Colesevelam ameliorates non-alcoholic steatohepatitis and obesity in mice
Phillipp Hartmann, Yi Duan, Yukiko Miyamoto, Münevver Demir, Sonja Lang, Elda Hasa, Patrick Stern, Dennis S. Yamashita, Mary Ann Conrad, Lars Eckmann, Bernd Schnabl
Abstract
BACKGROUND: Obesity, 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. METHODS: Germ-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. RESULTS: Colesevelam 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. CONCLUSIONS: Colesevelam ameliorates Western diet-induced steatohepatitis and obesity in microbiome-humanized mice.