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

• Published in: Nature communications Vol. 12; no. 1; p. 7316
• Main Authors: Zindel, Joel, Mittner, Jonas, Bayer, Julia, April-Monn, Simon L., Kohler, Andreas, Nusse, Ysbrand, Dosch, Michel, Büchi, Isabel, Sanchez-Taltavull, Daniel, Dawson, Heather, Gomez de Agüero, Mercedes, Asahina, Kinji, Kubes, Paul, Macpherson, Andrew J., Stroka, Deborah, Candinas, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-12-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/21; 13/31; 13/51; 38; 38/1; 38/91; 631/250/516; 64/60; 692/308/575; 692/4020/1503; Abdomen; Abdominal surgery; Adhesion; Amphiregulin; Animals; Bacteria; Complications; Contamination; Disease Models, Animal; Epidermal growth factor; Epidermal growth factor receptors; Epithelium - pathology; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Genetic transformation; Growth factors; Heparin; Humanities and Social Sciences; Humans; Infertility; Intraabdominal surgery; Mesothelium; Mice; Mice, Inbred C57BL; Microbial contamination; Microorganisms; Molecular modelling; multidisciplinary; Myofibroblasts; Pain; Peritoneum; Peritonitis; Peritonitis - pathology; Scars; Science; Science (multidisciplinary); Signaling; Surgery; Tissue Adhesions - genetics; Tissue Adhesions - metabolism; Tissue Adhesions - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27612-x

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.
Abdominal surgery can often lead to complications including the formation of peritoneal adhesions and the molecular mechanisms underlying this process are still unknown. Here, the authors suggest that bacterial contamination drives adhesion formation through mesothelial EGFR signalling.