Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats.
OBJECTIVE
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.
Keshavarzian
Ali
A
Department of Internal Medicine, Division of Digestive Disease and Nutrition, Rush University Medical Center, Chicago, IL 60612, USA. Ali_Keshavarzian@rush.edu
Farhadi
Ashkan
A
Forsyth
Christopher B
CB
Rangan
Jayanthi
J
Jakate
Shriram
S
Shaikh
Maliha
M
Banan
Ali
A
Fields
Jeremy Z
JZ
D000273:Adipose Tissue / Q000473:pathology; D000437:Alcoholism / Q000150:complications*; D000818:Animals; D002908:Chronic Disease; D019446:Endotoxemia / Q000209:etiology*; D000431:Ethanol / Q000633:toxicity; D005234:Fatty Liver / Q000209:etiology; D005235:Fatty Liver, Alcoholic / Q000209:etiology*; D007249:Inflammation / Q000209:etiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000503:physiopathology; D007422:Intestines / Q000473:pathology / Q000503:physiopathology*; D008099:Liver / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000652:urine; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II