Our lab is interested in the development of the vertebrate digestive tract, and the molecular foundations of commensal/symbiotic host-bacterial interactions within the gut. We have combined functional genomic strategies and gnotobiotics (raising normal, transgenic and knockout mice under germ-free conditions) to identify the effects of introducing specific members of the normal gut microflora on gut gene expression and development. In addition, by sequencing the entire genome of Bacteroides thetaiotaomicron, a prominent and genetically manipulatable component of the mouse and human intestinal microflora, we can monitor how its colonization of germ-free mice influences both bacterial and host gene expression. We are now turning to zebrafish as a model organism, taking advantage of the transparency of the developing fish gut and the power of this genetic system to examine the factors that determine how bacteria are able to establish residency within specific regions of the intestine, and the impact of their colonization on establishment and function of the gut ecosystem. The long-term objective of our work is to help define how co-evolution of bacterial symbionts and their host influences postembryonic development, and how shifts in microbial ecology affect host gene expression and physiology. These gnotobiotic models hold the promise of elucidating how elements of the microflora affect health and contribute, under certain conditions, to the pathogenesis of both intestinal and extra-intestinal diseases.