Spatially restricted immune and microbiota-driven adaptation of the gut [Spatial Transcriptomics]
The intestine is characterized by an environment where host requirements for efficient nutrient and water absorption are consequently paired with the requirement to establish and maintain tolerance to the outside environment. The organ is anatomically organized into the small intestine (SI) which specializes in nutrient absorption and the colon which specializes in water resorption. The transcriptional and cellular circuits that define intestinal regionalization and their robustness, adaptability, and resilience to changes in the local environment are not well characterized. Here, we generated a comprehensive survey of the spatial and cellular landscape of the murine intestine to demonstrate the steady state transcriptional landscape of the murine intestine is robust, adaptable, and resilient to perturbation. We characterized the transcriptional landscape of the full length of the intestine and show it is established independently of the microbiota and is not under circadian regulation. In the colon, these regional circuits were characterized by unique subsets of structural cells. Moreover, we identified a spatial adaptation to the microbiota in the colon characterized by the emergence of unique structural cell subsets including an enterocyte, fibroblast, and goblet cell, with the later two co-occurring in space. Employing a model of acute spatiotemporal damage allowed us to show the spatial landscape and adaptations we identified are both resilient to inflammation. Our results demonstrate that intestinal circuits are under host control and spatial adaptations in the steady state as well as in the process of recovery from tissue damage in the inflamed state are primarily characterized by changes to structural cell types such as epithelial and stromal cells. Overall design: Intestinal tissue was collected from WT SPF, GF, or FMT treated mice as well as DSS treated mice. Tissue was partitioned into segments covering the duodenum, jejunum, ileum, and colon and then swiss rolled and embedded in OCT for freshly frozen sample generation used for spatial transcriptomics data generation using 10x Visium technology. Samples were compared to establish the steady state spatial transcriptome of the intestine, the spatial transcriptome regulated by microbiota, and finally the impact of inflammation and recovery from inflammation on the spatial transcriptome of the intestine. 3 biological replicates were included for each tissue segment for SPF and GF mice and 2 biological replicates were included for each tissue segment for FMT treated mice. 1 biological replicate was generated for DSS treated tissue.