Colesevelam Reduces Ethanol-Induced Liver Steatosis in Humanized Gnotobiotic Mice.

Noemí Cabré,Bernd Schnabl,Mary Conrad,Dennis Yamashita,Patrick Stern,Cristina Llorente,Yi Duan

doi:10.3390/cells10061496

Abstract

Alcohol-related liver disease is associated with intestinal dysbiosis. Functional changes in the microbiota affect bile acid metabolism and result in elevated serum bile acids in patients with alcohol-related liver disease. The aim of this study was to identify the potential role of the bile acid sequestrant colesevelam in a humanized mouse model of ethanol-induced liver disease. We colonized germ-free (GF) C57BL/6 mice with feces from patients with alcoholic hepatitis and subjected humanized mice to the chronic–binge ethanol feeding model. Ethanol-fed gnotobiotic mice treated with colesevelam showed reduced hepatic levels of triglycerides and cholesterol, but liver injury and inflammation were not decreased as compared with non-treated mice. Colesevelam reduced hepatic cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1) protein expression, although serum bile acids were not lowered. In conclusion, our findings indicate that colesevelam treatment mitigates ethanol-induced liver steatosis in mice.

Highlights

Alcohol abuse is one of the most important causes for liver disease worldwide [1].Alcohol-related liver disease includes steatosis, fibrosis, cirrhosis, and alcoholic hepatitis [2].Alcoholic hepatitis is the most severe form of alcohol-related liver disease with mortality ranging from 20% to 50% at 28 days and up to 70% at 90 days [3,4]
To determine the effect of colesevelam in a mouse model of ethanol-induced liver disease, germ-free C57BL/6 mice were colonized with stool from two patients with alcoholic hepatitis (Table 1) and subjected to the chronic-binge ethanol feeding model [23]
Histological analysis confirmed that ethanol feeding inCells 2021, 10, x FOR PEER REVIEW creased lipid droplets in H&E- and Oil Red O-stained liver sections, while colesevelam decreased lipid droplet accumulation following ethanol feeding (Figure 3i,k). These results indicate that colesevelam treatment reduces ethanol-induced liver steatosis

Summary

Introduction

Alcohol abuse is one of the most important causes for liver disease worldwide [1].Alcohol-related liver disease includes steatosis, fibrosis, cirrhosis, and alcoholic hepatitis [2].Alcoholic hepatitis is the most severe form of alcohol-related liver disease with mortality ranging from 20% to 50% at 28 days and up to 70% at 90 days [3,4]. Alcohol abuse is one of the most important causes for liver disease worldwide [1]. Alcohol-related liver disease includes steatosis, fibrosis, cirrhosis, and alcoholic hepatitis [2]. Alcoholic hepatitis is the most severe form of alcohol-related liver disease with mortality ranging from 20% to 50% at 28 days and up to 70% at 90 days [3,4]. Current therapies for alcoholic hepatitis remain limited to corticosteroids, almost half of patients cannot tolerate or do not respond to corticosteroid therapy [5,6]. Liver transplantation is the only curative therapy [9,10], but there is limited acceptance of early transplantation as the standard of care treatment

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