Intestinal microbiome-macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability in mice

Anna Isaacs-Ten, Marta Echeandia, Mar Moreno-Gonzalez, Arlaine Brion, Andrew Goldson, Mark Philo, Angela M. Patterson, Aimee Parker, Mikel Galduroz, David Baker, Simon M. Rushbrook, Falk Hildebrand, Naiara Beraza

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)
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Abstract

Background and Aims: 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. 

Approach and Results: To address this, we have used two experimental models, administering alpha-naphtylisocyanate or feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet, to induce cholestatic liver disease in germ-free mice and germ-free mice conventionalized with the microbiome from wild-type, specific pathogen-free animals. Next, we have inhibited macrophage activation by depleting these cells using clodronate liposomes and inhibiting the inflammasome with a specific inhibitor of NOD-, LRR-, and pyrin domain-containing protein 3. 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 through activation of the inflammasome, overall leading to increased endotoxin flux into the cholestatic liver. 

Conclusions: We demonstrate that the intestinal microbiome contributes to cholestasis-mediated cell death and inflammation through mechanisms involving activation of the inflammasome in macrophages.

Original languageEnglish
Pages (from-to)2090-2108
Number of pages19
JournalHepatology
Volume72
Issue number6
Early online date13 Mar 2020
DOIs
Publication statusPublished - Dec 2020

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