MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome

Carolin Wohlfarth, Stefanie Schmitteckert, Janina D. Härtle, Lesley A. Houghton, Harsh Dweep, Marina Fortea, Ghazaleh Assadi, Alexander Braun, Tanja Mederer, Sarina Pöhner, Philip P. Becker, Christine Fischer, Martin Granzow, Hubert Mönnikes, Emeran A. Mayer, Gregory Sayuk, Guy Boeckxstaens, Mira M. Wouters, Magnus Simrén, Greger LindbergBodil Ohlsson, Peter Thelin Schmidt, Aldona Dlugosz, Lars Agreus, Anna Andreasson, Mauro D'Amato, Barbara Burwinkel, Justo Lorenzo Bermejo, Ralph Röth, Felix Lasitschka, Maria Vicario, Marco Metzger, Javier Santos, Gudrun A. Rappold, Cristina Martinez, Beate Niesler

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.∗61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform HTR4b-2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.∗61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

Original languageEnglish (US)
Article number14680
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Receptors, Serotonin, 5-HT4
Irritable Bowel Syndrome
MicroRNAs
Single Nucleotide Polymorphism
Binding Sites
Protein Isoforms
Gastrointestinal Motility
Brain Diseases
Jejunum
Diarrhea
Down-Regulation
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • General

Cite this

Wohlfarth, C., Schmitteckert, S., Härtle, J. D., Houghton, L. A., Dweep, H., Fortea, M., ... Niesler, B. (2017). MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome. Scientific Reports, 7(1), [14680]. https://doi.org/10.1038/s41598-017-13982-0

MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome. / Wohlfarth, Carolin; Schmitteckert, Stefanie; Härtle, Janina D.; Houghton, Lesley A.; Dweep, Harsh; Fortea, Marina; Assadi, Ghazaleh; Braun, Alexander; Mederer, Tanja; Pöhner, Sarina; Becker, Philip P.; Fischer, Christine; Granzow, Martin; Mönnikes, Hubert; Mayer, Emeran A.; Sayuk, Gregory; Boeckxstaens, Guy; Wouters, Mira M.; Simrén, Magnus; Lindberg, Greger; Ohlsson, Bodil; Schmidt, Peter Thelin; Dlugosz, Aldona; Agreus, Lars; Andreasson, Anna; D'Amato, Mauro; Burwinkel, Barbara; Bermejo, Justo Lorenzo; Röth, Ralph; Lasitschka, Felix; Vicario, Maria; Metzger, Marco; Santos, Javier; Rappold, Gudrun A.; Martinez, Cristina; Niesler, Beate.

In: Scientific Reports, Vol. 7, No. 1, 14680, 01.12.2017.

Research output: Contribution to journalArticle

Wohlfarth, C, Schmitteckert, S, Härtle, JD, Houghton, LA, Dweep, H, Fortea, M, Assadi, G, Braun, A, Mederer, T, Pöhner, S, Becker, PP, Fischer, C, Granzow, M, Mönnikes, H, Mayer, EA, Sayuk, G, Boeckxstaens, G, Wouters, MM, Simrén, M, Lindberg, G, Ohlsson, B, Schmidt, PT, Dlugosz, A, Agreus, L, Andreasson, A, D'Amato, M, Burwinkel, B, Bermejo, JL, Röth, R, Lasitschka, F, Vicario, M, Metzger, M, Santos, J, Rappold, GA, Martinez, C & Niesler, B 2017, 'MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome', Scientific Reports, vol. 7, no. 1, 14680. https://doi.org/10.1038/s41598-017-13982-0
Wohlfarth, Carolin ; Schmitteckert, Stefanie ; Härtle, Janina D. ; Houghton, Lesley A. ; Dweep, Harsh ; Fortea, Marina ; Assadi, Ghazaleh ; Braun, Alexander ; Mederer, Tanja ; Pöhner, Sarina ; Becker, Philip P. ; Fischer, Christine ; Granzow, Martin ; Mönnikes, Hubert ; Mayer, Emeran A. ; Sayuk, Gregory ; Boeckxstaens, Guy ; Wouters, Mira M. ; Simrén, Magnus ; Lindberg, Greger ; Ohlsson, Bodil ; Schmidt, Peter Thelin ; Dlugosz, Aldona ; Agreus, Lars ; Andreasson, Anna ; D'Amato, Mauro ; Burwinkel, Barbara ; Bermejo, Justo Lorenzo ; Röth, Ralph ; Lasitschka, Felix ; Vicario, Maria ; Metzger, Marco ; Santos, Javier ; Rappold, Gudrun A. ; Martinez, Cristina ; Niesler, Beate. / MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{e38998d08d284749ba1e72d2d9262d63,
title = "MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome",
abstract = "Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.∗61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform HTR4b-2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.∗61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.",
author = "Carolin Wohlfarth and Stefanie Schmitteckert and H{\"a}rtle, {Janina D.} and Houghton, {Lesley A.} and Harsh Dweep and Marina Fortea and Ghazaleh Assadi and Alexander Braun and Tanja Mederer and Sarina P{\"o}hner and Becker, {Philip P.} and Christine Fischer and Martin Granzow and Hubert M{\"o}nnikes and Mayer, {Emeran A.} and Gregory Sayuk and Guy Boeckxstaens and Wouters, {Mira M.} and Magnus Simr{\'e}n and Greger Lindberg and Bodil Ohlsson and Schmidt, {Peter Thelin} and Aldona Dlugosz and Lars Agreus and Anna Andreasson and Mauro D'Amato and Barbara Burwinkel and Bermejo, {Justo Lorenzo} and Ralph R{\"o}th and Felix Lasitschka and Maria Vicario and Marco Metzger and Javier Santos and Rappold, {Gudrun A.} and Cristina Martinez and Beate Niesler",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-13982-0",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - MiR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome

AU - Wohlfarth, Carolin

AU - Schmitteckert, Stefanie

AU - Härtle, Janina D.

AU - Houghton, Lesley A.

AU - Dweep, Harsh

AU - Fortea, Marina

AU - Assadi, Ghazaleh

AU - Braun, Alexander

AU - Mederer, Tanja

AU - Pöhner, Sarina

AU - Becker, Philip P.

AU - Fischer, Christine

AU - Granzow, Martin

AU - Mönnikes, Hubert

AU - Mayer, Emeran A.

AU - Sayuk, Gregory

AU - Boeckxstaens, Guy

AU - Wouters, Mira M.

AU - Simrén, Magnus

AU - Lindberg, Greger

AU - Ohlsson, Bodil

AU - Schmidt, Peter Thelin

AU - Dlugosz, Aldona

AU - Agreus, Lars

AU - Andreasson, Anna

AU - D'Amato, Mauro

AU - Burwinkel, Barbara

AU - Bermejo, Justo Lorenzo

AU - Röth, Ralph

AU - Lasitschka, Felix

AU - Vicario, Maria

AU - Metzger, Marco

AU - Santos, Javier

AU - Rappold, Gudrun A.

AU - Martinez, Cristina

AU - Niesler, Beate

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.∗61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform HTR4b-2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.∗61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

AB - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.∗61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform HTR4b-2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.∗61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

UR - http://www.scopus.com/inward/record.url?scp=85032663500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032663500&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-13982-0

DO - 10.1038/s41598-017-13982-0

M3 - Article

AN - SCOPUS:85032663500

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 14680

ER -