Inducible, but not constitutive, pancreaticREG/Regisoforms are regulated by intestinal microbiota and pancreatic diseases

Abstract

TheREG/Reggene locus encodes for a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whetherREG/Regfamily members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in human and mouse, pancreas and gut differed inREG/Regisoform levels and preferences, with duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, selectRegmembers in gut and pancreas. TheseRegmembers had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as “inducible” and others as “constitutive”. Indeed, also in models of pancreatic-ductal adenocarcinoma and pancreatitis, only inducibleRegmembers were upregulated in pancreas. While intestinalRegexpression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation ofREG/Regisoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinatedRegresponse.