The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation

Schrumpf, Elisabeth; Kummen, Martin; Valestrand, Laura; Greiner, Thomas U.; Holm, Kristian; Arulampalam, Velmurugesan; Reims, Henrik M.; Baines, John F.; Bäckhed, Fredrik; Karlsen, Tom H.; Blumberg, Richard S.; Hov, Johannes R.; Melum, Espen

doi:10.1016/j.jhep.2016.09.020

Cited by 60 publications

(60 citation statements)

References 36 publications

(41 reference statements)

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“…Several mechanisms may explain the increase of the bile acids pool, including upregulation of cholesterol 7α‐hydroxylase (Cyp7A1) induced by both chronic and acute alcohol consumption and/or a decrease in bile acids excretion in the bile and subsequent release in the plasma in the context of AH. Moreover, it has also been suggested that the intestinal microbiota can contribute to biliary inflammation, which could impair bile acids circulation. These hypotheses are supported by the increased levels of primary and conjugated plasma bile acids in the Cir_sAH patients and decrease in the proportion of secondary plasma bile acids and total faecal bile acids.…”

Section: Discussionmentioning

confidence: 71%

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

Ciocan

Voican

Wrzosek

et al. 2018

Aliment Pharmacol Ther

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Section: Discussionmentioning

confidence: 71%

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

Ciocan

Voican

Wrzosek

et al. 2018

Aliment Pharmacol Ther

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“…While in models of acute hepatic injury such as acetaminophen- and alcohol-induced hepatotoxicity GF mice were protected from hepatic disease 25, 26 . In a spontaneous biliary inflammation model, GF NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice 9 . It might be that in those models immune-mediated mechanisms were dominant, and the microbiota might be participated in immune cell activation.…”

Section: Discussionmentioning

confidence: 95%

“…The gut microbiota can influence or modulate chronic liver disease 7 . In the absence of the intestinal microbiota, germ-free mdr2 -/- mice had exacerbated primary sclerosing cholangitis 8 , while germ-free NOD.c3c4 mice had attenuated spontaneous biliary inflammation 9 . Whether the gut microbiota participates in the hepatobiliary pathogenesis during C. sinensis infection is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

The gut microbiota regulates mouse biliary regenerative responses

Liu¹,

Yan²,

Zhang³

et al. 2019

Preprint

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17Injury to the biliary epithelium triggers cholangiopathies. However, factors involved in 18 regulating the pathogenesis remains incompletely understood. Here, we report that the 19 gut microbiota is important in regulating hepatobiliary fibroproliferative regenerative 20 process. In helminth Clonorchis sinensis-induced bile duct injury model, wild-type mice 21 showed more extensive peribiliary fibroproliferative responses than non-littermate IL-33-22 deficient mice. However, these reactions could be attenuated by co-housing of the 23 animals together. In the meantime, the relatively fibroproliferative-resistant IL-33-24 deficient mice could become fibroproliferative-responsive especially in large intrahepatic 25 bile duct by antibiotics treatment. Furthermore, microbiota-derived metabolite butyrate 26 was able to inhibit biliary organoid expansion in vitro and temper 3,5-diethoxycarbonyl-27 1,4-dihydrocollidine-induced biliary fibrosis in vivo. Together, our data implies a potential 28 way of management of hepatobiliary diseases by modulating gut microbiota. 29 30 31 3 32 33The biliary tree including intrahepatic and extrahepatic bile ducts (IHBD and EHBD) 34 forms the primary path by which bile is secreted by the liver then transported to the gut. 35Disruption of the epithelial lining of bile ducts triggers hepatobiliary inflammation, 36 fibrosis, and even malignant transformation, which collectively were referred as 37 cholangiopathies. The cholangiopathies account for substantial morbidity and mortality 38 and are often progressive that lead to end-stage liver disease. Despite the severe 39 disease phenotypes, the molecular and cellular effectors and their relationships to 40 cholangiopathies remain poorly defined 1 . 41A number of animal models have been generated to provide in vivo tools to 42 investigate the mechanisms of biliary repair and, eventually, to test the efficacy of 43 innovative treatments 2 . Each of the animal model has its own limitations in translating 44 to human settings. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC)-feeding in mice 45 recapitulated pathogenic hallmarks of human primary sclerosing cholangitis (PSC) 3 . 46Clonorchis sinensis is a food-borne helminth that naturally cause cholangiopathies 4,5 . 47During progression of biliary injury induced by the worm, a disorganized expansion of 48 bile ducts and recruitment of inflammatory cells known as ductular reaction (DR) 49 become so prominent that not only biliary epithelial but also the peribiliary glands 50 (PBGs), clusters of epithelial cells residing in the submucosal compartment of the bile 51 duct, show hyperplasia and proliferation. PBGs participate in the secretion of neutral, 52 carboxylated, and sulphated mucins into the bile duct lumen. The term adenomatous 53 hyperplasia or chronic proliferative cholangitis has been used to describe this 54 4 phenomenon 6 . What is the underlying molecular and cellular mechanisms of these 55 biliary responses remains incompletely understood. 56The gut microbiota can influence or m...

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“…The sections were blindly scored on the following parameters: portal inflammation (0–3), dilatations of intrahepatic bile ducts (0–3), fibrosis (0–3), and bile infarcts (0–2), where a score of 0 indicates no pathology, as previously described (Schrumpf et al. ). Portal inflammation and dilatation of intrahepatic bile ducts are the two most pronounced features in this mouse model (Koarada et al.…”

Section: Methodsmentioning

confidence: 99%

The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation

et al. 2017

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Natural killer T (NKT) cells are activated by lipid antigens presented by CD1d molecules and represent a major lymphocyte subset of the liver. NOD.c3c4 mice spontaneously develop biliary inflammation in extra‐ and intrahepatic bile ducts. We demonstrated by flow cytometry that invariant NKT (iNKT) cells were more abundant in the thymus, spleen, and liver of NOD.c3c4 mice compared to NOD mice. iNKT cells in NOD.c3c4 mice displayed an activated phenotype. Further, NOD and NOD.Cd1d ‐/‐ mice were irradiated and injected with NOD.c3c4 bone marrow, and injection of NOD.c3c4 bone marrow resulted in biliary infiltrates independently of CD1d expression in recipient mice. Activation or blocking of NKT cells with α‐galactosylceramide or anti‐CD1d antibody injections did not affect the biliary phenotype of NOD.c3c4 mice. NOD.c3c4.Cd1d ‐/‐ mice were generated by crossing NOD.Cd1d ‐/‐ mice onto a NOD.c3c4 background. NOD.c3c4.Cd1d ‐/‐ and NOD.c3c4 mice developed the same extent of biliary disease. This study demonstrates that iNKT cells are more abundant and activated in the NOD.c3c4 model. The portal inflammation of NOD.c3c4 mice can be transferred to irradiated recipients, which suggests an immune‐driven disease. Our findings imply that NKT cells can potentially participate in the biliary inflammation, but are not the primary drivers of disease in NOD.c3c4 mice.

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The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation

Cited by 60 publications

References 36 publications

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

The gut microbiota regulates mouse biliary regenerative responses

The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation

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