Authors
C. BROERS (1), B. VAN HOUTTE (2), P. VERMEERSCH (3), N. PEERSMAN (3), J. TACK (2), A. PAUWELS (2) / [1] KU Leuven, Leuven, Belgium, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, [2] KU Leuven, leuven, Belgium, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, [3] UZ Leuven, Leuven, Belgium, Laboratoriumgeneeskunde
Introduction Proton pump inhibitors (PPIs) are effective in healing oesophagitis, however 30% of non-erosive gastro-oesophageal reflux disease (NORD) patients remain symptomatic while taking PPIs. In these patients, oesophageal hypersensitivity is considered an important pathophysiological mechanism. Serotonin (5-HT) is predominantly found in the central nervous system and in the gastro-intestinal (GI) tract. 5-HT plays a major role in the regulation of GI secretion, motility and sensitivity, and has been associated with emotion regulation. Acute tryptophan depletion (ATD) temporarily reduces the availability of tryptophan (TRP), thereby decreasing central and peripheral 5-HT synthesis. From previous studies, ATD is known to affect GI physiology and enhance visceral pain perception in the colon.
Aim
To study the effect of ATD on oesophageal sensitivity in healthy volunteers (HV).
Methods Oesophageal multimodal sensitivity was assessed after intragastric infusion of an amino-acid mixture (AA-mix) containing 15 AAs with TRP (control condition) or without TRP (ATD condition). After an incubation period of 5 hours, a probe with a balloon was positioned in the distal oesophagus. Thermal (recirculating a heated saline solution through the balloon), mechanical (increasing balloon volume), electrical (2 stimulation electrodes) and chemical sensitivity (modified Bernstein) were tested. Stimulus intensities were evaluated for first perception, pain perception threshold (PPT) and pain toleration threshold (PTT). At 3 time points blood samples were collected for biochemical analysis. General mood was assessed by the Positive and Negative Affect Schedule (PANAS) and the State-Trait Anxiety Inventory (STAI) questionnaires. Results were analyzed using paired t-tests and two-way ANOVA repeated measures and corrected for multiple testing (Bonferroni correction). A p-value of <0.05 was considered significant.
Results We compared control condition with ATD in 11 HV (4m/7f, mean age 24y [range 21y-33y]. ATD significantly reduced plasma levels of TRP, 5 and 7 hours after administration of the AA-mix (5h: 139.0 µmol/L [97.1-175.1] vs. 6.1 µmol/L [3.3-21.1], 7h: 65.6 µmol/L [53.0-133.1] vs. 6.1 µmol/L [4.8-12.2], p<0.0001). ATD significantly decreased the PPT during chemical stimulation (p=0.03) with a pronounced effect size (Cohen’s d+=0.75) (Table 1). However, ATD had no significant influence on sensitivity to the other stimulation modalities. There was no significant difference in PANAS and STAI-State scores before, during and after the stimulations for the 2 conditions. Table 1: Results of oesophageal multimodal stimulation for control condition and acute tryptophan depletion (ATD). Results are presented as median [25th –75th percentile]. n=11, unless indicated otherwise since only HV reaching the sensitivity thresholds were taken into account for analysis. Temperature stimulation (°C) PPT control: 42.66°C [40.56-46.71] vs. PPT ATD: 43.71°C [41.22-46.65], p=0.53 PTT control: 46.43°C [45.00-49.04] vs. PTT ATD: 46.32°C [44.42-51.88], p=0.56 Mechanical stimulation (ml) PPT control: 17.70ml [16.00-19.40] vs. PPT ATD: 16.65ml [11.70-21.50], p=0.23 PTT control (n=9): 22.10ml [20.35-24.35] vs. PTT ATD (n=9): 25.00ml [17.90-30.80], p=0.17 Electrical stimualtion(mA) 1st perception control: 6.33mA [4.17-6.83] vs. 1st perception ATD: 6.00mA [4.33-13.33], p=0.17 PPT control: 11.83mA [8.50-14.33] vs. PPT ATD: 10.00mA [8.00-19.83], p=0.41 Chemical stimulation (ml) 1st perception control: 10.00ml [7.00-18.00] vs.1st perception ATD: 8.00ml [6.00-11.00], p=0.27 PPT control: 25.00ml [14.00-29.00] vs. PPT ATD: 14.00ml [13.00-24.00], p=0.03 PTT control: 34.00ml [24.00-42.00] vs. PTT ATD: 26.00ml [16.00-36.00], p=0.23
Conclusions To our knowledge, this is the first study to address the effect of ATD on oesophageal multimodal sensitivity in health. ATD significantly decreased pain perception threshold during chemical stimulation, without affecting sensitivity to mechanical, thermal or electrical stimulation. The findings may have implications for the understanding and treatment of refractory GORD or functional heartburn.
