The Stomach in Health and Disease
Altered motility and increased sensitivity to mechanical distention have been implicated in the generation of symptoms from the stomach, especially in patients with functional dyspepsia (FD) and gastroparesis.
The GI tract conveys information to the brain through mechanosensitive and nutrient sensing pathways and both may induce perception. Traditionally, sensing of the presence of nutrients is considered to be volumetric by the stomach and nutritive in the intestine. This concept implies a dominant role for mechanoreceptors in gastric nutrient sensing and no role for gastric chemosensing in food-related conscious perception.
On the other hand, the stomach is not totally devoid of chemosensing capacity: the presence of amino acids and peptones in the gastric lumen stimulates gastric acid secretion through enhanced gastrin release from G-cells, which express the pH-sensitive and peptone-activated calcium sensing receptor. To date, such a pathway has not been implicated in perception of gastric filling or the generation of satiation signals in man.
In the interdigestive state, upper GI motility is characterised by the recurrent contractility pattern of the migrating motor complex (MMC). Although well preserved throughout mammalian species, the role of the MMC has remained unclear. Recent observations have identified a role for gastric phase III of the MMC in signalling the return of hunger after meals. Surprisingly, in man, motilin rather than ghrelin was identified as the initiator of phase III and the associated increase in hunger. The clock or luminal sensing mechanism that controls release of motilin from the duodenum remains to be identified.
Gastric accommodation is a relaxation of the proximal stomach, triggered by the arrival of nutrients in the oropharynx, stomach or duodenum, which allows storage of the ingested meal (figure 1).
(Enlarge Image)
Figure 1.
Schematic outline of neural pathways and receptors involved in the control of the accommodation reflex in man. The identity of the nutrient sensors that trigger activation of the accommodation reflex and of other potentially involved neurotransmitters and receptors requires additional studies. CNS, central nervous system; cGMP, cyclic guanosine monophosphine; NO, nitric oxide; VIP, vasoactive intestinal peptide.
The classical concept that "gastric accommodation serves to prevent a rise in intra-gastric pressure (IGP) during food intake" was recently challenged. In studies in man, nutrient ingestion induces an initial drop in intra-gastric pressure (IGP), followed by gradual pressure recovery until maximal satiation (figure 2A). The drop in IGP is mediated by nitric oxide and contributes to gastric nutrient volume tolerance while the rise in IGP from nadir determines satiation. These changes are sensitive to a number of mechanical and pharmacological interventions, suggesting a potential target for therapeutic interventions aimed at controlling meal volume.
(Enlarge Image)
Figure 2.
(A) Example of intragastric pressure response and satiation score evolution during intragastric nutrient infusion. Nutrient infusion induces an initial drop in pressure, followed by gradual recovery associated with rising satiation scores. (B) Schematic conceptual model of gastric mechanoreceptors, relative to the muscular compartment. The four panels represent the modelled differential behaviour of 'in series' tension receptors and 'in parallel' elongation receptors during distension or contraction.
Historically, delayed gastric emptying has been considered the major mechanism underlying symptoms in FD and gastroparesis. Recent studies in diabetic and idiopathic gastroparesis showed a poor correlation of the pattern and severity of symptoms with the severity of delay in gastric emptying. This was confirmed in a recent integrated statistical analysis of prokinetic therapy trials in idiopathic and diabetic gastroparesis. Studies in both idiopathic and diabetic gastroparesis have identified other mechanisms, including visceral hypersensitivity and impaired gastric accommodation as stronger determinants of the symptom pattern and severity. However, a recent controlled trial targeting visceral hypersensitivity with nortriptyline in idiopathic gastroparesis also failed to demonstrate meaningful symptomatic benefit. Identification of the mechanoreceptors in the stomach whose inappropriate activation generates symptoms in disordered motility may unravel novel therapeutic targets for symptom control.
Gastric filling and the accompanying pressure changes are likely to play a major role in gastric satiation signalling and sensitivity to distention (figure 1). In humans, low-volume distension of the proximal stomach induces sensations of satiety and higher volume distention leads to discomfort, nausea and pain. Animal studies have shown that gastric distension triggers stretch-sensitive ('in parallel') as well as tension-sensitive ('in series') mechanoreceptors that convey information to the brain via vagal and splanchnic nerves. The response of different mechanoreceptors to distention or relaxation varies according to the type (figure 2B). Studies using isobaric and iso-volumetric distensions of the proximal stomach support the hypothesis that gastric mechanosensitivity in man relies mainly on tension-sensitive ('in series') mechanoreceptors. Hence, gastric smooth muscle relaxation is expected to decrease activation of these mechanoreceptors.
Based on the putative involvement of tension-sensitive mechanoreceptors, decreasing gastric smooth muscle tone may decrease symptoms induced by gastric filling, for instance, in patients with impaired gastric accommodation. Pharmacological studies in healthy volunteers identified the 5-HT1 receptor as a target for enhancing gastric relaxation (figure 1). This approach was evaluated in FD, showing a beneficial symptomatic effect of enhancing gastric accommodation by the anxiolytic 5-HT1A agonist buspirone in a pilot study and by tandospirone in a multicentre trial. In both studies, anxiolytic effects did not explain the symptomatic benefit on FD symptoms. Acotiamide is a combined muscarinic autoreceptor antagonist and cholinesterase inhibitor, which also targets impaired accommodation, among other mechanisms. In a phase III study in Japan, acotiamide was superior to placebo in improving functional dyspeptic symptoms, leading to approval for this indication in Japan. A phase III programme is ongoing in Europe.
In health and disease, transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying reflux events. TLESRs occur mainly during the postprandial period, triggered by gastric distension, which activates mechanoreceptors in the proximal stomach. Gastric accommodation is the physiological response to meal-induced gastric distention, and so its relation to TLESR and reflux events has been studied in health and in patients with GORD. Using IGP as a marker of gastric accommodation, a significant negative correlation was found between meal-induced accommodation and the occurrence of TLESRs and reflux events in the first postprandial hour, both in health and disease. This mechanistic observation suggests that accommodation and TLESRs are closely linked, probably through activation of tension-sensitive mechanoreceptors that also trigger TLESRs (figure 3). This may help explain the frequent overlap between dyspepsia and GORD. Moreover, treatment targeting impaired accommodation has the potential to be beneficial not only to FD but also to patients with GORD.
(Enlarge Image)
Figure 3.
Schematic outline of gastric events and their relationships in response to nutrient ingestion. TLESR, transient lower oesophageal sphincter relaxation.
The concept of gastric nutrient perception being exclusively mechanosensitive or volumetric is challenged by recent data. First, animal studies have shown the expression of taste receptors on ghrelin cells in the stomach, and bitter taste receptor agonists can alter ghrelin release, gastric motility and food intake in mice. Second, preliminary evidence in man shows that intragastric administration of a bitter taste receptor agonist inhibits the drop in IGP and the amount of food ingested until maximum satiation. Transient receptor potential channels are involved in luminal sensing and can influence gastric motility and nutrient tolerance in man. The identity and expression of gastric nutrient sensors in man requires further study, and the effect of activation or inhibition on gastric sensorimotor function may lead to novel therapeutic approaches.
Neurogastric Physiology
Altered motility and increased sensitivity to mechanical distention have been implicated in the generation of symptoms from the stomach, especially in patients with functional dyspepsia (FD) and gastroparesis.
Gastric Sensitivity
The GI tract conveys information to the brain through mechanosensitive and nutrient sensing pathways and both may induce perception. Traditionally, sensing of the presence of nutrients is considered to be volumetric by the stomach and nutritive in the intestine. This concept implies a dominant role for mechanoreceptors in gastric nutrient sensing and no role for gastric chemosensing in food-related conscious perception.
On the other hand, the stomach is not totally devoid of chemosensing capacity: the presence of amino acids and peptones in the gastric lumen stimulates gastric acid secretion through enhanced gastrin release from G-cells, which express the pH-sensitive and peptone-activated calcium sensing receptor. To date, such a pathway has not been implicated in perception of gastric filling or the generation of satiation signals in man.
Interdigestive Motility
In the interdigestive state, upper GI motility is characterised by the recurrent contractility pattern of the migrating motor complex (MMC). Although well preserved throughout mammalian species, the role of the MMC has remained unclear. Recent observations have identified a role for gastric phase III of the MMC in signalling the return of hunger after meals. Surprisingly, in man, motilin rather than ghrelin was identified as the initiator of phase III and the associated increase in hunger. The clock or luminal sensing mechanism that controls release of motilin from the duodenum remains to be identified.
Intragastric Pressure as a Measure of Gastric Accommodation
Gastric accommodation is a relaxation of the proximal stomach, triggered by the arrival of nutrients in the oropharynx, stomach or duodenum, which allows storage of the ingested meal (figure 1).
(Enlarge Image)
Figure 1.
Schematic outline of neural pathways and receptors involved in the control of the accommodation reflex in man. The identity of the nutrient sensors that trigger activation of the accommodation reflex and of other potentially involved neurotransmitters and receptors requires additional studies. CNS, central nervous system; cGMP, cyclic guanosine monophosphine; NO, nitric oxide; VIP, vasoactive intestinal peptide.
The classical concept that "gastric accommodation serves to prevent a rise in intra-gastric pressure (IGP) during food intake" was recently challenged. In studies in man, nutrient ingestion induces an initial drop in intra-gastric pressure (IGP), followed by gradual pressure recovery until maximal satiation (figure 2A). The drop in IGP is mediated by nitric oxide and contributes to gastric nutrient volume tolerance while the rise in IGP from nadir determines satiation. These changes are sensitive to a number of mechanical and pharmacological interventions, suggesting a potential target for therapeutic interventions aimed at controlling meal volume.
(Enlarge Image)
Figure 2.
(A) Example of intragastric pressure response and satiation score evolution during intragastric nutrient infusion. Nutrient infusion induces an initial drop in pressure, followed by gradual recovery associated with rising satiation scores. (B) Schematic conceptual model of gastric mechanoreceptors, relative to the muscular compartment. The four panels represent the modelled differential behaviour of 'in series' tension receptors and 'in parallel' elongation receptors during distension or contraction.
Role of Gastric Dysmotility as a Cause of Symptoms in Dyspepsia and Gastroparesis
Historically, delayed gastric emptying has been considered the major mechanism underlying symptoms in FD and gastroparesis. Recent studies in diabetic and idiopathic gastroparesis showed a poor correlation of the pattern and severity of symptoms with the severity of delay in gastric emptying. This was confirmed in a recent integrated statistical analysis of prokinetic therapy trials in idiopathic and diabetic gastroparesis. Studies in both idiopathic and diabetic gastroparesis have identified other mechanisms, including visceral hypersensitivity and impaired gastric accommodation as stronger determinants of the symptom pattern and severity. However, a recent controlled trial targeting visceral hypersensitivity with nortriptyline in idiopathic gastroparesis also failed to demonstrate meaningful symptomatic benefit. Identification of the mechanoreceptors in the stomach whose inappropriate activation generates symptoms in disordered motility may unravel novel therapeutic targets for symptom control.
Identity of Gastric Mechanoreceptors
Gastric filling and the accompanying pressure changes are likely to play a major role in gastric satiation signalling and sensitivity to distention (figure 1). In humans, low-volume distension of the proximal stomach induces sensations of satiety and higher volume distention leads to discomfort, nausea and pain. Animal studies have shown that gastric distension triggers stretch-sensitive ('in parallel') as well as tension-sensitive ('in series') mechanoreceptors that convey information to the brain via vagal and splanchnic nerves. The response of different mechanoreceptors to distention or relaxation varies according to the type (figure 2B). Studies using isobaric and iso-volumetric distensions of the proximal stomach support the hypothesis that gastric mechanosensitivity in man relies mainly on tension-sensitive ('in series') mechanoreceptors. Hence, gastric smooth muscle relaxation is expected to decrease activation of these mechanoreceptors.
Enhancing Accommodation in FD
Based on the putative involvement of tension-sensitive mechanoreceptors, decreasing gastric smooth muscle tone may decrease symptoms induced by gastric filling, for instance, in patients with impaired gastric accommodation. Pharmacological studies in healthy volunteers identified the 5-HT1 receptor as a target for enhancing gastric relaxation (figure 1). This approach was evaluated in FD, showing a beneficial symptomatic effect of enhancing gastric accommodation by the anxiolytic 5-HT1A agonist buspirone in a pilot study and by tandospirone in a multicentre trial. In both studies, anxiolytic effects did not explain the symptomatic benefit on FD symptoms. Acotiamide is a combined muscarinic autoreceptor antagonist and cholinesterase inhibitor, which also targets impaired accommodation, among other mechanisms. In a phase III study in Japan, acotiamide was superior to placebo in improving functional dyspeptic symptoms, leading to approval for this indication in Japan. A phase III programme is ongoing in Europe.
Role of Impaired Accommodation in the Overlap Between Dyspepsia and GORD
In health and disease, transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying reflux events. TLESRs occur mainly during the postprandial period, triggered by gastric distension, which activates mechanoreceptors in the proximal stomach. Gastric accommodation is the physiological response to meal-induced gastric distention, and so its relation to TLESR and reflux events has been studied in health and in patients with GORD. Using IGP as a marker of gastric accommodation, a significant negative correlation was found between meal-induced accommodation and the occurrence of TLESRs and reflux events in the first postprandial hour, both in health and disease. This mechanistic observation suggests that accommodation and TLESRs are closely linked, probably through activation of tension-sensitive mechanoreceptors that also trigger TLESRs (figure 3). This may help explain the frequent overlap between dyspepsia and GORD. Moreover, treatment targeting impaired accommodation has the potential to be beneficial not only to FD but also to patients with GORD.
(Enlarge Image)
Figure 3.
Schematic outline of gastric events and their relationships in response to nutrient ingestion. TLESR, transient lower oesophageal sphincter relaxation.
Emerging Role of Gastric Nutrient Sensing in the Perception of Gastric Filling and Control of Hunger and Satiation
The concept of gastric nutrient perception being exclusively mechanosensitive or volumetric is challenged by recent data. First, animal studies have shown the expression of taste receptors on ghrelin cells in the stomach, and bitter taste receptor agonists can alter ghrelin release, gastric motility and food intake in mice. Second, preliminary evidence in man shows that intragastric administration of a bitter taste receptor agonist inhibits the drop in IGP and the amount of food ingested until maximum satiation. Transient receptor potential channels are involved in luminal sensing and can influence gastric motility and nutrient tolerance in man. The identity and expression of gastric nutrient sensors in man requires further study, and the effect of activation or inhibition on gastric sensorimotor function may lead to novel therapeutic approaches.
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