Exploring the Microbiome-Gut-Brain Axis in Psychoneurological Symptoms for Children with Solid Tumors

摘要 人体内有数以万亿计的微生物，其数量是人体数量的10倍 细胞。这些与人类相关的微生物及其基因组的集合被称为“人类微生物群”。多过 其中90%的微生物生活在胃肠道，平均代表500个物种。随着时代的发展 高通量测序技术和生物信息学工具(例如，16S核糖体RNA或16S rRNA测序 和鸟枪式元基因组学分析)，最近在阐述肠道微生物组的关键作用方面取得了进展 对人类的健康和疾病起着至关重要的作用。肠道组成和功能的严重紊乱(失调) 微生物组与癌症的发生、化疗代谢和治疗相关的症状毒性有关。 目前关于肠道微生物群在癌症中的科学状态只是在最近才开始在动物模型和 在诊断和治疗癌症的儿童中，也没有很好地研究过与癌症有关的问题。 与治疗相关的毒性。这项拟议的研究将探索肠道微生物群失调是 与癌症治疗相关的胃肠道感染和精神神经学症状有关。为了检验我们的假设，这个 K99/R00提案将执行三个具体目标：目标1将表征肠道的纵向变化 用16S rRNA技术比较7-18岁实体瘤患儿和健康儿童的微生物组 K99阶段的测序；R00阶段将专注于两个特定的目标：Aim 2将筛选特定的微生物 16S rRNA基因全序列测定在癌症儿童和健康同胞中的种类和病原体 基因组鸟枪式元基因组学分析；目标3将检查肠道微生物组和胃肠道感染之间的关系 基于一个概念模型的实体瘤儿童在化疗过程中的神经心理症状 微生物组-肠道-脑轴，使用16S rRNA测序和鸟枪式元基因组分析。关于我的 癌症儿童的专门知识和富有成效的研究项目、当前和未来的培训、研究指导和 动机，以及非常支持的研究环境，我将准备领导这个拟议的项目。我们的发现 将有助于确定癌症治疗症状潜在的生物学机制，并将导致 可能精确的干预目标(例如，益生菌和益生菌补充剂)。这项建议包括 16S rRNA测序、大数据QIIME 2分析和全基因组猎枪等尖端技术 元基因组学在癌症治疗相关胃肠道和精神神经症状中的创新应用及其可测试性 概念上的微生物组-肠道-脑轴框架。总之，K99/R00赠款代表着一个独特的机会 我要学习新的方法和发展我的专业技能，以成功地过渡到一名独立的护士 专注于儿科肿瘤学症状科学的生物心理社会机制(即肠道微生物组)的科学家。

ABSTRACT The human body hosts tens of trillions of microbes, which number is 10 times greater than the number of human body cells. The collection of these human-associated microbes and their genomes is called the “human microbiome”. More than 90% of these microbes live in the gastrointestinal (GI) tract, representing 500 species on average. With the development of high-throughput sequencing technology and bioinformatics tools (e.g., 16S ribosomal RNA or 16S rRNA sequencing and shotgun metagenomics analysis), recent progress has been made to elaborate the critical role that the gut microbiome is playing in human health and disease. A significant disruption (dysbiosis) of the composition and function of the gut microbiome is associated with carcinogenesis, chemotherapeutic metabolism, and treatment-related symptom toxicities. The current state of the science on the gut microbiome in cancer has been only recently starting in animal models and adults and has not been well investigated in children diagnosed and treated for cancer, nor with associations with cancer treatment-related toxicities. This proposed study will explore the hypothesis that dysbiosis of the gut microbiome is associated with cancer treatment-related GI and psychoneurological symptoms. In order to test our hypothesis, this K99/R00 proposal will execute three specific aims: Aim 1 will characterize the longitudinal changes of the gut microbiome in children aged 7-18 years with solid tumors as compared with their healthy siblings using 16S rRNA sequencing during the K99 Phase; the R00 Phase will focus on two specific aims: Aim 2 will screen specific microbial species and pathogens in children with cancer and healthy siblings following 16S rRNA gene sequencing using whole- genome shotgun metagenomics analysis; and Aim 3 will examine associations between the gut microbiome and GI and psychoneurological symptoms in children with solid tumors throughout chemotherapy based on a conceptual model of the microbiome-gut-brain axis, using 16S rRNA sequencing and shotgun metagenomics analysis. With respect to my expertise and productive research projects in children with cancer, current and future trainings, research mentoring and motivations, and the very supportive research environment, I will be prepared to lead this proposed project. Our findings will help identify potential biological mechanisms underlying symptoms of cancer treatment, and will lead to potentially precise targets for interventions (e.g., prebiotic and probiotic supplementations). This proposal includes cutting-edge approaches such as 16s rRNA sequencing, big data QIIME 2 analytics and whole-genome shotgun metagenomics with the innovative use in cancer treatment-related GI and psychoneurological symptoms and a testable conceptual microbiome-gut-brain axis framework. In summary, the K99/R00 grant represents a unique opportunity for me to learn new approaches and develop my professional skills to successfully transition into an independent nurse scientist focusing on the biopsychosocial mechanisms (i.e., gut microbiome) of symptom science in pediatric oncology.