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RESEARCH ARTICLE
Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease
Katie Lloyd, Stamatia Papoutsopoulou, Emily Smith, Philip Stegmaier, Francois Bergey, Lorna Morris, Madeleine Kittner, Hazel England, Dave Spiller, Mike H. R. White, Carrie A. Duckworth, Barry J. Campbell, Vladimir Poroikov, Vitor A. P. Martins dos Santos, Alexander Kel, Werner Muller, D. Mark Pritchard, Chris Probert, Michael D. Burkitt, The SysmedIBD Consortium
Disease Models & Mechanisms 2020 13: dmm044040 doi: 10.1242/dmm.044040 Published 27 November 2020
Katie Lloyd
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
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  • ORCID record for Katie Lloyd
Stamatia Papoutsopoulou
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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  • ORCID record for Stamatia Papoutsopoulou
Emily Smith
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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Philip Stegmaier
3geneXplain GmbH, Wolfenbuettel 38302, Germany
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Francois Bergey
4LifeGlimmer GmbH, Berlin 12163, Germany
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Lorna Morris
4LifeGlimmer GmbH, Berlin 12163, Germany
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Madeleine Kittner
4LifeGlimmer GmbH, Berlin 12163, Germany
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Hazel England
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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  • ORCID record for Hazel England
Dave Spiller
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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Mike H. R. White
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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Carrie A. Duckworth
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
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  • ORCID record for Carrie A. Duckworth
Barry J. Campbell
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
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Vladimir Poroikov
5Institute of Biomedical Chemistry, Moscow 119435, Russia
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Vitor A. P. Martins dos Santos
4LifeGlimmer GmbH, Berlin 12163, Germany
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Alexander Kel
3geneXplain GmbH, Wolfenbuettel 38302, Germany
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Werner Muller
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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D. Mark Pritchard
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
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Chris Probert
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
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Michael D. Burkitt
1Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3GE, UK
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
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  • For correspondence: michael.burkitt@manchester.ac.uk
6www.sysmedIBD.eu

Handling Editor: Elaine R. Mardis

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ABSTRACT

Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.

This article has an associated First Person interview with the joint first authors of the paper.

Footnotes

  • Competing interests

    V.A.P.M.d.S. is a shareholder and director of GeneXplain GmbH. A.K. is a shareholder and director of LifeGlimmer GmbH.

  • Author contributions

    Conceptualization: M.H.R.W., W.M., C.P., M.D.B.; Methodology: K.L., S.P., P.S., H.E., C.A.D., B.J.C., V.P., V.A.P.M.d.S., M.D.B.; Software: P.S.; Validation: P.S.; Formal analysis: K.L., S.P., P.S., F.B., L.M., M.K., A.K., M.D.B.; Investigation: K.L., S.P., E.S., M.K., H.E., A.K., M.D.B.; Resources: D.S., V.A.P.M.d.S., W.M., D.M.P.; Data curation: K.L., S.P., P.S., F.B., H.E., D.S., A.K., M.D.B.; Writing - original draft: P.S., L.M., H.E., A.K., M.D.B.; Writing - review & editing: K.L., S.P., E.S., D.S., C.A.D., B.J.C., V.P., V.A.P.M.d.S., W.M., D.M.P., C.P., M.D.B.; Visualization: F.B., L.M., H.E., D.S., V.A.P.M.d.S., M.D.B.; Supervision: D.S., B.J.C., V.A.P.M.d.S., W.M., D.M.P., C.P., M.D.B.; Project administration: V.A.P.M.d.S., A.K., W.M., C.P.; Funding acquisition: M.H.R.W., V.A.P.M.d.S., A.K., W.M., C.P.

  • Funding

    This work was supported by the European Union Seventh Framework Programme (FP7/2012-2017) under the SysmedIBD grant, agreement no. 305564.

  • Supplementary information

    Supplementary information available online at https://dmm.biologists.org/lookup/doi/10.1242/dmm.044040.supplemental

  • Received December 31, 2019.
  • Accepted September 8, 2020.
  • © 2020. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Inflammatory bowel diseases
  • NF-κB
  • Drug repositioning
  • Interdisciplinary research
  • Organoids
  • Macrolide
  • Ulcerative colitis
  • Crohn's disease

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RESEARCH ARTICLE
Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease
Katie Lloyd, Stamatia Papoutsopoulou, Emily Smith, Philip Stegmaier, Francois Bergey, Lorna Morris, Madeleine Kittner, Hazel England, Dave Spiller, Mike H. R. White, Carrie A. Duckworth, Barry J. Campbell, Vladimir Poroikov, Vitor A. P. Martins dos Santos, Alexander Kel, Werner Muller, D. Mark Pritchard, Chris Probert, Michael D. Burkitt, The SysmedIBD Consortium
Disease Models & Mechanisms 2020 13: dmm044040 doi: 10.1242/dmm.044040 Published 27 November 2020
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RESEARCH ARTICLE
Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease
Katie Lloyd, Stamatia Papoutsopoulou, Emily Smith, Philip Stegmaier, Francois Bergey, Lorna Morris, Madeleine Kittner, Hazel England, Dave Spiller, Mike H. R. White, Carrie A. Duckworth, Barry J. Campbell, Vladimir Poroikov, Vitor A. P. Martins dos Santos, Alexander Kel, Werner Muller, D. Mark Pritchard, Chris Probert, Michael D. Burkitt, The SysmedIBD Consortium
Disease Models & Mechanisms 2020 13: dmm044040 doi: 10.1242/dmm.044040 Published 27 November 2020

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