A Model of Antibiotic-induced Gut Dysbiosis and Depressive Symptomatology

项目摘要 新兴的微生物-肠道-大脑轴研究表明肠道微生物在疾病中的重要作用 建立和治疗神经系统疾病，包括抑郁症。估计有3亿或 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，抗生素治疗使人类易患 神经精神疾病的发展，包括抑郁症。一种被提出的机制是抗生素 给药改变了肠道微生物组的结构和功能， 神经活性化合物的合成减少。然而，抗生素诱导的机制 抑郁症仍不清楚。在这个K 01奖项的建议，我建议使用一种新的非人类灵长类动物模型， 普通绒猴（Callithrix jacchus），研究抗生素诱导抑郁症的机制。 绒猴作为一个强大的模型，因为它们在生理和行为后遗症方面与人类相似。 具体目标如下：1.表征肠道微生物组结构和功能的变化， 抗生素治疗后的绒猴行为，2.评价抗生素治疗的累加效应， 社会隔离对绒猴抑郁性行为诱发的影响; 3.评价治疗 粪便微生物群移植对治疗饥饿诱导的生态失调绒猴抑郁症的影响我 计划给予广谱抗生素鸡尾酒（有或没有额外的压力源）和研究变化 在行为、免疫概况、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逆转行为， 生理和微生物的变化，并比较其疗效， 氟西汀（一种常用的抗抑郁药）。这项研究的结果将产生新的 假设，作为竞争竞争性校外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影响的转化模型的第一步 抗生素使用对微生物组调节和抑郁症的发展的影响。我还建立了一个培训 计划和指导团队获得神经生物学，代谢组学和多组学数据分析的关键技能。我 长期目标是成为微生物群-肠-脑轴研究的领导者，并将绒猴建立为 动物模型，以研究肠-脑轴通讯在神经精神疾病中的作用。

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.