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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., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1-overexpressing (SIRT oe ) and hepatocyte-specific SIRT1-KO (knockout) mice (SIRT hep-/- ) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24-norursodeoxycholic acid) was tested in BDL/SIRT oe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2 -/- ) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRT oe mice showed exacerbated parenchymal injury whereas SIRT hep-/- mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRT oe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRT hep-/- hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRT oe mice. Interestingly, both SIRT1 overexpression and hepatocyte-specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine-tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage., (© 2018 The Authors Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Introduction: Response to hepatitis C treatment is known to differ by race; and, limited data suggests by ethnicity as well. A lower efficacy of HCV therapy in Latinos has been observed; whether higher doses may improve the response is unknown., Material and Methods: This study used the available data from the patients enrolled in the PROGRESS study and stratified it by race and ethnicity. The primary objectives were to evaluate the early viral kinetic pattern in Latino patients and to assess whether it was improved by higher doses of Peg-IFN alfa-2a and/or RBV, as compared to Caucasian and African American patients., Results: From a total of 1145 patients, 51 (4%) were classified Latino, 886 (77%) Caucasian, 124 (11%) African American and 84 (7%) other. Latinos had a similar virological response between the treatment groups at week 4; but by week 12, achieved a greater response with the higher intensified dose of peginterferon alfa-2a, and remained so at week 72. Caucasians had a greater response at week 4 and week 12 with the intensified dose; but by week 72, the response became similar between the treatment groups. The virological responses for African Americans were unaffected by the doses; and by week 12, were lower than both Latinos and Caucasians. In conclusion, this retrospective analysis provides further evidence for racial/ethnic differences in the response to peginterferon alfa-2a (40KD) plus ribavirin therapy in patients with HCV. Although the sample sizes in this analysis are small for generalized conclusions, the findings are of importance to physicians treating Latinos.