Abstract
Alcohol overconsumption disrupts the gut microbiota and intestinal barrier, which decreases the production of beneficial microbial metabolic byproducts and allows for translocation of pathogenic bacterial-derived byproducts into the portal-hepatic circulation. As ethanol is known to damage liver sinusoidal endothelial cells (LSEC), here we evaluated dietary supplementation with a previously studied synbiotic on gut microbial composition, and hepatocyte and LSEC integrity in mice exposed to ethanol. We tested a chronic-binge ethanol feeding mouse model in which C57BL/6 female mice were fed ethanol (5% vol/vol) for 10 days and provided a single ethanol gavage (5 g/kg body weight) on day 11, 6 h before euthanasia. An ethanol-treatment group also received oral supplementation daily with a synbiotic; and an ethanol-control group received saline. Control mice were pair-fed and isocalorically substituted maltose dextran for ethanol over the entire exposure period; they received a saline gavage daily. Ethanol exposure decreased gut microbial abundance and diversity. This was linked with diminished expression of adherens junction proteins in hepatocytes and dysregulated expression of receptors for advanced glycation end-products; and this coincided with reduced expression of endothelial barrier proteins. Synbiotic supplementation mitigated these effects. These results demonstrate synbiotic supplementation, as a means to modulate ethanol-induced gut dysbiosis, is effective in attenuating injury to hepatocyte and liver endothelial barrier integrity, highlighting a link between the gut microbiome and early stages of acute liver injury in ethanol-exposed mice.
Highlights
Overconsumption of alcohol can contribute to chronic liver diseases, resulting in hepatic steatosis, alcoholic hepatitis, with progression to fibrosis, cirrhosis, and hepatocellular carcinoma
We found that synbiotic supplementation protects the expression of intestinal epithelial barrier proteins in the proximal colon and decreases hepatic markers for inflammation and oxidative stress (4-HNE), and decreases steatosis induced by chronic-binge ethanol exposure [14]
Since we previously reported that synbiotic synbiotic supplementation protected against hepatic steatosis and markers of oxidative stress [14], supplementation protected against hepatic steatosis and markers of oxidative stress [14], we analyzed weliver analyzed liver sections in mice forexpression the protein of Advanced glycation end-products (AGE)
Summary
Overconsumption of alcohol can contribute to chronic liver diseases, resulting in hepatic steatosis, alcoholic hepatitis, with progression to fibrosis, cirrhosis, and hepatocellular carcinoma (reviewed elsewhere [1]). Chronic ethanol exposure leads to defenestration in liver sinusoidal endothelial cells (LSEC) [2], which allows for sinusoidal blood and contents to associate with hepatocytes, hepatic stellate cells, and Kupffer cells [3]. Acute toxin exposure, such as acetaminophen and ethanol induces gaps in the LSEC and induces centrilobular sinusoidal collapse which reduces blood flow, and impairs the microcirculatory exchange of nutrients and clearance of waste products [4]. Oxidative metabolites of ethanol, such as acetaldehyde and reactive oxygen species (ROS), are main contributors to alcoholic liver injury (ALD). Oxidation of alcohol in the liver yields acetaldehyde by mainly alcohol dehydrogenase and to a lesser extent
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