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Abstract
This dissertation establishes geography as a unifying principle for understanding intestinal homeostasis, arguing that position fundamentally dictates biological outcome. This work comprises several investigations that use a computationally driven discovery approach and the integration of complex, regionally sampled transcriptomic datasets to reveal a multi-scale model of intestinal immunity. At the systems level, peripheral neurons and epithelial cells form an integrated surveillance infrastructure that coordinates rapid barrier protection. Regionally, the transcription factor GATA4 functions as a master zoning regulator that partitions the small intestine into specialized functional districts. Within these districts, secretory IgA provides molecular border control that enforces spatial segregation between host and virome. At the tissue structure level, organized lymphoid tissues (i.e., Peyer's patches) exhibit region-specific transcriptional profiles. Inside Peyer's patches, specialized microfold gatekeeper cells undergo microbial-induced reprogramming, demonstrating that even specialized immune niches are susceptible to geographic tuning. These findings underscore the idea that, rather than just using molecular signatures to distinguish between friend and foe, the immune system maintains homeostasis partly by enforcing where in the body various microorganisms are allowed. When geographic organization fails at any scale, the cascade of consequences can result in bacteria colonizing inappropriate locations, molecular boundaries collapsing, and cellular positioning becoming disrupted. This framework suggests the necessity of tissue-regionalized medicine---therapeutic interventions that selectively target specific niches within the body. Beyond advancing intestinal immunology, this work establishes a conceptual architecture and methodological toolkit for spatially informed discovery that is applicable to diverse biological systems.