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Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice
University of Massachusetts Medical School Faculty Publications
  • Patrick Lowe, University of Massachusetts Medical School
  • Benedek Gyongyosi, University of Massachusetts Medical School
  • Abhishek Satishchandran, University of Massachusetts Medical School
  • Arvin Iracheta-Vellve, University of Massachusetts Medical School
  • Aditya Ambade, University of Massachusetts Medical School
  • Karen Kodys, University of Massachusetts Medical School
  • Donna Catalano, University of Massachusetts Medical School
  • Doyle V. Ward, University of Massachusetts Medical School
  • Gyongyi Szabo, University of Massachusetts Medical School
UMMS Affiliation
Department of Medicine, Division of Gastroenterology; Center for Microbiome Research; Department of Microbiology and Physiological Systems; Graduate School of Biomedical Sciences, Translational Science Program; UMass Metabolic Network
Publication Date
3-28-2017
Document Type
Article
Abstract

BACKGROUND: Alcohol-induced intestinal dysbiosis disrupts homeostatic gut-liver axis function and is essential in the development of alcoholic liver disease. Here, we investigate changes in enteric microbiome composition in a model of early alcoholic steatohepatitis and dissect the pathogenic role of intestinal microbes in alcohol-induced liver pathology.

MATERIALS AND METHODS: Wild type mice received a 10-day diet that was either 5% alcohol-containing or an isocaloric control diet plus a single binge. 16S rDNA sequencing defined the bacterial communities in the cecum of alcohol- and pair-fed animals. Some mice were treated with an antibiotic cocktail prior to and throughout alcohol feeding. Liver neutrophils, cytokines and steatosis were evaluated.

RESULTS: Acute-on-chronic alcohol administration induced shifts in various bacterial phyla in the cecum, including increased Actinobacteria and a reduction in Verrucomicrobia driven entirely by a reduction in the genus Akkermansia. Antibiotic treatment reduced the gut bacterial load and circulating bacterial wall component lipopolysaccharide (LPS). We found that bacterial load suppression prevented alcohol-related increases in the number of myeloperoxidase- (MPO) positive infiltrating neutrophils in the liver. Expression of liver mRNA tumor necrosis factor alpha (Tnfalpha), C-X-C motif chemokine ligand 1 (Cxcl1) and circulating protein monocyte chemoattractant protein-1 (MCP-1) were also reduced in antibiotic-treated alcohol-fed mice. Alcohol-induced hepatic steatosis measured by Oil-Red O staining was significantly reduced in antibiotic treated mice. Genes regulating lipid production and storage were also altered by alcohol and antibiotic treatment. Interestingly, antibiotic treatment did not protect from alcohol-induced increases in serum aminotransferases (ALT/AST).

CONCLUSIONS: Our data indicate that acute-on-chronic alcohol feeding alters the microflora at multiple taxonomic levels and identifies loss of Akkermansia as an early marker of alcohol-induced gut dysbiosis. We conclude that gut microbes influence liver inflammation, neutrophil infiltration and liver steatosis following alcohol consumption and these data further emphasize the role of the gut-liver axis in early alcoholic liver disease.

Rights and Permissions
Copyright: © 2017 Lowe et al.
DOI of Published Version
10.1371/journal.pone.0174544
Source
PLoS One. 2017 Mar 28;12(3):e0174544. doi: 10.1371/journal.pone.0174544. eCollection 2017. Link to article on publisher's site
Comments

Co-author Arvin Iracheta-Vellve is a doctoral student in the Translational Science program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to Article in PubMed

PubMed ID
28350851
Creative Commons License
Creative Commons Attribution 4.0
Citation Information
Patrick Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, et al.. "Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice" Vol. 12 Iss. 3 (2017) ISSN: 1932-6203 (Linking)
Available at: http://works.bepress.com/gyongyi_szabo/208/