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.
Highlights
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
Using RNA-Sequencing, we show that the activation and trans-differentiation of the mesothelial cell niche are driven by epidermal growth factor receptor (EGFR)-signaling, which is significantly upregulated in the presence of gut microbes
The peritoneal button (PB) and cecal ligation and puncture (CLP) components comprise a modular model system with a defined and localized sterile injury due to the PB (Fig. 1a, left panel) and a limited septic insult from the CLP (Fig. 1a, right panel). Both models could be applied individually or in combination (PB + CLP), allowing us to separate the effect of surgical trauma from the effect due to bacterial contamination
Summary
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. Post-surgical peritoneal adhesions are a major health burden for patients and health care providers[6] They are the leading cause of life-threatening intestinal occlusions[7,8,9] and in the United States alone they are responsible for over 300,000 additional abdominal operations per year with annual costs of several billion dollars[6]. Using RNA-Sequencing, we show that the activation and trans-differentiation of the mesothelial cell niche are driven by EGFR-signaling, which is significantly upregulated in the presence of gut microbes These findings are recapitulated in biopsies from human patients. Peritoneal adhesions are reduced in a mouse model by targeting EGFR-signaling with the FDA-approved small molecule inhibitor Gefitinib[15]
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