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Keywords:

  • duodenal acidification;
  • duodenogastric reflex;
  • gastric barostat;
  • ondansetron;
  • visceral sensitivity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

Background  Duodenal acid infusion induces gastric relaxation and sensitization to distension in healthy volunteers. The acid-sensitive mechanism is still unknown. We hypothesized that 5HT3-blockade can inhibit the acid-induced duodenogastric sensorimotor reflex in healthy volunteers.

Methods  Fourteen healthy volunteers were included in a randomized, double-blind placebo-controlled cross-over trial. An infusion tube with attached pH-electrode was positioned in the duodenum and a barostat balloon was located in the gastric fundus. Proximal gastric volume and sensitivity to distension were assessed before and during duodenal acid infusion and after pretreatment with intravenous (i.v.) ondansetron (a 5HT3-receptor antagonist, 8 mg) or saline. An overall perception score (0–6) and an assessment of nine dyspeptic symptoms by visual analogue scales (VAS) were obtained. Results are given as mean ± SEM.

Key Results  Ondansetron had no effect on duodenal pH and on the acid-induced increase of proximal gastric volume (increase of 80 ± 20 vs 83 ± 15 mL after ondansetron and placebo; effect of acid <0.001, between treatments ns). After ondansetron, the overall perception score during duodenal acidification and gastric distension was significantly decreased compared with placebo (= 0.01). There was no effect of ondansetron on the individual dyspeptic symptoms.

Conclusions & Inferences  Ondansetron decreased gastric sensitivity during duodenal acid infusion and gastric distension. 5HT3-receptors are involved in acid-induced duodenogastric sensitization, but not in the duodenogastric inhibitory motor reflex.


Abbreviations: 
AUC

area under the curve

EC

enterochromaffin cells

FD

functional dyspepsia

5-HT

5-hydroxytryptamine

IBS

irritable bowel syndrome

MDP

minimal distending pressure

VAS

visual analogue scale

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

The pathophysiology of functional dyspepsia (FD) is only partially elucidated. Several mechanisms have been implicated, including delayed gastric emptying, impaired gastric accommodation to a meal, hypersensitivity to gastric distension, abnormal duodenojejunal motility, Helicobacter pylori infection, and central nervous system dysfunction. Increasing evidence shows that FD is a heterogeneous disorder, with some reports showing different pathophysiological mechanisms underlying different symptom patterns.1

In a subgroup of FD patients, an altered duodenal reaction to acid and an increased duodenal exposure time to acid in the interdigestive and late postprandial period were proposed as a mechanism that contributes to unexplained upper gastrointestinal (GI) symptoms. 2,3Functional dyspepsia patients with duodenal acid exposure above the normal range had higher scores of several dyspeptic symptoms.3

Short duodenal infusion of hydrochloric acid was found to induce nausea in a subgroup of FD patients but not in healthy controls, suggesting duodenal hypersensitivity to acid.2 Furthermore, it was shown that the duodenal motor response to acid was decreased in FD, resulting in reduced clearance of exogenous duodenal acid.2,4,5 These sensorimotor alterations were found to be chemospecific as acid but not lipid or dextrose induced significant symptoms in patients.4 Other groups have shown that duodenal lipid infusion, but not dextrose, can also enhance the perception of gastric distension in healthy volunteers and in patients.6

Duodenal acid exposure may be involved in symptom generation through direct activation of chemosensitive afferent pathways, as well as by altering gastric sensorimotor function through duodenogastric reflex pathways.

In healthy subjects, duodenal acid infusion sensitizes the proximal stomach and the duodenum to distension and prolonged duodenal acidification is able to induce dyspepsia-like symptoms.7–10 We demonstrated that duodenal acid infusion causes relaxation of the proximal stomach and decreases antral motility, indicating an acid-sensitive inhibitory duodenogastric reflex.7,8 Several observations from animal studies suggest that duodenal acid may induce the release of 5-hydroxytryptamine (5HT) from enterochromaffin cells (EC) and subsequent activation of a 5HT3-receptor on mucosal vagal afferents.11–16 Furthermore, ondansetron, a specific 5HT3-receptor antagonist, decreased intensity of nausea during gastric distension and duodenal lipid perfusion in man.17 However, the type of receptor involved in the acid-sensitive duodenogastric reflex in humans is unknown. The aim of the present study is to investigate the involvement of 5HT3-receptor in the acid-sensitive duodenogastric sensorimotor reflex in healthy volunteers.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

Study subjects

We included 14 healthy volunteers (7 men; age 19–34 years) in a placebo-controlled, double-blind randomized cross-over study. None of the subjects had GI symptoms, history of GI disease or drug allergies, nor were they taking any medication. Written informed consent was obtained from each participant. The protocol had been approved by the Ethical Committee of the University Hospital before initiation of the study.

Recording technique

On the morning after an overnight fast, an assembly including a calibrated pH electrode with an antimony pH sensor and a thin infusion tube (outer diameter 2 mm) was introduced through the mouth and positioned in the second part of the duodenum under fluoroscopic control. Subsequently, a double lumen polyvinyl tube (Salem sump tube 14 Ch; Sherwood Medical, Petit Rechain Belgium) with an adherent plastic bag (1200 mL capacity; 17 cm maximal diameter), finely folded, was introduced through the mouth and secured to the subject’s chin with adhesive tape. The position of the bag in the gastric fundus was briefly checked fluoroscopically. Duodenal pH was continuously monitored during the study and recorded using an ambulatory data logger (MicroDigitrapper, Synectics Medical, Stockholm, Sweden).

The polyvinyl tube was then connected to a computer-driven programmable volume-displacement barostat device (Synectics Visceral Stimulator, Stockholm, Sweden). The barostat device can deliver volume ramps or pressure steps at different rates, while simultaneously monitoring pressure and volume at a sampling rate of eight samples per second. To unfold the intragastric balloon, it was inflated with a fixed volume of 300 mL of air for 2 min with the volunteer in a recumbent position, and again deflated completely. After a 10 min equilibration period, the participants were positioned in a comfortable sitting position with the knees slightly bent (80°) in a bed, specifically designed for that purpose, for the remainder of the experiment.

Study design

All volunteers underwent a gastric barostat study with duodenal acid infusion on two separate occasions, at least 1 week apart. In a double-blind randomized cross-over fashion, ondansetron or saline was intravenously administered during the study.

The study design is visualized in Fig. 1. After a 30 min accommodation period, minimal intragastric distending pressure (MDP) was determined as the lowest pressure level that provides an intrabag volume of 30 mL or more. This pressure level equilibrates the intra-abdominal pressure. Subsequently, we performed the first series of sequential isobaric distensions in stepwise increments of 2 mmHg, starting from MDP and each step lasting for 2 min, while the corresponding intragastric volume was recorded. Subjects were instructed to score their perception of upper abdominal sensations at the end of every distension step, using a rating scale that combines verbal descriptors on a scale graded 0–6. This score is referred to as the overall perception score. Descriptors indicated that a score of 0 represented no perception; a score of 1 and 2 represented vague and definite perception of mild sensation respectively; a score of 3 and 4 represented vague and definite perception of moderate sensation respectively; a score of 5 indicated discomfort and a score of 6 represented a painful sensation, which was to be instantaneously reported and led to immediate discontinuation of the distension protocol. This validated perception score has been used extensively in our laboratory and by other groups.18–20 Nine dyspeptic symptoms (discomfort, fullness, bloating, nausea, heartburn, belching, epigastric burning, satiety, and epigastric pain) were scored at the same time points by 100 mm visual analogue scales (VAS). The end point of each sequence of distensions was established at an intrabag volume of 1000 mL or when the subjects first reported discomfort or pain (score 5 or 6). After a 10 min period of deflation, the pressure level was set at MDP + 2 mmHg. The intrabag volume at this pressure was recorded during 15 min and then 8 mg (4 mL) ondansetron (Zofran®, GlaxoSmithKline, Genval, Belgium) or saline (4 mL) was injected intravenously over 5 min in a randomized, double-blind fashion: the syringe with the product was prepared by a nurse who was not involved in the rest of the experiment. After 30 min, 0.1N hydrochloric acid was infused in the duodenum until at the end of the experiment at a rate of 5 mL min−1. Twenty minutes after the start of duodenal acid infusion, a second sequence of stepwise isobaric distensions with the assessment of symptoms was repeated in the same fashion as during the first series of distensions (Fig. 1). During the interval between the two series of distensions, subjective sensations were scored every 5 min, using VAS scores as previously explained.8,9

image

Figure 1.  Schematic outline of the study design. MDP, minimal distending pressure.

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Data analysis

For each step in the two series of stepwise distensions, the volume that corresponded to the set intrabag pressure was determined by averaging the recordings for each 2 min distension step. Gastric compliance for both distension series was computed by a linear regression analysis as the slope of the pressure–volume curve during the first four distension steps that the majority (86%) of the volunteers had undergone. The perception threshold pressure and volume were defined as the lowest pressure, relative to MDP, and volume that evokes a perception score of one or more in case the first discernible perception exceeded a vague mild perception. The discomfort threshold pressure and volume were the lowest pressure relative to MDP and volume that corresponded to a perception score of 5 or more, in case score 6 (‘pain’) and not score 5 (‘discomfort’) was first reported.

For the interval between the two series of distensions, the intrabag volume was calculated as the mean balloon volume over consecutive 5-min intervals. This volume is a measure of the gastric tone as the intrabag pressure is kept constant. The interval between the distensions was further subdivided into three periods by the administration of ondansetron or saline and by the start of acid perfusion (Fig. 1). The average intrabag volume and average VAS-score for the different symptoms were calculated for the three periods.

The pH-data were analyzed by computing the fractional time of pH < 4. Both pH and fractional time of pH < 4 were averaged for 5 min-intervals and for the three periods during the interval between distensions.

Statistical analysis

The number of subjects was calculated to show a 30% difference in the overall perception score with a power of 90% and statistical significance of 5%, based on a previous study of our group.8 Level of statistical significance was set at 0.05. Data are presented as means ± SE.

All statistical analyses were performed with sas for Microsoft Windows, version 9.2, and SAS Enterprise guide, version 4.2 (SAS Institute Inc., Cary, NC, USA).

Analysis of the distensions  For the analysis of the distensions, the first four steps, that the majority of the volunteers (86%) had undergone, were used.

The gastric compliance during distensions in the two treatment arms was compared by a paired student’s t-test. Perception and discomfort thresholds were compared by a Wilcoxon signed ranks test, as the data were not normally distributed as indicated by a Kolmogorov–Smirnov test.

To test the effect of duodenal acidification on the overall perception score and the VAS-scores within each treatment arm, a first series of two multilevel models (one per treatment arm) was estimated for each dependent variable, using ‘proc mixed’ in SAS. A (dichotomous) ‘period’ variable (first and second series of stepwise distensions, i.e., before and during acidification), the intrabag pressure (continuous variable) and a period by pressure interaction term were entered as fixed effects. The pressure was also entered as a random effect, as well as a random (i.e., subject-specific) intercept; random effects are only used to model the (co)variance structure of the data (within-as well as between-subject variability) correctly. In this model, the period by pressure interaction effect represents the difference in slope of the pressure symptom curve before duodenal acidification compared to during acidification. The period main effect represents an overall (i.e., over all pressure levels) difference in symptom (or perception) score before compared to during acidification (i.e., a downward or upward shift of the whole pressure–symptom curve without a difference in slope).

To test for an effect of treatment on the overall perception score and the VAS-scores within each series of distensions (before and during acidification), a second series of two multilevel models (one before, one during acidification) was estimated for each dependent variable (the overall perception score and the VAS-scores for the individual symptoms). Intrabag pressure, treatment arm (ondansetron and placebo) and a pressure by treatment interaction were entered as fixed effects, with random effects as described above. The pressure by treatment interaction effect represents the difference of the slope of the pressure-symptom curve between both treatments. The treatment main effect represents an overall (i.e., over all pressure levels) difference in symptom (or perception) score between treatments (i.e., a downward or upward shift of the whole pressure-symptom curve without a difference in slope).

Analysis of the interval between distensions  A third multilevel analysis was estimated to test for an effect of treatment during the interval between both series of stepwise distensions, for each dependent variable. In this case, a period variable was created to indicate the period before and during duodenal acidification. The mean values of the VAS-scores for the dyspeptic symptoms, intrabag volumes, pH and fractional time of pH < 4 for these two time periods were sequentially entered as the dependent variables. Period (before and during acidification), treatment arm (ondansetron and placebo) and a period by treatment interaction were entered as fixed effects, with a random period effect as well as a random intercept. The period by treatment interaction effect represents the difference of the slope of the time-symptom (or time-pH, time-volume) curve between both treatments. The period main effect represents an overall (i.e., over both treatments) difference in the dependent variables before compared to during acidification.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

Distensions

Duodenogastric motor reflex  Minimal distending pressure was similar in both treatment conditions (8.1 ± 0.5 vs 8.3 ± 0.5 mmHg, ns). Ondansetron did not influence the acid-induced increment of proximal gastric compliance during isobaric distensions [38 ± 6 before acidification vs 61 ± 9 mL mmHg−1 during acidification after ondansetron pretreatment (< 0.001) and 36 ± 3 vs 56 ± 5 mL mmHg−1 (= 0.001) after saline pretreatment; between treatments ns] (Fig. 2).

image

Figure 2.  Compliance of the proximal stomach during isobaric gastric distensions. During duodenal acidification (shaded bar), the proximal gastric compliance was increased compared with the period before duodenal acid infusion (solid bar). Ondansetron did not alter this reflex. Student’s t-test for paired data, before vs during duodenal acidification; *< 0.001, #< 0.01.

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Duodenogastric sensory reflex  The perception threshold pressure was neither influenced by acidification, nor was it altered by ondansetron [11.3 ± 0.7 before acidification vs 11.1 ± 0.9 mmHg during acidification (ns) after ondansetron pretreatment and 11.1 ± 0.5 vs 11.3 ± 0.7 mmHg (ns) after placebo; between treatments ns]. Duodenal acidification significantly decreased the discomfort threshold pressure in both treatment conditions (19.1 ± 0.8 vs 17.3 ± 1.1 mmHg (= 0.02) after ondansetron and 19.0 ± 1.2 vs 17.0 ± 1.1 mmHg (= 0.01) after placebo administration; between treatments ns). The perception threshold volume increased with borderline significance after ondansetron treatment during duodenal acidification (154 ± 32 vs 227 ± 39 mmHg, = 0.05) and increased significantly after placebo (131 ± 24 vs 168 ± 26, = 0.02). There was no significant difference of the perception threshold volume between ondansetron and placebo treatment. Neither acidification, nor ondansetron altered the discomfort threshold volume [480 ± 65 vs 530 ± 49 mL (ns) after ondansetron and 479 ± 54 vs 480 ± 47 mL (ns) after placebo; between treatments ns].

The overall perception score during gastric distension during duodenal acid infusion was significantly reduced after ondansetron pretreatment compared with placebo (between-treatment difference in slope of the pressure-perception curve as represented by the treatment by pressure interaction effect = 0.01) (Fig. 3). After placebo administration, the overall perception score significantly increased during duodenal acidification compared with the distensions before acid infusion (period by pressure interaction ns; period main effect < 0.01). After ondansetron pretreatment, perception scores during acidification were comparable to the scores before acid infusion (period by pressure interaction ns; period main effect ns) (Fig. 3).

image

Figure 3.  Overall perception score (0–5) during isobaric gastric distensions. (A) After ondansetron pretreatment, no acid-induced sensitization to gastric distension was observed. (B) During duodenal acidification (dashed line, triangles) significantly higher perception scores during gastric distension were observed compared with the scores before acid infusion (solid line, squares). (C) Before duodenal acid infusion, during the first series of stepwise distensions, scores in both treatment groups were comparable. (D) During duodenal acidification, the overall perception score after placebo pretreatment (dashed line, triangle) across the different pressures was significantly higher compared with the scores after ondansetron (solid line, squares). *< 0.01 for period main effect; #= 0.01 for pressure by treatment interaction and < 0.01 for treatment main effect.

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After both ondansetron and placebo treatment, duodenal acidification significantly increased the symptom scores for discomfort, fullness, heartburn, and satiety (Table 1). Scores for bloating significantly increased only after placebo pretreatment and scores for epigastric burning only after ondansetron (Table 1). However, there were no significant differences between both treatments for the different individual dyspeptic symptoms (pressure by treatment interaction ns for all symptoms).

Table 1.   Influence of duodenal acidification on VAS-scores for dyspeptic symptoms during the interval between distensions. The P-values of the multilevel model for the pressure by period interaction term and the period main effect (acidification) are given for both treatment arms. There were no significant differences between placebo and ondansetron treatment
SymptomOndansetronPlacebo
Pressure by periodPeriod main effectPressure by periodPeriod main effect
  1. Bold values indicates statistically significant differences.

Discomfort0.790.0050.210.02
Fullness0.66<0.00010.570.01
Bloating0.810.070.950.02
Nausea0.04<0.00010.008<0.0001
Heartburn0.13<0.00010.960.01
Belching0.920.880.770.78
Epigastric burning0.860.0040.720.06
Satiety0.25<0.00010.150.004
Epigastric pain0.390.600.430.52

Interval between distensions

Duodenal acid exposure  Complete pH-data were available for 86% (12/14) of volunteers because of failed registration by the recording device in two cases. Mean pH before acid infusion was 5.5 ± 0.1 (range 4.6–6.1) in the ondansetron treatment arm and 5.7 ± 0.2 (range 4.8–6.4) in the placebo studies (ns), confirming the correct position of the tip of the pH electrode and the perfusion catheter in the duodenum. During acid perfusion, pH dropped to 2.3 ± 0.4 and 2.4 ± 0.4, respectively (main effect for period < 0.0001, treatment by period interaction ns). Similar results were obtained for fractional time of pH < 4, which increased significantly during acid perfusion (8.1 ± 2.0 vs 7.8 ± 1.9% before acid perfusion for ondansetron and placebo, respectively and 72.2 ± 7.5 vs 72.6 ± 7.6% during duodenal acid perfusion; main effect for period < 0.0001, treatment by period interaction ns).

Duodenogastric motor reflex  Both after ondansetron and placebo administration, duodenal acidification induced a significant relaxation of the proximal stomach that was not influenced by ondansetron (volume increase of 80 ± 20 vs 83 ± 15 mL; main effect for period < 0.001, period by treatment interaction ns) (Fig. 4).

image

Figure 4.  Volume of the barostat balloon in the proximal stomach during the interval period. After both ondansetron (solid line, squares) and saline (dashed line, triangles), duodenal acid perfusion induced a significant relaxation of the proximal stomach. There was no influence of ondansetron on this duodenogastric motor reflex. *< 0.001 for main effect for period; period by treatment interaction ns.

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Sensory effects of duodenal acidification  Duodenal acid perfusion induced higher symptom scores for discomfort, which were not influenced by ondansetron (main effect for period < 0.05; period by treatment interaction ns) There was no influence of duodenal acid or ondansetron pretreatment on the other dyspeptic symptoms.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

We previously showed that prolonged duodenal acid perfusion induced dyspeptic symptoms in healthy volunteers and that a subset of FD patients with predominant nausea had a reduced clearance of exogenous acid and an increased endogenous duodenal acid exposure.3,8 Moreover, the patients with increased duodenal acid exposure had more severe dyspeptic symptoms.8 The mechanism involved in mediating duodenal acid-induced sensitivity is still unknown.

In the present study, we showed that the acid-induced increment of the overall perception score during gastric distension in healthy volunteers was blocked after pretreatment with ondansetron, a 5HT3-receptor antagonist. No significance was reached for an effect on individual dyspeptic symptoms. There was also no effect of ondansetron on symptoms before gastric distension. Finally, proximal gastric motor response to acid and distension was not altered by blocking the 5HT3-receptor.

Serotonin is an important signaling molecule and neurotransmitter in the GI tract. Almost 95% of the body’s serotonin is contained in the gut, where it is synthesized by the EC subtype of enteroendocrine cells and to a lesser degree by serotonergic neurons of the myenteric plexus.21 Endoluminal stimuli such as acid and pressure induce the release of serotonin by EC.21–23 Certain intravenous chemotherapeutic agents can also induce serotonin release by EC. Subsequently, serotonin binds to 5HT3-receptors on extrinsic primary afferents that convey the sensory signal to the brain. Specific 5HT3-antagonists, such as ondansetron, granisetron and tropisetron reduce chemotherapy-induced nausea and vomiting by inhibiting the activation of intestinal vagal afferents.24,25 Immunohistochemical studies with vagal denervation experiments in rats confirm the presence of 5HT3-receptors on mucosal vagal afferents.16

In the present study, we hypothesized that the gastric sensorimotor response to duodenal acid could be reduced by blocking the duodenal 5HT3-receptor. It is critical that the observed effects result from a peripheral blockade rather than a central symptom-modifying influence by ondansetron. There are several arguments in favor of a predominantly peripheral action of 5HT3-receptor antagonists. In sheep, low intensity non-painful duodenal distension inhibits gastric motility. This response is abolished by low doses of granisetron administered peripherally but not centrally, suggesting a peripheral site of action for this 5HT3-antagonist.23 Moreover, alosetron and ondansetron do not alter fundus tone and sensitivity during gastric distensions in healthy volunteers without applying an extra stimulus to the duodenum,26,27 which is another argument against a general, i.e., most likely central, symptom-modifying effect. In this study, we showed a reduction of overall perception scores during the combination of gastric distensions and duodenal acidification, probably caused by a peripheral blockade of the 5HT3-receptor on extrinsic vagal afferents in the duodenal mucosa.

However, there is also evidence that 5HT3-antagonists modulate visceral perception at the level of the central nervous system. Alosetron induces deactivation of the emotional motor system, associated with a reduction of GI symptoms, in response to rectal balloon distension in irritable bowel syndrome (IBS) patients.28,29 Whether this is solely the result of a central action of alosetron or an indirect consequence of a peripheral effect or a combination of both, are still unclear. It is also unclear if this putative central mechanism is also important in non-IBS patients. Moreover, these observations do not exclude a peripheral action after duodenal stimulation.

Feinle et al. previously showed that ondansetron reduced symptoms during gastric distensions and duodenal lipid perfusion.17 Kuo et al. reported that after maximal ingestion of a nutrient drink, alosetron decreased the overall symptom score and nausea in both dosage groups (0.5 and 1 mg) and bloating only in the high dose group (1 mg).30 Whether this symptom reduction is caused by decreased activation of duodenal 5HT3-receptors after lipid-induced 5HT-release remains to be established.

Neither the duodenal acid-induced gastric relaxation nor the proximal gastric volumes during distensions were influenced by ondansetron. Our data are in agreement with Feinle et al. who showed that ondansetron had no effect on the lipid-induced gastric relaxation.17 Besides 5HT, there is also evidence for involvement of cholecystokinin acting at CCK1-receptors in this pathway.31

Contrary to the use in female diarrhea-predominant IBS patients, studies with 5HT3-antagonists in FD are scarce.21 In a multicenter placebo-controlled dose-finding study of alosetron in FD, Talley et al. showed that alosetron 1 mg b.d. induced an adequate relief of abdominal discomfort or pain in a higher proportion of patients compared to placebo.32 This difference was only present after 2 weeks of daily treatment and only in female patients. Alosetron 0.5 mg b.i.d. was also superior to placebo for reduction of early satiety and postprandial fullness.32 Dizdar et al. reported decreased postprandial nausea in a FD/IBS overlap syndrome after Giardia infection after two oral doses of ondansetron.33 There was no effect on gastric emptying time or other symptoms. Unfortunately, data on duodenal acid exposure are lacking in both studies. Taking into account the results of the present study in healthy volunteers, future studies with 5HT3-antagonists in subgroups of patients with increased duodenal acid exposure are needed.

The limitations of our studies include the number of subjects, only single intravenous administration and one fixed dose of ondansetron, short term acidification and a study group of healthy volunteers instead of patients. The results of Talley et al. indicate that longer treatment may be necessary for sufficient blockade of the receptor.32 This might be especially important in the subgroup of FD patients with chronic duodenal acidification, where sensitization phenomena may occur.3 In this study, we used the same dose as applied for chemotherapy-induced nausea and vomiting as a starting point, but it is unclear whether a higher dose is necessary for sufficient blockade of the receptors on the luminal vagal afferents. Dose-ranging studies, preferably with oral administration, are necessary to clarify this point. Short term acidification in healthy volunteers may not be adequate to mimic the situation in dyspeptic patients with increased duodenal acid exposure. In previous studies, we showed that only longer-term duodenal acidification could induce dyspeptic symptoms in healthy volunteers without applying an extra stimulus such as gastric distensions.8 This raises the concern that 20–30 min of acidification may not be long enough to induce sufficient dyspeptic symptoms to evaluate the therapeutic effect of a 5HT3-antagonist, which may have contributed to the negative results on the individual dyspeptic symptoms.

In conclusion, we confirmed that duodenal acidification sensitizes the proximal stomach to distension and induces a relaxation of the proximal stomach in healthy volunteers. We showed that pretreatment with a single intravenous dose of ondansetron, a 5HT3-antagonist, partially inhibits the acid-induced duodenogastric sensitization reflex, without altering the motor reflex pathway.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

TV is a research fellow and LVO is a postdoctoral research fellow of the Flanders Research Foundation (FWO), Belgium. This study is supported by a Methusalem grant from the University of Leuven to Prof. J. Tack.

Author contribution

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References

TV, GK and RV performed the research. JT designed the research study. TV and LVO analyzed the data. TV, LVO and JT wrote the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contribution
  9. Competing interests
  10. References