Evolutionary Dynamics of the Human Gut Microbiome During Colonization

项目摘要 人类肠道微生物组与健康密切相关，其生态组成受到破坏 与许多疾病有关。通过粪便微生物组移植（FMT）操纵微生物组， 其中将来源于健康供体粪便的微生物菌株引入患者的肠道群落， 对某些疾病是有效的治疗方法，但对其他疾病则不太有效。在一些情况下， FMT不能解决疾病，入侵菌株不能殖民，但原因不明，甚至何时 菌株确实定殖，但仍然不能保证健康的临床结果。小鼠实验进化研究 和蜜蜂微生物组已经表明，入侵宿主的菌株迅速适应，通过物理 粘附于宿主细胞、与常驻菌株竞争以及逃避宿主免疫系统。尽管如此 强有力的实验支持的重要性，适应在殖民地，其作用，在人类肠道 微生物群很少受到关注。最近，我们和其他人发现微生物组可以在 几个月甚至几天，但这种快速进化对殖民过程的影响仍然存在。 未知将适应和殖民化联系起来的主要障碍在于以下统计挑战： 从嘈杂的宏基因组数据中量化适应的完整景观。在这里，我建议开发新的 统计方法，阐明有关殖民化的进化过程中， 微生物组，并将其应用于FMT接受者的最大数据集之一。 我的实验室的主要目标是了解微生物组如何在一系列背景和时间尺度下进化。本 最后，我提出的MIRA研究计划的总体目标是阐明进化的 允许菌株定殖的过程。为了充分量化的模式，克里思，和目标的演变， 肠道微生物组及其与定植的相关性，我们将开发能够检测 目前无法检测到的进化事件，包括（1）在宿主体内发生的进化变化， 短时间尺度和（2）在较长时间尺度上跨主机。为了说明我们的统计数据的潜力， 创新，我们将研究FMT接受者，因为入侵菌株与常驻菌株的身份可以被 容易区分。然而，FMT代表了更普遍的殖民化现象的一个例子 与我的实验室正在研究的一系列群体和问题有关，包括进化在婴儿中的作用 在出生时经历微生物的涌入，在抗生素和益生菌的消耗期间经历菌株更替，以及 沿着肠道定居所需的进化适应的空间隔离。总之，成功 这项工作的完成不仅将产生量化经济发展所需的统计创新， 微生物组，而且还阐明了进化在殖民化中的重要性，这些知识有望产生 更有效的微生物组疗法

PROJECT SUMMARY The human gut microbiome is intimately connected with health, with disruptions of its ecological composition associated with numerous diseases. Manipulations of the microbiome via fecal microbiome transplants (FMTs), in which microbial strains derived from healthy donor stool are introduced to a patient's gut community, have been found to be effective treatments for certain diseases, but less effective for others. In several cases in which FMTs fail to resolve a disease, invading strains fail to colonize, but it is unknown why, and even when strains do colonize, a healthy clinical outcome still is not guaranteed. Experimental evolution studies in mouse and bee microbiomes have shown that strains invading a host rapidly adapt, enabling colonization via physical adherence to host cells, competition with resident strains, and evasion of the host immune system. Despite this strong experimental support for the importance of adaptation during colonization, its role in the human gut microbiome has received little attention. Recently, we and others found that microbiome can evolve rapidly on months and even days, but the impacts of this rapid pace of evolution on the colonization process remains unknown. The main roadblock to linking adaptation and colonization lies in the statistical challenges of quantifying the full landscape of adaptations from noisy metagenomic data. Here I propose to develop new statistical methods that elucidate the evolutionary processes relevant for colonization in the microbiome and apply them to one of the largest datasets of FMT recipients. My lab's main goal is to understand how microbiomes evolve in a range of contexts and timescales. To this end, the overarching objective of my proposed MIRA research program is to elucidate the evolutionary processes that permit colonization of a strain. To fully quantify the mode, tempo, and targets of evolution in the gut microbiome and their relevance to colonization, we will develop novel methodology capable of detecting evolutionary events that are undetectable presently, including evolutionary changes (1) arising within hosts on short timescales and (2) across hosts on longer time scales. To illustrate the potential of our statistical innovations, we will study FMT recipients given that the identities of invading versus resident strains can be easily distinguished. However, FMTs represent an example of a more general phenomenon of colonization relevant to a range of cohorts and questions that my lab is studying, including the role of evolution in infants experiencing an influx of microbes at birth, strain turnover during consumption of antibiotics and probiotics, and spatial segregation of evolutionary adaptations needed for colonization along the gut. In sum, successful completion of this work will not only generate statistical innovations needed to quantify evolution in the microbiome, but also elucidate the importance of evolution in colonization, knowledge that promises to yield more efficacious microbiome therapies.