Acute Pancreatitis: Surgery, Pathophysiology and Probiotic Prophylaxis

Acute pancreatitis is a challenging disease with a clinical course that is often difficult to predict. In severe acute pancreatitis, mortality increases significantly if intestinal bacteria translocate from the intestine and infect pancreatic necrosis. Surgical and prophylactic treatment strategies are challenged by complex pathophysiology of the disease. This thesis addresses some key aspects of acute pancreatitis: surgical management, pathophysiology and probiotic prophylaxis. Outcome in patients treated surgically in the UMC Utrecht between 1988 and 2001 was in line with reports in literature. Further scientific research is needed to identify the optimal surgical technique to remove infected pancreatic necrosis. If the colon seems to have become necrotic during acute pancreatitis, resection is the preferred strategy to prevent potential colonic perforation or additional complications during follow up. Retroperitoneal spread of pancreatic enzymes is often the cause of colonic involvement in severe acute pancreatitis. Gallstones are a major cause of acute pancreatitis, but the role of bile composition in the pathogenesis of gallstone pancreatitis is unknown. In a rat model of gallstone pancreatitis, hydrophobic model biles induced severe acute pancreatitis, whereas hydrophilic model biles did not. Phospholipids reduced and cholesterol crystals increased severity. These results confirm a role of bile composition in biliary pancreatitis. Bacterial translocation during the course of acute pancreatitis is of major influence to outcome. Animal models have been proven indispensable as a tool to study its pathophysiology, but some major aspects of bacterial translocation, including origin of translocating bacteria, remain unclear. The colon is often identified as the source of translocating bacteria. However, in a rat model, subtotal colectomy prior to acute pancreatitis resulted in duodenal bacterial overgrowth which correlated significantly with bacterial translocation to the pancreas. This confirms a role for the small bowel in the pathophysiology of bacterial translocation. Prophylactic antibiotics do not improve outcome. Prophylactic multispecies probiotics may offer an effective alternative to reduce bacterial translocation. A multispecies probiotic mixture (Ecologic 641) was specifically designed to target three major aspects of bacterial translocation: 1) small bowel bacterial overgrowth, 2) mucosal barrier failure and 3) immune responses. In a rat model of acute pancreatitis modification of intestinal flora with Ecologic 641 reduced pathogen growth in the duodenum and reduced bacterial translocation. Clinical course was less fulminant and late mortality was reduced in rats receiving probiotics. Specific cytokine signatures were associated with early mortality or bacteraemia potentially causing late mortality. Probiotics reduced pro-inflammatory immune responses, and indirectly seemed to reduce late phase immune paralysis. In a mouse model of acute pancreatitis, probiotics completely prevented late phase mucosal barrier failure. A number of issues concerning probiotics remain to be addressed. These include clinical efficacy, the effect of timing of probiotic treatment, locations and mechanisms of probiotic action, and choice of probiotic strains for specified pathophysiological targets. However, data presented and discussed in this thesis demonstrate that prophylactic multispecies probiotics possess great potential as a future prophylactic treatment strategy in acute pancreatitis.