Elucidation of Host and Bacterial Factors that Influence Resilience and Robustnes

描述(申请人提供)：人体肠道微生物--被称为“微生物区系”--代表着一个由500多个物种和100万亿个细胞组成的充满活力和多样化的群落。在过去的十年里，基因组学的进步极大地促进了对这种复杂的多物种共生体的表征。已发现微生物区系中的门水平的组成变化可以由环境、宿主和细菌因素引起，与人类疾病相关并促进人类疾病。这一研究领域的下一个前沿是了解微生物区系中潜在的有害变化是如何发生的，以及如何纠正这种变化以治疗疾病。在这里，我描述了一种系统生物学方法，以确定微生物区系稳健性(对扰动的抵抗力)和弹性(从扰动中恢复)的分子和细胞决定因素。指导我的研究计划的首要假设是，细菌和宿主衍生的属性都有助于微生物区系的组成完整性。为了解决这一假设，我将采用一种适用于高通量和实时调查宿主相关微生物群落动态的共生斑马鱼宿主模型系统。我的提案的目标1将识别天然斑马鱼细菌分离株中的细菌基因，该分离株需要抵抗入侵物种的定居。目标2将解决暂时性宿主免疫抑制对微生物区系多样性和功能的影响。在目标3中，我将调查物种灭绝事件对微生物区系组成和功能的影响，这可能是抗生素使用的结果。在这项工作中所做的观察将为设计更有效的益生菌和治疗方案提供信息，以治疗与微生物区系病原性变化有关的疾病。

DESCRIPTION (provided by applicant): The microorganisms of the human intestinal tract-known as the 'microbiota'-represent a dynamic and diverse community made up of over 500 species and 100 trillion cells. Advancements in genomics over the last decade have greatly facilitated the characterization of this complex multi-species symbiont. It has been found that phylum-level compositional shifts in the microbiota, which can be induced by environmental, host and bacterial factors, correlate with and promote human disease. The next frontier in this research field is to understand how potentially deleterious shifts in the microbiota occur and how such shifts might be corrected to treat disease. Herein I describe a systems biology approach to identify molecular and cellular determinants of microbiota robustness (resistance to perturbation) and resilience (recovery from perturbation). The overarching hypothesis guiding my research plan is that both bacteria and host-derived properties contribute to the compositional integrity of the microbiota. To address this hypothesis, I will employ a gnotobiotic zebrafish host model system that is amenable to high-throughput and real time investigation of host-associated microbial community dynamics. AIM 1 of my proposal will identify bacterial genes within a natural zebrafish bacterial isolate required to resist the colonization of an invasive species. AIM 2 will address the consequences of temporary host immunosuppression on the diversity and function of the microbiota. And in AIM 3 I will investigate the role of specie extinction events, which can be a consequence of antibiotic use, on the composition and function of the microbiota. Observations made during this work will inform the design of more effective probiotic and therapeutic regimes for treating diseases associated with pathogenic alterations of the microbiota.