Retrospective Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2022; 28(21): 2334-2349
Published online Jun 7, 2022. doi: 10.3748/wjg.v28.i21.2334
Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study
Sabrina Berens, Yuanjun Dong, Nikola Fritz, Jutta Walstab, Mauro D'Amato, Tenghao Zheng, Verena Wahl, Felix Boekstegers, Justo Lorenzo Bermejo, Cristina Martinez, Stefanie Schmitteckert, Egbert Clevers, Felicitas Engel, Annika Gauss, Wolfgang Herzog, Robin Spiller, Miriam Goebel-Stengel, Hubert Mönnikes, Viola Andresen, Frieling Thomas, Jutta Keller, Christian Pehl, Christoph Stein-Thöringer, Gerard Clarke, Timothy G Dinan, Eamonn M Quigley, Gregory Sayuk, Magnus Simrén, Jonas Tesarz, Gudrun Rappold, Lukas van Oudenhove, Rainer Schaefert, Beate Niesler
Sabrina Berens, Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg 69120, Germany
Yuanjun Dong, Nikola Fritz, Verena Wahl, Cristina Martinez, Stefanie Schmitteckert, Gudrun Rappold, Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
Yuanjun Dong, Felicitas Engel, Jonas Tesarz, Rainer Schaefert, Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
Jutta Walstab, Department of Human Molecular Genetics, University of Heidelberg, Heidelberg 69120, Germany
Mauro D'Amato, Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio 48160, Spain
Mauro D'Amato, IKERBASQUE, Basque Foundation for Science, Bilbao 48001, Spain
Mauro D'Amato, Tenghao Zheng, Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
Felix Boekstegers, Justo Lorenzo Bermejo, Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
Cristina Martinez, Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Av. Alcalde Rovira Roure, Lleida 25198, Spain
Egbert Clevers, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven 3000, Belgium
Annika Gauss, Department of Gastroenterology, Infectious Diseases and Intoxications, University of Heidelberg, Heidelberg 69120, Germany
Wolfgang Herzog, Department of General Internal Medicine and Psychosomatics, Heidelberg University, Heidelberg 69120, Germany
Robin Spiller, Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2QL, United Kingdom
Miriam Goebel-Stengel, Helios Klinikum Rottweil, Rottweil 78628, Germany
Hubert Mönnikes, Department of Medicine, Institute of Neurogastroenterology (H.M.), Martin-Luther-Hospital, Belin 14193, Germany
Viola Andresen, Israelitisches Krankenhaus in Hamburg, Hamburg 22297, Germany
Frieling Thomas, Internal Medicine II, Helios Klinikum Krefeld, Krefeld 47805, Germany
Jutta Keller, Israelitisches Krankenhaus Hamburg, Hamburg 22297, Ghana
Christian Pehl, Krankenhaus Vilsbiburg, Vilsbiburg 84137, Germany
Christoph Stein-Thöringer, Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Gerard Clarke, Timothy G Dinan, Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
Eamonn M Quigley, Medicine in Digestive Disorders, Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist, Houston, TX 77030, United States
Gregory Sayuk, Division of Gastroenterology, Washington University School of Medicine, Department of Psychiatry, School of Medicine, John Cochran Veteran Affairs Medical Center, St. Louis, MO 63110, United States
Magnus Simrén, Department of Internal Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg SE-41685, Sweden
Gudrun Rappold, Beate Niesler, Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
Lukas van Oudenhove, Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03748, United States
Lukas van Oudenhove, Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven 3000, Belgium
Rainer Schaefert, Department of Psychosomatic Medicine, Division of Internal Medicine, University Hospital Basel, Basel CH-4031, Switzerland
Beate Niesler, Department of Human Molecular Genetics, Heidelberg University, Heidelberg 69120, Germany
Author contributions: Mönnikes H, Keller J, Walstab J and Wahl V performed the experiments; Dong Y, Berens S, Schaefert R, Clevers E and Walstab J carried out data analyses; Berens S, Engel F, Gauss A, Herzog W, Spiller R, Clarke G, Dinan TG, Quigley EM, Sayuk G, Simrén M, Tesarz J, Sayuk G and IBS-Net Germany characterized and enrolled the patients; Dong Y, Berens S, and Schaefert R drafted the manuscript; all authors contributed to discussing and editing of the manuscript; Niesler B, Schaefert R and van Oudenhove L designed and supervised the study and revised and finalized the manuscript; Berens S and Dong Y equally contributed to the paper; Schaefert R and Niesler B shared last authorship.
Institutional review board statement: The study was reviewed and approved by the Ethical Committee, Medical Faculty of the Heidelberg University Hospital (approval No. S067/2010).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: APC Microbiome Ireland has conducted studies in collaboration with several companies, including GSK, Pfizer, Cremo, Suntory, Wyeth, Mead Johnson, Nutricia, 4D Pharma, and DuPont. Dinan TG has been an invited speaker at meetings organized by Servier, Lundbeck, Janssen, and AstraZeneca and has received research funding from Mead Johnson, Cremo, Suntory Wellness, Nutricia, and 4D Pharma. Clarke G has been an invited speaker at meetings organized by Janssen and is receipt of research funding from Pharmavite. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this report.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Beate Niesler, PhD, Academic Fellow, Full Professor, Senior Scientist, Department of Human Molecular Genetics, Heidelberg University, Neuenheimer Feld 366, Heidelberg 69120, Germany. beate.niesler@med.uni-heidelberg.de
Received: July 19, 2021
Peer-review started: July 19, 2021
First decision: August 9, 2021
Revised: August 21, 2021
Accepted: April 22, 2022
Article in press: April 22, 2022
Published online: June 7, 2022
ARTICLE HIGHLIGHTS
Research background

Over the past decades, genetic evidence on the key players within the serotonergic system including the serotonin type 3 (5-HT3) receptor subunit genes (HTR3) accumulated showing association with irritable bowel syndrome (IBS) as well as mental illnesses. However, it has never been explored whether associations of the single-nucleotide polymorphisms (SNPs) of HTR3 genes to depressive and anxiety symptoms can be replicated within IBS.

Research motivation

In order to address this knowledge gap, This multicenter observational study focused on a large IBS patient cohort comprising 768 participants from centers in Germany, Sweden, the United States, the United Kingdom, and Ireland.

Research objectives

The objectives are: (1) To explore the associations between functional HTR3 polymorphisms and psychosomatic burden within an IBS population; (2) To investigate the impact of the HTR3 SNP score on psychosomatic burden, based on our hypothesis that the observed number of minor alleles was associated with specific mental characteristics in IBS patients; and (3) To perform a functional analysis of variant 5-HT3AC receptors.

Research methods

In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs — HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A — were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.

Research results

Bringing together high quality data as well as methodological expertise, our results show that: (1) In the dominant model, HTR3C c.489C>A was correlated with depressive and anxiety symptoms in IBS; (2) A higher number of minor alleles (i.e., the higher the SNP score, which was computed by combining the individual SNP status of HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A) was linked to more severe depressive symptoms in IBS; and (3) The potential relevance of the HTR3C SNP was corroborated in functional assays showing changes in the expression level of 5-HT3AC variant receptors.

Research conclusions

Our results provide the first evidence that the accumulation of HTR3 SNPs (reflected by the SNP score computed by HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A) may play a role in the pathophysiology of depressive and anxiety symptoms in IBS.

Research perspectives

We are confident that these results are of interest to your readership, as they contribute substantially to update current knowledge regarding the role of accumulation of HTR3 SNPs in depressive and anxiety symptoms in IBS patients. In turn, our data will contribute towards standardization and harmonization of genetic research strategies in IBS.