Multiomic definition of generalizable endotypes in human acute pancreatitis

Acute pancreatitis (AP) is sudden onset pancreas inflammation that causes multiple organ dysfunction syndrome (MODS) and death in certain individuals who develop AP yet minimal systemic inflammation in others. Here, we show that this observed diversity in systemic response and outcome is accompagnied by diversity in molecular subtypes that can be identified using computational analysis of clinical and multiomic data. We integrated co-incident whole blood transcriptomic, plasma proteomic, and serum metabolomic data at serial time points from a cohort of patients presenting with AP and systematically evaluated four different metrics for patient similarity, using unbiased mathematical, biological and clinical measures of internal and external validity. Our results identify four distinct and stable AP endotypes that are characterized by pathway and biomarker combination stereotypes into hypermetabolic, hepatopancreaticobiliary, catabolic and innate immune endotypes. The catabolic endotype in AP strikingly recapitulates a disease endotype previously reported in acute respiratory distress syndrome, a recognized complication of AP. Our findings demonstrate that clinically-relevant and generalizable endotypes exist in AP.

Experimental Models in Syrian Golden Hamster Replicate Human Acute Pancreatitis

The hamster has been shown to share a variety of metabolic similarities with humans. To replicate human acute pancreatitis with hamsters, we comparatively studied the efficacy of common methods, such as the peritoneal injections of caerulein, L-arginine, the retrograde infusion of sodium taurocholate, and another novel model with concomitant administration of ethanol and fatty acid. The severity of pancreatitis was evaluated by serum amylase activity, pathological scores, myeloperoxidase activity, and the expression of inflammation factors in pancreas. The results support that the severity of pathological injury is consistent with the pancreatitis induced in mice and rat using the same methods. Specifically, caerulein induced mild edematous pancreatitis accompanied by minimal lung injury, while L-arginine induced extremely severe pancreatic injury including necrosis and neutrophil infiltration. Infusion of Na-taurocholate into the pancreatic duct induced necrotizing pancreatitis in the head of pancreas and lighter inflammation in the distal region. The severity of acute pancreatitis induced by combination of ethanol and fatty acids was between the extent of caerulein and L-arginine induction, with obvious inflammatory cells infiltration. In view of the advantages in lipid metabolism features, hamster models are ideally suited for the studies of pancreatitis associated with altered metabolism in humans.