Intestinal bacteria and epithelial barrier disruption after alcohol and burn injury

与酒精有关的创伤和烧伤仍然是美国人相当大的健康和经济负担 社会。研究表明，受伤时醉酒的患者更容易患上 与非烧伤患者相比，烧伤患者的发病率和死亡率明显更高 受伤时喝醉了。然而，酒精(乙醇)促进烧伤后的机制 发病机制在很大程度上仍不清楚。肠道屏障功能障碍常常与酒精暴露有关 和重伤。我们的研究表明，酒精中毒合并中度烧伤可导致 肠道组织损伤、渗漏和细菌移位在24小时内显著增加 受伤。我们进一步观察到microRNA(miR-7a和miR-150)和microRNA的表达下降 酒精致小鼠肠上皮细胞(IEC)生物发生成分DROSHA和ArgAerte-2的研究 还有烧伤。此外，乙醇合并烧伤增加了细菌负荷(肠杆菌科)。 小肠。肠杆菌科细菌的增加可能会扰乱细菌/宿主的相互作用，并 激活IECs上表达的模式识别受体(PRR)增强炎症反应 导致酒精和烧伤后的肠道组织损伤和渗漏。我们的假设是 酒精和烧伤后肠道革兰氏阴性菌(即肠杆菌科)的蓄积 扰乱肠道微生物区系与上皮细胞的相互作用，这种相互作用因microRNA动态平衡的改变而加剧， 因此，最终导致肠道炎症和屏障破坏。这一假设将在三个目标中进行检验，这是一个公认的 小鼠酒精中毒及烧伤模型的建立。目标1中的研究旨在描绘 乙醇和烧伤引起肠道细菌改变影响肠屏障的机制 受伤后的正直。目标2将确定肠道细菌的变化是单独发生还是与 缺氧诱导因子-1α的增加影响miR-150和miR-7a的表达以及是否修复miR-150和/或 酒精和烧伤后肠上皮细胞中的miR-7a减少肠道炎症并改善 屏障完整性。此外，目标3中的研究将确定是否重新开始用益生菌治疗动物。 酒精和烧伤后肠道微生物区系和肠道屏障的完整性。调查结果来自 这些研究将揭示肠道微生物区系在乙醇中毒和烧伤后肠道渗漏中的新作用。 并反过来可能有助于开发新的治疗策略，用于治疗患有联合 酒精侮辱和烧伤。

Alcohol-related traumatic and burn injuries remain a considerable health and economic burden to the American society. Studies have shown that patients who are intoxicated at the time of injury are more susceptible to infection and exhibit significantly higher morbidity and mortality compared to burn patients who are not intoxicated at the time of injury. Yet, the mechanism by which alcohol (ethanol) enhances post burn pathogenesis remains largely unclear. Gut barrier dysfunction is frequently associated with ethanol exposure and major injury. We have shown that the ethanol intoxication combined with moderate burn injury causes intestinal tissue damage, leakiness, and a significant increase in bacterial translocation within 24 hours after injury. We further observed a decrease in the expression of microRNA (miR-7a and miR-150) and microRNA biogenesis components Drosha and Argonaute-2 in intestinal epithelial cells (IEC) one day following alcohol and burn injury. Moreover, ethanol combined with burn injury increases bacterial load (Enterobacteriaceae) in the small intestine. Such an increase in Enterobacteriaceae may disrupt the bacteria/host interactions and potentiate the inflammatory response by activating pattern recognition receptors (PRR) expressed on IECs leading to intestine tissue damage and leakiness following ethanol and burn injury. Our hypothesis is that accumulation of Gram-negative bacteria (i.e. Enterobacteriaceae) in intestine following ethanol and burn injury perturbs gut microbiota-epithelial interactions, which become exacerbated by altered microRNA homeostasis, thus, culminating in gut inflammation and barrier disruption. The hypothesis will be tested in 3 Aims in a well-established mouse model of ethanol intoxication and burn injury. Studies in Aim 1 are designed to delineate the mechanism by which ethanol and burn induced changes in intestinal bacteria influence intestine barrier integrity following injury. Aim 2 will determine whether changes in gut bacteria alone or in combination with an increase in HIF-1α influence the expression of miR-150 and miR-7a and whether restoration of miR-150 and/or miR-7a in intestinal epithelial cells following alcohol and burn injury reduces gut inflammation and improves barrier integrity. Furthermore studies in Aim 3 will determine whether treatment of animals with probiotics reestablishes gut microbiota and intestine barrier integrity following alcohol and burn injury. The findings from these studies will reveal a novel role for gut microbiota in gut leakiness following ethanol intoxication and burn injury and in turn may help in developing new therapeutic strategies for patients suffering from a combined insult of ethanol and burn injury.