Fetuses are commonly understood to develop in a sterile environment, and it is generally understood that bacterial invasion of the intrauterine environment predisposes the pregnancy to preterm birth. In preliminary experiments using culture and advanced metagenomics techniques, we have discovered that the fetus harbors bacteria that are apparently nonpathogenic and that appear to sort as if they home to niche environments within the feto-placental unit. Our data in animals agrees with our data indicating that human meconium at birth contains bacterial DNA. The proposed project is designed to expand our preliminary data to a larger cohort of fetuses and to experimentally test whether bacteria that are normally found in fetal meconium or in placenta distribute to these sites if administered to the amniotic fluid or to the maternal blood. We believe that the discovery of a physiological bacterial flora in the fetus could explain the endogenous stimulation of immune development in the fetal brain and possibly other tissues. Furthermore, we expect that if nonpathogenic species of bacteria cross from mother to fetus and reside in specific niches, we could leverage this basic biological information to design therapeutics aimed at manipulating the balance of nonpathogenic to pathogenic bacteria in fetuses threatening preterm labor as a result of chronic maternal infection. Therapeutics based on targeted transgenic bacteria would also be possible.