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

: 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.; Simren, M.; Lindberg, G.; Ohlsson, B.; Schmidt, P.T.; Dlugosz, A.; Agreus, L.; Andreasson, A.; D'Amato, M.; Burwinkel, B.; Bermejo, J.L.; Röth, R.; Lasitschka, F.; Vicario, M.; Metzger, M.; Santos, J.; Rappold, G.A.; Martinez, C.; Niesler, B.

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Scientific Reports 7 (2017), Art. 14680, 14 S.
ISSN: 2045-2322
Deutsche Forschungsgemeinschaft DFG
NI 926/4-1
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer IGB ()

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.