Investigating the pathomechanisms of impaired intestinal anastomotic healing in the context of inflammatory bowel disease with focus on immune and mesenchymal cell interaction

• Applicants: Privatdozent Dr. Philipp-Alexander Neumann; Dr. Marie-Christin Weber
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521834138

Medical therapy is still the first line approach for treatment of inflammatory bowel diseases (IBD) and as such oftentimes successful in inducing disease remission. Still, more than 50% of patients with Crohn’s disease and up to 30% of patients with ulcerative colitis require surgical interventions at least once in their lifetime. In most cases, surgical resection of the diseased bowel segments is necessary, followed by surgical suturing in form of anastomosis formation to restore the bowel continuity. Impaired anastomotic healing can lead to anastomotic leakage potentially resulting in abscess formation, peritonitis or even sepsis. Patients with IBD are at higher risk of developing anastomotic leakage due to overwhelming intestinal inflammation and immunosuppressive medical therapy. In order to develop optimal perioperative therapies to dampen inflammatory activity in patients with IBD without inhibiting the healing process, a detailed understanding of the pathomechanisms behind impaired anastomotic healing in these patients is required. During wound healing processes, the precisely orchestrated interaction of immune cells and mesenchymal cells is essential to enable the formation of a functional scar tissue. The aim of this project is thus to investigate the timely cellular and humoral events during anastomotic healing in the context of acute inflammation during colitis as well as immunosuppressive therapy as present in patients with IBD to identify new therapeutic targets to reduce anastomotic complications in these patients. The following sub-objectives will be attended to during this project: First, the effect of colitis as well as immunosuppressive therapy on the recruitment and activation of immune cells (granulocytes, macrophages) and mesenchymal cells to the anastomotic site will be investigated using an in vivo murine IBD model in combination with intestinal anastomosis surgery. Secondly, the effect of altered cytokine and growth factor signaling caused by colitis and immunosuppressive therapy on mesenchymal cell activation and expression of ECM molecules and matrix degrading enzymes within the anastomosis will be investigated. Finally, the findings from the in vivo experiments will be translated to a human ex vivo/in vitro model system using primary intestinal fibroblasts to study the effects of the identified target molecules on the regenerative capacity of these mesenchymal cells. The results of this study shall enhance our understanding of the healing processes after bowel resection surgery in IBD patients and aim to identify therapeutic targets that promote anastomotic healing.

• DFG Programme: Research Grants