Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation

 描述（由申请人提供）：长期过量使用酒精能够损害身体几乎每个器官和系统。长期饮酒对大脑的不良影响不仅包括精神疾病，还包括严重的酒精相关神经炎症和脑损伤。我们和其他人所做的工作表明，长期酒精暴露会导致肠道氧化应激，上皮屏障破坏，肠道渗漏增强，以及随后的全身性内毒素血症和炎症。我们最近的工作已经开始确定特定的酒精诱导的肠道微生物群（生态失调）的变化，并表明慢性饮酒导致致病性革兰氏阴性菌的显着扩张，可能导致全身性内毒素血症的发展。此外，我们早期的工作表明，长期酒精暴露增加磷酸二酯酶-4（PDE 4）的表达和活性，降低细胞cAMP，并引发单核细胞/巨噬细胞，导致内毒素诱导的炎性细胞因子（如TNF α）的过度表达。此外，酒精暴露导致大脑二十二碳六烯酸（DHA）缺乏，这可能有助于大脑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态失调、全身性内毒素血症和炎症反应升高通过TLR 4和PDE 4介导的信号传导、DHA缺乏、小胶质细胞活化、神经炎症和损伤诱导/加剧酒精相关的神经病理学。这项拟议的研究是一项内外部合作的努力，结合了相关的专业知识，以调查复杂的相互作用机制，包括肠道生态失调，全身性内毒素血症和炎症反应（UofL），以及酒精诱导的神经病理学（NIAAA）中的大脑DHA缺乏。此外，翻译方面将检查特定的机制为基础的策略，在减轻酒精引起的损伤的治疗潜力。本申请的具体目的是：目的1：确定酒精介导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炎症的发展相关联。目的2：研究PDE 4在与DHA缺乏和损伤相关的酒精诱导的脑炎症信号传导中的作用。目标3：评价三种干预策略在减轻酒精介导的脑炎症和损伤中的治疗效果，这些干预策略针对（i）肠道生态失调，（ii）PDE 4活性和（iii）DHA缺乏。

 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.