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. (Hepatology 2020;72:2090-2108). T he intestine is a selective barrier that prevents pathogenic bacteria translocating to the systemic circulation, while simultaneously allowing nutrient absorption. In the intestine, crosstalk regulation among the microbiome, the immune system, and epithelial cells is essential to preserve barrier function. (1,2) Intestinal permeability is tightly regulated by the immune system as inflammatory cytokines (e.g., tumor necrosis factor [TNF] and interferon gamma) modulate the expression of tight junction (TJ) proteins. (3) In the intestine, the microbiome shapes the immune system, rendering a tolerant environment where microbes and host cells can coexist. (1,2) Reciprocally, inflammation can determine the composition of the intestinal microbiome, (4,5) adding another layer of complexity to the regulation of intestinal permeability and barrier function. The "leaky gut" hypothesis proposes that chronic liver disease is associated with breaching of the
Here, we describe that the SIRT1/mTOR axis regulates metabolic rewiring, inflammasome activation, and autophagy in macrophages, in which SIRT1 overexpression actively contributes to aggravate cholestatic liver disease progression in mice.
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