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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 and Pöhner, Sarina, et al. (2017) In Scientific Reports 7(1).
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... (More)

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.

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@article{9e276d9e-f2ac-4b74-807b-8609c09ce36a,
  abstract     = {<p>Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT<sub>4</sub> receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT<sub>4</sub>R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.∗61 T &gt; C within the 5-HT<sub>4</sub> 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 &gt; C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.</p>},
  articleno    = {14680},
  author       = {Wohlfarth, Carolin and Schmitteckert, Stefanie and Härtle, Janina D. and Houghton, Lesley A. and Dweep, Harsh and Fortea, Marina and Assadi, Ghazaleh and Braun, Alexander and Mederer, Tanja and Pöhner, Sarina and Becker, Philip P. and Fischer, Christine and Granzow, Martin and Mönnikes, Hubert and Mayer, Emeran A. and Sayuk, Gregory and Boeckxstaens, Guy and Wouters, Mira M. and Simrén, Magnus and Lindberg, Greger and Ohlsson, Bodil and Schmidt, Peter Thelin and Dlugosz, Aldona and Agreus, Lars and Andreasson, Anna and D'Amato, Mauro and Burwinkel, Barbara and Bermejo, Justo Lorenzo and Röth, Ralph and Lasitschka, Felix and Vicario, Maria and Metzger, Marco and Santos, Javier and Rappold, Gudrun A. and Martinez, Cristina and Niesler, Beate},
  issn         = {2045-2322},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {MiR-16 and miR-103 impact 5-HT<sub>4</sub> receptor signalling and correlate with symptom profile in irritable bowel syndrome},
  url          = {http://dx.doi.org/10.1038/s41598-017-13982-0},
  volume       = {7},
  year         = {2017},
}