Research Article: Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice

Date Published: March 28, 2017

Publisher: Public Library of Science

Author(s): Patrick P. Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, Aditya Ambade, Karen Kodys, Donna Catalano, Doyle V. Ward, Gyongyi Szabo, Gianfranco D. Alpini.


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.

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.

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).

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.

Partial Text

The National Institute on Alcohol Abuse and Alcoholism reports that 17 million adults in the US have an alcohol use disorder, approximately 1.4 million adults receive treatment for this disorder, and close to 88,000 people die each year of alcohol related causes [1]. Chronic excessive alcohol use can lead to liver cirrhosis and alcoholic hepatitis, a condition with high mortality. The trigger(s) for acute alcoholic hepatitis are yet to be identified; however, the importance of the gut-liver axis is increasingly recognized in alcoholic liver disease and in decompensation in other chronic liver diseases.

This study provides, for the first time, insight into the microbiome changes that occur in the mouse model of early acute alcoholic steatohepatitis. The model does not induce differences in the α-diversity of or the β-diversity between intestinal bacterial communities in alcohol and pair-fed mice. However specific taxonomic shifts did reflect important changes in the makeup of the bacterial community in alcohol-fed mice and represent early indicators of developing alcoholic liver disease. Specifically, we identify Akkermansia decrease as an early change in alcohol-induced intestinal dysbiosis. Our data also reveal the influence of gut bacterial load on liver neutrophil infiltration, inflammation signaling and steatotic changes.

This study supports the hypothesis that the gut microbiota are impacted by alcohol consumption and that the acute-on-chronic feeding model alters the microflora at multiple taxonomic levels. We conclude that gut microbes influence liver inflammation, neutrophil infiltration and liver steatosis following alcohol consumption and these data further emphasize the gut-liver axis, even in early alcohol-induced inflammation.




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