Orai1 in pancreatic ductal cells mediates pancreas-intestinal crosstalk in experimental acute pancreatitis via the secretion of antimicrobial peptide REG3B in pancreatic juice

Pancreatic ductal epithelial cells (PDECs) play a crucial role in the development of acute pancreatitis (AP). We and others have previously shown that Orai1 inhibitor confers protection against AP severity. In this study, we aim to investigate the effect and the underlying mechanisms of Orai1 in PDECs on experimental AP and its-associated intestinal damage. We found that Orai1 deletion in PDECs markedly mitigated the prolonged elevation of calcium and preserved the decreased mitochondrial membrane potential due to sodium taurocholate (NaT) or palmitoleic acid (POA) exposure. PDECs-specific Orai1 deletion notably lessened pancreatitis severity and restored the impaired pancreatic juice secretion during AP. Increased expression of tight junction proteins and decreased intestinal permeability and inflammation were observed in duodenal and colonic tissue of PDECs-specific Orai1 knockout mice. Furthermore, the deletion of Orai1 protected against pancreatitis-associated dysbiosis in the duodenum, but not in the colon. Mechanically, this protective effect was partially attributed to the enhanced secretion of REG3B in pancreatic juice during AP. Finally, intraperitoneal administration of REG3B partially alleviated AP severity and pancreatitis-associated intestinal injury and inflammation. Collectively, these findings suggest that Orai1 inhibitor may serve as potential therapeutic strategy for the management of AP and associated intestinal injury.