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

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, Kinji Asahina, Paul Kubes, Andrew J. Macpherson, Deborah Stroka and Daniel Candinas
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Joel Zindel: University of Bern
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
Paul Kubes: University of Calgary
Andrew J. Macpherson: University of Bern
Deborah Stroka: University of Bern
Daniel Candinas: University of Bern

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27612-x

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