Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation

 描述(申请人提供)：长期过量饮酒几乎能够损害身体的每一个器官和系统。长期饮酒对大脑的不利影响不仅包括精神障碍，还包括与酒精相关的严重神经炎和脑损伤。我们和其他人所做的工作表明，慢性酒精暴露会导致肠道氧化应激、上皮屏障破坏、肠道渗漏增加，以及随之而来的全身内毒素血症和炎症。我们最近的工作已经开始识别酒精引起的肠道微生物区系的特定变化(生物失调)，并表明长期饮酒会导致致病革兰氏阴性细菌的显著扩张，这可能导致全身内毒素血症的发展。此外，我们早期的工作表明，慢性酒精暴露增加了磷酸二酯酶-4(PDE4)的表达和活性，降低了细胞cAMP，并启动了单核/巨噬细胞，导致内毒素诱导的炎性细胞因子如TNFa的过度表达。此外，酒精暴露会导致脑部二十二碳六烯酸(DHA)缺乏，这可能导致脑部炎症和神经退行性病变的发展/增强。我们假设酒精介导的肠道生物失调、全身性内毒素血症和炎症反应升高通过TLR4和PDE4介导的信号、DHA缺乏、小胶质细胞激活、神经炎症和损伤诱导/加剧了酒精相关的神经病理。这项拟议的研究是一项内外合作的努力，结合相关专业知识，研究酒精诱导的神经病理中涉及肠道生物失调、全身性内毒素血症和炎症反应(UofL)以及脑DHA缺乏(NIAAA)的复杂交互机制。此外，翻译方面将审查特定的基于机制的策略在减轻酒精诱导的损伤方面的治疗潜力。应用的具体目的是：目的1：确定酒精引起的肠道细菌组成和肠道通透性的变化，并将这些变化与外周内毒素血症和脑部炎症的发生联系起来。目的：研究PDE4在酒精诱导的DHA缺乏和损伤相关的脑炎性信号转导中的作用。目的：评价三种干预策略在减轻酒精所致的脑组织炎症和损伤中的疗效。

 DESCRIPTION (provided by applicant): Long-term excessive use of alcohol is capable of damaging nearly every organ and system in the body. The adverse effects of chronic alcohol consumption on the brain include not only psychiatric disorders but also severe alcohol-related neuroinflammation and brain damage. Work done by us and others has shown that chronic alcohol exposure causes intestinal oxidative stress, epithelial barrier disruption, enhancement of gut leakiness, and consequent systemic endotoxemia and inflammation. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiota (dysbiosis), and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Moreover, our earlier work has shown that chronic alcohol exposure increases the expression and activity of phosphodiesterase-4 (PDE4), decreases cellular cAMP, and primes monocytes/macrophages, leading to exaggerated expression of endotoxin-inducible inflammatory cytokines, such as TNFa. Additionally, alcohol exposure leads to a deficiency in brain docosahexanoeic acid (DHA) which likely contributes to the development/augmentation of cerebral inflammation and neurodegenerative pathologies. We hypothesize that alcohol-mediated enteric dysbiosis, systemic endotoxemia and elevated inflammatory responses induce/exacerbate alcohol-associated neuropathologies, via TLR4- and PDE4-mediated signaling, DHA deficiency, microglial activation, neuroinflammation and injury. The proposed study is an intramural-extramural collaborative effort that combines the relevant expertise to investigate the complex interactive mechanisms involving intestinal dysbiosis, systemic endotoxemia and inflammatory responses (UofL), and cerebral DHA deficiency in alcohol-induced neuropathologies (NIAAA). Moreover, a translational aspect will examine the therapeutic potential of specific mechanism-based strategies in mitigating alcohol-induced injury. The Specific aims of the application are: Aim 1: Determine alcohol mediated changes in the gut bacterial composition and intestinal permeability and correlate these changes to the development of peripheral endotoxemia and brain inflammation. Aim 2: Examine the role of PDE4 in alcohol-induced brain inflammatory signaling associated with DHA deficiency and injury. Aim 3: Evaluate the therapeutic efficacy of three intervention strategies targeting (i) enteric dysbiosis, (ii) PDE4 activity, and (iii) DHA deficiency in attenuating alcohol mediated brain inflammation and injury.