SUMMARY/ABSTRACT The gastrointestinal mucosa functions as an interface between the luminal contents and the underlying tissue compartments, and is thus vital in maintaining mucosal and systemic homeostasis. The gut lumen houses a numerically vast and taxonomically diverse prokaryotic microbiota. In health, the mucosa and microbiota thrive in a mutually beneficial symbiotic arrangement. Both host and microbe have evolved a complex system of mutual perception, response and reaction. These events are mediated in part by the ability of the intestinal epithelia to respond to specific members of the microbiota by the production of reactive oxygen species (ROS), that serve to activate multiple cellular pathways involved in the maintenance of gut homeostasis. This proposal will employ in vivo systems including extensive use of germ-free mice, or mice gnotobiotically colonized with known ROS inducing bacteria. Additionally, taxonomic analysis of microbiota in neonatal mice will be used to identify other bacteria with functional effects on the gut mucosa. The proposal will study microbial influences on known and novel signaling pathway, and characterize the regulatory effects on gut survival, differentiation and proliferation. Our overall objectives are to define the participants, events, and processes involved in host microbial contact and how this interaction influences intestinal homeostasis, development and restitution. ROS and redox-stimulated pathways likely represent a conserved mechanism by which the host interacts with its commensal microbiota, and thus presents an attractive target for therapeutic manipulation.