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

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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.