Intestinal HIF‐1α Deletion Exacerbates Alcoholic Liver Disease through Inducing Intestinal Dysbiosis and Barrier Dysfunction

Abstract

ObjectivesAlcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia Induced Factor 1α (HIF‐1α) has been implicated in transcriptional regulation of intestinal barrier integrity and inflammation. We aimed to test the hypothesis that HIF‐1α plays a critical role in gut microbiota homeostasis and the maintenance of intestinal barrier integrity in a mouse model of ALD.MethodsWide type (WT) and intestinal epithelial‐specific HIF‐1α knockout mice (IEhif‐1α−/−) were pair‐fed modified Lieber‐DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 24 days. Serum levels of ALT and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated.ResultsAlcohol feeding increased serum levels of ALT and LPS, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif‐1α−/− mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin‐1 and occludin, in IEhif‐1α−/− mice. In addition, cathelicidin‐related antimicrobial peptide (CRAMP) and intestinal trefoil factor (ITF) were further decreased by alcohol in IEhif‐1α−/− mice. Metagenomic analysis showed an increased gut dysbiosis with a significantly decreased firmicutes/bacteroidetes ratio in IEhif‐1α−/− mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif‐1α−/− mice were observed. Non‐absorbable antibiotics treatment reversed the liver steatosis in both WT and IEhif‐1α−/− mice.ConclusionIntestinal HIF‐1α is essential for the adaptation response to alcohol exposure‐induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.