Prenatal Alcohol and Neuroimmunity

7.项目摘要/摘要 在动物模型和人类队列中的研究都证明了产前酒精的广泛影响 暴露(PAE)对免疫功能的影响。我们第一次表明，PAE会导致更严重的 成年后因免疫挑战而导致的炎症病程延长，这似乎有其 起源于一种从出生起就存在的促炎偏见。炎症，肠道通透性增加，以及 肠道微生物区系的变化与多种疾病的发病机制有关。 精神障碍，包括抑郁和焦虑。值得注意的是，大约90%的胎儿酒精携带者 谱系障碍(FASD)在生活中的某个时候会遇到心理健康问题，患有抑郁症和 焦虑是最常见的。然而，免疫/炎症功能和心理健康结果之间的联系 在FASD领域没有得到很好的研究，而且到目前为止还没有研究PAE对肠道影响的出版物 结构、功能和微生物区系组成，也不知道这些变化是否可能导致免疫系统的变化 功能。目前的提案将通过探索PAE引起的复杂相互作用来填补这些空白 肠道结构、功能、微生物区系组成、免疫功能和情绪失调的改变 (在此称为不利的精神健康后果)。干预的潜在有益影响(S) 将探索包括药物治疗和粪便移植在内的策略，并翻译成 实验将调查PAE诱导的情绪失调和肠道改变之间的可能联系 人类队列中的微生物区系组成。我们的目标是探索潜在的PAE的新生物标志物并提供信息 未来的临床策略，以改善FASD患者的健康和福祉。我们的具体目标是： 1)确定PAE对肠道结构、功能和微生物区系组成的影响以及这些影响的方式 免疫功能，并为情绪失调的风险/弹性奠定基础；2)调查 药物治疗对改善PAE引起的肠道结构、功能和功能改变的疗效 微生物区系组成、免疫功能和情绪失调；3)评估粪便的疗效 微生物区系移植改善PAE引起的肠道结构、功能、微生物区系改变 组成、免疫功能和情绪失调；以及4)将这项工作转化为人类队列 研究PAE诱导的肠道通透性改变、微生物区系组成和 成人FASD患者的情绪调节障碍。我们的工作假设是PAE：影响结构和 肠道屏障的功能，导致对管腔产品的渗透性增加；导致肠道微生物区系的转移 肠道-脑轴的组成和信号改变；这些变化一起可能是 早期促炎偏见和终生免疫功能紊乱，最终对精神障碍产生负面影响 健康状况。这项研究将为PAE相关风险和复原力的潜在因素提供独特的见解。

7. Project Summary/Abstract Studies in both animal models and human cohorts have demonstrated broad impacts of prenatal alcohol exposure (PAE) on immune function. We showed, for the first time that PAE results in a more severe and prolonged course of inflammation in response to immune challenge in adulthood, which appears to have its origins in a proinflammatory bias that is present from birth. Inflammation, increased gut permeability, and changes in gut microbiota composition have been implicated in the pathogenesis of wide range of diseases/ disorders, including depression and anxiety. Notably, approximately 90% of individuals with Fetal Alcohol Spectrum Disorders (FASD) experience mental health problems at some point in their lives, with depression and anxiety being the most common. Yet links between immune/inflammatory function and mental health outcomes are not well studied in the FASD field, and to date there are no publications examining PAE effects on gut structure, function, and microbiota composition, nor whether such changes may underlie alterations in immune function. The present proposal will fill these gaps by exploring the complex interplay among PAE-induced alterations in gut structure, function, and microbiota composition, immune function, and emotional dysregulation (operationalized here as adverse mental health outcomes). The potential beneficial impact(s) of intervention strategies including pharmacological treatments and fecal transplant will be explored, and a translational experiment will investigate possible associations between PAE-induced emotional dysregulation and altered gut microbiota composition in a human cohort. Our goal is to explore potential novel biomarkers of PAE and inform future clinical strategies to improve health and well-being of individuals with FASD. Our Specific Aims are to: 1) Determine the effects of PAE on gut structure, function and microbiota composition and how these may affect immune function and set the stage for risk for/resilience to emotional dysregulation; 2) Investigate the effectiveness of pharmacological treatments in ameliorating PAE-induced alterations in gut structure, function, microbiota composition, immune function, and emotional dysregulation; 3) Evaluate the efficacy of fecal microbiota transplantation in ameliorating PAE-induced alterations in gut structure, function, microbiota composition, immune function, and emotional dysregulation; and 4) Translate this work to a human cohort by investigating associations among PAE-induced alterations in gut permeability, microbiota composition, and emotional dysregulation in adults with FASD. Our working hypothesis is that PAE: impacts structure and function of the gut barrier, leading to increased permeability to luminal products; causes a shift in gut microbiota composition and altered signaling in the gut-brain axis; and together, these changes may be key drivers of the early proinflammatory bias and lifelong perturbations in immune function that ultimately negatively impact mental health status. This research will provide unique insight into factors underlying PAE-related risk and resilience.