Colesevelam ameliorates non-alcoholic steatohepatitis and obesity in mice

Phillipp Hartmann,Dennis Yamashita,Patrick Stern,Münevver Demir,Mary Conrad,Yi Duan,Bernd Schnabl,Yukiko Miyamoto,Elda Hasa,Lars Eckmann,Sonja Lang

doi:10.1007/s12072-022-10296-w

Abstract

BackgroundObesity, non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality worldwide. Bile acid dysregulation is a pivotal part in their pathogenesis. The aim of this study was to evaluate the bile acid sequestrant colesevelam in a microbiome-humanized mouse model of diet-induced obesity and steatohepatitis.MethodsGerm-free C57BL/6 mice were associated with stool from patients with NASH and subjected to 20 weeks of Western diet feeding with and without colesevelam.ResultsColesevelam reduced Western diet-induced body and liver weight gain in microbiome-humanized mice compared with controls. It ameliorated Western diet-induced hepatic inflammation, steatosis, fibrosis and insulin resistance. Colesevelam increased de novo bile acid synthesis and decreased hepatic cholesterol content in microbiome-humanized mice fed a Western diet. It further induced the gene expression of the antimicrobials Reg3g and Reg3b in the distal small intestine and decreased plasma levels of LPS.ConclusionsColesevelam ameliorates Western diet-induced steatohepatitis and obesity in microbiome-humanized mice.

Highlights

The prevalence of obesity is 19.5% in countries of the Organization for Economic Cooperation and Development [1]
Germ-free C57BL/6 mice were associated with fecal microbiota from two patients with non-alcoholic steatohepatitis (NASH) (Table 1) and subjected to feeding of a Western diet over 20 weeks
Colesevelam treatment resulted in lower absolute body weight and reduced body weight gain compared with Western diet-fed control mice (Fig. 1A–B)

Summary

Introduction

The prevalence of obesity (body mass index ≥ 30 kg/m2) is 19.5% in countries of the Organization for Economic Cooperation and Development [1]. Lifestyle modifications, including a well-balanced diet and daily physical exercise, are the primary treatment options for obesity, NAFLD and NASH [5]. Non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality worldwide. Results Colesevelam reduced Western diet-induced body and liver weight gain in microbiome-humanized mice compared with controls. Colesevelam increased de novo bile acid synthesis and decreased hepatic cholesterol content in microbiome-humanized mice fed a Western diet. It further induced the gene expression of the antimicrobials Reg3g and Reg3b in the distal small intestine and decreased plasma levels of LPS. Conclusions Colesevelam ameliorates Western diet-induced steatohepatitis and obesity in microbiome-humanized mice

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