Introduction
The human gastrointestinal (GI) tract is colonized by more than 100 trillion of microorganisms [1-3]. A large number of diverse microbial species residing in the GI tract play a major role in multiple aspects of host physiology, including the maturation of the systemic and mucosal immune responses, and production and absorption of nutrients [1-3]. There is growing evidence supporting the concept that compositional and functional alterations of the gut microbiome, called intestinal dysbiosis, are associated with the pathogenesis of not only the GI tract but also that of extra-GI disorders [1-3]. Moreover, recent studies have highlighted the importance of intestinal dysbiosis in the development of several pancreatic diseases, such as acute pancreatitis, chronic pancreatitis, and pancreatic cancer [4, 5].
Type 1 autoimmune pancreatitis (AIP) is a pancreatic manifestation of systemic IgG4-related disease (IgG4-RD), a newly established disease entity [6-8]. AIP and IgG4-RD are diagnosed based on elevated serum concentrations of IgG4 antibodies (Abs) and massive infiltration of IgG4-expressing plasma cells into the affected organs [6-8]. Although the immunopathogeneses of AIP and IgG4-RD have been poorly understood, recent identification of candidate autoantigens (autoAgs) strongly suggests that these disorders are driven by excessive adaptive immunity against such target antigens (Ags) [9-11]. Indeed, effector T cell subpopulations, such as T helper type 2 cells, regulatory T cells, and follicular helper T cells, are involved in the generation of IgG4 Ab responses [6]. In addition to the demonstration of the role of adaptive immune responses, studies have provided evidence that innate immunity also affects the development of AIP and IgG4-RD [12-17]. For example, enhanced production of the innate immunity cytokines type I IFN and IL-33 is a prominent feature of experimental AIP and human IgG4-RD [14, 16-19]. Moreover, stimulation of peripheral blood monocytes and basophils isolated from patients with type 1 AIP promotes IgG4 Ab production by B cells isolated from healthy controls in the presence of microbe-associated molecular patterns (MAMPs) [12, 13]. Pathogenic roles played by toll-like receptors (TLRs) recognizing MAMPs have been also implicated because several TLRs are expressed at higher levels in the pancreas and salivary glands of patients with IgG4-RD [15, 17].
Although disturbances in innate immunity underlie the immunopathogenesis of AIP and IgG4-RD, it remains largely unknown whether intestinal dysbiosis promotes the pathogenic innate immune responses characterizing these disorders. We recently provided evidence that intestinal dysbiosis increases the sensitivity to experimental AIP through the activation of type I IFN and IL-33-mediated signaling pathways [20]; however, the role of intestinal dysbiosis in human AIP has not been clarified. In this study, we explored the compositional changes in fecal microbiota in samples obtained from patients with type 1 AIP, before and after treatment with prednisolone (PSL), and found that the induction of remission might be associated with complete disappearance ofKlebsiella species (spp ). Thereafter, we determined the pathogenicity of Klebsiella pneumoniae (K. pneumoniae ) in murine experimental AIP.