Alcohol Preference Impacts Multi-Organ Transcriptome in MetALD.

BACKGROUND/OBJECTIVES: Alcohol use disorder (AUD) is a major public health issue with rising global occurrence and metabolic consequences. Modeling the addictive behaviors associated with AUD remains inadequate and elusive. Even more so, models that are representative of AUD in concert with excessive caloric intake are limited. Some consequences of chronic alcohol use overlap with the metabolic phenotype of hypercaloric diets. Recently characterized metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD) helps to differentiate these conditions. This study aims to investigate metabolic phenotypes and gene expression alterations in MetALD mice that are grouped by alcohol preference based on blood phosphatidylethanol levels and alcohol consumption.

METHODS: Mice were fed high-fat and chow diets, with water and 10% EtOH, for 13 weeks. mRNA sequencing was performed across multiple tissues including brain, liver, skeletal muscle, ileum, and white adipose tissue, and gut microbiome diversity was evaluated via 16S sequencing.

RESULTS: Key findings included reduced glucagon in alcohol-preferring mice with no significant differences in dyslipidemia and hepatic steatosis. Additionally, we observed reduced gut microbiome diversity and Wnt signaling with elevated acute-phase response genes in ileum tissue. Reduced Wnt and Hippo signaling in the brain and liver, respectively, was also revealed. Other gene ontologies discovered included increased neural inflammation and adipose mitochondrial translation. Nek3, Ntf3, Cux1, and Irf6 expression changes were shared across at least three tissues and may be potential biomarkers of alcohol addiction.

CONCLUSIONS: This novel model assists future intervention research in the characterization of MetALD and identifies potential biomarkers of alcohol preference.