Gut Microbiota Dysbiosis in Major Depressive Disorder is Associated with Altered Production of Aryl Hydrocarbon Receptor Ligands and Altered Microglia Function

重度抑郁症中的肠道微生物群失调与芳基烃受体配体的产生改变和小胶质细胞功能改变有关

• 批准号: 10371654
• 负责人: RYAN RAMPERSAUD
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371654
• 关键词: Address; Adolescent Psychiatry; Aftercare; Antidepressive Agents; Aryl Hydrocarbon Receptor; Bacteria; Biological Assay; Blood; Blood specimen; Brain; Child Psychiatry; Clinical; Clinical Research; Communication; Communities; Complex; Disease; Etiology; Feces; Fellowship; Foundations; Functional disorder; Genes; Health; Immune system; In Vitro; Individual; Indoles; Inflammation; Inflammatory; Investigation; Knowledge; Lactobacillus; Link; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mentors; Metagenomics; Microglia; National Institute of Mental Health; Neurobiology; Neuroglia; Organism; Pathogenesis; Pathway interactions; Physicians; Plasma; Process; Production; Program Development; Receptor Signaling; Reporter; Reporting; Research; Research Design; Research Personnel; Role; Route; Sampling; Selective Serotonin Reuptake Inhibitor; Serum; Shotguns; Signal Pathway; Signal Transduction; Source; Strategic Planning; Structure; Testing; Tryptophan; Tryptophan Metabolism Pathway; aryl hydrocarbon receptor ligand; bacterial genetics; burden of illness; career; career development; cellular targeting; cohort; depressive symptoms; design; dysbiosis; experience; gut microbes; gut microbiome; gut microbiota; gut-brain axis; implementation design; in vitro Assay; metabolomics; microbial; microbial community; microbiome; microbiome composition; microbiota-gut-brain axis; microorganism; neurodevelopment; neuroinflammation; neuropsychiatric disorder; new therapeutic target; novel; novel therapeutics; pathogen; response; restoration; skills; stool sample; treatment response

PROJECT SUMMARY/ABSTRACT Major Depressive Disorder (MDD) is a common disorder whose etiology remains unclear and likely multifactorial. Serotonin reuptake inhibitors (SSRIs), fail to fully reduce the burden of disease, highlighting need for additional studies into the pathogenesis of MDD. Alterations in gut microbiota composition (termed “dysbiosis”) leading to altered signaling along the route of communication between the gut and the brain (termed the gut -microbiota- brain axis) represents a novel modifiable target associated with MDD. While several studies have linked dysbiosis to MDD, our understanding of how these changes contribute to altered signaling along this gut-microbiota-brain axis and depressive symptoms remains limited. This proposal aims to determine how changes in the activity of an understudied pathway of tryptophan metabolism (the indole pathway) by the gut microbiota contributes to the pathophysiology of MDD. Using stool and blood samples from a well characterized cohort of unmedicated MDD subjects along with healthy controls and samples from these same unmedicated subjects after 8 weeks of antidepressant treatment, the candidate will address two aims. First, using a shotgun metagenomics approach, changes in the capacity of the gut microbiota to produce metabolites of the indole pathway associated with MDD will be assessed. This will be related to changes in serum levels of indoles, activation of the aryl hydrocarbon receptor, and the ability to modulate the activity of microglia. Next, these parameters will be assessed after antidepressant treatment to identify changes associated with successful treatment. This study is novel given its use of unmedicated, well characterized MDD subjects and our assessment of gut microbiome community structure/function within the same individual after treatment (which has never been done previously). The candidate will leverage a number of approaches including 1) metagenomics 2) metabolomics 3) in vitro assays and 4) bacterial genetics to interrogate mechanisms of gut-brain axis signaling involved in the pathophysiology of MDD. This proposal presents a five-year research career development program designed to provide a foundation for future research endeavors as an independent physician -investigator researcher. The candidate is currently a Child and Adolescent Psychiatry Fellow (in a three-year research fellowship) at UCSF. This proposal builds on the candidate's previous experience studying host-pathogen interactions and the role of Lactobacillus species in health and disease. This proposal will integrate new domains of expertise by his mentors, including the study of the role of dysbiosis of complex microbial communities in the etiology of disease, neurodevelopment and the neurobiological basis of depression, and design/implementation of clinical studies by his mentors, Dr. Wolkowitz, Dr. Mellon, and Dr. Lynch. These skills fill critical gaps in the candidate's knowledge and the plan outlined here will provide the candidate with a unique set of skills enabling him to transition to an independent research career focused on gut-microbiota-brain axis signaling in neuropsychiatric disease.

项目总结/摘要 重性抑郁障碍（MDD）是一种常见的疾病，其病因尚不清楚， 多因素的5-羟色胺再摄取抑制剂（SSRIs）未能完全减轻疾病负担， 对MDD发病机制的进一步研究。肠道微生物群组成的改变（称为 “生态失调”），导致肠道和大脑之间的通讯路线沿着的信号改变 （称为肠道-微生物群-脑轴）代表了与MDD相关的新的可改变的靶点。而 一些研究已经将生态失调与MDD联系起来，我们对这些变化如何改变 沿着这个肠道-微生物群-大脑轴的信号传导和抑郁症状仍然有限。 这项建议旨在确定如何在活性的变化，一个未充分研究的途径色氨酸 肠道微生物群的代谢（吲哚途径）有助于MDD的病理生理学。使用大便 以及来自未用药MDD受试者沿着健康对照的充分表征队列的血液样本 以及来自这些相同的未用药受试者的样本，在抗抑郁药治疗8周后， 将实现两个目标。首先，使用霰弹枪宏基因组学方法，肠道容量的变化 将评估微生物群产生与MDD相关的吲哚途径的代谢物的能力。这将是 与吲哚类血清水平的变化、芳烃受体的激活以及 调节小胶质细胞的活性。接下来，将在抗抑郁药治疗后评估这些参数， 确定与成功治疗相关的变化。这项研究是新颖的，因为它使用未经药物治疗的， 特征性MDD受试者和我们对肠道微生物群落结构/功能的评估， 治疗后的同一个体（以前从未进行过）。候选人会利用一个数字 包括1）宏基因组学2）代谢组学3）体外测定和4）细菌遗传学的方法， 探究MDD病理生理学中涉及的肠-脑轴信号传导机制。 该提案提出了一项为期五年的研究职业发展计划，旨在为以下方面提供基础： 未来的研究努力作为一个独立的医生-调查研究员。候选人目前是一名 儿童和青少年精神病学研究员（在一个为期三年的研究奖学金）在加州大学旧金山分校。该提案基于 候选人以前研究宿主-病原体相互作用和乳酸杆菌物种的作用的经验 健康和疾病。这项建议将整合他的导师的新专业领域，包括研究 复杂微生物群落的生态失调在疾病的病因学、神经发育和 抑郁症的神经生物学基础，并设计/实施临床研究，他的导师，博士。 沃尔克维茨梅隆博士林奇博士这些技能填补了候选人的知识和计划中的关键空白 这里概述的将为候选人提供一套独特的技能，使他能够过渡到一个独立的 研究生涯主要集中在神经精神疾病的肠道微生物群-脑轴信号。