Intestinal ELF4 Deletion Exacerbates Alcoholic Liver Disease by Disrupting Gut Homeostasis
Description
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. Wide type (WT) and Intestinal epithelial specific ELF4 knockout (Elf4-/-) mice were pair-fed the Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 21 days. Serum levels of triglyceride (TG), the alanine aminotransferase (ALT) and aspartate transaminase (AST) were determined. RNA-Seq was used to quantify the gene expression of livers. Fecal microbiota was assessed with 16s rRNA sequencing. And fecal metabolite profiles were quantified with ultrahigh performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS). Intestinal ELF4 deficiency resulted in dysfunction of the intestinal barrier. Tight junction associated genes including TJP1 and OCLN had decreased expression in both Elf4-/- mice and ELF4-/- CACO2 cells. 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. What’s more, an increase in the phylum Proteobacteria was positively correlated with higher LPS levels. 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 feeding significantly increased serum levels of TG, ALT and AST in Elf4-/- mice but not in WT mice. Alcohol feeding decreased the Tjp1 mRNA expression, which was further exacerbated by ELF4 deletion. 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.