Genetic and immunologic aspects of acute pancreatitis: An odyssey

Abstract

Acute pancreatitis is the leading cause of acute hospitalization for gastrointestinal diseases. The course of acute pancreatitis is often mild and self-limiting, but in 15-25% of patients, pancreatitis is severe with an increased mortality risk. Infectious complications, and especially bacterial infection of pancreatic necrosis, are commonly accepted as the major cause of death for patients with this disease. The aim of the research described in this thesis was to gain more insight in some of the determinants of acute pancreatitis, including the risk of developing the severe form of acute pancreatitis or complications during the disease. Part 1 of this thesis reports on five genetic association studies with a focus on genes involved in intestinal barrier function, the innate immune system and the renin-angiotensin-system. We explored genetic variants in Myosin IXB (MYO9B) and two tight junction adaptor genes (PARD3 and MAGI2) in Dutch and German patients with acute pancreatitis. We showed that two variants in MYO9B were associated with acute pancreatitis, but not with complications of the disease. We also studied single nucleotide polymorphisms in genes of the Toll-like receptor pathway (TLR-2, TLR-4, CD14, MyD88, IRAK3 and IRAK4), in the MBL2 gene encoding mannose-binding lectin (MBL), and in NOD2/CARD15. These genes belong to the innate immune system, but also play a role in mucosal barrier function. One of the haplotypes of the MBL2 gene was associated with the development of acute pancreatitis. A loss-of-function variant in the NOD2/CARD15 gene was associated with an increased risk of dying from acute pancreatitis in a combined cohort of Dutch, German and US patients. The other genes studied did not show association with development, course or outcome of acute pancreatitis. Using a combined cohort of Dutch, German and British patients with acute pancreatitis, we showed that the renin gene appears to be associated with the development of acute pancreatitis. Also a genetic variant resulting in lower ACE activity was associated with alcohol-related acute pancreatitis. In Part 2, we investigated whether FXR, a nuclear bile salt receptor, together with one of its target genes FGF19, and FGF21, an atypical fibroblast growth factor that functions as a hormone in the digestive tract, are involved in the pathogenesis of acute pancreatitis. Using a mouse model of acute pancreatitis, we showed that FXR knock-out mice did not develop more severe pancreatitis than wild-type mice. In addition, in patients with acute pancreatitis, FXR genetic variants were not associated with the disease. Additionally, we addressed the role of FGF21 in acute pancreatitis. FGF21 levels were clearly elevated in patients with acute pancreatitis, but this was not specific for this disease. We could not show association of FGF21 genetic variants with acute pancreatitis. In Part 3, the impact of pretreatment with probiotics on intestinal barrier function in rats with acute pancreatitis was explored to further unravel the pathophysio­logy of acute pancreatitis and to try and understand the effects of probiotics at the level of the small bowel mucosa. Finally, the role of FXR in inflammatory bowel disease was studied further.