Significant dyspeptic symptoms were found in 417 (20.6%). Overlapping reflux symptoms were present in 141 (33.8%). In this group, symptoms were more frequent and more severe. Dyspeptic symptoms induced weight loss (12.7%) and absenteeism (12.4%), affected daily life (61.2%) and generated use of healthcare resources, such as medical consultations (61.4%) and medication (70.9%). Factor analysis revealed a three‐component structure with factor 1 including fullness, bloating and early satiety, factor 2 including nausea and vomiting and factor 3 including discomfort, pain, belching and reflux. If forced in a four‐factor model, the analysis separates belching as independent factor. Dyspeptic symptoms are frequent in the general population, with overlapping reflux symptoms and increased symptom burden in about a third.

Effect of different prokinetic agents and a novel enterokinetic agent on postoperative ileus in rats

BACKGROUND/AIM The effects of different prokinetic agents, the motilide erythromycin and the substituted benzamides metoclopramide and cisapride, were investigated in a rat model of postoperative ileus. These effects were compared with that of granisetron, a 5-hydroxytryptamine (5-HT3) receptor antagonist, and a novel enterokinetic agent, prucalopride, a 5-HT4 receptor agonist. METHODS Different degrees of inhibition of gastrointestinal transit, measured by the migration of Evans blue, were achieved by skin incision, laparotomy, or laparotomy plus mechanical stimulation of the gut. RESULTS Metoclopramide decreased the transit after laparotomy with or without mechanical stimulation, whereas cisapride increased it after all three operations. Granisetron had no effect on the transit after the three operations when given alone. Prucalopride tended to increase the transit after laparotomy with or without mechanical stimulation when given alone. However, statistical significance was only reached when prucalopride was combined with granisetron. Erythromycin, a motilin receptor agonist, did not improve postoperative ileus in the rat. CONCLUSIONS Cisapride, but not metoclopramide or erythromycin, is able to improve postoperative ileus in the rat. The results suggest that a combination of 5-HT3 receptor antagonist and 5-HT4 receptor agonist properties may be required to obtain a beneficial effect on surgery induced ileus in the rat. Furthermore, they indirectly indicate that stimulation of the excitatory mechanisms is not able to overcome the inhibitory influence of the neural reflex pathways activated during abdominal surgery.

Effect of cannabidiol on sepsis‐induced motility disturbances in mice: involvement of CB1 receptors and fatty acid amide hydrolase

Abstract  Sepsis is an inflammatory condition that is associated with reduced propulsive gastrointestinal motility (ileus). A therapeutic option to treat sepsis is to promote intestinal propulsion preventing bacterial stasis, overgrowth and translocation. Recent evidence suggests that anti‐oxidants improve sepsis‐induced ileus. Cannabidiol, a non‐psychotropic component of Cannabis sativa, exerts strong anti‐oxidant and anti‐inflammatory effects without binding to cannabinoid CB1 or CB2 receptors. Cannabidiol also regulates the activity of fatty acid amide hydrolase (FAAH) which is the main enzyme involved in endocannabinoid breakdown and which modulates gastrointestinal motility. Because of the therapeutic potential of cannabidiol in several pathologies, we investigated its effect on sepsis‐induced ileus and on cannabinoid receptor and FAAH expression in the mouse intestine. Sepsis was induced by treating mice with lipopolysaccharides for 18 h. Sepsis led to a decrease in gastric emptying and intestinal transit. Cannabidiol further reduced gastrointestinal motility in septic mice but did not affect gastrointestinal motility in control mice. A low concentration of the CB1 antagonist AM251 did not affect gastrointestinal motility in control mice but reversed the effect of cannabidiol in septic mice. Sepsis was associated with a selective upregulation of intestinal CB1 receptors without affecting CB2 receptor expression and with increased FAAH expression. The increase in FAAH expression was completely reversed by cannabidiol but not affected by AM251. Our results show that sepsis leads to an imbalance of the endocannabinoid system in the mouse intestine. Despite its proven anti‐oxidant and anti‐inflammatory properties, cannabidiol may be of limited use for the treatment of sepsis‐induced ileus.

TRPV1 receptors on unmyelinated C‐fibres mediate colitis‐induced sensitization of pelvic afferent nerve fibres in rats

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis‐induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single‐fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N‐(4‐tertiarybutylphenyl)‐4‐(3‐chlorophyridin‐2‐yl)tetrahydropyrazine‐1(2H)carboxamide (BCTC; 0.25–5 mg kg−1) or its vehicle (hydroxypropyl‐β‐cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A‐fibre neurons, was performed in the dorsal root ganglia L6–S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C‐fibres. BCTC did not significantly affect the C‐fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C‐fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Aδ‐fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up‐regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis‐induced sensitization of pelvic afferent C‐fibres to CRD, while Aδ‐fibres are neither sensitized by colitis nor affected by TRPV1 inhibition.

Role of oxidative stress in the pathogenesis of septic ileus in mice.

Abstract  We investigated the role of oxidative stress in the pathogenesis of septic ileus. Sepsis was induced by intraperitoneal (i.p.) injection of lipopolysaccharides (LPS, 20 mg kg−1) in mice. The effect of two i.p. injections of superoxide dismutase [polyethylene glycol (PEG)‐SOD, 4000 U kg−1] and catalase (PEG‐CAT, 15 000 U kg−1) was investigated on gastric emptying, intestinal transit and total nitrite plasma concentrations. We also performed immunohistochemical experiments on gastric and ileal tissue. LPS significantly delayed gastric emptying and intestinal transit while plasma nitrite levels increased. Polyethylene glycol (PEG)‐SOD reversed the endotoxin‐induced delay in gastric emptying and improved the delay in intestinal transit without effect on plasma nitrite levels. PEG‐CAT slightly improved the delay in gastric emptying without effect on intestinal transit. Immunohistochemistry showed the presence of nitrotyrosine (NT) and 4‐hydroxy‐2‐nonenal (HNE) in the gastric and ileal mucosa of LPS‐treated mice. Treatment with PEG‐SOD or PEG‐CAT of LPS mice diminished the presence of NT or HNE in both tissues. In addition, LPS induced a significant increase in inducible nitric oxide synthase (iNOS)‐positive residential macrophages in the external musculature of stomach and ileum, which significantly decreased after PEG‐SOD or PEG‐CAT treatment. The present results support a role for oxidative and nitrosative stress in the pathogenesis of septic ileus in mice.

Effects of mu- and kappa-opioid receptors on postoperative ileus in rats

In a rat model of postoperative ileus, induced by abdominal surgery, we investigated the effect of mu- and kappa-opioid receptors. Different degrees of inhibition of the gastrointestinal transit, measured by the migration of Evans blue, were achieved by skin incision, laparotomy or laparotomy plus manipulation of the gut. Morphine (1 mg/kg), a preferential mu-opioid receptor agonist, significantly inhibited the transit after skin incision, while the transit after the laparotomy with or without manipulation was not significantly affected. Fedotozine (5 mg/kg), a peripheral kappa-opioid receptor agonist, enhanced the transit after laparotomy plus manipulation, while naloxone (1 mg/kg), a non-specific opioid receptor antagonist, further inhibited the transit after laparotomy plus manipulation. Naloxone and fedotozine alone had no effect on the transit after skin incision or laparotomy without manipulation. However, naloxone prevented the effect of morphine on the transit after skin incision and of fedotozine on the laparotomy plus manipulation. These results support a role for peripheral kappa-opioid receptors in the pathogenesis of postoperative ileus induced by abdominal surgery.

Review article : gastrointestinal sensory and motor disturbances in inflammatory bowel disease -clinical relevance and pathophysiological mechanisms

Background  It is well known that inflammation has a profound impact on the neuromuscular apparatus of the gastrointestinal tract during the inflammatory insult and in periods of remission, at the site of inflammation and at distance from this site. The importance of this interaction is illustrated by the higher prevalence of functional gut disorders in patients with inflammatory bowel disease.

Cell-Free DNA: An Upcoming Biomarker in Transplantation.

After organ transplantation, donor‐derived cell‐free DNA (ddcfDNA) can be detected in the recipients blood and urine. Different ddcfDNA quantification techniques have been investigated but a major breakthrough was made with the introduction of digital droplet PCR and massive parallel sequencing creating the opportunity to increase the understanding of ddcfDNA kinetics after transplantation. The observations of increased levels of ddcfDNA during acute rejection and even weeks to months before histologic features of graft rejection point to a possible role of ddcfDNA as an early, noninvasive rejection marker. In this review, we summarize published research on ddcfDNA in the transplantation field thereby elaborating on its clinical utility.