Common mechanisms of the microbiota-gut-brain axis in alcohol use disorder and depression: A genetically informed investigation

7.项目总结 大约三分之一的寻求酒精使用障碍(AUD)治疗的人也有较大的 抑郁障碍。这些人使用更多的医疗保健资源，但复发和 在治疗后有更大程度的残疾。因此，澳元已经很高的公共卫生成本是 当其他精神健康问题同时发生时，可能会加剧。此外，没有经验支持 AUD和伴发抑郁症的治疗及对伴发抑郁症的辅助治疗 病例对降低AUD复发率无效。该项目的目的是促进人类疾病的科学和治疗。 AUD和共生抑郁症通过研究微生物区系-肠道-脑轴的共同机制， 特别是涉及消化、免疫和认知过程。对栖息的微生物物种的干扰 肠道(即微生物区系)与饮酒、情绪和认知控制有关。同样，炎症性的 标记物和认知控制与AUD和抑郁症有关。广泛的研究表明 这些系统是相互关联的；肠道微生物区系的紊乱会增加循环炎症 标志物，然后影响大脑和行为。因此，整个微生物区系-肠道-的生物机制- 脑轴可以单独治疗，也可以联合治疗AUD和伴发抑郁症。这个 该项目的总体目标是确定有前景的AUD和共发性抑郁症的治疗目标。 具体地说，这项研究的目的是研究微生物区系-肠道-脑轴的三个组成部分：(1)肠道 微生物区系特征，(2)炎性细胞因子，(3)认知控制。该项目还旨在(4) 了解遗传因素是如何与微生物-肠道-脑轴的影响相关的，这已经被 在这方面的研究中被大大忽视了。为了实现这些研究目标，该项目使用了来自 NIAAA资助的AUD治疗研究和NIMH资助的认知控制研究。这两项研究都有 收集微生物区系-肠道-脑轴的数据，以及研究基因表达的作用的数据 和一般的遗传风险。分析将调查这些机制是否解释了澳元之间的协变 和抑郁症状。此外，探索性分析将研究从肠道到 免疫功能，这是AUD和抑郁症的基础。首席研究员艾林森博士也将 追求培训目标，这将拓宽他的技能集，使他能够(1)检查肠道微生物区系，(2) 研究炎性细胞因子和其他生物标志物，以及(3)管理认知的实验室任务 控制力。为了指导他的培训和研究，埃林森博士组建了一个首屈一指的导师团队，与 跨越微生物区系-肠道-脑轴和遗传学的专业知识。因此，随着他的发展，他将得到支持 启动以患者为中心的遗传信息研究计划所需的技能和专业知识 AUD和共生状态的生物标志物。

7. Project Summary Approximately one in three people seeking treatment for alcohol use disorder (AUD) also have major depressive disorder. These individuals use more health care resources but are twice as likely to relapse and have a greater level of disability after treatment. Consequently, the already high public health costs of AUD are likely exacerbated when other mental health problems co-occur. Further, there are no empirically supported treatments for AUD and comorbid depression, and applying an adjunct treatment for depression in comorbid cases is ineffective for reducing AUD relapse rates. This project aims to advance the science and treatment of AUD and co-occurring depression by investigating shared mechanisms across the microbiota-gut-brain axis, specifically involving digestive, immune, and cognitive processes. Disturbances to microbial species inhabiting the gut (i.e., microbiota) have been linked to alcohol use, mood, and cognitive control. Similarly, inflammatory markers and cognitive control are associated with AUD and depression. Extensive research has demonstrated that these systems are interrelated; disturbances to gut microbiota can increase circulating inflammatory markers, which then affect the brain and behavior. Thus, biological mechanisms across the microbiota-gut- brain axis may be targeted individually, or in tandem, to treat AUD and co-occurring depression. The overarching goal of this project is to identify promising treatment targets for AUD and co-occurring depression. Specifically, the research aims will investigate three components of the microbiota-gut-brain axis: (1) gut microbiota characteristics, (2) inflammatory cytokines, and (3) cognitive control. This project also aims to (4) understand how genetic factors are related to the effects of the microbiota-gut-brain axis, which has been greatly overlooked in this line of research. To achieve these research aims, this project uses data from an NIAAA-funded treatment study of AUD and an NIMH-funded study of cognitive control. Both studies have collected data across the microbiota-gut-brain axis, as well as data for examining the role of gene expression and general genetic risk. Analyses will investigate whether these mechanisms explain covariation among AUD and depressive symptoms. Further, exploratory analyses will investigate biological pathways, from gut to immune functioning, that underlie AUD and depression. The principal investigator, Dr. Ellingson, will also pursue training aims, which will broaden his skill set and enable him to (1) examine gut microbiota, (2) investigate inflammatory cytokines and other biomarkers, and (3) administer laboratory tasks of cognitive control. To guide his training and research, Dr. Ellingson has assembled a premiere mentorship team with expertise spanning the microbiota-gut-brain axis and in genetics. Thus, he will be supported as he develops skills and expertise necessary to launch a genetically informative, patient-oriented research program on biomarkers of AUD and co-occurring conditions.