DSS‐induced intestinal damage exacerbates liver injury by acute alcohol exposure in mice: role of intestinal hypoxia‐inducible factor 1α

Abstract

Inflammatory bowel diseases (IBD) are characterized by repeated injury of the mucosa and loss of the intestinal epithelial barrier function, which has also been considered one of the major contributors to the development of alcoholic liver disease (ALD). Hypoxia induced factor 1α (HIF1α) plays a critical role in the intestinal barrier integrity by regulating several mucus and tight junction protecting genes. In this study, we hypothesize that intestinal HIF1α deletion increases intestinal permeability resulting in an elevation of endotoxemia in the dextran sulfate sodium (DSS)‐induced colitis murine model, and this exacerbates acute alcohol‐induced liver injury. To test this hypothesis, Wide type (WT) and intestinal epithelial‐specific HIF1α knockout (IEhif‐1α−/−) mice were fed 3% dextran sodium sulfate (DSS) in drinking water for 7 days and a bolus of alcohol at 6g/kg was gavaged 6 hours before sacrificing. DSS decreased body weight of the WT mice, and this decrease was more significant in the IEhif‐1α−/− mice. Intestinal inflammation and mucosal abnormality were increased in the IEhif‐1α−/− mice than that in the WT mice, along with an elevated serum LPS concentration, indicating an increase in intestinal barrier permeability. Binge alcohol, in addition to DSS, further damaged barrier function and increased serum LPS concentrations. Further analyses showed that DSS+alcohol induced a decrease in the expression of caludin‐1 and intestinal trefoil factor, which play an important role in intestinal barrier integrity. Intestine epithelial HIF1α deletion aggravated this effect. Unlike alcohol exposure, DSS treatment alone did not affect liver function in either WT or IEhif‐1α−/− mice, as determined by serum ALT and AST analysis. However, ALT and AST levels were significantly elevated in DSS + alcohol treatment groups, and these elevations were more pronounced in IEhif‐1α−/− mice. HIF‐1α deletion also enhanced alcohol‐induced hepatic triglyceride concentration in DSS‐treated mice. Hepatic histology analysis showed that IEhif‐1α−/− mice had an increased fat accumulation and inflammatory cell infiltration, confirming the hepatic steatosis and liver injury. In conclusion, our results demonstrated that DSS‐induced colitis increases intestinal permeability and endotoxemia, resulting in an worsened liver steatosis and injury due to binge alcohol exposure. Deleting intestinal HIF1α further exacerbates these deleterious effects. Targeting intestinal HIF1α might be an effective strategy for the treatment of colitis‐associated ALD.Support or Funding InformationSupported by NIH and Veterans Administration.