Intestinal HIF-1α deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction

Tuo Shao; Cuiqing Zhao; Fengyuan Li; Zelin Gu; Limimg Liu; Lihua Zhang; Yuhua Wang; Liqing He; Yunhuan Liu; Qi Liu; Yiping Chen; Hridgandh Donde; Rui Wang; Venkatakrishna R Jala; Shirish Barve; Shao-Yu Chen; Xiang Zhang; Yongping Chen; Craig J McClain; Wenke Feng

doi:10.1016/j.jhep.2018.05.021

Intestinal HIF-1α deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction

J Hepatol. 2018 Oct;69(4):886-895. doi: 10.1016/j.jhep.2018.05.021. Epub 2018 May 25.

Authors

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

Affiliations

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.

Keywords: Alcoholic Liver Disease; Gut Microbiota; Gut-Liver axis; Hypoxia-Inducible Factor-1α; Intestinal Barrier.

MeSH terms

Animals
Dysbiosis*
Feces / microbiology
Hepatitis / etiology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
Intestinal Mucosa / metabolism
Intestines / microbiology*
Liver Diseases, Alcoholic / etiology*
Male
Metagenomics
Mice
Mice, Inbred C57BL

Substances

HIF1A protein, human
Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit

Abstract

MeSH terms

Substances

Grants and funding