Lactobacillus GG Treatment Ameliorates Alcohol-induced Intestinal Oxidative Stress Gut Leakiness and Liver Injury in a Rat Model of Alcoholic Steatohepatitis

摘要

Since only 30% of alcoholics develop alcoholic liver disease (ALD), a factor other than heavy alcohol consumption must be involved in development of alcohol-induced liver injury. Animal and human studies suggest that bacterial products such as endotoxin are the second key co-factor and oxidant-mediated gut leakiness is one of the sources of endotoxemia. Probiotics have been used to prevent and treat diseases associated with gut-derived bacterial products and disorders associated with gut leakiness. Indeed, “probiotic” Lactobacillus has been successfully used to treat alcohol-induced liver injury in rats. But, the mechanism of action of the potential beneficial effects of Lactobacillus in alcohol liver injury is not known. We hypothesized that probiotics could preserve normal barrier function in an animal model of ALD by preventing alcohol-induced oxidative stress and thus prevent development of hyperpermeability and subsequent alcoholic steatohepatitis. Male Sprague-Dawley rats were gavaged with alcohol twice daily (8gm/kg) for 10 weeks. In addition, alcoholic rats were also treated with once daily gavage of either 2.5 10⁷ live Lactobacillus GG (LGG) or vehicle. Intestinal permeability (baseline and 10wk) was determined using a sugar bolus and GC analysis of urinary sugars. Intestinal and liver tissues were analyzed for markers of oxidative stress and inflammation. In addition livers were assessed histologically for severity of alcoholic steatohepatitis (ASH) and total fat (steatosis). Alcohol-LGG fed rats had significantly (p≤ .05) less severe ASH than alcohol-vehicle fed rats. LGG also improved alcohol-induced gut leakiness and significantly blunted alcohol-induced oxidative stress and inflammation in both intestine and the liver. LGG probiotic gavage significantly ameliorated alcoholic steatohepatitis in rats. This improvement was associated with reduced markers of intestinal and liver oxidative stress and inflammation and preserved gut barrier function. Our study provides a scientific rationale to test probiotics for treatment and/or prevention of alcoholic liver disease in man.