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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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 Lindberg
  • 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
Organisations
External organisations
  • Heidelberg University
  • University of Leeds
  • Mayo Clinic Florida
  • Vall d'Hebron University Hospital
  • Karolinska Institute
  • Martin-Luther-Hospital
  • Washington University in St. Louis
  • University Hospitals Leuven
  • Karolinska University Hospital
  • Skåne University Hospital
  • German Cancer Research Centre
  • University Hospital Heidelberg
  • Wurzburg University Medical Center
  • St James's University Hospital
  • National Center for Toxicological Research
  • Autonomous University of Barcelona
  • University of California, Los Angeles
  • University of Gothenburg
  • Stockholm University
  • Public Health Direction and Biodonostia Research Institute
  • Fraunhofer Institute for Interfacial Engineering and Biotechnology
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Gastroenterology and Hepatology
Original languageEnglish
Article number14680
JournalScientific Reports
Volume7
Issue number1
StatePublished - 2017 Dec 1
Peer-reviewedYes