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

Abstract

BackgroundAlcohol-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 methodsWild 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.ResultsAcute-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).ConclusionsOur 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.

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

“…Alcoholic hepatitis did not modify the overall composition of the intestinal microbiota in patients without cirrhosis. A similar result has been recently reported in a mouse model of acute‐on‐chronic alcohol feeding . However, we observed an increase in the abundance of Dorea, Wolbachia and Rothia in noCir_AH patients.…”

“…Conversely, the abundance of bacteria of the Bacteroidetes phylum was lower. Interestingly, these changes are consistent with data from other studies that investigated the intestinal microbiota in alcoholic liver disease and in other liver diseases such as NAFLD, suggesting that these changes may be related to cirrhosis and impaired liver function rather than to the cause of liver disease. These results also confirms the increase seen in Bifidobacterium genus in severe alcoholic hepatitis patients that we previousely reported in a smaller sample of severe alcoholic hepatitis patients .…”

Association of suboptimal health status with intestinal microbiota in Chinese youths

“…Li et al 21 Actinobacteria increased in acute-on-chronic alcohol mice while decreased in cirrhotic patients. 35,36 Increased Synergistetes was found in bile from individuals with opisthorchiasis. 37 As mentioned above, these bacterial abundances are altered in several diseases, but it is difficult to clarify how these bacteria affect the level of ALT/AST.…”

Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice

“…However, the choice of antibiotics is also important: a cocktail of four antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) improved hepatic inflammation and steatosis but did not protect from alcohol-induced increases of ALT/AST aspartate aminotransferase. (42) Furthermore, the nonabsorbable broad-spectrum antibiotic paromomycin failed to improve ALD in patients. (43) Since different antibiotics have various effects on systemic bile acid composition and concentrations as well as on ALD in general, antibiotics have to be carefully selected for future clinical trials.…”