This project stems from an ERC STG grant that I received in 2007 (DENDROworld) in which we analyzed several aspects of the homeostasis of the gut and how defects in controlling this process could result in different pathologies, including inflammatory bowel disease (IBD) and cancer. In the present project, we will continue working on the immune homeostasis of the gut and we will focus on fundamental questions in mucosal immunity.Three important and novel questions will be addressed in this project. The first aims at understanding how the gut microbiota is restrained from reaching systemic sites and hence it is tolerated only locally. We think that we have identified a new barrier at mucosal sites that avoids systemic spreading of bacteria via the blood stream. This is a very selective barrier that resembles the blood brain barrier and occurs at the level of enteric endothelial cells. The second question is closely related and tries to identify the role of the microbiota in the establishment/maintenance of this barrier and to understand its role during infection with enteric pathogens or in other circumstances (like pregnancy, liver disease). Finally, we want to characterize the activity of an anti-inflammatory mediator that we have identified. This is a short isoform of the well-known cytokine called TSLP. We think that this isoform is the one involved in the homeostasis of the intestine as it is the only one produced by epithelial cells in health and is downregulated during chronic inflammation.This project is divided into three major aims.1. Analysis of a putative gut vascular barrier that resembles the blood brain barrier and of the mechanisms leading to its disruption2. Analysis of the role of the microbiota in the formation and maintenance of the Gut vascular barrier (GVB).3. Elucidation of the activity of TSLP short isoform.This is a multidisciplinary project requiring expertise in mucosal immunology, microbiology, bioinformatics and endothelium.