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

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 arose from the mesothelium. This transformation was driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands Amphiregulin and Heparin-binding Epidermal Growth Factor, were sufficient to induce these changes. Correspondingly, EGFR inhibition led to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients were enriched in EGFR positive cells of mesothelial origin and human mesothelium showed 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE186658 | GEO | 2021/11/08

REPOSITORIES: GEO

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Project description:Rationale: Adhesion formation is a frequent complication after abdominal surgery. Adhesion formation might be reduced by laparoscopic surgery, however sound evidence is lacking. Colorectal surgery would be a good clinical model to investigate adhesion formation between open and laparoscopic surgery because of the adhesion formation propensity of colorectal surgery. However, a randomized controlled study to provide direct evidence is unlikely because of large numbers of patients needed for such a trial and the difficulty to check for adhesion formation at second surgery. Therefore we investigate adhesion formation after laparoscopic and open colorectal surgery for malignancy at liver surgery for metastases. Objective: The aim of our study is to compare the incidence of adhesions after laparoscopic versus open surgery for colorectal malignancies during liver resection for colorectal metastases. Study design: The study is designed as a prospective observational cohort study. Study population: All consecutive, adult patients undergoing laparotomy or laparoscopy for intended liver resection or radio frequency ablation for liver metastases of a colorectal malignancy in whom inspection of the middle and lower abdomen is possible to map adhesions. Main study parameters/endpoints: * Primary endpoint is incidence of adhesions to the ventral abdominal wall around the site of the original incision. * Secondary endpoints are episodes of bowel obstruction between index surgery and liver surgery; total incidence of adhesions; extent of adhesions; Zühlke classification of adhesions; performance of adhesiolysis; duration of adhesiolysis; peroperative complications: enterotomy, seromuscular injury, inadvertent organ injury during adhesiolysis; postoperative complications: delayed diagnosed perforation, SAE’s. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This study is an observational study. The existence of adhesions will be assessed during laparotomy or laparoscopy for the treatment of liver metastases. The laparotomy is indicated for medical treatment and should not be enlarged solely for the assessment of adhesions nor will the operating time be influenced for this purpose. Adhesions and peroperative complications have to be scored by the operating surgeon during or directly after surgery. The postoperative complications have to be scored during the postoperative course by the doctors on the ward. These assessments do not interfere with the treatment of the patients.

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

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