Perioperative gut microbiome modulation to prevent infection-related postoperative complications following bowel surgery for inflammatory bowel disease

• Applicant: Dr. Kamacay Cira
• Subject Area: General and Visceral Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552519942

Patients with inflammatory bowel disease (IBD) require surgical interventions at a notably higher frequency compared to the general population. They begin their surgical journey in an already compromised state. This unavoidable circumstance leads to higher postoperative septic complications, including anastomotic leakage (AL), higher rates of reoperations, increased morbidity, and even mortality. In this proposal, we hypothesize that the increased risk of postoperative complications in patients with IBD is attributable to the combination of a preexisting and substantial disruption of the intestinal barrier, alterations in microbiota composition and function, local intestinal Phosphate (Pi) depletion due to chronic inflammation, and the compounding effect of immunosuppressive or antibiotic treatments as well as nutritional deficiencies. Therefore, the primary objective of this project is to investigate the complex interplay between the gut microbiome, intestinal inflammation/immunity, and anastomotic healing by modeling the real-world clinical circumstances of anastomotic surgery as occurs in patients with IBD, to further our understanding of the pathogenesis of gut-derived sepsis in active colitis. This should be achieved by investigating the contribution of a preoperatively altered composition (community structure, membership, diversity and richness) and function (metabolites, local mineral composition - e.g. Pi) of the gut microbiome, on septic complications, specifically AL, aggravated by Western diet (high fat, low fiber), antibiotic use, immunosuppression, perioperative local extracellular depletion of Pi, and surgical stress, following colorectal surgery in a murine model of chemically induced active colitis. Comprehensive histological, molecular, and microbiological analyses will be conducted and accompanied by endoscopic evaluations of the anastomoses on the day of surgery and postoperative day 3 and 7. Furthermore, the model will be used to explore the therapeutic potential of a known oral cytoprotective polymer, Pi-PEG, to mitigate postoperative septic complications. Utilizing Pi-PEG to suppress bacterial virulence, promote beneficial microbiota growth, and shield the gut from bacterial invasion, stands in stark contrast to the current strategy of antibiotic treatments. Unlike antibiotics, which indiscriminately eliminate microbiota, including health-promoting probiotic organisms, the approach applied in this project aims at selectively targeting harmful bacteria while preserving beneficial microbiota. By elucidating the underlying pathophysiological mechanisms in appropriate animal models, this project shall contribute to a better understanding of intestinal anastomotic healing and identify therapeutic targets for future intervention studies aimed at preventing AL, particularly in vulnerable patient populations such as those with IBD, thereby informing clinical strategies for improving surgical outcomes and clinical care.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. John Alverdy