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.

This study was conducted to develop novel ceramic bone substitute that resembles the autologous bone behavior when used as graft material. Solid-state reaction at 1100°C was performed to synthesize β-tricalcium phosphate (β-TCP) and biphasic calcium phosphate (BCP). The ceramics were further analyzed to characterize phase composition, microstructural properties, cytocompatability and then challenged to regenerate critical bone defects in the parietal bone of rabbits. X-ray diffraction analysis confirmed the production of β-TCP and indicated the synthesis of novel BCP composed of β-TCP and silicocarnotite (calcium phosphate silicate mineral). The cytocompatibility test with human osteoblast cell line revealed enhanced cell proliferation on the BCP ceramic. The novel BCP induced the filling of about 73% of the bone defect with a newly formed bone tissue and an almost complete degradation after 12 weeks of healing. This novel ceramic resembles the autologous bone properties of complete degradation and efficient enhancement of bone formation, making it promising as bone graft material.

Alcohol binge drinking is a heavy pattern of alcohol consumption increasingly used by young people. In a previous study, we reported that young drinkers with a 2-year history of binge alcohol consumption had an overactivation of the innate immune system and peripheral inflammation when compared with controls. In the present study, we measured several biolipids that are fatty acid derivatives belonging to the acylethanolamide or 2-acylglycerol families in the plasma of the same subjects (n = 42; 20 men and 22 women). We found that during abstinence, alcohol binge drinkers had elevated plasma levels of oleoylethanolamide, palmitoleoylethanolamide, arachidonoylethanolamide, dihomo-γ-linolenoyl ethanolamide and linoleoyl ethanolamide, which positively correlated with changes in the mRNA expression of key inflammatory markers in peripheral blood mononuclear cells, such as toll-like receptors (TLR4), pro-inflammatory cytokines/chemokines interleukin-1 beta, interleukin-6 and monocyte chemoattractant protein-1, and cyclooxygenase-2. Additionally, plasma oleoylethanolamide positively correlated with plasma levels of high mobility group box-1, which is a danger-associated molecular pattern and an endogenous TLR4 agonist, specifically in female alcohol binge drinkers. No changes were observed in 2-acylglycerols in alcohol binge drinkers, although sex-related differences in these bioactive lipids as well as in palmitoleoylethanolamide and docosatetraenoylethanolamide levels were detected. These results extend the previous clinical findings observed in patients diagnosed with long-term alcohol use disorder to young users and suggest a prominent role for these lipids in the response to acute alcohol exposure.

In recent years, there has been an exciting focus of research attempting to understand neuropsychiatric disorders from a holistic perspective in order to determine the role of gut microbiota in the aetiology and pathogenesis of such disorders. Thus, the possible therapeutic benefits of targeting gut microbiota are being explored for conditions such as stress, depression or schizophrenia. Growing evidence indicates that there is bidirectional communication between gut microbiota and the brain that has an effect on normal CNS functioning and behavioural responses. Alcohol abuse damages the gastrointestinal tract, alters gut microbiota and induces neuroinflammation and cognitive decline. The relationship between alcohol abuse and hypothalamic-pituitary-adrenal axis activation, inflammation and immune regulation has been well documented. In this review, we explore the connection between microbiota, brain function and behaviour, as well as the mechanisms through which alcohol induces microbiota dysbiosis and intestinal barrier dysfunction. Finally, we propose the study of psychobiotics as a novel pharmaceutical strategy to treat alcohol use disorders.

IntroductionChronic alcohol consumption is known to cause gut dysbiosis (changes in microbiota composition and/or function, disruptive of the normal host–microbiota interactions). However, little is known about the changes that alcohol binge drinking induces in the gut microbiota. Here, we have tested the hypothesis that a protocol of alcohol binge drinking, known to induce neuroinflammation in previous studies, also promotes intestinal dysbiosis, and we explored how oleoylethanolamide (OEA, an acylethanolamide proven to counteract alcohol binge drinking-induced neuroinflammation) pretreatment modulates alcohol-induced dysbiosis.MethodsAlcohol binges were forced by gavage three times per day during 4 consecutive days; OEA pretreatment (intraperitoneal or intragastric) was administered before each alcohol gavage. Stool microbiota composition was assessed by next-generation 16S rRNA gene sequencing, prior and after the 4-day alcohol binge protocol.ResultsAlcohol binge drinking reduced the richness of the gut microbiota and changed the microbial community, reducing Lactobacillus among other genera. Pretreatment with OEA in the alcohol-administered rats decreased the richness, evenness, and Shannon indices to a greater extent with respect to alcohol alone, also changing the community structure. Microbial interactions in the association network were further decreased following OEA administration in the alcohol group, with respect to the water administration. The synergistic interaction between alcohol binge and OEA was affected by the route of administration of OEA, since oral and i.p. administrations differently changed the community structure.ConclusionResults suggest that alcohol binge drinking produces a clear dysbiosis in animals; we observed that the well-known protective actions of OEA in the context of alcohol abuse might not be related to OEA-induced changes in alcohol-induced dysbiosis. These are observational results, and thus, further research will be needed for a complete understanding of the biological significance of the observed changes.