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

Abstract

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)-α 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 of Klebsiella species from feces in two of the three analyzed patients with type 1 AIP. To assess the pathogenicity of Klebsiella species, mild experimental AIP was induced in MRL/MpJ mice by repeated injections of 10 μg of polyinosinic-polycytidylic acid [poly(I:C)], in combination with oral administration of heat-killed Klebsiella pneumoniae. The AIP pathology score was significantly higher in MRL/MpJ mice that received both oral administration of heat-killed K. pneumoniae and intraperitoneal injections of poly(I:C) than in those administered either agent alone. Pancreatic accumulation of pDCs capable of producing large amounts of IFN-α and IL-33 was also significantly higher in mice that received both treatments. These data suggest that intestinal colonization by K. pneumoniae may play an intensifying role in the development of type 1 AIP.

Intestinal Dysbiosis and Autoimmune Pancreatitis

“…Alterations in gut microbiota composition may function as a disease intensifier rather than a direct pathogenic factor through activation of pDCs which produce IFN-α and IL-33 and M2 macrophages which express TLR7. It should be noted, however, that recent data regarding fecal microbiota composition in human AIP were obtained by using a limited number of patients ( 22 , 36 ). Thus, fecal microbiota analyses using a large number of AIP patients are absolutely required.…”

“…Oral administration of prednisolone (PSL) induces clinical remission in most cases of AIP and IgG4-RD (11)(12)(13)(14). We initially addressed alterations in fecal microbiota composition in three patients with IgG4-associated AIP (22). Although a variety of alterations in fecal microbiota were seen after induction of remission in these three patients, the most striking finding was the complete disappearance of Klebsiella pneumoniae (K. pneumoniae) from the feces in two of three patients.…”

“…We found that the severity of experimental AIP was greater in mice treated with oral administration of K. pneumoniae and injection of 10 μg of poly (I:C) than in those with either treatment alone. Moreover, the development of severe AIP in mice that received both treatments was accompanied by pancreatic accumulation of pDCs producing IFN-α and IL-33 ( 22 ). These data strongly suggest that gut colonization of K. pneumoniae increases the sensitivity of AIP through activation of pDCs which produce IFN-α and IL-33.…”

“…The second possibility is that pDCs or M2 macrophages in the pancreas are directly activated by intestinal bacteria translocated into this organ. We think that the latter is more likely because pancreatic pDCs isolated from mice exhibiting AIP produced large amounts of IFN-α and IL-33 upon stimulation with K. pneumoniae ( 22 ). Moreover, the fact that pDCs from the Peyer’s patches are unable to produce IFN-α upon stimulation with TLR7 and TLR9 ligands supports the second option ( 38 ).…”

“…However, little has been understood regarding the molecular mechanisms of intestinal dysbiosis and how they induce chronic fibro-inflammatory responses in the pancreas of AIP patients. Recently, we found that intestinal dysbiosis causes chronic fibro-inflammatory responses in the pancreas through activation of plasmacytoid dendritic cells (pDCs) with the ability to produce a large amount of IFN-α and IL-33 ( 21 , 22 ). In this Mini-review article, we discuss the relationship between intestinal dysbiosis and AIP.…”