Micron-scale Spatial Metagenomic Mapping of Microbial Biogeography in the Gastrointestinal Tract

项目摘要 人胃肠道（GI）的肠道微生物组在宿主代谢中起关键作用， 免疫力和体内平衡肠道微生物组的生态失调通常与物种多样性的丧失有关， 这可能导致对代谢失调的易感性增加， 不受阻碍地扩散。例如，艰难梭菌感染（CDI）是一种典型的细菌感染 胃肠道感染是医院获得性感染的主要原因，具有严重的负面后果，包括死亡。 目前CDI的治疗包括使用粪便微生物群移植（FMT），其目的是恢复CDI的功能。 破坏肠道环境和健康微生物组。不幸的是，这些疗法的机制并不清楚 被理解为控制胃肠道微生物定植的规则尚未确定。我们有 一直在发展空间宏基因组学作为一种独特的和通用的方法来描绘微观尺度的空间 我们假设肠道中的微生物组织在肠道微生物组生态学中起着重要作用。这里 本更新申请，我们提出了3个具体目标：1）扩展空间宏基因组学的现有技术 通过在单细胞基因组学中采用新方法来提高通量并实现新的能力， 肠道微生物组的全基因组分析，2）将空间宏基因组学应用于人类和小鼠粪便 样品以描绘粪便微生物组移植后微生物组恢复的过程，以及3）杠杆作用 我们独特的机器人培养组学系统，用于分离肠道中未发现的菌株， 推动社区聚集的互动。这些拟议的研究构成了一个令人兴奋的和协调一致的 推动健康和患病状态下人类肠道微生物组的空间分布。通过结合 通过我们的方法实现的创新概念和技术进步，这一努力将创造新的途径， 机械地探索肠道微生物组在健康和疾病中的作用。

PROJECT SUMMARY The commensal microbiome of the human gastrointestinal (GI) tract plays a critical role in host metabolism, immunity, and homeostasis. Dysbiosis of the gut microbiome is often associated with a loss in species diversity, which can lead to increased susceptibility to metabolic dysregulation and higher chances for pathogens to proliferate unhindered. For instance, Clostridioides difficile infections (CDI) is an archetypical bacterial infection of the GI tract and a leading cause of hospital-acquired infections with severe negative outcomes including death. Current treatment of CDI includes the use of fecal microbiota transplantation (FMT), which aims to restore the disrupted gut milieu with a health microbiome. Unfortunately, the mechanism of such therapies is not well understood as the rules governing microbial colonization of the GI tract have not been determined. We have been developing spatial metagenomics as a unique and versatile approach to delineate the micron-scale spatial organization of microbes in the gut that we hypothesize to play a major role in gut microbiome ecology. Here in this renewal application, we propose 3 specific aims to 1) expand current techniques for spatial metagenomics by adopting new approaches in single-cell genomics to increase throughput and enable new capabilities for whole-genome analysis of the gut microbiome, 2) apply spatial metagenomics to human and mouse fecal samples to delineate the process of microbiome recovery after fecal microbiome transplantation, and 3) leverage our unique robotic culturomics system to isolate undiscovered strains in the gut and identify interspecies interactions that drive community assemblage. These proposed studies constitute an exciting and concerted push toward spatial profiling of the human gut microbiome in healthy and diseased states. Through a combination of innovative conceptual and technical advances enabled by our approach, this effort will create new avenues to mechanistically explore the role of the gut microbiome in health and disease.