Gastric motor function alterations have been implicated in the pathogenesis of functional dyspepsia with postprandial distress syndrome (PDS). Prucalopride, a 5-TH4 agonist, is known to stimulate gastrointestinal motility. We aimed to evaluate the effect of prucalopride on gastric sensorimotor function in healthy subjects (HV).
Barostat and intragastric pressure (IGP) measurements were performed in 17 HV (59% females, age 29.4 ± 2.7 y) after treatment with placebo or prucalopride (2 mg) (single-blind cross-over). Isobaric stepwise distensions and gastric sensations were assessed to determine gastric compliance and sensitivity. Gastric accommodation (GA) with the barostat was quantified before and after ingestion of 200 ml of a nutrient drink (ND). GA measured by IGP was quantified as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation (60 ml/min).
Prucalopride did not affect barostat assessed gastric compliance or sensitivity. No differences were observed in GA after prucalopride. During the barostat study, 10 min after the meal, 7 HVs reported significantly higher ratings for nausea after prucalopride (p < 0.001), and vomiting was induced in 4 of the HVs. A positive correlation was observed between the delta mean perception of nausea with the delta mean increase of intra-balloon volume before and after meal ingestion (r = 0.37, p = 0.03). During IGP measurements, no effect on nutrient tolerance was observed and increased cramp severity scores were observed which were associated with a significant increase of distal IGP (r = 0.78, p < 0.0001).
Prucalopride does not enhances gastric accommodation but it might increase sensitivity to gastric distention. Furthermore, the increase in sensitivity seems to be related to an increase in nausea with distension. Clinicaltrials.gov: NCT04429802.

Functional dyspepsia (FD) is defined as the presence of gastroduodenal symptoms in the absence of organic disease that is likely to explain the symptoms. Joint hypermobility (JH) refers to the increased passive or active movement of a joint beyond its normal range and is characteristically present in patients with joint hypermobility syndrome (JHS), which is a hypermobile subtype of Ehlers-Danlos syndrome (EDS). Recent reports have highlighted the co-existence of FD with Ehlers-Danlos syndrome. Our aim was to study the prevalence of JHS in FD compared with healthy subjects and to study the impact of co-existing JHS on gastric motility, nutrient tolerance, and dyspeptic symptoms in FD.
FD patients filled out a dyspepsia symptom severity score. Intragastric pressure (IGP) was measured with high-resolution manometry (HRM) during the intragastric infusion of nutrition drink (ND, 1.5 Kcal/ml, 60 ml/min) until maximal satiation in healthy subjects and FD. We compared IGP profiles and nutrient tolerance in HS and FD with or without JHS.
JHS was present in 54% of FD patients (n = 39, 41.2 ± 2.2 years old) and 7% of healthy subjects (n = 15, 27.3 ± 2.3 years old). IGP drop and nutrient tolerance were lower in non-JHS-FD compared with JHS-FD and HS (AUC JHS-FD: -17.9 ± 2.5 vs. non-JHS-FD: -13.0 ± 3.3 mmHg min, p = 0.2, HS:-19.6 ± 2.9 mmHg min; ND tolerance non-JHS-FD: 671.0 ± 96.0 vs. JHS-FD: 842.7 ± 105.7 Kcal, p = 0.25, HS: 980.0 ± 108.1 Kcal).
JHS often co-exists with FD. Non-JHS-FD was characterized by decreased accommodation and lower nutrient tolerance characterized compared with JHS-FD. Clinicaltrials.gov, reference number NCT04279990.

BACKGROUND: Disturbances of gastric motor function of functional dyspepsia (FD) have been implicated in the pathogenesis of the symptoms, and hence, motility modifying agents are considered for its treatment. Mirtazapine was recently shown to improve symptoms and increase nutrient tolerance in FD patients with weight loss. We aim to evaluate the effect of mirtazapine on gastric sensorimotor function in healthy volunteers (HV).
METHODS: Thirty-one HV underwent an intragastric pressure (IGP) and barostat measurements on separate days before and after 3 weeks of placebo or mirtazapine (15 mg). Gastric compliance, sensitivity and accommodation (GA) measured by the barostat. GA was quantitated as the difference (delta) in intra-balloon volume before and after ingestion of 200 mL of a nutrient drink (ND). GA measured by IGP was quantitated as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation.
RESULTS: Mirtazapine significantly increased the bodyweight of subjects (67.8±3.7 to 69.1±3.7 kg; P=.01). Barostat results showed no effect on gastric compliance, sensitivity, and GA. Nutrient tolerance was not affected after treatment (1170±129.4 vs 1104±133.6 kcal; P=.4), and mirtazapine was associated with lower symptom ratings. The IGP drop during meal ingestion was significantly suppressed (area under the curve: -43.3±4.5 mm Hg vs -28.9±3.1 mm Hg; P=.005).
CONCLUSIONS: In HVs, the occurrence of weight gain and decreased meal-induced symptoms in spite of a suppressed meal-induced IGP drop, point towards a central mode of action. Mirtazapine does not display changes in gastric sensorimotor function that could explain its beneficial effects on symptoms and nutrient tolerance in FD.

Rapid gastric balloon distension to discomfort threshold activates the \"pain neuromatrix\" and deactivates exteroceptive sensory and \"default mode network\" regions. However, little is known about brain mechanisms underlying tolerance of meal-induced gastric distension. We aimed to directly compare brain responses to gradual balloon distension and intragastric nutrient infusion and to explore the role of differential gut peptide release in these responses.
Brain responses to balloon- and nutrient-induced distension (to individually titrated pain or maximal satiation threshold) were measured in 15 healthy volunteers using H215O-PET on 2 separate days in counterbalanced order. The effects of increasing gastric distension and plasma levels of ghrelin and peptide YY3-36 (PYY3-36) on neural activity were assessed.
Balloon distension progressively activated pain-responsive regions and deactivated exteroceptive sensory and \"default mode network\" areas. During nutrient infusion, \"pain neuromatrix\" regions and the orbitofrontal cortex were progressively deactivated, while the midbrain was activated. Plasma levels of PYY3-36 and ghrelin increased and decreased, respectively, during nutrient infusion only; decreasing ghrelin levels correlated with increasing midbrain activity.
Different brain responses to gastric balloon distension and intragastric nutrient infusion are associated with nutrient-induced gut-brain signals, particularly to the midbrain, where these signals may interfere with both descending pain modulatory and mesolimbic reward processes. Deactivation of the \"pain neuromatrix\" during nutrient infusion may constitute the neurophysiological mechanism underlying the tolerance of normal meal volumes in health without induction of (painful) symptoms. Nutrient-induced deactivation of the orbitofrontal cortex may represent a key interoceptive meal termination signal.

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.