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

Abstract

Abstract Objective 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, ask how contamination of gut microbes influences post-surgical adhesion formation. Methods We make use of an experimental mouse model that allows to investigate how wound repair and adhesion formation differs between sterile injury vs. sterile injury in combination with microbial contamination. We use genetic lineage tracing, bulk- and single-cell RNA-Sequencing to identify potential mechanisms of the observed differences. Next, we use two human cohort studies to confirm the target identified by RNA-Sequencing. Finally, the identified targets are experimentally confirmed by going back to the mouse model. Results 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. 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.