Liver metabolomics identifies bile acid profile changes at early stages of alcoholic liver disease in mice

Abstract

Alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. The liver sustains the earliest and the greatest degree of tissue injury due to chronic alcohol consumption and it has been estimated that alcoholic liver disease (ALD) accounts for almost 50% of all deaths from cirrhosis in the world. In this study, we used a modified Lieber-DeCarli (LD) diet to treat mice with alcohol and simulate chronic alcohol drinking. Using an untargeted metabolomics approach, our aim was to identify the various metabolites and pathways that are altered in the early stages of ALD. Histopathology showed minimal changes in the liver after 6 weeks of alcohol consumption. However, untargeted metabolomics analyses identified 304 metabolic features that were either up- or down-regulated in the livers of ethanol-consuming mice. Pathway analysis revealed significant alcohol-induced alterations, the most significant of which was in the FXR/RXR activation pathway. Targeted metabolomics focusing on bile acid biosynthesis showed elevated taurine-conjugated cholic acid compounds in ethanol-consuming mice. In summary, we showed that the changes in the liver metabolome manifest very early in the development of ALD, and when minimal changes in liver histopathology have occurred. Although alterations in biochemical pathways indicate a complex pathology in the very early stages of alcohol consumption, bile acid changes may serve as biomarkers of the early onset of ALD.