Abstract
Alcohol liver disease (ALD) is characterized by intestinal barrier disruption and gut dysbiosis. Dysfunction of E74-like ETS transcription factor 4 (ELF4) leads to colitis. We aimed to test the hypothesis that intestinal ELF4 plays a critical role in maintaining the normal function of intestinal barrier and gut homeostasis in a mouse model of ALD. Intestinal ELF4 deficiency resulted in dysfunction of the intestinal barrier. Elf4-/- mice exhibited gut microbiota (GM) dysbiosis with the characteristic of a larger proportion of Proteobacteria. The LPS increased in Elf4-/- mice and was the most important differential metabolite between Elf4-/- mice and WT mice. Alcohol exposure increased liver-to-body weight ratio, and hepatic inflammation response and steatosis in WT mice. These deleterious effects were exaggerated in Elf4-/- mice. Alcohol exposure significantly increased serum levels of TG, ALT, and AST in Elf4-/- mice but not in WT mice. In addition, alcohol exposure resulted in enriched expression of genes associated with cholesterol metabolism and lipid metabolism in livers from Elf4-/- mice. 16S rRNA sequencing showed a decrease abundance of Akkermansia and Bilophila in Elf4-/- mice. In conclusion, intestinal ELF4 is an important host protective factor in maintaining gut homeostasis and alleviating alcohol exposure-induced hepatic steatosis and injury.