Investigating the influence of human milk oligosaccharides on bacterial-immune dynamics in the gravid vaginal tract - Project Summary The vaginal microbiota during pregnancy is an important reservoir for infant microbial seeding, but factors that impact the composition are complex and largely unknown. Vaginal presence of neonatal pathogens, like group B Streptococcus and extraintestinal pathogenic Escherichia coli, are associated with increased risk for adverse infant outcomes. Current antibiotic-based therapeutics are not optimal given the rise in antibiotic resistant bacterial strains, off-target microbial alterations, and potential long-lasting adverse outcomes for the neonate. Thus, it is critical to identify factors that impact the vaginal microbiota during pregnancy to identify alternative methods of limiting colonization and transmission of pathogens. Human milk oligosaccharides (HMOs) may be one such factor that can impact the vaginal microenvironment during pregnancy. HMOs are the third most abundant solid component in human breast milk, with over 100 unique HMOs identified thus far. HMOs provide health benefits to breastfed infants, like promoting the growth of beneficial microbes and limiting adhesion and invasion of pathogens in the gastrointestinal tract. HMOs are present in maternal circulation as early as gestational week 10 and the presence of specific HMOs are correlated with composition of the vaginal microbiota. This suggests there is a broader impact of HMOs in the mother that has not been explored. Our central hypothesis is that HMOs within the vaginal microenvironment act on both the microbial community and on the host to impact pathogen colonization and immune homeostasis. This hypothesis will be tested in the following specific aims: 1) identify utilization of HMOs by vaginal bacteria and the impact of HMO supplementation on vaginal microbial communities, and 2) investigate the potential of exogenous HMOs to confer a health-associated state on the vaginal microenvironment. We will use a combination of vaginal swabs from pregnant human donors, mini-bioreactor arrays, human vaginal epithelial organoids, and gravid humanized microbiota mice to explore the interplay between HMOs, vaginal bacteria, and the host response during pregnancy. This proposal will provide the applicant with training in organoids as a model system, animal models of pregnancy, and microbiome analyses, while expanding on the applicant’s previous background in immunology. Training will take place at Baylor College of Medicine under the mentorship of leading experts in the human microbiome and host-microbe interactions. Ultimately, this proposal seeks to identify if HMOs impact the vaginal microenvironment during pregnancy and assess their potential as a novel therapeutic alternative to antibiotics to limit pathogen colonization during pregnancy.
