A Model of Antibiotic-induced Gut Dysbiosis and Depressive Symptomatology

抗生素引起的肠道菌群失调和抑郁症状模型

• 批准号: 10449734
• 负责人: Jonathan Brent Clayton
• 金额: $ 12.67万
• 依托单位: UNIVERSITY OF NEBRASKA OMAHA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449734
• 关键词: Anhedonia; Animal Model; Antibiotic Therapy; Antibiotics; Antidepressive Agents; Behavior; Behavioral; Brain; Callithrix; Callithrix jacchus jacchus; Clinical Research; Clinical Treatment; Communication; Complex; Control Groups; Data; Data Analyses; Desire for food; Development; Disease; Endocrine; Event; Extramural Activities; Fluoxetine; Funding; Goals; Hormones; Human; Hydrocortisone; Immune; Immune system; Inflammatory; Intervention; Knowledge; Life; Measures; Mental Depression; Mentored Research Scientist Development Award; Mentorship; Metabolic; Microbiology; Modeling; Morbidity - disease rate; Multiomic Data; Neomycin; Neurobiology; Neurosecretory Systems; Pathologic; Patients; Persons; Physiological; Population; Predisposition; Probiotics; Production; Research; Research Personnel; Risk; Rodent Model; Role; Signal Pathway; Social Characteristics; Social Controls; Social isolation; Structure; Study models; Testing; Therapeutic; Therapeutic Effect; Training; Vancomycin; animal model development; antimicrobial; bacterial metabolism; cytokine; depressive behavior; depressive symptoms; design; dietary; dysbiosis; epidemiology study; fecal transplantation; gut bacteria; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; gut-brain axis; inflammatory marker; metabolomics; microbiome; microbiota-gut-brain axis; nervous system disorder; neuropsychiatric disorder; nonhuman primate; novel; novel therapeutics; prevent; skills; social separation; stressor; symptomatology; translational model; vocalization

PROJECT SUMMARY Emerging microbiota-gut-brain axis research demonstrates an important role of gut microbes in the establishment and treatment of nervous system disorders, including depression. An estimated 300 million or nearly 4% of the human population suffers from depression globally. Depression is a complex multifactorial disease and recent epidemiological studies indicate that antibiotic treatment predisposes humans to the development of neuropsychiatric disorders, including depression. One proposed mechanism is that antibiotic administration alters gut microbiome structure and function as well as hinders gut-brain communication through decreased synthesis of neuroactive compounds. However, the mechanisms by which antibiotics induce depression remain unclear. In this K01 award proposal, I propose to use a novel nonhuman primate model, the common marmoset (Callithrix jacchus), to investigate the mechanisms by which antibiotics induce depression. Marmosets serve as a powerful model due to their human-like similarity in physiological and behavioral sequelae. My specific aims are as follows: 1. Characterize changes in gut microbiome structure and function as well as behavior in marmosets following antibiotic treatment, 2. Evaluate the additive effect of antibiotic treatment and social separation on induction of depressive symptomatology in marmosets, and 3. Evaluate the therapeutic effect of fecal microbiota transplantation on treatment of depression in antibiotic-induced dysbiotic marmosets. I plan to administer a broad-spectrum antibiotic cocktail (with and without additional stressors) and study changes in behavior, immune profiles, neuroendocrine hormone levels, gut microbiome structure and function and gut bacterial metabolites. I also plan to study the role of fecal microbiota transplantation in reversing behavioral, physiological and microbiological changes in marmosets administered antibiotics and compare its efficacy to fluoxetine (a commonly prescribed antidepressant). The results from this research will generate novel hypotheses, serve as critical preliminary data necessary to compete for competitive extramural funding, and represent the first step towards establishing the common marmoset as a translational model for studying effects of antibiotic use on microbiome modulation and the development of depression. I have also established a training plan and mentorship team to gain critical skills in neurobiology, metabolomics and multi-omics data analysis. My long term goal is to become a leader in microbiota-gut-brain axis research and to establish marmosets as an animal model to study the role of gut-brain axis communication in neuropsychiatric disorders.

项目总结 新兴的微生物区系-肠道-脑轴研究表明肠道微生物在 建立和治疗神经系统疾病，包括抑郁症。估计有3亿人或 全球近4%的人口患有抑郁症。抑郁症是一个复杂的多因素 疾病和最近的流行病学研究表明，抗生素治疗使人类容易患上 神经精神障碍的发展，包括抑郁症。一种被提出的机制是抗生素 给药改变肠道微生物群的结构和功能，并通过 神经活性物质的合成减少。然而，抗生素诱导的机制 抑郁症仍不清楚。在这个K01奖项的提案中，我建议使用一种新的非人类灵长类动物模型，即 普通绒猴(Callithrix Jacchus)，研究抗生素导致抑郁的机制。 由于在生理和行为后遗症方面与人类相似，绒猴可以作为一个强大的模型。 我的具体目标如下：1.描述肠道微生物群结构和功能的变化以及 抗生素治疗后绒猴的行为，2.评估抗生素治疗的相加效应和 社会隔离对诱发猕猴抑郁症状的影响，以及3.评价治疗效果 粪便微生物区系移植对抗生素诱导的厌生性绒猴抑郁的治疗作用。我 计划实施广谱抗生素鸡尾酒(有无额外压力)和研究变化 在行为、免疫状况、神经内分泌激素水平、肠道微生物组结构和功能以及肠道 细菌代谢物。我还计划研究粪便微生物群移植在扭转行为方面的作用， 抗菌素对恒河猴生理和微生物学的影响及其疗效比较 氟西汀(一种常用的抗抑郁药)。这项研究的结果将产生新颖的 假设，作为竞争竞争性外部资金所必需的关键初步数据，以及 代表了建立普通绒猴作为研究效果的翻译模型的第一步 抗生素的使用对微生物群调节和抑郁症的发展的影响。我还建立了一项培训 计划和指导团队，以获得神经生物学、代谢组学和多组学数据分析方面的关键技能。我的 长期目标是成为微生物-肠道-脑轴研究的领先者，并将绒猴作为一种 动物模型研究肠道-脑轴通讯在神经精神障碍中的作用。