Intestinal ELF4 Deletion Exacerbates Alcoholic Liver Disease by Disrupting Gut Homeostasis

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.