Evaluating the impact of human milk oligosaccharides on the vaginal microenvironment

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Project Summary Formation and maturation of the human microbiota is associated with lifelong health outcomes, and its initial composition is heavily influenced by the maternal vaginal microbiota. Perturbations to the maternal vaginal microbiota in pregnancy or intrapartum are associated with increased risk of multiple health disorders from preterm birth to developing immune or metabolic disease later in life. Factors that promote an optimal transfer of microbes to the infant are undefined, and to date, knowledge of this critical process is largely descriptive or correlative. We seek to overcome this barrier by applying recent advances in model development, particularly the use of gnotobiotic animals, three-dimensional tissue culture, and cultivation of complex microbial communities, to generate experimental evidence for host and microbial factors shaping the maternal vaginal environment during pregnancy. With these models in hand, we will test a hypothesis proposing an entirely novel mechanism of maternal influence on the initial infant microbiota. Breastfeeding is consistently associated with improved infant health, reduced risk of infectious disease, and accelerated immune and microbial maturation within the gut. Human milk oligosaccharides (HMOs), the third most abundant component of breastmilk, serve as prebiotics for the developing microbiota and shape immune development and tolerance at the gut epithelium. Quite recently, it has become apparent that HMOs are systemically present during pregnancy, suggesting a wider influence on maternal and fetal biology than previously appreciated. Clinical studies have correlated maternal serum HMOs with vaginal microbiome signatures and genetic variants in HMO production are linked with vaginal pathogen colonization and risk for preterm birth. The central hypothesis of this proposal is that HMOs modulate the maternal vaginal microenvironment in pregnancy to promote growth of beneficial microbes for seeding the infant gut and to concurrently support barrier function and limit maternal inflammation. We will test this hypothesis by: 1) Characterizing the biological activity of HMOs towards human vaginal communities in vitro and in humanized gnotobiotic mice, and 2) Evaluating immunomodulatory impacts of HMOs at the vaginal mucosa using human vaginal organoids and gnotobiotic and germ-free mouse models. This research approach is a complementary merger of the applicant’s background in microbial pathogenesis and animal models of vaginal colonization and host-microbiome interactions, and the institutional strengths of BCM in the areas of human microbiome clinical research, human organoid development, and microbiome innovation and therapeutics. This high impact project will apprise the basic biology of HMO activity in the vaginal tract and provide a therapeutic tactic to better harness the potential of HMOs in modulating vaginal microbes and immunity. The breadth of experience necessary to complete this project is readily available through the combination of the applicant’s experience and supporting collaborators, and will lay the foundation for new findings, publications, and an exciting research trajectory.