Influence of ghrelin on the gastric accommodation reflex and on meal-induced satiety in man

Abstract  Ghrelin increases gastric tone in the fasting state and enhances gastric emptying in gastroparesis. The aims of the study were to evaluate the effect of ghrelin on postprandial gastric tone and on meal-induced satiety in health. Ten healthy volunteers underwent a barostat study on two occasions. After determination of intra-abdominal pressure (minimal distending pressure, MDP), isobaric volume measurement was performed for 90 min at MDP + 2 mmHg. After 20 min, ghrelin (40 μg) or saline was administered i.v. over 30 min in a double-blind-randomized cross-over design, followed 10 min later by a liquid meal (200 mL, 300 kcal). Stepwise isobaric distentions (+2 mmHg per 2 min) were performed 60 min after the meal. Data (mean ± SEM) were compared using paired Student's t -test and anova . Separately, a satiety drinking test (15 mL min⁻¹ until satiety score 5) was performed on 10 subjects twice, after treatment with placebo or ghrelin. Ghrelin infusion significantly inhibited gastric accommodation (mean volume increase adjusted means 108.0 ± 50 vs 23.0 ± 49 mL, P  = 0.03, ancova with the premeal postinfusion volume as covariate) and reduced postprandial gastric volumes (197.2 ± 24.6 vs 353.5 ± 50.0 mL, P  = 0.01). Pressures inducing perception or discomfort during postprandial gastric distentions were not altered. During satiety testing, ghrelin did not alter nutrient volume ingested till maximal satiety (637.5 ± 70.9 vs 637.5 ± 56.2 mL, ns). Ghrelin administered during the meal significantly inhibits gastric accommodation in health, but this is not associated with early satiation.     

Cannabinoid receptor 1 signalling dampens activity and mitochondrial transport in networks of enteric neurones

Abstract Cannabinoid (CB) receptors are expressed in the enteric nervous system (ENS) and CB₁ receptor activity slows down motility and delays gastric emptying. This receptor system has become an important target for GI‐related drug development such as in obesity treatment. The aim of the study was to investigate how CB₁ ligands and antagonists affect ongoing activity in enteric neurone networks, modulate synaptic vesicle cycling and influence mitochondrial transport in nerve processes. Primary cultures of guinea‐pig myenteric neurones were loaded with different fluorescent markers: Fluo‐4 to measure network activity, FM1‐43 to image synaptic vesicles and Mitotracker green to label mitochondria. Synaptic vesicle cluster density was assessed by immunohistochemistry and expression of CB₁ receptors was confirmed by RT‐PCR. Spontaneous network activity, displayed by both excitatory and inhibitory neurones, was significantly increased by CB₁ receptor antagonists (AM‐251 and SR141716), abolished by CB₁ activation (methanandamide, mAEA) and reduced by two different inhibitors (arachidonylamide serotonin, AA‐5HT and URB597) of fatty acid amide hydrolase. Antagonists reduced the number of synaptic vesicles that were recycled during an electrical stimulus. CB₁ agonists (mAEA and WIN55,212) reduced and antagonists enhanced the fraction of transported mitochondria in enteric nerve fibres. We found immunohistochemical evidence for an enhancement of synaptophysin‐positive release sites with SR141716, while WIN55,212 caused a reduction. The opposite effects of agonists and antagonists suggest that enteric nerve signalling is under the permanent control of CB₁ receptor activity. Using inhibitors of the endocannabinoid degrading enzyme, we were able to show there is endogenous production of a CB ligand in the ENS.     

Immune dysfunction in patients with functional gastrointestinal disorders

Abstract There is increasing evidence for involvement of the immune system in functional gastrointestinal disorder (FGID), including onset after acute gastrointestinal infections, genotypes resulting in altered cytokine expression and abnormal presence of immune cells. Our aim was to assess cellular and humoral immune responses in (i) FGIDs, compared to healthy subjects and (ii) acute vs unspecified onset FGIDs. Lymphocytic [interleukin (IL)‐5, IL‐10, IL‐13 and interferon γ (IFN‐γ)] and monocytic [IL‐10, IL‐12, tumour necrosis factor (TNF)‐α] cytokine production was characterized at baseline and after stimulation with phytohemagglutinine and anti‐CD28 or lipopolysaccharide (LPS) in controls (n = 32), irritable bowel syndrome (IBS) (n = 30), functional dyspepsia (FD) (n = 23) and non‐cardiac chest pain (NCCP) (n = 15). Serum IL‐6 and IL‐10 concentrations were compared, and the immunophenotype was assessed using fluorescent‐activated cell sorter. Findings were compared for acute vs unspecified onset FGID. Compared to controls, stimulated lymphocyte expression of IL‐5 and IL‐13 was enhanced in IBS, FD and NCCP (all P < 0.05). Conversely, the stimulated monocytic IL‐12 and lymphocytic IL‐10 expression were reduced in IBS and FD, while IFN‐γ expression was also reduced in FD patients. Except for an increase in the numbers of CD3⁺CD45RA⁺CD45RO⁺ cells, no distinct cellular profile was detected. Patients with a presumed acute onset of their symptoms had higher serum IL‐10 levels and more CD3⁺CD45RA⁺CD45RO⁺ cells, while TNF‐α levels following stimulation with LPS were higher in FD patients reporting an acute onset. A shift towards a Th2 cytokine profile is present in FGID, while the cellular immunophenotype remains largely unchanged. Further research is indicated and could provide new therapeutic strategies for these disorders.     

Oesophageal tone and sensation in the transition zone between proximal striated and distal smooth muscle oesophagus

Abstract  Previous studies have shown that the proximal striated muscle oesophagus is less compliant and more sensitive than the distal smooth muscle oesophagus. Conventional and high resolution manometry described a transition zone between striated and smooth muscle oesophagus. We aimed to evaluate oesophageal tone and sensitivity at the transition zone of oesophagus in healthy volunteers. In 18 subjects (seven men, mean age: 28 years) an oesophageal barostat study was performed. Tone and sensitivity were assessed using stepwise isobaric distensions with the balloon located at transition zone and at distal oesophagus in random order. To study the effect induced on transition zone by a previous distension at the distal oesophagus and vice versa, identical protocol was repeated after 7 days with inverted order. Initial distension of a region is referred to as 'naïf' distension and distension of a region following the distension of the other segment as 'primed' distension. Assessment of three oesophageal symptoms (chest pain, heartburn and 'other') was obtained at the end of every distension step. Compliance was significantly higher in the transition zone than in the distal oesophagus (1.47 ± 0.14 vs 1.09 ± 0.09 mL mmHg⁻¹, P  = 0.03) after 'naif' distensions. This difference was not observed during 'primed' distensions. Higher sensitivity at transition zone level was found in 11/18 (61%) subjects compared to 6/18 (33%, P  < 0.05) at smooth muscle oesophagus. Chest pain and 'other' symptom were more often induced by distention of the transition zone, whereas heartburn was equally triggered by distension of either region. The transition zone is more complaint and more sensitive than smooth muscle oesophagus.     

Cortical deactivations during gastric fundus distension in health: visceral pain‐specific response or attenuation of ‘default mode’ brain function? A H215O‐PET study

Abstract Gastric distension activates a cerebral network including brainstem, thalamus, insula, perigenual anterior cingulate, cerebellum, ventrolateral prefrontal cortex and potentially somatosensory regions. Cortical deactivations during gastric distension have hardly been reported. To describe brain areas of decreased activity during gastric fundus distension compared to baseline, using data from our previously published study (Gastroenterology, 128, 2005 and 564). H₂¹⁵O‐brain positron emission tomography was performed in 11 healthy volunteers during five conditions (random order): (C₁) no distension (baseline); isobaric distension to individual thresholds for (C₂) first, (C₃) marked, (C₄) unpleasant sensation and (C₅) sham distension. Subtraction analyses were performed (in SPM2) to determine deactivated areas during distension compared to baseline, with a threshold of P_{uncorrected_voxel_level} < 0.001 and P_{corrected_cluster_level} < 0.05. Baseline–maximal distension (C₁–C₄) yielded significant deactivations in: (i) bilateral occipital, lateral parietal and temporal cortex as well as medial parietal lobe (posterior cingulate and precuneus) and medial temporal lobe (hippocampus and amygdala), (ii) right dorsolateral and dorso‐ and ventromedial PFC, (iii) left subgenual ACC and bilateral caudate head. Intragastric pressure and epigastric sensation score correlated negatively with brain activity in similar regions. The right hippocampus/amygdala deactivation was specific to sham. Gastric fundus distension in health is associated with extensive cortical deactivations, besides the activations described before. Whether this represents task‐independent suspension of ‘default mode’ activity (as described in various cognitive tasks) or an visceral pain/interoception‐specific process remains to be elucidated.     

Assessment of gastric sensorimotor function in paediatric patients with unexplained dyspeptic symptoms and poor weight gain

Recent studies indicate that impaired meal accommodation or hypersensitivity to distention are highly prevalent in adult functional dyspepsia (FD). Our aim was to investigate whether similar abnormalities also occur in paediatric FD. Sixteen FD patients (15 girls, 10-16 years) were studied. The severity (0-3; 0, absent; 3, severe) of eight dyspeptic symptoms (epigastric pain, fullness, bloating, early satiety, nausea, vomiting, belching and epigastric burning) and the amount of weight loss were determined by questionnaire. All children underwent a gastric barostat study after an overnight fast to determine sensitivity to distention and meal-induced accommodation, which were compared with normal values in young adults (18-22 years). On a separate day, all patients underwent a gastric emptying breath test. A mean weight loss of 4.8 +/- 0.9 kg was present in 14 children. Compared with controls, patients had lower discomfort thresholds to gastric distention (8.8 +/- 1.0 mmHg vs 13.9 +/- 1.9 mmHg, P < 0.02) and gastric accommodation (87 +/- 25 mL vs 154 +/- 20 mL P < 0.04). Hypersensitivity to distention and impaired accommodation were present in respectively nine (56%) and 11 (69%) patients. No relationship was found between barostat and gastric emptying, which was delayed in only three patients. The majority of children with unexplained epigastric symptoms have abnormalities of gastric sensorimotor function.     

The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers

As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteers.     

Symptom pattern and pathophysiological correlates of weight loss in tertiary-referred functional dyspepsia

Abstract  In patients with gastrointestinal symptoms, weight loss is an alarm symptom, indicative of organic disease. Recent studies reported weight loss in subsets of functional dyspepsia (FD) patients. The aim of this study was to analyse symptom patterns associated with weight loss in tertiary care FD. Six hundred and thirty-six FD patients (67% female, mean age 43 years) completed a dyspepsia questionnaire, and underwent gastric emptying and gastric barostat studies. After identifying independent symptom domains through orthogonal factor analysis, patients were clustered on the basis of symptom profile. Clusters were compared in terms of their association with weight loss and gastric emptying or sensorimotor function. Weight loss (4.2 kg on average) correlated most strongly with early satiety followed by nausea and vomiting ( ρ respectively 0.38, 0.28 and 0.23, all P  < 0.0001). Factor analysis revealed three factors: Factor 1 characterized by nausea, vomiting and early satiety; factor 2 by early satiety, postprandial fullness and bloating; and factor 3 by pain, epigastric burning and belching. Subsequent cluster analysis revealed six patient clusters. The most severe cluster, which loaded high on all three factors, and a cluster dominated factor 2 were associated with the highest average weight loss (6.8 and 8.0 kg, respectively). The former cluster was also characterized by visceral hypersensitivity and delayed gastric emptying. The lowest weight loss occurred in the two clusters that had depressed scores for both early satiety associated factors (2.4 and 2.5 kg, respectively). In tertiary care FD, weight loss is strongly associated with two early satiety associated symptom clusters.     

Influence of abuse history on gastric sensorimotor function in functional dyspepsia

Abstract  Patients with functional gastrointestinal disorders have elevated rates of sexual or physical abuse, which may be associated with altered rectal sensorimotor function in irritable bowel syndrome. The aim was to study the association between abuse history and gastric sensorimotor function in functional dyspepsia (FD). We studied gastric sensorimotor function with barostat (sensitivity, compliance and accommodation) and gastric emptying test in 233 consecutive FD patients from a tertiary care centre (162 women, mean age 41.6 ± 0.9). Patients filled out self-report questionnaires on history of sexual and physical abuse during childhood or adulthood. Eighty-four patients (out of 198, 42.4%) reported an overall history of abuse [sexual and physical in respectively 30.0% (60/200) and 20.3% (42/207)]. FD patients reporting general as well as severe childhood sexual abuse have significantly lower discomfort thresholds during gastric distension [respectively 10.5 ± 0.4 vs 7.5 ± 1.0 mmHg above minimal distending pressure (MDP), P  = 0.014 and 10.5 ± 0.4 vs 6.6 ± 1.2 mmHg above MDP, P  = 0.007]. The corresponding intra-balloon volume was also significantly lower (respectively 579 ± 21 vs 422 ± 59 mL, P  = 0.013 and 579 ± 19 vs 423 ± 79 mL, P  = 0.033). Gastric accommodation was significantly more pronounced in patients reporting rape during adulthood (91 ± 12 vs 130 ± 40 mL, P  = 0.016). Abuse history was not associated with differences in gastric emptying. A history of abuse is associated with alterations in gastric sensorimotor function in FD. Particularly sexual abuse, rather than physical abuse, may influence gastric sensitivity and motor function.