Intestinal microbiome‐macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability

Isaacs-Ten, Anna, Echeandia, Marta, Moreno-Gonzalez, Mar, Brion, Arlaine, Goldson, Andrew, Philo, Mark, Patterson, Angela M., Parker, Aimee, Galduroz, Mikel, Baker, David, Rushbrook, Simon M., Hildebrand, Falk and Beraza, Naiara (2020) Intestinal microbiome‐macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability. Hepatology, 72 (6). pp. 2090-2108. ISSN 0270-9139

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Mounting evidence supports an association between cholestatic liver disease and changes in the composition of the microbiome. Still, the role of the microbiome in the pathogenesis of this condition remains largely undefined. To address this, we have used two experimental models, administering ANIT or feeding a 0.1%DDC diet, to induce cholestatic liver disease in germ‐free mice and germ‐free mice conventionalized with the microbiome from WT SPF animals. Next, we have inhibited macrophage activation by depleting these cells using clodronate‐liposomes and inhibiting the inflammasome with a specific inhibitor of Nlrp3. Our results demonstrate that cholestasis, the accumulation of bile acids in the liver, fails to promote liver injury in the absence of the microbiome in vivo. Additional in vitro studies supported that endotoxin sensitizes hepatocytes to bile acid‐induced cell death. We also demonstrate that during cholestasis, macrophages contribute to promoting intestinal permeability and to altered microbiome composition via the activation of the inflammasome, overall leading to increased endotoxin flux into the cholestatic liver. In conclusion, we demonstrate that the intestinal microbiome contributes to cholestasis‐mediated cell death and inflammation via mechanisms involving the activation of the inflammasome in macrophages.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 21 Mar 2020 01:31
Last Modified: 06 Jan 2021 00:54
DOI: 10.1002/hep.31228

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