miR-16 and miR-103 impact 5-HT                        4                         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 Lindberg; Bodil 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

doi:10.1038/s41598-017-13982-0

miR-16 and miR-103 impact 5-HT ₄ 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^*

^*Corresponding author for this work

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Abstract

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT ₄ receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT ₄ R 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-HT ₄ 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 language	English
Article number	14680
Pages (from-to)	1-14
Number of pages	14
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-13982-0
Publication status	Published - 31 Oct 2017
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Wohlfarth, C., Schmitteckert, S., Härtle, J. D., Houghton, L. A., Dweep, H., Fortea, M., Assadi, G., Braun, A., Mederer, T., Pöhner, S., Becker, P. P., Fischer, C., Granzow, M., Mönnikes, H., Mayer, E. A., Sayuk, G., Boeckxstaens, G., Wouters, M. M., Simrén, M., ... Niesler, B. (2017). miR-16 and miR-103 impact 5-HT ₄ receptor signalling and correlate with symptom profile in irritable bowel syndrome. Scientific Reports, 7(1), 1-14. Article 14680. https://doi.org/10.1038/s41598-017-13982-0

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title = "miR-16 and miR-103 impact 5-HT 4 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-HT 4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT 4 R 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-HT 4 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",

note = "Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher. ",

year = "2017",

month = oct,

day = "31",

doi = "10.1038/s41598-017-13982-0",

language = "English",

volume = "7",

pages = "1--14",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Springer, Springer Nature",

number = "1",

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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-HT ₄ receptor signalling and correlate with symptom profile in irritable bowel syndrome', Scientific Reports, vol. 7, no. 1, 14680, pp. 1-14. https://doi.org/10.1038/s41598-017-13982-0

miR-16 and miR-103 impact 5-HT ₄ receptor signalling and correlate with symptom profile in irritable bowel syndrome. / Wohlfarth, Carolin; Schmitteckert, Stefanie; Härtle, Janina D. et al.
In: Scientific Reports, Vol. 7, No. 1, 14680, 31.10.2017, p. 1-14.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - miR-16 and miR-103 impact 5-HT 4 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

N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2017/10/31

Y1 - 2017/10/31

N2 - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT 4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT 4 R 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-HT 4 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-HT 4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT 4 R 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-HT 4 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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U2 - 10.1038/s41598-017-13982-0

DO - 10.1038/s41598-017-13982-0

M3 - Article

C2 - 29089619

AN - SCOPUS:85032663500

SN - 2045-2322

VL - 7

SP - 1

EP - 14

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 14680

ER -

miR-16 and miR-103 impact 5-HT ₄ receptor signalling and correlate with symptom profile in irritable bowel syndrome

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