Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide

Abstract

The authors contributed equally to this work. BACKGROUND AND PURPOSEChronic alcohol consumption alters the gut-brain axis, but little is known about alcohol binge episodes on the functioning of the intestinal barrier. We investigated the influence of ethanol binges on bacterial translocation, gut inflammation and immunity, and tight junction (TJ) structure and the ability of the biolipid oleoylethanolamide (OEA) to prevent ethanol binge-induced intestinal barrier dysfunction. EXPERIMENTAL APPROACHOEA was injected i.p. before repeated ethanol administration by oral gavage. Plasma, spleen, liver and mesenteric lymph nodes (MLN) were collected in sterile conditions for determination of bacterial load. Immune/inflammatory parameters, TJ proteins and apoptotic markers were determined in colonic tissue by RT-PCR and Western blotting. TJ ultrastructure was examined by transmission electron microscopy. KEY RESULTSEthanol binges induced bacterial translocation to the MLN (mainly) and spleen. Colonic tissues showed signs of inflammation, and activation of innate (Toll-like receptor-4) and adaptive (IgA) immune systems and TJ proteins (occludin and claudin-3) were decreased after ethanol binges. Pretreatment with OEA reduced intestinal inflammation and immune activation and partially preserved the TJ structure affected by alcohol binges but had no effect on alcohol-induced apoptosis. Ultrastructural analyses of colonic TJs revealed dilated TJs in all ethanol groups, with less electron-dense material in non-pretreated rats. The protective effects of i.p. OEA did not reduce bacterial translocation to the MLN. However, intragastric OEA administration significantly reduced plasma LPS levels and bacterial translocation to the MLN. CONCLUSION AND IMPLICATIONSOEA-based pharmacotherapies could potentially be useful to treat disorders characterized by intestinal barrier dysfunction, including alcohol abuse.

Protein inhibitor of activated STAT1 Ser503 phosphorylation‐mediated Elk‐1 SUMOylation promotes neuronal survival in APP/PS1 mice

“…Blinding and random assignment of animals to different groups in this study were similar to that of another study (Anton et al, 2018) and in accordance of the guidelines of BJP. The wild-type animals were randomly divided to control and experimental groups.…”

Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

“…Among the factors that induce the strong immune activation caused by alcohol abuse are: (1) a TLR4 direct agonism; (2) the upregulation of plasma LPS, which is also a TLR4 agonist; and (3) the overproduction of DAMPS such as HMGB1, which magnifies TLR4 activation (Figure 1). It has been shown that OEA reduces the expression of TLR4 innate immune receptors and its signaling pathway both in the brain and in the gut after ethanol binges (Crews et al, 2013; Antón et al, 2017a, 2018). Regarding the increase of plasma LPS, it is very interesting to note that pretreatment with OEA appears to modulate, at least partially, the alcohol-induced increase in plasma levels of LPS (Antón et al, 2017a), reducing the TLR4 activation and inflammation.…”

“…Interestingly, we recently found that OEA pretreatment reduces alcohol-induced elevations in circulant LPS, a reduction that is partial under intraperitoneal (i.p.) treatment (Antón et al, 2017a) and almost total under oral OEA administration (Antón et al, 2018). The origin of such decrease in plasma LPS levels could be a direct action of OEA in the intestinal barrier, modulating gut inflammation and bacteria/bacterial products translocation from the intestinal lumen to the systemic circulation (Antón et al, 2018).…”

Aberrations in peripheral inflammatory cytokine levels in substance use disorders: a meta‐analysis of 74 studies

“…Accumulated evidence suggests that at least part of the drug‐induced inflammation arises from peripheral origins, and in particular from the gut, morphine‐induced gut epithelial barrier dysfunction and subsequent bacteria translocation in mice via Toll‐like receptor signaling [68]. A recent study showed that ethanol binges mainly induced bacterial translocation to the mesenteric lymph nodes and activation of immune systems in rats [69]. Methamphetamine also induced the release of TNF‐α, which leads to intestinal barrier lesion in humans by inducing apoptosis in epithelial cells and altering the structure and function of tight junctions [70].…”