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Gastroduodenal motility

Tack, Jan; Janssen, Pieter

Current Opinion in Gastroenterology: November 2010 - Volume 26 - Issue 6 - p 647–655
doi: 10.1097/MOG.0b013e32833ece1e
Stomach and duodenum: Edited by Mitchell L. Schubert

Purpose of review Abnormalities of gastroduodenal motility are considered key players in the pathogenesis of upper gastrointestinal symptoms in disorders such as functional dyspepsia and gastroparesis. Abnormalities of sensory control are considered another important factor that contributes to symptom generation. This review summarizes recent progress in our understanding of gastroduodenal motility and sensitivity in health and in disease.

Recent findings Although gastric and small intestinal motility remain an important focus of research, including the application of the SmartPill (SmartPill Corp., Buffalo, New York, USA) wireless motility monitoring capsule, duodenal sensitivity and low-grade duodenal inflammation are new areas of interest in the pathogenesis of functional dyspepsia. A number of genetic polymorphisms associated with functional dyspepsia are being investigated, but large-scale studies are still lacking. Central processing of visceral stimuli, and its role in the pathogenesis of functional dyspepsia, is another important emerging topic. Therapeutic studies have reported on novel pharmacological approaches in functional dyspepsia and gastroparesis, as well as gastric electrical stimulation in the treatment of refractory gastroparesis.

Summary There is gradual progress in our understanding of the pathogenesis of gastroduodenal symptoms. Areas of recent advances including the recognition of low-grade duodenal inflammation, the role of central nervous system processing in visceral hypersensitivity and the exploration of novel pharmacotherapeutic approaches.

Translational Research Center for Gastrointestinal Diseases (TARGID), University of Leuven, Leuven, Belgium

Correspondence to Jan Tack, Translational Research Center for Gastrointestinal Diseases (TARGID), University of Leuven, University Hospital Gasthuisberg, O&N I – bus 701, Herestraat 49, B-3000 Leuven, Belgium Tel: +32 16 34 42 25; fax: +32 16 34 44 19; e-mail:

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Functional dyspepsia and gastroparesis are two highly prevalent conditions [1]. Based on Rome III criteria, functional dyspepsia is defined as the presence of symptoms thought to originate in the gastroduodenal region (early satiation, postprandial fullness, epigastric pain or burning), in the absence of any organic, systemic or metabolic disease that is likely to explain the symptoms [2]. Gastroparesis is diagnosed in case of severely delayed gastric emptying in the absence of mechanical obstruction and can be caused by a variety of gastrointestinal and systemic causes including diabetic, idiopathic, and postsurgical. The underlying pathophysiology and optimal treatment approach to functional dyspepsia and gastroparesis remain largely unclear [1]. Nevertheless, abnormalities of gastric sensory and motor function are considered key players in symptom generation in functional dyspepsia and gastroparesis. This review summarizes progress in our understanding of gastric sensorimotor function that appeared in the literature since January 2009.

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Using the medical records system of Olmsted County, Minnesota, the age-adjusted prevalence of gastroparesis was estimated at 9.6 and 37.8 per 100 000 person-years for men and women, respectively. Overall survival was significantly lower than the age-specific and sex-specific expected survival for the Minnesota population [3]. Functional dyspepsia is also a truly chronic condition. In a 10-year prospective follow-up study in a random sample of the Icelandic population, functional dyspepsia remained stable over the 10-year period, but there was some turnover in symptoms and increased intensity and frequency of gastrointestinal pain over time. Taking into account medical care seeking and persistence over time, it is clear that functional dyspepsia continues to pose a heavy burden on the healthcare system [4].

Based on the Rome III definition, functional dyspepsia is further subdivided into two new diagnostic categories of meal-induced dyspeptic symptoms [postprandial distress syndrome (PDS), characterized by postprandial fullness and early satiation] and epigastric pain syndrome (EPS, characterized by epigastric pain and burning) [2]. A number of recent studies have investigated the validity of the proposed distinction between EPS and PDS in the general population and in patient samples.

In a population-based study of dyspeptic symptoms in the Belgian general population, significant dyspeptic symptoms were found in 21%. Factor analysis revealed three or four factors reminiscent of EPS, PDS, nausea/vomiting, and potentially belching [5]. These observations support the Rome III subdivision of functional dyspepsia and the separation of nausea/vomiting and belching disorders. A population-based questionnaire and endoscopy study in Scandinavia also provided support to the Rome III subclassification: functional dyspepsia was found in 15.7% of the population. The sample could be subdivided into EPS and PDS, and major anxiety was associated with PDS but not EPS [6•]. In a population-based questionnaire and endoscopy study in Italy, 11% were found to have functional dyspepsia, again with a good separation between EPS and PDS. Smoking was associated with PDS, whereas unemployment, divorce, and IBS were associated with both EPS and PDS [7•].

In 364 consecutive functional dyspepsia patients in Japan, considerable overlap (55%) between EPS and PDS was observed. Moreover, a number of patients could not be classified as functional dyspepsia according to Rome III because the onset of their symptoms was less than 6 months earlier [8]. The authors propose to use shorter duration criteria for application of the Rome III definitions in Japan.

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Control of gastroduodenal sensorimotor function in humans

The control of human gastroduodenal sensorimotor function is only partially understood. One of the reasons is the limited number of pharmacological tools that can be used to specifically block or stimulate neural receptors in humans. The role of serotonin (5-HT) in the control of gastrointestinal functions is particularly difficult to study, due to the large number of receptors that are expressed in the gastrointestinal tract and the lack of specific antagonists. After intravenous administration of the selective serotonin reuptake inhibitor citalopram, which enhances the actions of 5-HT, antral and intestinal motility were enhanced, and small intestinal phase 3 was stimulated, whereas gastric phase 3 was suppressed.

These data suggest that 5-HT is involved in the generation of intestinal phase 3 [9].

The involvement of endocannabinoids in the control of gastric sensorimotor function was studied using the endocannabinoid CB1 receptor antagonist rimonabant versus placebo in healthy controls. Administration of rimonabant did not alter gastric sensitivity to distension, but inhibited meal-induced gastric relaxation. These observations suggest involvement of endocannabinoids in the gastric accommodation reflex [10•].

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Assessment of gastric sensory and motor function

A number of tests to evaluate gastric neuromuscular function are available, including measures of gastric emptying, contractility, electrical activity, regional motility of fundus, antrum or pylorus, and tests of gastric sensitivity and compliance [11,12]. The correlation of abnormalities in these tests and the symptom pattern has been poor and inconsistent, and improving the techniques to measure gastric sensorimotor function, their application or interpretation, is an ongoing area of intense research.

Scintigraphy and the 13C-octanoic acid breath test are both well accepted and commonly applied to assess gastric emptying rate. Traditionally, emptying of solids is considered the most sensitive and reliable indicator of impaired gastric motor function, and liquid emptying is less well studied. In a study of 40 patients with symptoms suggestive of gastroparesis, solid and liquid emptying were measured by scintigraphy. The authors found that solid emptying was delayed in 25% and liquid emptying was delayed in 33%, with an overlap of only 8% [13]. The authors conclude that adding liquid emptying enhances the diagnostic yield of a gastric emptying study. Nevertheless, the relevance of delayed emptying to explanation of symptoms and therapeutic choices still needs to be established.

The SmartPill (SmartPill Corp., Buffalo, New York, USA) is a recently developed nondigestible capsule that records luminal pH, temperature, and pressure during transit through the gastrointestinal tract, and these data are transmitted to an ambulatory data recorder. The device, therefore, provides a measure of gastric emptying time, small bowel transit time, and whole gut transit time. Gastric emptying times and whole gut transit times measured with the capsule in healthy volunteers correlate well with scintigraphic measurement of the same parameters [14]. In a US multicentre study, the antral and duodenal motor patterns prior to and following gastric emptying, as assessed by the SmartPill capsule, were compared between 71 healthy controls and 42 gastroparetic patients. The number of contractions and the motility index were significantly lower in gastroparesis. The differences were significant in diabetic gastroparesis and less pronounced in idiopathic gastroparesis [15]. These observations confirm the ability of the SmartPill capsule to detect abnormalities in upper gastrointestinal motility profiles.

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Putative pathophysiological mechanisms and symptom generation

Although the number of putative pathophysiological mechanisms that may contribute to the generation of symptoms in functional dyspepsia and gastroparesis is large, the exact contribution of each of these is a matter of controversy. The main mechanisms include abnormalities of gastroduodenal motor function, visceral hypersensitivity, increased duodenal acid exposure, altered secretion of gastrointestinal hormones, postinfectious and low-grade inflammatory states, autonomic nerve dysfunction, and genetic predisposition.

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Abnormalities of gastroduodenal motility

Mainly based on studies in idiopathic gastroparesis and using patient recall of symptoms, severely delayed emptying has been associated with symptoms of postprandial fullness, nausea, and vomiting, but the association is rather poor. In order to improve the association between emptying rate and symptoms, symptoms were assessed during and after the meal in 388 patients who underwent a gastric emptying study. In those with delayed emptying, higher symptom scores were obtained for postprandial fullness, bloating, and epigastric pain. Symptoms correlated well with the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) questionnaire, which evaluated symptoms based on recall, suggesting that simultaneous symptom assessment with the test meal does not yield superior associations with gastric emptying rate [16].

In a study in 161 consecutive functional dyspepsia patients from Leuven, the relationship between PAGI-SYM scores and gastric sensorimotor function was assessed. Gastric emptying rate contributed significantly to the severity of the PAGI-SYM and several of its subscales. In multivariate analysis, no significant correlations were found for sensitivity to gastric distension, gastric accommodation or Helicobacter pylori status. These observations suggest that the PAGI-SYM may be especially useful in assessing the influence of gastroprokinetic drugs on dyspeptic symptoms [17].

In a prospective study of 68 gastroparesis patients, gastric emptying scintigraphy, quality-of-life scales, and symptom questionnaires for gastroparesis symptoms and abdominal pain were obtained. Abdominal pain was found in 90% of patients, often induced by meal ingestion. Abdominal pain ratings were comparable to those for vomiting and nausea. Pain intensity ratings did not correlate with gastric emptying rate, but had an impact on quality of life [18]. These observations identify pain as a significant symptom in gastroparesis.

Delayed gastric emptying is a frequent finding in diabetic patients, and this has been attributed to diabetes-induced disruption of the interstitial cells of Cajal (ICC) network, causing gastric dysrhythmias and impaired motor coordination. On the contrary, hyperglycaemia by itself is also able to affect ICC function. In a study that used endoscopically placed electrodes to map gastric electrical rhythm in healthy volunteers, hyperglycaemic clamping induced uncoupling and isolated tachygastrias, mainly confined to the distal stomach [19].

In a study in 31 functional dyspepsia patients, symptom pattern, electrogastrography and antoduodenal motility were studied. Abnormal motor function could be demonstrated in the vast majority of patients, by electrogastrography (71%), antral motility (81%), or duodenal motility (74%). However, these abnormalities were not correlated to each other and were not significantly correlated to the symptom pattern [20].

Harberson et al.[21] evaluated full-thickness antral biopsy specimens of 28 gastroparesis patients and compared with controls undergoing resection. The total number of nerve cell bodies was significantly decreased in gastroparesis, and a mild lymphocytic infiltrate in the myenteric plexus was mainly found in diabetic gastroparesis. Reduction in ICC numbers or abnormal ICC morphology was mainly found in idiopathic gastroparesis. These observations show the heterogeneity of histological abnormalities in gastroparesis. In a similar study of full-thickness antral biopsy specimens from 41 gastroparesis patients undergoing gastric electrical stimulation with the Enterra device, depletion or decreased numbers of ICCs were found in a large subset of patients. ICC integrity did not correlate with symptom severity, sex, or gastric emptying rate, but significant correlations were found with electrogastrography parameters and with a favourable outcome of gastric electrical stimulation with the Enterra device (Medtronic, Fridley, Minnesota, USA) [22].

Weight loss is a symptom that accompanies or is a consequence of functional dyspepsia in a subset of patients. In a study of 636 consecutive functional dyspepsia patients, the relationship between weight loss, symptom pattern, and gastric sensorimotor dysfunction was analysed by factor and cluster analysis. Three symptom factors were identified: 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. Cluster analysis revealed six clusters, and the highest weight loss was found in association with the most severe cluster, which loaded high on all three factors, and a cluster dominated by factor 2 [23]. This analysis, therefore, identified early satiation as the cardinal symptom underlying weight loss in functional dyspepsia.

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Duodenal acid exposure and sensitivity

Increased duodenal acid exposure, attributable to defective motor clearance, has been reported in a subset of functional dyspepsia patients based on a relatively small pilot study [24]. In a study from Japan, increased symptom ratings during duodenal acid infusion were observed in 44 functional dyspepsia patients compared with 19 healthy controls, confirming increased sensitivity to duodenal acidification in functional dyspepsia [25]. In a study from the USA, using wireless pH monitoring capsules clipped to the duodenum in 32 functional dyspepsia patients and 17 healthy controls, functional dyspepsia patients were shown to have significantly lower pH values during meals and during the daytime. Relationship with symptoms, however, was poor [26].

To further elucidate the contribution of duodenal acidification to symptom generation, 12 healthy controls were studied during fasting and postprandially, with simultaneous duodenal perfusion of physiological saline or acid 0.2N in a double-blind cross-over fashion. During acid perfusion, symptom scores for discomfort, bloating, nausea, and epigastric burning were significantly higher than during physiological saline infusion. These observations support the pathophysiological relevance of increased duodenal acid exposure [27].

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Gastrointestinal hormones

Ghrelin is a peptide hormone, produced by enteroendocrine cells in the gastric mucosa, which has been shown to affect gastric motility in humans [28,29]. In a study from Japan, gastric emptying and ghrelin plasma levels were measured in 112 functional dyspepsia patients. In this study, ghrelin levels were significantly lower in the PDS subgroup of functional dyspepsia, and a significant correlation was found with the rate of gastric emptying: low ghrelin plasma levels were correlated with slower gastric emptying [30]. In a study from Korea, plasma ghrelin levels before and after a gastric emptying test meal were measured in 42 patients with dysmotility-like functional dyspepsia and 14 healthy volunteers. Patients had significantly lower preprandial ghrelin levels, and in a subset of patients the postprandial decrease in ghrelin levels was absent. In this study, ghrelin levels before or after the meal were not correlated to gastric emptying parameters, indicating that the pathophysiological relevance of ghrelin in functional dyspepsia requires additional studies [31].

In a study from Sweden, oxytocins levels before and after a meal were studied in 19 diabetes patients with upper gastrointestinal symptoms. In those with normal emptying, an increase in oxytocins plasma levels occurred postprandially, whereas this was absent in those with delayed emptying. Cholecystokin and gastrin levels did not differ among these groups [32]. Further studies of the role of oxytocins in gastrointestinal function and symptom generation seem warranted.

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Infection and inflammation

Studies in adults have established a role for bacterial gastroenteritis in the pathogenesis of functional dyspepsia symptoms [33]. A number of studies provide evidence for persisting low-grade inflammation in a subgroup of patients with (postinfectious) functional dyspepsia.

In a population-based study from the UK, increased duodenal eosinophil counts were associated with functional dyspepsia, whereas mast cell hyperplasia was associated with the irritable bowel syndrome (IBS) [34•]. In a retrospective study of 155 duodenal biopsy samples that were labelled normal after routine clinical evaluation, duodenal eosinophilia was associated not only with allergy but also with functional dyspepsia, and more specifically with PDS [35]. These studies do not clarify an allergic or postinfectious origin of increased duodenal eosinophil numbers.

The Leuven group studied duodenal biopsies in postinfectious and unspecified-onset functional dyspepsia [36]. In the postinfectious functional dyspepsia (PI-functional dyspepsia) group only, focal aggregates of T cells, especially CD8+ cells, were found. The number of CD4+ cells in duodenal villi and around crypts was lower, whereas the number of CD68+ cells around crypts was higher in this group. As biopsies were taken on average 10 months after symptom onset, they are indicative of persisting changes in the cellular immunological response following a previous inflammatory event, rather than the normal inflammatory process following the initial gastrointestinal infection [36]. Persisting signs of duodenal inflammation were confirmed in a study from Japan, which found a high prevalence of histological duodenitis and significantly increased numbers of CCR2-positive macrophages on duodenal biopsies in 136 PI-functional dyspepsia patients compared with healthy controls [37].

In addition to histological signs of immune activation in the duodenum, systemic cellular and humoral immune responses were also studied in PI-functional dyspepsia and unspecified-onset functional dyspepsia, and compared with IBS and noncardiac chest pain [38]. Changes in the cytokine expression profile, such as elevated stimulated IL-5 and IL-13 production and decreased stimulated IFN-γ and IL-10 production, were comparable for functional dyspepsia and IBS, and some changes in immune function were more pronounced in the PI-functional dyspepsia group [38]. These observations are suggestive of ongoing duodenal and systemic immune activation in PI-functional dyspepsia.

Dizdar et al.[39] compared duodenal biopsies in patients with persisting symptoms after treated Giardia infection with those in patients with complete symptom resolution after the same treatment. Patients with persisting symptoms had higher numbers of CCK cells but lower numbers of enterochromaffin cells. Plasma CCK levels correlated significantly with dyspepsia scores, whereas postinfectious IBS symptoms were associated with lower plasma 5-hydroxy-indole acetic acid. These findings implicate CCK in post-Giardia dyspepsia.

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Genetic susceptibility

Population studies suggest presence of a genetic factor contributing to functional dyspepsia, as there is an increased risk for dyspepsia in those with a positive family history of indigestion [40].

Previous studies had already linked functional dyspepsia, to a G-protein beta 3 (GNβ3) subunit gene polymorphism (C825T) [41]. In a study from Japan, the GNB3 85TT polymorphism was not associated with functional dyspepsia as a group, but only with epigastric pain syndrome symptoms [42]. Another Japanese study in 91 functional dyspepsia patients and 93 controls failed to find an association with a functional polymorphism in the 5-HT2A receptor [43]. The same group evaluated the 779TC polymorphism of the CCK1 receptor in 124 functional dyspepsia patients and 119 controls. They found no overall association with functional dyspepsia, but 779 T carriers in men had a significantly higher risk of PDS [44]. These findings await confirmation in larger patient samples.

Camilleri et al.[45] studied the 7028C and 3010G polymorphisms in mitochondrial DNA in 699 controls and patients with functional disorders. Compared with 7028T, the 7028C is associated with higher maximum tolerated volume during a nutrient challenge test (lower satiation). Slower gastric emptying was statistically associated with 3010G compared with 3010A. These findings show that variations in mitochondrial DNA may be associated with altered gastric function and warrant further studies in functional dyspepsia and eating disorders.

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Dysfunction of the autonomic nervous system

Autonomic imbalance, especially impaired vagal activity, has been implicated in the pathogenesis of functional dyspepsia and of gastroparesis. In addition, several studies have shown a role for psychosocial factors in the pathogenesis of gastric sensorimotor disorders, and autonomic nerve dysfunction has been proposed as a mediator in this association. In a study in 27 patients with major depression studied before and after treatment with antidepressants, increased amounts of tachygastria were found, suggestive of increased sympathetic modulation. Further increases in tachygastria were seen after treatment with selective serotonin or noradrenaline reuptake inhibitors, but this was not associated with aggravation of epigastric symptoms [46].

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Visceral hypersensitivity

Visceral hypersensitivity is considered a key phenomenon underlying unexplained gastrointestinal symptoms, but the underlying mechanisms, the scope of sensations involved in visceral hypersensitivity, and the triggers that cause hypersensitivity are largely unknown. An increasing number of observations point toward abnormal central processing of gastric stimuli in functional dyspepsia.

Van Oudenhove et al.[47] performed a PET study in 25 functional dyspepsia patients and 11 controls during baseline, gastric balloon, or sham distension. Balloon distension was associated with a lack of pregenual anterior cingulated cortex activation in patients only. Patients showed no dorsal pons and amygdala deactivation during distension and sham, respectively. Anxiety correlated negatively with pregenual anterior cingulated and positively with dorsal pons activity. The authors interpreted these observations as arousal-anxiety-driven failure of pain modulation. In the same patient group, brain activation patterns and symptom ratings during balloon distension were influenced by gastric hypersensitivity as well as abuse history. These observations provide evidence for central mechanisms of hypersensitivity contributing to symptom generation in functional dyspepsia [48].

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Treatment of gastric sensorimotor dysfunction

Pharmacological approaches to correct abnormal gastric motility or sensitivity are considered a valid therapeutic approach in upper gastrointestinal motor disorders. Gastrointestinal prokinetics, drugs that stimulate gastric smooth muscle contractions, have long been considered the drugs of choice for the treatment of functional dyspepsia and gastroparesis [49]. Traditional prokinetic agents are dopamine2 receptor (D2) antagonists or 5-HT4 receptor agonists [49]. Velusetrag is a novel type of 5-HT4 receptor agonist. In a radioscintigraphy gastrointestinal transit study of acute and repeated dosing with 5–50 mg of velusetrag in healthy volunteers and patients with chronic constipation, the drug dose-dependently accelerated gastric emptying and enhanced colonic filling at 6 h in both groups [50]. Velusetrag is currently under development for the treatment of chronic constipation.

There is a clear need for new targets for the treatment of upper gastrointestinal sensorimotor disorders. Acotiamide (Z-338) is a novel compound that enhances acetylcholine release via antagonism of the M1 and M2 muscarinic receptors and was shown to enhance gastric accommodation in animal studies [51]. In animals, acotiamide restored delayed gastric emptying and feeding inhibition induced by restraint stress, and this was accompanied by decreased hypothalamic expression of stress mediators like neuromedin U [52]. In a European phase 2a trial comparing placebo, 50, 100, and 300 mg doses, a 100 mg dose of acotiamide three time daily (t.i.d.) improved functional dyspepsia symptoms and quality of life, and this was at least in part attributed to an improvement of gastric accommodation [53]. In two similar phase 2 trials in Japan, which included 1156 patients and evaluated doses between 50 and 200 mg, a 100 mg dose was found to be superior to placebo in alleviating meal-related symptoms in functional dyspepsia [54•]. A phase 3 trial program with acotiamide in functional dyspepsia is presently ongoing.

Motilin and ghrelin receptors are other targets that are under evaluation for the treatment of upper gastrointestinal motor disorders. The prokinetic actions of motilin receptor agonists are well established and erythromycin, a macrolide antibiotic with motilin receptor agonistic properties, is clinically applied to enhance severely delayed emptying [49]. However, use of erythromycin may cause QT prolongation and has been associated with potentially fatal arrhythmias, especially when patients were concurrently using inhibitors of cytochrome CYP3A. Azithromycin is another macrolide antibiotic that is devoid of inhibition of cytochrome isoenzymes. In a study that used small bowel manometry to evaluate the effects of azithromycin and erythromycin administered intravenously, azithromycin was at least as potent as erythromycin in stimulating antral contractility [55]. Azithromycin may, therefore, provide an alternative to erythromycin for gastroprokinetic applications. Novel motilin receptor agonists are being developed for these therapeutic indications. GSK962040, a small molecule motilin agonist, was shown to stimulate contractions of rabbit and human stomach preparations in vitro[56]. The drug is currently under evaluation for the treatment of diabetic gastroparesis.

Acute intravenous administration of ghrelin stimulates interdigestive and postprandial motor activity, and this has been the rationale to develop ghrelin agonists for the treatment of upper gastrointestinal motor dysfunction [28,29]. These effects were confirmed in a study of prolonged ghrelin infusion, in which gastric emptying rate was enhanced, whereas small intestinal and colonic transit were not altered [57]. Intravenous administration of ghrelin prior to and during meal intake in healthy volunteers inhibits meal-induced gastric accommodation, but this is not associated with a change in meal-induced satiation [58].

TZP-101 is a novel ghrelin agonist, under development for the treatment of gastroparesis and postoperative ileus. In a proof-of-concept study with cross-over design, intravenous administration of 80–600 μg/kg in 10 patients with diabetic gastroparesis significantly enhanced gastric emptying rate and reduced postprandial symptom ratings [59•]. In a study with 4-day infusion of 20–600 μg/kg in diabetic gastroparesis patients, TZP-101 provided significant improvement in symptom intensities as assessed by the Gastroparesis Cardinal Symptom Index [60]. The optimum dose seemed to be 80 μg/kg, and the drug was well tolerated [60].

An alternative approach to prokinetics in the treatment of gastroparesis is the intrapyloric injection of botulinum toxin. In an open-label study in patients with postvagotomy gastroparesis, botulinum toxin injection was associated with a reduction of gastroparesis symptoms at 1 and 3 months and symptom recurrence by 6 months [61]. Although this observation suggests efficacy, previous sham-controlled study in gastroparesis failed to show significant symptomatic benefit of botulinum toxin injection [62].

Impaired gastric accommodation and visceral hypersensitivity, using fundic relaxants or visceral analgesics, are other potentially attractive targets for drug development in sensorimotor disorders of the upper gastrointestinal tract [49]. The anxiolytic 5-HT1A agonist buspirone was shown to dose-dependently relax the proximal stomach in healthy controls [63], suggesting a therapeutic potential for this class of drugs in the treatment of functional dyspepsia. A Japanese placebo-controlled study with the anxiolytic 5-HT1A agonist tandospirone 10 mg t.i.d. showed significant improvements in upper abdominal pain and discomfort and significant improvements in the state–trait anxiety inventory questionnaire and quality of life assessed with the Short Form-8 (SF-8). Although anxiety and SF-8 scores did not differ between both treatment arms, the improvement in trait anxiety scores was higher in responders to tandospirone. These observations suggest that central effects may have contributed to the therapeutic effect of tandospirone [64•].

In a European study, the novel 5-HT1A agonist R137696, previously shown to relax the proximal stomach [65], failed to provide symptomatic benefit in functional dyspepsia patients, but also did not alter visceral sensitivity or gastric accommodation compared with placebo [66].

Iberogast is a herbal mixture with beneficial effects on functional dyspepsia symptoms based on placebo-controlled studies, but the underlying mechanism of action is unclear [67]. In a multicentre placebo-controlled study from Germany, gastric emptying was measured in 103 functional dyspepsia patients before treatment and repeated after 4 weeks of therapy in those with delayed emptying. Significantly higher treatment response was observed with iberogast, but this was not associated with enhanced gastric emptying [68].

In case of refractory gastroparesis with nausea and vomiting, gastric electrical stimulation can be considered as a rescue therapy. However, the evidence of efficacy is based on mainly uncontrolled case series and one small clinical trial. In a multicentre controlled study in the USA, 55 patients with refractory diabetic gastroparesis were given implants of the Enterra gastric electrical stimulation system. The device was switched on for 6 weeks in all patients, and then randomly assigned to two 3-month treatment periods with the stimulator on or off, in a blinded fashion. Major reduction in nausea and vomiting occurred during the first 6-week period, and this was maintained during the blinded treatment period, regardless of the device being switched on or off [69•]. The results of this study suggest a major, persisting placebo effect of implants with the Enterra device, although a disease-modifying effect of 6 weeks of gastric electrical stimulation cannot be entirely excluded.

In 10 gastroparesis patients, electrocardiogram, electrogastrography, measurements of sensitivity to gastric distention with a barostat and PET brain scans were performed before and after Enterra implantation. During gastric electrical stimulation therapy, sensitivity to gastric distension was decreased, sympathovagal balance was decreased, and PET imaging showed increased activity in thalamic and caudate nuclei. The authors interpret these data as activation of vagal afferent pathways to influence CNS control mechanisms for nausea and vomiting, as well as efferent pathways decreasing gastric sensitivity [70].

In a study from Sweden, 27 patients underwent a slow caloric satiety drinking test with the Enterra device (temporarily or permanently implanted) switched on or off in a randomized fashion. Gastric electrical stimulation did not alter nutrient drink tolerance during short-term or long-term (6 months) assessment [71].

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Normal and abnormal gastroduodenal motility is an area of intense research, and this is driven by the quest to provide a better understanding of the pathophysiology underlying functional dyspepsia and gastroparesis. A new diagnostic tool is the SmartPill, a recently developed nondigestible wireless capsule that records luminal pH, temperature, and pressure during transit through the gastrointestinal tract, and therefore provides a measure of gastric emptying time, small bowel transit time, and whole gut transit time. Although gastric motility and dysmotility continue to be explored, research focus has partially shifted to duodenal sensitivity and postinfectious low-grade duodenal inflammation. A number of studies are investigating genetic susceptibilities for functional dyspepsia, but the available studies are hampered by low numbers of patients. The interaction between visceral hypersensitivity, altered brain processing of visceral stimuli, and psychosocial disorders is progressively being unravelled. Emerging pharmacological agents under evaluation for the treatment of gastroduodenal disorders include the M1 and M2 muscarinic receptor antagonist acotiamide, ghrelin receptor agonists, and novel motilin and 5-HT4 receptor agonists. The effects of gastric electrical stimulation, once considered a rescue therapy in refractory gastroparesis, have been less convincing in recent studies.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 674–675).

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brain–gut axis; duodenal acid exposure; duodenal inflammation; gastric electrical stimulation; gastric motility; gastroprokinetic drugs; visceral sensitivity

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