Sofie Verschueren

Review article: the role of gastric motility in the control of food intake.

Aliment Pharmacol Ther 2011; 33: 880–894

Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism

Objective Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms. Design Small intestinal permeability was quantified by a 2 h lactulose–mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: control; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: control; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech. Results Indomethacin, as a positive comparator (0.071±0.040 vs 0.030±0.022; p<0.0001), and public speech (0.059±0.040; p<0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose–mannitol ratio (0.042±0.021 vs 0.028±0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment. Conclusions Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man.

Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation

Background  The stomach relaxes upon food intake and thereby provides a reservoir while keeping the intragastric pressure (IGP) low. We set out to determine whether we could use IGP as a measurement for stomach accommodation during food intake.

Intragastric pressure as a determinant of food intake

Background  Different studies indicated a correlation between intragastric pressure (IGP) and satiation. Our aim was to investigate this correlation while artificially increasing the IGP.

Effect of pancreatic polypeptide on gastric accommodation and gastric emptying in conscious rats

Pancreatic polypeptide (PP) is an anorexigenic hormone released from pancreatic F cells upon food intake. We aimed to determine the effect of PP on gastric accommodation and gastric emptying in conscious Wistar HAN rats to investigate whether effects on motor function could contribute to its anorexigenic effects. Intragastric pressure (IGP) was measured through a chronically implanted gastric fistula during the infusion of a nutrient meal (Nutridrink; 0.5 ml/min). Rats were treated with PP (0, 33 and 100 pmol·kg(-1)·min(-1)) in combination with N(G)-nitro-L-arginine methyl ester (L-NAME; 180 mg·kg(-1)·h(-1)), atropine (3 mg·kg(-1)·h(-1)), or vehicle. Furthermore, the effect of PP was tested after subdiaphragmal vagotomy of the stomach. Gastric emptying of a noncaloric and a caloric meal after treatment with 100 pmol·kg(-1)·min(-1) PP or vehicle was compared using X-rays. PP significantly increased IGP during nutrient infusion compared with vehicle (P < 0.01). L-NAME and atropine significantly increased IGP during nutrient infusion compared with vehicle treatment (P < 0.005 and 0.01, respectively). The effect of PP on IGP during nutrient infusion was abolished in the presence of L-NAME and in the presence of atropine. In vagotomized rats, PP increased IGP compared with intact controls (P < 0.05). PP significantly delayed gastric emptying of both a noncaloric (P < 0.05) and a caloric (P < 0.005) meal. PP inhibits gastric accommodation and delays gastric emptying, probably through inhibition of nitric oxide release. These results indicate that, besides the well-known centrally mediated effects, PP might decrease food intake through peripheral mechanisms.

Su2072 The Bitter Taste Receptor Agonist Denatonium Benzoate Alters Intragastric Pressure Profiles During Nutrient Drink Test in Healthy Volunteers

Background: Bitter taste receptors are expressed in the stomach and the duodenum but their function is unclear. We assessed the effects of a potent bitter tastant on intragastric pressure (IGP, a measure of gastric accommodation) and satiation in response to a liquid meal. Methods: We conducted a single-blind crossover trial of 16 healthy volunteers (8 female; mean age 30±2 yrs; mean BMI 23.8±0.9) given 1 μmol/kg (0.1mL/kg) of a 10mM denatonium benzoate (DB) solution or placebo in random order on separate occasions at least 1 week apart. First, both a standard high-resolution manometry (HRM) catheter and a 4mm feeding catheter were positioned intra-gastrically via the nose with location confirmed by detection of the lower esophageal sphincter (LES) and/or fluoroscopy. After an adjustment period, DB or placebo was administered through the feeding catheter. After 30 min, nutrient drink (ND; 30% fat, 42% carbohydrate, 28% protein) was infused into the stomach at 60mL/ min until maximum satiation, at which point it was stopped. Satiation (scored on 0-5 scale) was assessed every minute. IGP was measured as average pressure over 5 channels in the proximal stomach at least 1cm below the LES, with 5-minute baseline measured 10 minutes before ND start. Outcomes were compared with paired t-test or Wilcoxon test as appropriate. All data are expressed as mean ± SEM unless otherwise stated. Results: Baseline IGP prior to ND infusion was similar between DB and placebo (Table). After DB treatment, the nutrientinduced drop in IGP from baseline (baseline-nadir) was inhibited (p=0.056) and delayed (p=0.007) compared to placebo. The total area under the IGP curve during nutrient infusion was significantly smaller after DB (p=0.021), consistent with attenuation of the gastric accommodation response (Figure). Satiation score at nadir IGP tended to be higher after DB vs placebo (p=0.087). The volume of ND ingested and the duration of the nutrient infusion were not statistically different between groups. No adverse effects were noted after either agent. Conclusion: The potent bitter tastant DB inhibits gastric accommodation to a meal, independently of taste receptor stimulation in the tongue. Themechanism and receptors involved in this action warrant further study.

Role of Y 2 receptors in the regulation of gastric tone in rats

We set out to determine the effect of peptide YY(3-36) (PYY(3-36)) on the gastric muscle tone in conscious rats by measuring intragastric pressure (IGP) during intragastric nutrient drink infusion. After an overnight fast, a chronically implanted gastric fistula was connected to a custom-made nutrient drink infusion system and a catheter to measure IGP. IGP was measured before and during the infusion of a nutrient drink (Nutridrink; 0.5 ml/min) until 10 ml was infused. Rats were treated with PYY(3-36) (0, 33, and 100 pmol·kg(-1)·min(-1)) in combination with a subcutaneous injection of the Y(2) receptor antagonists JNJ31020028 (10 mg/kg) or BIIE0246 (2 mg/kg). Experiments were also performed after subdiaphragmatic vagotomy and after pretreatment with 3 ml of nutrient drink (to mimic a fed state). IGP was compared as the average IGP during nutrient infusion, represented as means ± SE and compared using ANOVA. PYY(3-36) dose dependently increased the IGP during nutrient infusion (4.7 ± 0.3, 5.7 ± 0.5 and 7.3 ± 0.7 mmHg; P < 0.01) while JNJ31020028 and BIIE0246 could block this increase [4.4 ± 0.5 (P < 0.001) and 4.8 ± 0.4 (P < 0.05) mmHg, respectively]. Also in vagotomized rats, PYY(3-36) was able to significantly increase the IGP during, an effect attenuated by JNJ31020028. BIIE0246 and JNJ31020028 were not able to decrease the IGP when no PYY(3-36) was administered. PYY(3-36) increased gastric tone through an Y(2) receptor-mediated mechanism that does not involve the vagus nerve. Y(2) receptor antagonists were not able to decrease gastric tone without exogenous administration of PYY(3-36), indicating that Y(2) receptors do not play a crucial role in the determination of gastric tone in physiological conditions.

269 Acute Psychological Stress Increases Small Intestinal Permeability in Healthy Volunteers via CRH-Mediated Activation of Mast Cells

G A A b st ra ct s region, MRP4 was significantly down-regulated compared with expression in biopsies from healthy subjects (P,0.001, n=7-11). Conclusions: Key components of the GC-C/cGMP signalling pathway are expressed within human colonic mucosa. However, expression of the cGMP transporter MRP4 was significantly reduced in rectosigmoid biopsies from patients with IBS-C compared to biopsies from healthy subjects. Reduced MRP4 expression may result in reduced basal release of cGMP from intestinal epithelial cells in these patients and it may underlie some aspects of the pathophysiology of IBS. 1.Gastroenterology,2011,140(5),S1,S-538. Supported by NHMRC Australia, Ironwood Pharmaceuticals Inc.

Tu1976 A Method to Directly and Continuously Assess Gastric Emptying in Conscious Rats: Effect of Pancreatic Polypeptide and Atropine

Introduction: Gastric emptying (GE) in rats is mostly determined after gavaging a radioactive or colored meal, with determination of the percentage of food remaining in the stomach after sacrificing the animal as a measure for gastric emptying. We hereby present a novel method to directly and continuously assess gastric emptying of a liquid meal in conscious rats without the need to sacrifice animals. Methods: After an overnight fast, 6 Wistar HAN rats were placed in a custom-made Bolmann cage to minimize movement artefacts. Rats were treated with atropine (1 mg kg-1; subcutaneous), pancreatic polypeptide (PP; 100 pmol kg-1 min-1; intravenous infusion) or vehicle (administered on 2 occasions). 15 minutes after the start of the treatment, rats were gavaged with 3 ml of a liquid test meal containing 1% hydroxypropyl methylcellulose solution and 0.5 g ml-1 BaSO4 (0 cal). The abdomen was visualized as a dorsal projection using X-ray imaging (29 kV, 40mAs; Embracemammography device; Selenia software (Hologic)). X-ray imaging was possible throughout the whole experiment. In order to estimate the test meal fraction in the stomach, X-rays were taken every 5-10 minutes and analyzed using Image J software. After manually outlining the stomach, the software was used to calculate the area of the image of the stomach. The area directly after gavage of the meal was set at 100% and GE was expressed as the fraction of the original stomach area over time. The average percentage emptied over 60 minutes was compared. Data were represented as mean±S.E.M. and compared using a paired ttest (p 0.1). Atropine caused a significant delay in GE compared to vehicle (55.6±3.1 vs. 40.3±2.7% emptied over 60 minutes, p<0.01). Similarly, PP-treatment significantly inhibited GE (60.5±3.2 vs. 48.5±1.9% emptied over 60 minutes, p<0.05; Fig.1). Conclusion: Using X-rays to visualize a radio-opaque meal allows to determine gastric emptying in a continuous non-invasive manner. Both atropine and PP significantly delayed gastric emptying rate.