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Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling

Author

Listed:
  • Joel Zindel

    (University of Bern
    University of Calgary)

  • Jonas Mittner

    (University of Bern)

  • Julia Bayer

    (University of Bern)

  • Simon L. April-Monn

    (University of Bern)

  • Andreas Kohler

    (University of Bern)

  • Ysbrand Nusse

    (University of Calgary)

  • Michel Dosch

    (University of Bern)

  • Isabel Büchi

    (University of Bern)

  • Daniel Sanchez-Taltavull

    (University of Bern)

  • Heather Dawson

    (University of Bern)

  • Mercedes Gomez de Agüero

    (University of Bern)

  • Kinji Asahina

    (Keck School of Medicine of the University of Southern California
    Shiga University of Medical Science)

  • Paul Kubes

    (University of Calgary)

  • Andrew J. Macpherson

    (University of Bern)

  • Deborah Stroka

    (University of Bern)

  • Daniel Candinas

    (University of Bern)

Abstract

Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery.

Suggested Citation

  • Joel Zindel & Jonas Mittner & Julia Bayer & Simon L. April-Monn & Andreas Kohler & Ysbrand Nusse & Michel Dosch & Isabel Büchi & Daniel Sanchez-Taltavull & Heather Dawson & Mercedes Gomez de Agüero & , 2021. "Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27612-x
    DOI: 10.1038/s41467-021-27612-x
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    References listed on IDEAS

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    1. Adrian Fischer & Tim Koopmans & Pushkar Ramesh & Simon Christ & Maximilian Strunz & Juliane Wannemacher & Michaela Aichler & Annette Feuchtinger & Axel Walch & Meshal Ansari & Fabian J. Theis & Kenji , 2020. "Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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