Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation

肠道微生物组和 DHA 缺乏在酒精引起的神经炎症中的作用

基本信息

批准号：
9750566
负责人：
SHIRISH S BARVE
金额：
$ 33.75万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750566
关键词：
16S ribosomal RNA sequencing Acids Adverse effects Alcohol abuse Alcohol consumption Alcohol-Induced Disorders Alcohols Animals Anti-inflammatory Astrocytes Attenuated Bacteria Brain Brain Injuries Cells Cerebrum Chronic Complex Cyclic AMP Data Development Diet Encephalitis Endotoxemia Endotoxins Enteral Epithelial Ethanol Extramural Activities Feedback Functional disorder Gene Expression Gram-Negative Bacteria Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Intestinal permeability Intestines Knockout Mice Lactobacillus Lactobacillus casei rhamnosus Lead Leaky Gut Link Mediating Membrane Mental disorders Microglia Mus National Institute on Alcohol Abuse and Alcoholism Nerve Degeneration Omega-3 Fatty Acids Oxidative Stress PDE4B Pathogenicity Pathology Peripheral Permeability Play Populations at Risk Preventive Probiotics Process Production Proteins Proteobacteria Role Rolipram Signal Transduction Supplementation TLR4 gene TNF gene Therapeutic Tight Junctions Treatment Efficacy Universities Work alcohol effect alcohol exposure bacterial community base body system brain cell chronic alcohol ingestion cytokine dysbiosis feeding gut microbiome gut microbiota immune activation inhibitor/antagonist macrophage metagenomic sequencing monocyte neuroinflammation neuropathology next generation sequencing phosphodiesterase IV prevent probiotic supplementation public health relevance sequencing platform translational study

项目摘要

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.

描述（申请人提供）：长期过量饮酒几乎会损害身体的每个器官和系统。长期饮酒对大脑的不利影响不仅包括精神疾病，还包括严重的与酒精相关的神经炎症和炎症。我们和其他人所做的工作表明，长期接触酒精会导致肠道氧化应激、上皮屏障破坏、肠道渗漏增强，以及随之而来的全身性内毒素血症和炎症。酒精引起的肠道微生物群改变（生态失调），并表明长期饮酒会导致致病性革兰氏阴性菌显着扩张，从而可能导致全身性内毒素血症的发生。此外，我们早期的工作表明，长期饮酒会增加。磷酸二酯酶 4 (PDE4) 的表达和活性，降低细胞 cAMP，并启动单核细胞/巨噬细胞，导致内毒素诱导的炎症细胞因子的过度表达，例如与 TNFa 一样，酒精暴露会导致大脑二十二碳六烯酸 (DHA) 缺乏，这可能会导致脑部炎症和神经退行性病变的发展/加剧。我们发现，酒精介导的肠道菌群失调、全身性内毒素血症和炎症反应升高会诱发/加剧。酒精相关的神经病理学，通过 TLR4 和 PDE4 介导的信号传导、DHA 缺乏、小胶质细胞激活、神经炎症和损伤。是一项校内校外合作项目，结合了相关专业知识，研究涉及肠道菌群失调、全身性内毒素血症和炎症反应 (UofL) 以及酒精引起的神经病理学中脑 DHA 缺乏 (NIAAA) 的复杂相互作用机制。研究基于特定机制的策略在减轻酒精引起的损伤方面的治疗潜力。该应用的具体目标是：目标 1：确定酒精介导的肠道细菌组成和肠道通透性变化。将这些变化与外周内毒素血症和脑炎症的发展相关联目标 2：检查 PDE4 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：评估针对 (i) 的三种干预策略的治疗效果。肠道菌群失调，(ii) PDE4 活性，以及 (iii) DHA 缺乏可减轻酒精介导的脑部炎症和损伤。