Project 462866

It is becoming increasingly appreciated that the environment we are exposed to immediately after birth can have long-term consequences on our health. Nowhere in the body is this more relevant than the intestine: the primary site for nutrient absorption and microbial colonization. As such, the gut barrier that separates our body from the outside world must be conditioned in early life to maintain resilience against the dynamic lifestyle that we enjoy. Building this resilience relies of the intestinal immune system, yet we are only beginning to understand when and how this barrier is built. Using mice to model events in human life, we have recently discovered a transient activation of the intestinal immune system that coincides with a period of striking microbial growth in the developing colon. Remarkably, we find that inhibiting this immune activation in early life compromises resilience to experimental colitis in adulthood. The immediate objective of this research proposal is to determine the molecular pathways that direct the observed early life immune activation, the consequences of this response to intestinal barrier fortification and how it promotes lifelong integrity of the intestinal barrier. Our long-term goal is to harness our discoveries to prevent age-related intestinal diseases that continue to increase around the world.