Impact of gut microbial metabolism on host breath volatiles

项目摘要/摘要 肠道微生物组与各种疾病有关，如炎症性肠病、哮喘和 神经退行性疾病。尽管对这些疾病的研究取得了进展，但仍有 患者的表现和预后存在显著的异质性。肠道微生物群的个体间变异性 组成和代谢功能可能在一定程度上解释了疾病的个体间差异。表征 肠道微生物组的研究通常使用元基因组测序或标记基因测序 粪便中细菌的V4 16S序列；然而，这些方法在临床环境中并不总是可行的。 人类粪便必须获得并妥善储存，而且在收集地点和时间通常不容易获得 用于临床研究。对粪便或尿液的代谢分析也提供了有关 细菌存在于肠道微生物群中，然而，还有一种更方便的样本携带 与人类健康相关的信息。在这个项目中，我建议研究呼吸挥发性分布作为一种 用于描述肠道微生物群特征的介质。有800多种挥发性有机化合物(VOC)具有 在人类呼吸中被检测到，其中一些无法被宿主细胞新陈代谢解释。我猜想 肠道微生物区系将无法解释的VOCs贡献给宿主呼气VOC谱。在特定目标中1 我将表征灵芝属小鼠的呼吸VOC谱，以测试肠道微生物群组成对小鼠呼吸VOC的影响 呼气VOC图谱。在具体目标2中，我将展示细菌新陈代谢直接产生的VOCs 被宿主吸收，并在单克隆诺生菌小鼠模型中随呼吸排泄。最后，具体地说 目的3，通过比较元基因组学的结果，确定微生物组对人类呼吸的影响 作为最近完成的临床研究的一部分，用人类呼气VOCs对人类粪便进行测序。 这项调查将在圣路易斯的华盛顿大学进行，这是一所著名的微生物组研究机构 在安德鲁·考博士的实验室进行的研究，他是一位研究微生物组及其与 主持人。为了补充我的培训和专业知识，我将与奥黛丽·奥多姆博士的实验室合作- 约翰，呼吸波动特征方面的专家。进一步支持我的导师团队，Gautam Dantas博士将 作为我的论文委员会的联合发起人和主席，我提供了极好的建议。这是一次出色的训练 环境将确保所提出的研究计划为我未来提供严格的科学培训 医生兼科学家。

Project Summary/Abstract The gut microbiome has been implicated in various diseases such as inflammatory bowel disease, asthma, and neurodegenerative diseases. Despite the progress made in the studies of these diseases, there remains remarkable heterogeneity in patient presentation and prognosis. The interindividual variability in gut microbiome composition and metabolic functions may in part explain the interindividual variability in disease. Characterization of the gut microbiome is typically carried out using metagenomic sequencing or marker gene sequencing of the V4 16S sequence of bacteria in stool; however, these methods are not always possible in a clinical setting. Human stool must be acquired, properly stored, and is often not readily available at the site and time of collection for a clinical study. Metabolomic analysis of stool or urine also provides information about the functions of the bacteria present in the gut microbiome, however there is yet an even more convenient sample that carries information relevant to human health. In this project I propose to investigate the breath volatile profile as a medium for characterizing the gut microbiome. There are over 800 volatile organic compounds (VOC) that have been detected in human breath, some of them unexplained by host cellular metabolism. I hypothesize that the gut microbiota contributes otherwise unexplained VOCs to the host breath VOC profile. In Specific Aim 1 I will characterize the breath VOC profile of gnotobiotic mice to test the effect of gut microbiome composition on the breath VOC profile. In Specific Aim 2 I will show that bacterial metabolism directly produces VOCs that are absorbed by the host and excreted in breath with a monocolonized gnotobiotic mouse model. Finally, in Specific Aim 3, I will determine the effect of the microbiome on human breath by comparing the results of metagenomic sequencing of human stool with human breath VOCs collected as part of a recently completed clinical study. This investigation will take place at Washington University in St. Louis, a renowned institution for microbiome research, in the laboratory of Dr. Andrew Kau, an expert in the study of the microbiome and its interactions with the host. To supplement my training and expertise, I will collaborate with the laboratory of Dr. Audrey Odom- John, an expert in breath volatile profiling. Further supporting my mentorship team, Dr. Gautam Dantas will provide excellent advice as a co-sponsor and the chairperson of my thesis committee. This excellent training environment will ensure the research plan proposed provides rigorous scientific training for me as future physician-scientist.