Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats

Ali Keshavarzian, Ashkan Farhadi, Christopher B Forsyth, Jayanthi Rangan, Shriram Jakate, Maliha Shaikh, Ali Banan, Jeremy Z Fields
Journal of Hepatology 2009, 50 (3): 538-47

BACKGROUND/AIMS: Not all alcoholics develop liver disease (ALD). Thus, excessive ethanol consumption is necessary, but not sufficient, to induce alcoholic steatohepatitis (ASH) and ALD. Since endotoxemia is present in patients with ALD, it has been proposed that gut-derived, circulating endotoxin is the necessary co-factor for ASH. But, it is not known whether endotoxemia is the consequence or the trigger for ALD. Accordingly, the aim of the current study was to determine whether endotoxemia occurs prior to development of ASH and whether gut leakiness is the primary cause of the endotoxemia in an animal model of ASH.

METHODS: Time courses for development of gut hyperpermeability, nitric oxide production, oxidative injury to the gut, endotoxemia, and liver injury were assessed in rats during 10 weeks of daily alcohol gavage.

RESULTS: Liver fat and serum transaminase increased after 2 weeks, but evidence of liver cell injury and inflammation (ASH) occurred after 8 weeks. Gut leakiness, intestinal oxidative injury, and endotoxemia occurred in weeks 2-4 and progressed thereafter.

CONCLUSIONS: That alcohol-induced gut leakiness and endotoxemia preceded steatohepatitis indicates they are not the consequence of ALD. Our data support the hypothesis that gut leakiness resulting in endotoxemia is a key co-factor (trigger) for ASH.

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