Intestinal Microbiome‐Macrophage Crosstalk Contributes to Cholestatic Liver Disease by Promoting Intestinal Permeability in Mice

• DOI: 10.1002/hep.31228
• Publication Date: 2020-03-13T18:15:25Z
• Authors: 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
• Keywords: Intestinal Permeability; Pathogenesis; Liver disease

Background and Aims Mounting evidence supports an association between cholestatic liver disease changes in the composition of microbiome. Still, role microbiome pathogenesis this condition remains largely undefined. Approach 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 germ‐free mice conventionalized with from wild‐type, specific pathogen‐free animals. Next, inhibited macrophage activation by depleting these cells using clodronate liposomes inhibiting inflammasome inhibitor NOD‐, LRR‐, pyrin domain‐containing protein 3. Our results demonstrate that cholestasis, accumulation bile acids liver, fails promote injury absence vivo . Additional vitro studies supported endotoxin sensitizes hepatocytes bile‐acid–induced cell death. We also during macrophages contribute promoting intestinal permeability altered through inflammasome, overall leading increased flux into liver. Conclusions contributes cholestasis‐mediated death inflammation mechanisms involving macrophages.