Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

Haruta, Ikuko; Kikuchi, Ken; Hashimoto, Etsuko; Nakamura, Minoru; Miyakawa, Hiroshi; Hirota, Kaoru; Shibata, Noriyuki; Kato, Hidehito; Arimura, Yutaka; Kato, Yoichiro; Uchiyama, Takehiko; Nagamune, Hideaki; Kobayashi, Makio; Miyake, Yoichiro; Shiratori, Keiko; Yagi, Junji

doi:10.1038/labinvest.2010.40

Cited by 37 publications

(37 citation statements)

References 29 publications

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“…inoculations with avirulent E. coli resulted in none to mild inflammation around the bile duct in the liver. 18 Strikingly, in this study, the repeated exposure of C57BL/6 mice to heat-killed E. coli resulted in AIP-like pathological alterations in the pancreas beginning 1 week after the completion of an 8-week E. coli exposure period. In the same mice, pathological alterations were detected in the salivary glands, but not around the bile ducts in the liver.…”

Section: Discussionmentioning

confidence: 48%

“…Throughout this study, we used heat-killed E. coli, as in our previous study similar PBC-like autoimmune-mediated cholangitis was observed in the mouse livers of not only live-Streptococcus intermedius (S. i)-inoculated mice but also heat-killed-S. i-inoculated mice. 18 Representative mice at 1 week after the final E. coli inoculation showed marked cellular infiltration that consisted of mainly granulocytes, some lymphocytes, and a few plasma cells in the exocrine pancreas. In addition, tubular complexes derived from altered acini, that is, acinar transition, were observed ( Figure 1a).…”

Section: Pathology Of E Coli-inoculated C57bl/6 Micementioning

confidence: 99%

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A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Haruta

Yanagisawa

Kawamura

et al. 2010

Laboratory Investigation

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The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heatkilled Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.

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Section: Discussionmentioning

confidence: 48%

Section: Pathology Of E Coli-inoculated C57bl/6 Micementioning

confidence: 99%

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Haruta

Yanagisawa

Kawamura

et al. 2010

Laboratory Investigation

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“…47 This hypothesis postulates that microbial molecules arising from the intestine and reflecting microbial dysbiosis reach the liver through the portal circulation and initiate an aberrant cholangiocytic response, such as induction of cholangiocyte senescence (see below). In humans, genetic variants of fucosyl transferase 2, a molecule expressed in gut and cholangiocytes, participate in the synthesis of the H antigen oligosaccharide, which serves as a binding moiety for some intestinal bacteria.…”

Section: Pathogenesismentioning

confidence: 99%

Primary Sclerosing Cholangitis

2016

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“…More recently, it was shown that inoculation of Balb/c mice with Staphylococcus intermedius results in nonsuppurative cholangitis and anti-biliary epithelial cell and anti-nuclear antibody synthesis [31], as seen in patients with PSC [32]. In addition, several other infectious models, not the least of which is biliary cryptosporidiosis (which also causes sclerosing cholangitis in humans), demonstrate biochemical, histologic, and/or cholangiographic features of PSC; these and other models are reviewed in detail elsewhere [33].…”

Section: Evidence From Animal Models Supporting the Gut–liver Axis Ofmentioning

confidence: 99%

Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies

Tabibian

O’Hara

Lindor

2014

Scandinavian Journal of Gastroenterology

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Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis. PSC generally progresses to liver cirrhosis, is a major risk factor for hepatobiliary and colonic neoplasia, and confers a median survival to death or liver transplantation of only 12 years. Although it is well recognized that approximately 75% of patients with PSC also have inflammatory bowel disease (IBD), the significance of this association remains elusive. Accumulating evidence now suggests a potentially important role for the intestinal microbiota, and enterohepatic circulation of molecules derived there from, as a putative mechanistic link between PSC and IBD and a central pathobiological driver of PSC. In this concise review, we provide a summary of and perspectives regarding the relevant basic, translational, and clinical data, which, taken together, encourage further investigation of the role of the microbiota and microbial metabolites in the etiopathogenesis of PSC and as a potential target for novel pharmacotherapies.

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Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

Cited by 37 publications

References 29 publications

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies

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