Charting the role of microbial biogeography in gut inflammation with novel genome-scale microscopy methods

The composition and activity of the gut microbiota is a key modulator of Inflammatory Bowel Diseases (IBD). Importantly, the bacteria that reside within the gut are organized within distinct biogeographical niches, and niche occupancy can be a major contributor to IBD. Unfortunately, the biogeography of the gut microbiota, its modulation during intestinal inflammation and the specific gene expression programs that license niche occupancy remain largely unclear. The sheer complexity of this system poses a major challenge to addressing these questions: hundreds of bacterial species collectively express hundreds of thousands of genes, which, in turn, shape interactions with many gut cell types. Genome-scale sequencing methods have been the historic solution to this complexity, yet these methods naturally discard the spatial organization of this system and, thus, have provided limited insight into microbial biogeography. Here we address this limitation with new “genome-scale microscopy” methods. Our methods allow us to image and identify thousands of different RNA molecules within intact gut samples, and we will leverage our tools to map the microbial biogeography, gene expression and host response in a murine IBD model with three defined microbiota. Collectively, these measurements promise new insights into the role of microbial biogeography in gut inflammation.