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Inflammatory bowel disease
Original research
Alzheimer’s disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis
  1. Lena Erkert1,
  2. Reyes Gamez-Belmonte1,
  3. Melanie Kabisch1,
  4. Lena Schödel1,
  5. Jay V Patankar1,2,
  6. Miguel Gonzalez-Acera1,
  7. Mousumi Mahapatro1,
  8. Li-Li Bao1,
  9. Christina Plattner3,
  10. Anja A Kühl4,
  11. Jie Shen5,
  12. Lutgarde Serneels6,
  13. Bart De Strooper6,7,
  14. TRR241 IBDome Consortium,
  15. Markus F Neurath1,2,
  16. Stefan Wirtz1,2,
  17. Christoph Becker1,2
    1. 1Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
    2. 2Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
    3. 3Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
    4. 4iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
    5. 5Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
    6. 6VIB Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
    7. 7UK Dementia Research Institute@UCL, University College London, London, UK
    1. Correspondence to Professor Christoph Becker, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany; christoph.becker{at}uk-erlangen.de

    Abstract

    Objective Mutations in presenilin genes are the major cause of Alzheimer’s disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis.

    Design Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis.

    Results Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation.

    Conclusion Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.

    • GUT INFLAMMATION
    • IBD BASIC RESEARCH
    • INTESTINAL EPITHELIUM
    • EPITHELIAL BARRIER
    • MALNUTRITION

    Data availability statement

    Data are available in a public, open access repository. Data are available on reasonable request. Transcriptomic data of the IBDome cohort will be made available to the scientific community on acceptance of the manuscript. Bulk RNA sequencing data of Psen1 and Psen2 deficient mice have been submitted to ArrayExpress. The publicly available datasets used in this study are published under the accession codes: E-MTAB-9850 and GSE6731.

    https://doi.org/10.1136/gutjnl-2023-331622

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      Data availability statement

      Data are available in a public, open access repository. Data are available on reasonable request. Transcriptomic data of the IBDome cohort will be made available to the scientific community on acceptance of the manuscript. Bulk RNA sequencing data of Psen1 and Psen2 deficient mice have been submitted to ArrayExpress. The publicly available datasets used in this study are published under the accession codes: E-MTAB-9850 and GSE6731.

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      Footnotes

      • Collaborators Imke Atreya (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Raja Atreya (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Petra Bacher (Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany), (Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany), Christoph Becker (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Christian Bojarski (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Nathalie Britzen-Laurent (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Caroline Bosch-Voskens (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Hyun-Dong Chang (Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany), Andreas Diefenbach (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Microbiology, Infectious Diseases and Immunology), Claudia Günther (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Ahmed N. Hegazy (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Kai Hildner (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Christoph S. N. Klose (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Microbiology, Infectious Diseases and Immunology), Kristina Koop (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Susanne Krug (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Anja A. Kühl (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Moritz Leppkes (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Rocío López-Posadas (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Leif S.-H. Ludwig (Berlin Institute für Gesundheitsforschung, Medizinische System Biologie, Charité – Universitätsmedizin Berlin), Clemens Neufert (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Markus Neurath (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Jay Patankar (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Christina Plattner (Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria), Magdalena Prüß (Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany), Andreas Radbruch (Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany), Chiara Romagnani (Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany), Francesca Ronchi (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Microbiology, Infectious Diseases and Immunology), Ashley Sanders (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), (Max Delbrück Center für Molekulare Medizin, Charité – Universitätsmedizin Berlin), Alexander Scheffold (Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany), Jörg-Dieter Schulzke (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Michael Schumann (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Sebastian Schürmann (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Britta Siegmund (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Michael Stürzl (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Zlatko Trajanoski (Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria), Antigoni Triantafyllopoulou (Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany), (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Rheumatology and Clinical Immunology, Berlin, Germany), Maximilian Waldner (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Carl Weidinger (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany), Stefan Wirtz (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany), Sebastian Zundler (Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany).

      • Contributors Study concept, design, literature search, experiments, analysis, interpretation of data, critical revision of the manuscript, manuscript drafting: LE, RG-B and CB. Experimentation and analysis: LE, RG-B, MK, LSchödel, JVP, MG-A, L-LB, CP and SW. Material support: MM, JS, LSerneels, BDS and AAK. Intellectual contributions during manuscript editing, acquisition of funds and supervision: MFN, SW and CB. CB acts as guarantor.

      • Funding This work was funded by the DFG project TRR241 (A03, B05, C04 and Z03), CRC1181 (C05), CRU5024 (A03) and individual grants under project numbers 418055832 and 510624836. The Interdisciplinary Center for Clinical Research (IZKF: J68, A76, J96, A93) also supported this project. Parts of the results of this study are subject of the doctoral thesis of LE.

      • Competing interests None declared.

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.