• accommodation;
  • barostat;
  • functional dyspepsia;
  • prokinetic;
  • serotonin;


  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of gastric accommodation
  5. Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms
  6. Neuroregulation of the accommodation reflex and possible therapeutic targets
  7. References

Abstract  Functional dyspepsia (FD) is a highly prevalent gastrointestinal disorder and has a complex pathophysiology. Impaired fundic relaxation in response to a meal is present in 40% of patients with FD. This review focuses on impaired gastric accommodation of the stomach as a pathophysiological mechanism and the possible therapeutic targets that can be derived from the current knowledge of the neuroregulation of the accommodation reflex. First the different means of gastric accommodation assessment are described and the relationship between symptoms and impaired gastric accommodation. The different therapeutic options are subsequently discussed in view of their molecular target, based on the different receptor subtypes involved in the accommodation reflex. Although impaired gastric accommodation is highly prevalent in dyspeptic patients and basic knowledge about the accommodation reflex enables to develop pathophysiologically targeted therapies, it is unlikely that therapies aimed at dysaccommodation of the stomach will lead to symptom relief in all dyspeptic patients. A major challenge is the development of methods that readily identify impaired accommodation in clinical practice.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of gastric accommodation
  5. Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms
  6. Neuroregulation of the accommodation reflex and possible therapeutic targets
  7. References

According to international consensus, functional dyspepsia (FD) is defined as persistent or recurrent upper abdominal pain or discomfort in the absence of evidence of organic disease likely to explain the symptoms.1 The dyspeptic symptom complex comprises epigastric pain, bloating, early satiety, fullness, epigastric burning, belching, nausea and vomiting.

Several pathophysiological mechanisms have been described in patients with FD2,3 and include delayed gastric emptying, hypersensitivity to gastric distension, impaired gastric accommodation, Helicobacter pylori infection, altered duodenal response to acid or lipids, altered duodenojejunal motility and central nervous dysfunction. Although knowledge and insight into the different pathophysiological mechanisms involved in FD have increased over the last decades, management remains still difficult and sometimes disappointing. Moreover, certain apparently pathophysiologically based treatment options do not necessarily improve dyspeptic symptoms. For instance, treatment with ABT-229, a macrolide drug without antibiotic properties and strong gastroprokinetic activity, did not improve symptoms in FD patients with delayed gastric emptying.4

In the past, measuring gastric functions was mainly focused on assessing gastric emptying time. Over the last decade it has become clear that other pathophysiological mechanisms such as gastric/duodenal hypersensitivity and impaired postprandial fundic accommodation contribute to the dyspeptic symptom complex and pathophysiology of dyspepsia. This review will focus on the role of impaired gastric accommodation in FD and the currently available treatment options.

Measurement of gastric accommodation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of gastric accommodation
  5. Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms
  6. Neuroregulation of the accommodation reflex and possible therapeutic targets
  7. References

The role of the stomach in the digestion process is twofold. The proximal stomach serves mainly as a reservoir for ingested nutrients. In response to ingestion of a meal, the gastric tone of the proximal stomach decreases, resulting in an increased compliance and larger volume. This creates a storage capacity for the food before it is grinded and sieved by contraction in the distal stomach, and before coordinated release to the duodenum for further digestion. Different methods have been developed to measure gastric accommodation to a meal which can be basically divided into invasive and non-invasive methods5 (Table 1).

Table 1.   Different methods to assess gastric accommodation
Gastric barostatWell validated Current gold standard Also allows to measure gastric compliance and sensitivityInvasive, uncomfortable Non-physiologic
UltrasonographyNon-invasive No radiation burden Low cost and widely available Also allows to measure gastric emptyingUser-dependent Technical difficulties in some patients Measures volumes rather than tone
SPECTNon-invasive Several validation studiesRadiation burden Supine position Measures volumes rather than tone Expensive, limited availability
MRINon-invasive No radiation burdenExpensive, limited availability Supine position Measures volumes rather than tone Not well validated
ScintigraphyNon-invasive Also measures gastric emptyingRadiation burden Expensive, limited availability Not well validated
Drinking testSimple Low cost and widely availableNot well validated Limited reproducibility data

The intragastric barostat is regarded as the gold standard for the assessment of gastric accommodation.6,7 The barostat consists of a double-lumen polyvinyl tube with an adherent plastic bag with a maximum capacity of 1000–1200 ml.6–9 The finely folded bag is introduced through the mouth and positioned in the gastric fundus, which is usually checked fluoroscopically. The polyvinyl tube is connected to a barostat device which can deliver volume ramps or pressure steps at different rates.6 The barostat is currently the most extensively used and validated method to assess gastric accommodation.

Two- or three-dimensional abdominal ultrasound and magnetic resonance imaging (MRI) are two non-invasive radiological methods for the assessment of gastric accommodation. Conventional abdominal ultrasound can be used to estimate gastric volume by multiplying the proximal gastric area (measured by a section in a sagittal plane) and the proximal gastric diameter (measured by a section in an oblique plane). Gastric accommodation can be calculated by comparing pre- and postprandial volumes.9,10 The advantage of this technique is the non-invasive and inexpensive nature, and the potential for wide availability, in the absence of radiation burden. Moreover, simultaneous measurement of antral motility and gastric emptying is possible. The technique is however highly operator-dependent, and anatomical structures (e.g. ribs) and gas interposition may impair the assessment in certain individuals.

Recently, several novel tests have been proposed for the study of gastric accommodation, including scintigraphic analysis of meal distribution in the stomach and single-photon emission computed tomography (SPECT) of gastric volumes. It has been proposed that impaired accommodation of the proximal stomach is associated with distention of the antrum and redistribution of the meal to the distal stomach.11 Analysis of the distribution of a 99mTc pertechnate-labelled meal during gastric emptying tests provides an indirect measurement of gastric accommodation by calculating the intragastric distribution ratio. The latter is the ratio of radiolabel present in the proximal stomach to that present in the distal stomach.12 One methodological problem with this and other distribution-based techniques lies in the exact partition between distal and proximal stomach because of the lack of a consistent anatomical landmark and the low spatial resolution of the images.

Single-photon emission computed tomography imaging for assessing gastric accommodation is based on the principle that gastric mucosa can take up and excrete 99mTc-pertechnate after intravenous injection, and was first described in healthy volunteers as a non-invasive tool to measure gastric accommodation.13 Briefly, 20 mCi of 99mTc-pertechnate is injected i.v. and the assessment of gastric accommodation was performed with a SPECT gamma camera 30 min after the meal (10 orbit cycles). Stomach volumes are measured using specific software. The main advantage of this technique is its non-invasive character. Disadvantages are the cost, the radiation exposure and, compared with the barostat, the fact that gastric sensitivity cannot be measured simultaneously. Recently, it has been possible to decrease the radiation exposure of this technique by using a lower dose of 99mTc-pertechnate, while preserving high-quality images.14 Most recently, the possibility to combine SPECT imaging with scintigraphy was reported for the simultaneous assessment of gastric accommodation and gastric emptying for liquids and solids.15

Theoretically MRI scanning after a gadolinium-labelled meal could be useful to assess gastric accommodation. However, the technique has mainly been used to assess intragastric meal distribution and gastric emptying and has so far not been validated for the assessment of gastric accommodation.16,17 Moreover, MRI set-ups usually require the subject to be in a supine position, which is not the physiological postprandial position.

Finally, simple water load tests and satiety drinking tests were conducted for the assessment of gastric accommodation. Their proposed use is based on the assumption that impaired accommodation results in a limited gastric volume capacity, and that this is reflected in the maximum tolerated ingested volume. During the satiety drinking test, a peristaltic pump fills two beakers at a constant rate of 15–30 ml/min with a liquid meal, while subjects maintain oral intake at the filling rate. Delivery of nutrients by the pump, rather than drinking consecutive cups, helps to partially blind the subject to the nutrient volume that has been ingested. Satiation levels are scored at 5-min intervals. Tack et al. reported a good correlation between the maximum amount of calories ingested and gastric accommodation measured previously with a gastric barostat. There was no significant correlation with gastric emptying or gastric sensitivity to distension in the same multivariate analysis. Sensitivity and specificity of the test reached 92% and 86% respectively in predicting impaired accommodation, which was measured with a gastric barostat balloon on separate days.18 Previously, however, Boeckxstaens et al. did not find a good correlation between drinking capacity and gastric accommodation measured on a separate day with the gastric barostat in FD.19 It has been suggested that the difference in drinking rates (22.5 kcal/min in the former study, 150 kcal/min in the latter) underlies some of these discrepancies, as a slower drinking rate may be required to allow a full accommodation reflex.20 A major limitation in correlating the satiety drinking test and the gastric barostat is the difficulty in performing both tests simultaneously. In a study that combined scintigraphic imaging with a radiolabelled nutrient drinking test, proximal stomach filling showed the best correlation with satiety scores and with maximal tolerated volume.21 In a recent study, Gonenne et al. compared SPECT measurement of gastric volumes with the maximum tolerated volume in a nutrient drinking test at 45 kcal/min, and failed to find a good correlation between both.22 One of the limitations of satiety drinking tests for the evaluation or gastric volume capacity is the potential to be influenced by food-related subjective sensations (like taste or temperature) and psychological factors. In a recent study, Geeraerts et al. confirmed that experimentally induced anxiety was accompanied by increased satiety scores during a nutrient drinking test, but this was actually accompanied by a significant reduction in meal-induced accommodation.23

The water load test was also evaluated for the assessment of gastric accommodation in FD,19 but no significant difference in drinking capacity was found between dyspeptic patients with or without impaired accommodation and the test lacked reproducibility in another study.24 Hence, the water load test is currently not regarded as a surrogate test for gastric volume assessment.

Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of gastric accommodation
  5. Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms
  6. Neuroregulation of the accommodation reflex and possible therapeutic targets
  7. References

Several studies have demonstrated the occurrence of impaired gastric accommodation in FD. The prevalence of impaired accommodation varies around 40% of patients in tertiary referral centres (Table 2).

Table 2.   Correlation between dyspeptic symptoms and impaired gastric accommodation to a meal
StudynTechniquePrevalence (%)Symptom correlation
Tack et al.2340Barostat40Relevant or severe early satiety, weight loss
Kim et al.2432SPECT40Weight loss
Boeckxstaens et al.2544Barostat 5No correlation
Piessevaux et al.1240Scintigraphy50Relevant or severe early satiety
Bredenoord et al.31151SPECT43No correlation with presence of symptoms

Before the use of the barostat, abnormal food distribution in the stomach had already been established by scintigraphic and ultrasonographic studies.10,11,25,26 In patients with FD there is a preferential accumulation of food in the distal stomach, suggesting an impaired accommodation of the proximal stomach. The latter was confirmed in studies using the gastric barostat, showing a reduced fundic relaxation in response to a meal in patients with FD. In 40 consecutive patients with FD, we showed that impaired fundic relaxation was present in 40% of the patients. This was associated with symptoms of relevant (bothersome but not interfering with normal activity) or severe (interfering with normal activity) early satiety and weight loss. The relationship between impaired accommodation and relevant or severe early satiety was further supported by a correlation between the maximum amount of calories ingested at maximum satiety and the amplitude of the postprandial fundic relaxation.27 The prevalence of early satiety in the general US population was assessed by a telephonic survey in over 20 000 adults and was shown to be 23%.28 A number of other studies evaluated the prevalence of impaired gastric accommodation in patients with FD and the correlation with symptoms. Using SPECT imaging, Kim et al.29 found impaired accommodation in 40% of dyspeptic patients and this was correlated to weight loss; the symptom of early satiety was not assessed in this study. Scintigraphic assessment of intragastric food distribution also revealed a redistribution suggestive of impaired accommodation in 50% of the patients, and this was correlated to relevant or severe symptoms of early satiety.12 Seemingly conflicting data were obtained by Boeckxstaens et al.,30 who did not find a correlation between presence or severity of symptoms and impaired gastric accommodation. However in the latter study, and unlike most other studies, meal-induced gastric accommodation did not differ significantly between healthy volunteers and dyspeptic patients (183 ± 32 ml vs 157 ± 24 ml). Using the 10th percentile of the volume relaxation of healthy volunteers, impaired gastric accommodation was even less prevalent in dyspeptic patients in comparison to healthy volunteers. The absence of a difference in fundic relaxation between healthy volunteers and dyspeptic patients, which is likely to reflect a different subpopulation of dyspeptic patients, is therefore a major methodological drawback of this study when aiming at attributing symptoms to impaired gastric accommodation. Finally, measurements of gastric volumes with SPECT were reported in 214 patients with upper gastrointestinal symptoms, of which 151 had FD.31 The prevalence of impaired accommodation was 43%, but no correlation was found with the presence of symptoms based on a chart review. The severity of symptoms, which was correlated with symptoms in some previous studies,12,29 was not addressed.

The close correlation between impaired gastric accommodation and the severity of dyspeptic symptoms, especially early satiety, has been further investigated by experimental pharmacological interventions. Motilin receptor stimulation by motilin or erythromycin induces a contraction of the proximal stomach,32–34 which interferes with meal-induced accommodation when given at the time of meal ingestion. We showed that administration of erythromycin or motilin in healthy volunteers increases meal-induced satiety, which is reflected in decreased calorie intake.18,34 Relaxation of the proximal stomach can be induced via a vago-vagal pathway by distention of or presence of nutrients in the proximal gastrointestinal tract.35,36 This relaxation involves nitric oxide.37–39 Inhibition of nitric oxide synthase by NG-monomethyl-l-arginine (l-NMMA), impairs meal-induced fundic relaxation in healthy volunteers and is associated with early satiety.39 Finally, as mentioned above, experimentally induced anxiety in healthy subjects induced impaired accommodation and was accompanied by increased satiety scores during a nutrient drinking test.23 These additional studies give further support to the hypothesis that impaired accommodation is the mechanism generating the symptom of early satiety.

The exact site of symptom generation in patients with impaired accommodation is still a subject of controversy. Activation of tension receptors might occur in the proximal stomach when the latter is not relaxing in response to a meal. On the other hand, insufficient relaxation of the proximal stomach may force the ingested food into the distal stomach and cause distension and activation of mechanoreceptors in the distal stomach. Using a differential filling of a barostat balloon with air and water, Caldarella et al.40 studied the contribution of the proximal and distal stomach respectively. They found that the antrum is also more sensitive to distension in patients with FD, which was more pronounced after nutrient infusion into the duodenum. So overdistension of a hypersensitive antrum, secondary to an impaired gastric accommodation, may contribute to symptom perception in dyspeptic patients. In a recent study we used a double gastric barostat device to simultaneously monitor antral and fundic sensitivity to distension in healthy volunteers. We demonstrated that the distal and proximal stomach are both involved in the accommodation reflex to ingestion of a meal and that, at least in healthy volunteers, pressures needed to induce first perception or discomfort did not differ between the fundus and the antrum. Furthermore, distension of either site elicited a similar symptom pattern. However, because of the fact that the distal stomach is less compliant than the proximal stomach it is conceivable that distension of the distal stomach may generate more severe symptoms in response to the same volume distension, especially when proximal stomach relaxation is impaired.41

Neuroregulation of the accommodation reflex and possible therapeutic targets

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of gastric accommodation
  5. Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms
  6. Neuroregulation of the accommodation reflex and possible therapeutic targets
  7. References

Because of the high prevalence of gastric dysaccommodation and its potential contribution to symptom generation, the hypothesis that fundus-relaxing drugs may improve symptoms in dyspeptic patients with impaired accommodation is attractive. The neural regulation of the gastric accommodation reflex has been partially unraveled both from animal and human studies (Fig. 1). The current knowledge about different neurotransmitters and receptors that are involved, allows identifying and testing a number of possible therapeutic targets (Table 3). Gastric accommodation is a vago-vagal reflex that can be elicited by the presence of nutrients in the stomach or the duodenum, and by duodenal distension.35,36,42 The smooth muscle relaxation of the fundus involves activation of intrinsic inhibitory (nitrergic) motor neurones, presumably by acetylcholine acting on nicotinergic receptors or by serotonin (5-HT) acting on a 5-HT1-like receptor on inhibitory motor neurones.27,37–39,43


Figure 1.  Schematic overview of the accommodation reflex based on data from animals and humans. Ach, acetylcholine; 5-HT, 5-hydroxytryptamine (serotonin); NO, nitric oxide; CNS, central nervous system

Download figure to PowerPoint

Table 3.   Different therapeutic options in patients with impaired gastric accommodation based on the pharmacological target
Therapeutic targetTreatment optionEffectTolerance
5-HT1 receptorSumatriptanFundic relaxationVascular side effects on s.c. administration
No effect on intranasal application
BuspironeFundic relaxationDrowsiness
5-HT4 receptorTegaserodFundic relaxationDiarrhoea
CisaprideFundic relaxationDysrythmias
Alpha-2 receptorClonidineFundic relaxation via inhibition of ACH releaseDrowsiness, hypotension
cGMPNitratesFundic relaxation via direct effect on smooth muscles (induction of cGMP)Vascular side effects, headache
SildenafilFundic relaxation via direct effect on smooth muscles inhibition of cGMP breakdownVascular side effects

Acute pharmacological studies in healthy volunteers and patients have supported the data gained from the animals as to the involvement of nitrergic neurones and serotonergic receptors. Acute sublingual administration of glyceryl trinitrate improves meal-induced relaxation of the proximal stomach and reduces postprandial symptoms of pain and nausea in FD patients. However, the effect was short lasting (only 15 min) and prolonged used is usually associated with vascular side effects (hypotension and headache).44

One of the classical targets in nitric oxide signalling is soluble guanylate cyclase. Its basal activity, which is normally low, is increased even in the presence of very low levels of NO, hereby producing guanosine 3′,5′-cyclic monophosphate (cGMP), which has an inhibitory effect on smooth muscles. Sildenafil is an inhibitor of phosphodiesterase type 5, which normally catalyses the inactivation of cGMP, thereby enhancing the levels of cGMP and causing a smooth muscle relaxation in various organs.45 Pretreatment with 50 mg of sildenafil in healthy subjects before a meal resulted in a higher and prolonged gastric postprandial relaxation and had an effect on volume of first perception during barostat measurement.46 So, further studies to evaluate the effect of phosphodiesterase type 5 inhibitors on symptoms in patients with impaired accommodation seem warranted.

The involvement of serotonergic signalling in the accommodation reflex in humans is supported by several studies performed in healthy volunteers. Pretreatment with the serotonin re-uptake inhibitor (SSRI) paroxetine47 enhanced meal-induced gastric accommodation. The 5-HT receptor involved in humans has yet to be identified but experimental evidence in healthy volunteers supports a role for both 5-HT1 and 5-HT4 receptors. Pretreatment with the 5-HT4 receptor agonists cisapride (10 mg t.i.d.) or tegaserod (6 mg b.i.d.) significantly enhances postprandial fundic relaxation, indicating that 5-HT4 receptor activation may enhance the gastric accommodation reflex in man.8,48 Preliminary studies suggest that tegaserod may improve symptoms in FD patients with normal gastric emptying,49 and that tegaserod enhances gastric accommodation in this patient population.50

Similarly, subcutaneous administration of sumatriptan, a 5-HT1 receptor agonist, used in the treatment for migraine, relaxes the stomach in healthy subjects.51 In acute studies, sumatriptan could restore meal-induced gastric accommodation in patients with previously documented impaired accommodation and increase the total amount of calories that could be ingested at maximum satiety in patients with early satiety.27 As a result of the mode of administration (subcutaneous injection), cost and poor tolerability, sumatriptan is not suitable as a long-term treatment in FD. Sumatriptan is also available as a nasal spray. However, a placebocontrolled study in healthy volunteers failed to demonstrate a significant effect of intranasal administration of sumatriptan on proximal gastric motor function, probably because of a difference in bioavailability between subcutaneous and intranasal administration.52,53 Buspirone is a non-selective 5-HT1 agonist, normally used in the treatment of panic attacks, known to relax the proximal stomach.43 In a placebo-controlled study in patients with FD, buspirone was superior to placebo in ameliorating dyspeptic symptoms. This symptomatic relief was associated with an enhanced gastric accommodation to a meal.54 Another 5-HT1 agonist, R137696, was shown to induce a dose-dependent relaxation of the proximal stomach in healthy volunteers. However in a placebo controlled trial, there was no effect on symptoms, visceral hypersensitivity or gastric accommodatoion in patients with FD, suggesting desensitization.55,56

Studies of animals have shown that gastric tone is also modulated by the sympathetic nervous system. In particular, α2 adrenoreceptors located on presynaptic nerve terminals of enteric neurones modulate cholinergic input by inhibition of acetylcholine release.57,58 In human volunteers, clonidine, an α2 agonist, relaxes the stomach and reduces gastric sensation.59 Short-term subcutaneous administration of clonidine 0.5 mg was shown to reduce meal-induced symptoms in FD.60

Finally, a new prokinetic drug, itopride hydrochloride, with combined anti-acetylcholinesterasic and dopaminergic antagonist properties, looks promising for the treatment of dyspeptic patients. Open-label studies or comparative trials with mosapride or domperidone from Asia suggested theefficacy of this drug in patients with FD.61–63 In a recent phase 2 study, itopride at doses of 50–200 mg t.i.d. was superior to placebo in relieving FD symptoms;64 however, this could not be confirmed in a large phase 3 clinical trial. Although the drug has gastroprokinetic properties, its effect on gastric accommodation and sensitivity still needs to be unraveled.

In conclusion, the majority of studies confirm a high prevalence of impaired gastric accommodation to a meal in patients with FD. Observations in patients, as well as interventional studies in healthy volunteers are supportive of its role as a pathophysiological mechanism, in particular concerning symptoms of early satiety and weight loss. A number of potential therapeutic targets have been identified, but there are presently no established treatment options. Large multi-centre placebo-controlled trials to test new pharmacological targets based on the knowledge of neurological modulation of the gastric accommodation reflex are still lacking, and are mandatory to clarify the possible causal relationship between impaired gastric accommodation and symptom generation. Although the target seems attractive, it is conceivable that targeting a single pathophysiological mechanism will not provide symptom relief to all FD patients, because most of them present with multiple symptoms and have varying or even several underlying pathophysiological mechanisms. Therefore, although important and highly prevalent as pathophysiological mechanism, impaired gastric accommodation is unlikely to be the therapeutic nirvana for dyspeptic patients, in the absence of a method to readily identify those with impaired accommodation.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of gastric accommodation
  5. Impaired accommodation as a pathophysiological mechanism in FD and relation to dyspeptic symptoms
  6. Neuroregulation of the accommodation reflex and possible therapeutic targets
  7. References
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    Tack J, Delia T, Ligozio G et al. A phase II trial with tegaserod in functional dyspepsia patients with normal gastric emptying (abstr). Gastroenterology 2002; 120: A20.
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    Tack J, Coulie B, Wilmer A, Andrioli A, Janssens J. Effect of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000; 46: 46873.
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    Verplanken P, Levebvre R, Bogaert M. Pharmacological characterization of alpha adrenoreceptors in the rat gastric fundus. J Pharmacol Exp Ther 1984; 231: 40410.
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    Shenoy KT, Veenasree Leena KB. Efficacy and tolerability of itopride hydrochloride in patients with non-ulcer dyspepsia. J Indian Med Assoc 2003; 101: 3878.
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