Gut microbiome alterations in type 1 autoimmune pancreatitis after induction of remission by prednisolone

摘要

Although increasing evidence demonstrates the association between intestinal dysbiosis and pancreatic diseases such as chronic pancreatitis and pancreatic cancer, it remains largely unknown whether intestinal dysbiosis is involved in the immunopathogenesis of autoimmune pancreatitis (AIP). Recently, we found that intestinal dysbiosis mediates experimental AIP via the activation of plasmacytoid dendritic cells (pDCs), which can produce interferon (IFN)-alpha and interleukin (IL)-33. However, candidate intestinal bacteria, which promote the development of AIP, have not been identified. Fecal samples were obtained from type 1 AIP patients before and after prednisolone (PSL) treatment and subjected to 16S ribosomal RNA sequencing to evaluate the composition of intestinal bacteria. Induction of remission by PSL was associated with the complete disappearance ofKlebsiellaspecies from feces in two of the three analyzed patients with type 1 AIP. To assess the pathogenicity ofKlebsiellaspecies, mild experimental AIP was induced in MRL/MpJ mice by repeated injections of 10 mu g of polyinosinic-polycytidylic acid [poly(I:C)], in combination with oral administration of heat-killedKlebsiella pneumoniae. The AIP pathology score was significantly higher in MRL/MpJ mice that received both oral administration of heat-killedK. pneumoniaeand intraperitoneal injections of poly(I:C) than in those administered either agent alone. Pancreatic accumulation of pDCs capable of producing large amounts of IFN-alpha and IL-33 was also significantly higher in mice that received both treatments. These data suggest that intestinal colonization byK. pneumoniaemay play an intensifying role in the development of type 1 AIP.