Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure

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.

New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism

“…SCFAs, which are derived from dietary fiber fermentation by the commensal gut microbiota, provide an energy source for intestinal epithelial cells and regulate hepatic glucose and energy metabolism[ 43 - 45 ]. Butyrate-producing probiotic or butyrate supplementation improve intestinal permeability and inhibit HDAC1 expression to alleviate hepatic steatosis and injury[ 46 - 49 ]. In human studies, a reduction in SCFA concentrations, including acetic acid, propionic acid and butyric acid, was observed in patients with severe alcoholic hepatitis[ 43 ].…”

The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases

“…Though studies of the relationship between synbiotics and ALD are much lesser, the beneficial effect of synbiotics in attenuating chronic alcohol intake induced liver injury is observed in mice. 129,130 Synbiotic supplementation was also shown to decrease serum LPS levels in high-risk alcoholic participants and in patients with alcohol-related cirrhosis. 131,132 Intestinal Alkaline Phosphatase IAP is ubiquitously expressed by enterocytes in the proximal small intestine and exists in high concentrations within luminal vesicles secreted by enterocytes on the brush border of the microvilli.…”

Immunological mechanisms and therapeutic targets of fatty liver diseases

“…In murine models of ALD, treatment with probiotics, such as LGG, and synbiotics has shown efficacy in preventing ethanol-induced liver injury. 21,[137][138][139] Similarly, fecal transplant studies in mice have shown some promise. 135 To date, there are limited data on the efficacy of nonabsorbable antibiotics, probiotics or fecal transplants in patient populations; however, one study did find that fecal transplants improved outcomes in patients with alcohol use disorder (AUD).…”