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: 10592403
• 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/10592403
• 关键词: Anhedonia; Animal Model; Antibiotic Therapy; Antibiotics; Antidepressive Agents; Behavior; Behavioral; Biological; 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 acquisition; Life; Measures; Mental Depression; Mentored Research Scientist Development Award; Mentorship; Metabolic; 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.

项目摘要 新兴的微生物群 - 脑轴研究表明，肠道微生物在 神经系统疾病的建立和治疗，包括抑郁症。估计3亿或 近4％的人口在全球遭受抑郁症。抑郁是一个复杂的多因素 疾病和最近的流行病学研究表明，抗生素治疗使人类易于 神经精神疾病的发展，包括抑郁症。提出的一种机制是抗生素 管理会改变肠道微生物组的结构和功能，并通过 神经活性化合物的合成降低。但是，抗生素诱导的机制 抑郁尚不清楚。在此K01奖励建议中，我建议使用一种新颖的非人类灵长类动物模型，即 常见的摩尔果（Callithrix jacchus），以研究抗生素诱导抑郁症的机制。 由于其在生理和行为后遗症中的类似类似的相似性，摩尔果会成为一个强大的模型。 我的具体目的如下：1。表征肠道微生物组结构和功能的变化以及 抗生素治疗后果果中的行为，2。 社会分离莫莫果中的抑郁症状学和3。评估治疗性 粪便微生物群移植对抗生素诱导的不良生物果会治疗抑郁症的影响。我 计划管理广谱抗生素鸡尾酒（有和没有其他压力源）并进行研究变化 在行为，免疫谱，神经内分泌激素水平，肠道微生物组结构和功能和肠道 细菌代谢物。我还计划研究粪便菌群移植在逆转行为方面的作用， 摩尔莫斯群的生理和微生物变化施用了抗生素，并将其功效与 氟西汀（一种通常处方的抗抑郁药）。这项研究的结果将产生小说 假设，作为争夺竞争性壁外资金所必需的关键初步数据，以及 代表建立通用果酱作为研究效果的转化模型的第一步 在微生物组调节和抑郁症的发展上使用抗生素。我还建立了培训 计划和指导团队获得神经生物学，代谢组学和多摩学数据分析的关键技能。我的 长期目标是成为微生物群 - 脑轴研究的领导 动物模型研究肠道轴通信在神经精神疾病中的作用。