Novel pathomechanistic insights into the infected postoperative pancreatic fistula

• Applicant: Dr. Elke Demir
• Subject Area: General and Visceral Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524589371

Pancreatic fistula (PF) is one of the most feared and most problematic complications after pancreatic surgery. The pathophysiology of PF has been barely investigated and is thus poorly understood. In the past five years, our group has performed a series of prospective clinical investigations that uncovered a potential novel role for bacteria, and the type of inflammation within the pancreas, in the emergence of PF. In these studies, we found a striking correlation between the abundance of intestine-derived bacteria (such as Enterobacterales) or multi-drug resistant bacteria (MDRB) in the PF fluid and the occurrence of clinically relevant (Grade B/C) PF. Importantly, this correlation held true not only after pancreato-duodenectomy, but also after distal pancreatectomy, which is typically per se a less contaminated operation, without opening of the intestinal lumen. In our quest for the source of such intestinal bacteria in the PF fluid of DP patients, we recently systematically analysed the bacterial colonization of the human pancreatic duct in patients who underwent pancreatic resection. Here, we found that in the majority (72.2%) of cases, the pancreatic duct of the patients was sterile, which implied that the natural bacterial flora of the human pancreatic duct does not explain on its self the infection of post-operative PF. Therefore, the mechanisms leading to the infection of postoperative PF and to the subsequent trigger of complications deserve further investigation. The proposed project is intended to deepen the insights that our studies provided on the pathomechanisms of PF after pancreatic surgery. In Aim 1, we will analyse whether the more frequent occurrence of complications in the presence of intestinal bacteria in the PF fluid is due to a difference in the protease expression profile of intestinal vs. non-intestinal bacteria. In Aim 2, we will explore whether intestinal bacteria are delivered over lymphatic routes into the PF fluid. In Aim 3, we will analyse the extent of inflammation right at the pancreatic transection plane as a potential trigger that gives rise to the infection of PF. Collectively, over a clinical-microbiological-translational approach, the proposal aims to provide novel clinically actionable targets for preventing and combatting clinically relevant PF after pancreatic surgery.

• DFG Programme: Research Grants