title: Acute ethanol administration inhibits Toll-like receptor 4 signaling pathway in rat intestinal epithelia.
abstract: Excess alcohol intake, as in binge drinking, increases susceptibility to microbial pathogens. Alcohol impairs macrophage function by suppression of the Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of acute ethanol intake on the TLR4 pathway in rat intestinal epithelia, which usually encounters luminal antigens at first and participates in the development of intestinal immunity. Twenty Wistar rats were randomly assigned to an ethanol group given ethanol as a 25% (v/v) solution in water at 7.5 g/kg, or a control group given saline, by oral gavage daily for 3 days. The epithelial histology and ultrastructure, the intestinal microflora, peripheral and portal venous plasma lipopolysaccharide (LPS) levels, and somatostatin (SST) levels in the peripheral plasma and small intestine were evaluated. Somatostatin receptor 2 (SSTR2), TLR4, TANK binding kinase-1 (TBK1), activated nuclear factor-κB (NF-κB), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the intestinal mucosa were assayed. LPS responsiveness with or without SST pretreatment was assayed in vitro by quantification of TLR4, TBK1, activated NF-κB, IFN-γ and TNF-α in isolated intestinal epithelia. Mucosal damage was observed in the ethanol group by light and electron microscopy. Escherichia coli cultures were unchanged in rat intestine of the ethanol group compared with controls, but lactobacilli cultures were reduced (p < 0.05). LPS levels increased in peripheral and portal venous plasma (p < 0.05), but mucosal TLR4, TBK1, nuclear NF-κB, IFN-γ and TNF-α were unchanged in the ethanol group. LPS treatment in vitro up-regulated the level of TLR4, TBK1 and nuclear NF-κB as well as the production of IFN-γ and TNF-α in isolated intestinal epithelia in the control (p < 0.05), but not the ethanol group. The stimulatory effects of LPS on intestinal epithelia isolated from the control group were significantly inhibited by SST pretreatment (p < 0.05). The peripheral plasma and intestinal levels of SST and the mucosal expression of SSTR2 in the ethanol group were significantly higher than in the control group (p < 0.05). These findings suggest the hyposensitivity of intestinal epithelial TLR4 to LPS induced by acute alcohol abuse probably through ethanol per se and ethanol-enhanced intestinal mucosal SST pathway may be a novel mechanism for increased susceptibility to intestinal pathogens.
authors: Department of Gastroenterology, Sichuan Provincial Hospital, Chengdu 610041, PR China.
authors: Chao
authors: C
authors: Zhou
authors: Ji
authors: J
authors: Zhao
authors: Jing
authors: J
authors: Li
authors: Haiying
authors: H
authors: Wang
authors: Chengwei
authors: C
authors: Tang
mesh_terms: D000818:Animals; D000431:Ethanol / Q000008:administration & dosage*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000431:Ethanol