Microbial programming of host physiology

摘要 人们已经投入了大量的精力来对不同健康状态下栖息在我们体内的微生物进行分类 和疾病。同样紧迫的是对这些群落的分子途径的理解 微生物(我们的‘微生物群’)对我们的生理进行编程。这一过程从 在婴儿早期，微生物群首先在肠道中定居。在这一“关键时期”，微生物的输入需要 肠道、免疫和神经系统发育完全。在适当的时候，这些交互作用 为未来的健康提供基础，但当它被破坏时，它会使个人容易患病。因此， 确定这些事件的遗传调控因素是微生物组中最基本的问题之一 今天的研究。因此，我们的目标是全面识别控制 寄主生理学的微生物组编程。 在这里，我们提出了一套创新的方法，这将首次使我们能够分解微生物 对整个生物体中的反应网络进行编程--一个名副其实的“登月”微生物群。这是做的 通过使用简单、定义精致且高通量的可服从动物系统， 秀丽隐杆线虫。我们已经鉴定了线虫的天然微生物群，并表征了其广泛的 对寄主生理和发育的影响广度。我们认为，线虫系统是理想的 询问微生物组编程的影响有四个主要原因。首先，微生物暴露在 幼虫的发育决定了成虫的生理。其次，可供细菌使用的肠道生态位是 可与婴儿肠道结构、化学、免疫和消化环境相媲美。第三，潜在的东道主 反应途径被保存得很好。第四，在婴儿体内发现的大多数类型的微生物 肠道也会自然地滋生线虫。我们建议利用这一系统来阐明 通过采用两个互补的项目对微生物组进行重新编程。在项目1中，我们将生成第一个 微生物组规划对整个生物体宿主生理的影响的完整地图。这些研究 将使用我们正在开发的一种新的测序方法来量化微生物组编程的影响 在数百种动物体内的所有线虫959细胞上。在项目2中，我们将确定宿主基因 一种管理微生物编程的环境，使用的战略大大提高了吞吐量和 有针对性的基因中断的表型。根据初步数据，我们将首先描述 在这一过程中，高度冗余的受体介导的信号通路。这些研究的结果将 在生命早期确定促进健康微生物编程的宿主途径，并将有助于 制定治疗策略，旨在重新开启这一关键时期，以减轻成人疾病。

SUMMARY Much attention has been invested in cataloging the microbes that inhabit our bodies in various states of health and disease. Equally pressing is an understanding of the molecular pathways by which these communities of microbes (our `microbiome') program our physiology. This process occurs from the moment that the microbiome first colonizes the gut in early infancy. During this `critical period,' microbial input is required to complete development of the intestine, immune and nervous systems. When appropriate, these interactions provide a foundation for future health, but when it is disrupted, it predisposes individuals to disease. Thus, defining the genetic regulators of these events is one of the most fundamental questions in microbiome research today. Our goal is therefore to comprehensively identify the molecular pathways that govern microbiome programming of host physiology. Here, we propose a suite of innovative methods that will, for the first time, allow us to resolve microbial programming response networks in whole organisms—a veritable microbiome `moon shot'. This is made possible by employing a simple, exquisitely defined, and high-throughput amenable animal system, Caenorhabditis elegans. We have identified the C. elegans natural microbiome and characterized its wide breadth of influence on host physiology and development. We believe that the C. elegans system is ideal for interrogating the impact of microbiome programming for four main reasons. First, microbial exposures during larval development dictate adult physiology. Second, the intestinal niches that are available for bacteria are comparable to the infant gut structural, chemical, immune and digestive environment. Third, the potential host response pathways are well-conserved. Fourth, a majority of the types of microbes that are found in the infant gut also naturally colonize C. elegans. We propose to leverage this system to elucidate the networks of microbiome reprogramming by employing two complementary projects. In Project 1, we will generate the first complete map of the impact of microbiome programming on whole organism host physiology. These studies will use a new sequencing method that we are developing to quantify the impact of microbiome programming on all of C. elegans 959 cells in hundreds of animals at a time. In Project 2, we will identify the host genetic landscape that governs microbial programming using strategies that greatly enhance the throughput and phenotyping of targeted genetic disruptions. Based on preliminary data, we will first characterize the role of the highly redundant, receptor-mediated signaling pathways in this process. Results from these studies will identify host pathways that promote healthy microbial programming early in life, and will aid in the development of therapeutic strategies aimed at reopening this critical period to mitigate adult disease.