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.