Alcohol-related changes in the intestinal icrobiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice

Patrick P. Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, Aditya Ambade, Karen Kodys, Donna Catalano, Doyle V. Ward, G. Szabó

Research output: Contribution to journalArticle

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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 (Tnfα), 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.

Original languageEnglish
Article numbere0174544
JournalPLoS One
Volume12
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

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alcoholic hepatitis
Alcoholic Hepatitis
Neutrophil Infiltration
Infiltration
neutrophils
alcohols
inflammation
Alcohols
Inflammation
Liver
mice
antibiotics
liver
Anti-Bacterial Agents
digestive system
fatty liver
Dysbiosis
Alcoholic Liver Diseases
Cecum
Bacterial Load

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Alcohol-related changes in the intestinal icrobiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. / Lowe, Patrick P.; Gyongyosi, Benedek; Satishchandran, Abhishek; Iracheta-Vellve, Arvin; Ambade, Aditya; Kodys, Karen; Catalano, Donna; Ward, Doyle V.; Szabó, G.

In: PLoS One, Vol. 12, No. 3, e0174544, 01.03.2017.

Research output: Contribution to journalArticle

Lowe, PP, Gyongyosi, B, Satishchandran, A, Iracheta-Vellve, A, Ambade, A, Kodys, K, Catalano, D, Ward, DV & Szabó, G 2017, 'Alcohol-related changes in the intestinal icrobiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice', PLoS One, vol. 12, no. 3, e0174544. https://doi.org/10.1371/journal.pone.0174544
Lowe, Patrick P. ; Gyongyosi, Benedek ; Satishchandran, Abhishek ; Iracheta-Vellve, Arvin ; Ambade, Aditya ; Kodys, Karen ; Catalano, Donna ; Ward, Doyle V. ; Szabó, G. / Alcohol-related changes in the intestinal icrobiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. In: PLoS One. 2017 ; Vol. 12, No. 3.
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AU - Gyongyosi, Benedek

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AU - Iracheta-Vellve, Arvin

AU - Ambade, Aditya

AU - Kodys, Karen

AU - Catalano, Donna

AU - Ward, Doyle V.

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N2 - 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 (Tnfα), 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.

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