Tuo Shao1, Cuiqing Zhao2, Fengyuan Li3, Zelin Gu4, Limimg Liu2, Lihua Zhang5, Yuhua Wang6, Liqing He7, Yunhuan Liu5, Qi Liu8, Yiping Chen9, Hridgandh Donde10, Rui Wang11, Venkatakrishna R Jala12, Shirish Barve13, Shao-Yu Chen14, Xiang Zhang15, Yongping Chen16, Craig J McClain17, Wenke Feng18. 1. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Medicine, University of Louisville, Louisville, KY, USA; First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 2. Department of Medicine, University of Louisville, Louisville, KY, USA; Institute of Virology, Wenzhou University, Wenzhou, Zhejiang, China. 3. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Medicine, University of Louisville, Louisville, KY, USA. 4. Department of Medicine, University of Louisville, Louisville, KY, USA; College of Food Science and Technology, Jilin Agricultural University, Changchun, Jilin, China. 5. Department of Medicine, University of Louisville, Louisville, KY, USA. 6. College of Food Science and Technology, Jilin Agricultural University, Changchun, Jilin, China. 7. Department of Chemistry, University of Louisville, Louisville, KY, USA. 8. Department of Medicine, University of Louisville, Louisville, KY, USA; Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 9. Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 10. Department of Medicine, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA. 11. First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 12. Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA. 13. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Medicine, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA. 14. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA. 15. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Chemistry, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA. 16. First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: chenyongping@wmu.edu.cn. 17. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Medicine, University of Louisville, Louisville, KY, USA; Robley Rex Louisville VAMC, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA. Electronic address: craig.mcclain@louisville.edu. 18. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Medicine, University of Louisville, Louisville, KY, USA; First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA. Electronic address: wenke.feng@louisville.edu.
Abstract
BACKGROUND & AIMS: Alcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia inducible 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. METHODS: Wild-type (WT) and intestinal epithelial-specific Hif1a knockout mice (IEhif1α-/-) were pair-fed modified Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 24 days. Serum levels of alanine aminotransferase and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated. RESULTS: Alcohol feeding increased serum levels of alanine aminotransferase and lipopolysaccharide, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif1α-/- mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin-1 and occludin, in IEhif1α-/- mice. In addition, cathelicidin-related antimicrobial peptide and intestinal trefoil factor were further decreased by alcohol in IEhif1α-/- mice. Metagenomic analysis showed increased gut dysbiosis and significantly decreased Firmicutes/Bacteroidetes ratio in IEhif1α-/- mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif1α-/- mice were also observed. Non-absorbable antibiotic treatment reversed the liver steatosis in both WT and IEhif1α-/- mice. CONCLUSION: Intestinal HIF-1α is essential for the adaptative response to alcohol-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury. LAY SUMMARY: Alcohol consumption alters gut microbiota and multiple intestinal barrier protecting factors that are regulated by intestinal hypoxia-inducible factor 1α (HIF-1α). Absence of intestinal HIF-1α exacerbates gut leakiness leading to an increased translocation of bacteria and bacterial products to the liver, consequently causing alcoholic liver disease. Intestinal specific upregulation of HIF-1α could be developed as a novel approach for the treatment of alcoholic liver disease.
BACKGROUND & AIMS:Alcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia inducible 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. METHODS: Wild-type (WT) and intestinal epithelial-specific Hif1a knockout mice (IEhif1α-/-) were pair-fed modified Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltosedextrin for 24 days. Serum levels of alanine aminotransferase and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated. RESULTS:Alcohol feeding increased serum levels of alanine aminotransferase and lipopolysaccharide, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif1α-/- mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin-1 and occludin, in IEhif1α-/- mice. In addition, cathelicidin-related antimicrobial peptide and intestinal trefoil factor were further decreased by alcohol in IEhif1α-/- mice. Metagenomic analysis showed increased gut dysbiosis and significantly decreased Firmicutes/Bacteroidetes ratio in IEhif1α-/- mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif1α-/- mice were also observed. Non-absorbable antibiotic treatment reversed the liver steatosis in both WT and IEhif1α-/- mice. CONCLUSION: Intestinal HIF-1α is essential for the adaptative response to alcohol-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury. LAY SUMMARY:Alcohol consumption alters gut microbiota and multiple intestinal barrier protecting factors that are regulated by intestinal hypoxia-inducible factor 1α (HIF-1α). Absence of intestinal HIF-1α exacerbates gut leakiness leading to an increased translocation of bacteria and bacterial products to the liver, consequently causing alcoholic liver disease. Intestinal specific upregulation of HIF-1α could be developed as a novel approach for the treatment of alcoholic liver disease.
Authors: Tuo Shao; Zhen Chen; Vasily Belov; Xiaohong Wang; Steve H Rwema; Viksit Kumar; Hualong Fu; Xiaoyun Deng; Jian Rong; Qingzhen Yu; Lixin Lang; Wenyu Lin; Lee Josephson; Anthony E Samir; Xiaoyuan Chen; Raymond T Chung; Steven H Liang Journal: J Hepatol Date: 2020-03-05 Impact factor: 25.083