Long-term ethanol feeding enhances susceptibility of the liver to orally administered lipopolysaccharides in rats.
BACKGROUND
Endotoxin has been implicated in the pathogenesis and progression of alcoholic liver disease. However, it is still unclear how long-term ethanol feeding affects absorption of endotoxin from the intestine and susceptibility of the liver to gut-derived endotoxin. The object of this study was to determine the effect of long-term ethanol feeding on hepatic susceptibility to orally administered endotoxin.


METHODS
Male Wistar rats that weighed approximately 150 g were pair-fed with an ethanol-containing liquid diet or a control diet for 35 days. In some experiments, 0, 10, or 20 mg/kg of lipopolysaccharides (LPS) was added to the liquid diet for 7 days beginning on day 29. On day 36, the animals were killed for blood biochemistry and histologic examination of the liver. We also determined plasma endotoxin levels after 20 mg/kg of LPS administration using a gastric tube. In another set of experiments, we determined intestinal permeability using FD4 (fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4000 D).


RESULTS
With 10 mg/kg of LPS, serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels were significantly increased in the ethanol-fed rats but not in controls. After 20 mg/kg of LPS administration, more substantial increases in serum ALT and ALP levels were observed in ethanol-fed rats as compared with control diet-fed rats. Plasma endotoxin levels in long-term ethanol-fed rats were higher than those in control rats after intragastric administration of high-dose endotoxin (20 mg/kg). Furthermore, intestinal permeability to FD4 was increased by long-term ethanol administration.


CONCLUSIONS
Long-term ethanol feeding increases intestinal permeability to and absorption of endotoxin, which can sequentially enhance hepatic susceptibility to orally administered endotoxin. This model has potential as a subclinical experimental model for the study of alcoholic liver disease.
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hironao
H
Tamai
Yoshineri
Y
Horie
Shinzo
S
Kato
Hirokazu
H
Yokoyama
Hiromasa
H
Ishii
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D007408:Intestinal Absorption / Q000187:drug effects / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000276:immunology* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000276:immunology / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D008070:Lipopolysaccharides; D000431:Ethanol