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