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Influence of ghrelin on interdigestive gastrointestinal motility in humans

Background: Recent studies in animals have shown that ghrelin stimulates upper gastrointestinal motility through the vagus and enteric nervous system. The aim of the present study therefore was to simultaneously investigate the effect of administration of ghrelin on upper gastrointestinal motility and to elucidate its mode of action by measuring plasma levels of gastrointestinal hormones in humans. Materials and methods: Nine healthy volunteers (four males; aged 22–35 years) underwent combined antroduodenal manometry and proximal stomach barostat study on two separate occasions at least one week apart. Twenty minutes after the occurrence of phase III of the migrating motor complex (MMC), saline or ghrelin 40 μg was administered intravenously over 30 minutes in a double blind, randomised, crossover fashion. Ghrelin, motilin, pancreatic polypeptide, glucagon, and somatostatin were measured by radioimmunoassay in blood samples obtained at 15–30 minute intervals. The influence of ghrelin or saline on MMC phases, hormone levels, and intraballoon volume was compared using paired t test, ANOVA, and χ2 testing. Results: Spontaneous phase III occurred in all subjects, with a gastric origin in four. Administration of ghrelin induced a premature phase III (12 (3) minutes, p<0.001; gastric origin in nine, p<0.05), compared with saline (95 (13) minutes, gastric origin in two). Intraballoon volumes before infusion were similar (135 (13) v 119 (13) ml; NS) but ghrelin induced a longlasting decrease in intraballoon volume (184 (31) v 126 (21) ml in the first 60 minutes; p<0.05). Administration of ghrelin increased plasma levels of pancreatic polypeptide and ghrelin but motilin, somatostatin, and glucagon levels were not altered. Conclusions: In humans, administration of ghrelin induces a premature gastric phase III of the MMC, which is not mediated through release of motilin. This is accompanied by prolonged increased tone of the proximal stomach.

Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis.

Background : Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, is released from the stomach. Animal studies suggest that ghrelin stimulates gastrointestinal motor activity.

Effect of Erythromycin On Gastric-motility in Controls and in Diabetic Gastroparesis

The effect of three doses of erythromycin on interdigestive gastrointestinal motility and on plasma motilin levels was studied in healthy volunteers and patients with diabetic gastroparesis. Abnormalities of interdigestive motility were observed in 40% of the patients. In healthy volunteers, 40 mg erythromycin elicited a premature phase 3 that started in the stomach. In contrast to the spontaneous gastric phase 3, this erythromycin-induced phase 3 was not accompanied by a motilin peak. In patients with diabetic gastroparesis, 40 mg erythromycin induced a premature phase 3 in three patients, no response in one patient, and a burst of antral contractions in another patient. Doses of 200 and 350 mg erythromycin elicited a burst of antral phase-3-like contractions in both volunteers and patients, which was not accompanied by a motilin peak. This phase-3-like activity did not migrate to the small intestine and was not followed by a phase 1, but by a prolonged period of antral contractile activity. The number and amplitude of antral contractions after 200 or 350 mg erythromycin were significantly higher than after 40 mg. The motor patterns induced by different doses of erythromycin offer potential therapeutic applications.

Bitter taste receptors and α-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying

Ghrelin is a hunger hormone with gastroprokinetic properties but the factors controlling ghrelin secretion from the stomach are unknown. Bitter taste receptors (T2R) and the gustatory G proteins, α-gustducin (gust) and α-transducin, are expressed in the gut and are involved in the chemosensation of nutrients. This study aimed to investigate whether T2R-agonists affect (i) ghrelin release via α-gustducin and (ii) food intake and gastric emptying via the release of ghrelin. The mouse stomach contains two ghrelin cell populations: cells containing octanoyl and desoctanoyl ghrelin, which were colocalized with α-gustducin and α-transducin, and cells staining for desoctanoyl ghrelin. Gavage of T2R-agonists increased plasma octanoyl ghrelin levels in WT mice but the effect was partially blunted in gust−/− mice. Intragastric administration of T2R-agonists increased food intake during the first 30 min in WT but not in gust−/− and ghrelin receptor knockout mice. This increase was accompanied by an increase in the mRNA expression of agouti-related peptide in the hypothalamus of WT but not of gust−/− mice. The temporary increase in food intake was followed by a prolonged decrease (next 4 h), which correlated with an inhibition of gastric emptying. The delay in emptying, which was partially counteracted by ghrelin, was not mediated by cholecystokinin and GLP-1 but involved a direct inhibitory effect of T2R-agonists on gastric contractility. This study is unique in providing functional evidence that activation of bitter taste receptors stimulates ghrelin secretion. Modulation of endogenous ghrelin levels by tastants may provide novel therapeutic applications for the treatment of weight -and gastrointestinal motility disorders.

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

Aliment Pharmacol Ther 2011; 33: 880–894

Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces.

Background: Severe duodeno-gastro-oesophageal reflux (DGOR) is a risk factor for oesophagitis and Barrett’s oesophagus. Patients with non-erosive reflux disease (NERD) have a slight increase in DGOR. Patients with gastro-oesophageal reflux disease (GORD), who are taking proton pump inhibitors (PPIs), still have reflux but of weakly acidic pH and persistence of bile. In these two groups of patients, heartburn might be due to increased oesophageal mucosal permeability and dilated intercellular spaces (DIS). We aimed to assess whether experimental short exposure of the oesophageal mucosa to bile acids, in low concentrations (at acidic, weakly acidic and neutral conditions) can increase mucosal permeability and provoke DIS. Methods: Rabbit oesophageal mucosa was studied in diffusion and Ussing chambers. We assessed the effects of different solutions containing bile acids, applied to the mucosal side, on transepithelial electrical resistance (RT) and permeability to fluorescein. The diameter of intercellular spaces was assessed by using transmission electron microscopy. Results: Incubation of oesophageal mucosa with acidic solutions (pH 2.0) containing a range of bile acids (0.5–5 mmol/l) markedly decreased RT and increased mucosal permeability. Weakly acidic solutions (pH 5.0), and to some extent neutral solutions (pH 7.4), containing some bile acids also decreased RT and increased permeability, although the effects were much less marked and in some combinations no effect was seen. Exposure to bile acids provoked DIS in acid and weakly acidic conditions but not in neutral (pH 7.4) solutions. Conclusions: Experimental short exposure of the oesophageal mucosa to solutions with a bile acid concentration and acidity similar to that observed in the gastric contents of patients with NERD or ERD, and who are taking PPIs, may impair oesophageal mucosal integrity and even induce dilated intercellular spaces. Such a situation could, theoretically, underlie the occurrence and/or persistence of symptoms in these patients.

Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro

Background and aims: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (GHRP-6)) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. Methods: In vivo, the dose dependent effects (1–150 nmol/kg) of ghrelin, GHRP-6, and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (l-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 µM) on electrical field stimulation (EFS) induced responses was studied in fundic strips in the absence and presence of L-NAME. Results: Ghrelin, GHRP-6, and capromorelin accelerated gastric emptying in an equipotent manner, with bell-shaped dose-response relationships. In the presence of atropine or l-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned EFS induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6, and capromorelin. Conclusion: The 14C octanoic breath test is a valuable technique to evaluate drug induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.

Taste receptors of the gut: emerging roles in health and disease

Recent progress in unravelling the nutrient-sensing mechanisms in the taste buds of the tongue has triggered studies on the existence and role of chemosensory cells in the gut. Indeed, the gastrointestinal tract is the key interface between food and the human body and can sense basic tastes in much the same way as the tongue, through the use of similar G-protein-coupled taste receptors. These receptors ‘taste’ the luminal content and transmit signals that regulate nutrient transporter expression and nutrient uptake, and also the release of gut hormones and neurotransmitters involved in the regulation of energy and glucose homeostasis. Hence, they play a prominent role in the communication between the lumen, epithelium, smooth muscle cells, afferent nerve fibres and the brain to trigger adaptive responses that affect gastrointestinal function, food intake and glucose metabolism. This review summarises how sensing of nutrients by taste receptors along the gut plays a key role in the process of digestion, and how disturbances or adaptations of these chemosensory signalling pathways may contribute to the induction or resolution of a number of pathological conditions related to diabetes, obesity, or diet-induced symptom generation in irritable bowel syndrome. Targeting these receptors may represent a promising novel route for the treatment of a number of these diseases.

Nutrient sensing in the gut: new roads to therapeutics?

The release of gut hormones involved in the control of food intake is dependent on the acute nutritional status of the body, suggesting that chemosensory mechanisms are involved in the control of their release. G protein-coupled taste receptors similar to those in the lingual system, that respond to sweet, bitter, umami, and fatty acids, are expressed in endocrine cells within the gut mucosa, and coordinate, together with other chemosensory signaling elements, the release of hormones that regulate energy and glucose homeostasis. In health, these nutrient sensors are likely to function as inhibitors to excessive nutrient exposure, and their malfunction may be responsible for a variety of metabolic dysfunctions associated with obesity; they may thus be considered as new therapeutic targets.

Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus

Motilin, a 22-amino acid gastrointestinal peptide, and ghrelin, the natural ligand of the growth hormone secretagogue receptor, form a new group of structurally related peptides. Several lines of evidence suggest that motilin and ghrelin are involved in the control of gastrointestinal motility by the activation of receptors on enteric neurons. The aim of this study was to look for the existence of motilin, ghrelin, and their respective receptors in the myenteric plexus of the guinea pig. We used longitudinal muscle/myenteric plexus (LMMP) preparations and cultures of myenteric neurons of the guinea pig ileum, immunohistochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR). Most of the motilin-immunoreactive (IR; 72.8%) and motilin receptor-IR (68.9%) neurons were also positive for neuronal nitric oxide synthase (nNOS), 72.8% and 68.9%, few for choline acetyl transferase (ChAT), 11.4% and 11.9%, respectively. In contrast, ghrelin was mainly colocalized with ChAT (72.2%), and only 3.6% of ghrelin-positive cells showed nNOS-IR in the LMMP. Neither motilin nor the motilin receptor or ghrelin colocalized with calbindin. RT-PCR studies revealed motilin, ghrelin, and ghrelin receptor mRNA transcripts in LMMP preparations and in cultured myenteric neurons. In conclusion, this study, for the first time, provides direct evidence for the existence of motilin and ghrelin in myenteric neurons and suggests that both peptides may play a role in the activation of the enteric nervous system and hence in the regulation of gastrointestinal motility.