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

项目总结 人胃肠道的共生微生物群在宿主代谢中起着关键作用。 免疫力和动态平衡。肠道微生物群的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，并增加病原体感染的几率 不受阻碍地扩散。例如，艰难梭状芽胞杆菌感染(Cdi)就是典型的细菌感染。 这是胃肠道感染的主要原因之一，也是导致包括死亡在内的严重负面后果的医院获得性感染的主要原因。 目前对CDI的治疗包括使用粪便微生物区系移植(FMT)，其目的是恢复 用健康的微生物群破坏了肠道环境。不幸的是，这种疗法的机制不是很好。 据了解，胃肠道微生物定植的规则尚未确定。我们有 我一直在发展空间元基因组学，作为一种独特和通用的方法来描绘微米级的空间 肠道微生物的组织，我们假设它在肠道微生物生态中起主要作用。在这里 这一更新应用，我们提出了3个具体目标：1)扩展现有的空间元基因组学技术 通过采用单细胞基因组学的新方法来增加产量并实现新的能力 肠道微生物组的全基因组分析，2)空间元基因组学在人类和小鼠粪便中的应用 描述粪便微生物组移植后微生物组恢复过程的样本，以及3)杠杆 我们独特的机器人培养系统，用于分离肠道中未发现的菌株并鉴定物种间 推动社区聚集的相互作用。这些拟议的研究构成了令人兴奋和协调一致的 推动健康和疾病状态下的人类肠道微生物组的空间图谱。通过组合 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 从机械上探索肠道微生物群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.