The impact of ampicillin and breast milk oligosaccharides on the infant microbiome and immune functions

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PROJECT SUMMARY Intrapartum antibiotic prophylaxis (IAP) of pregnant women with ampicillin (AMP) to prevent neonatal group B Streptococcus (GBS) disease has had a major impact to reduce infection-associated morbidity and mortality in the immediate newborn period over recent decades. However, with this reduced incidence of early-onset GBS disease, antibiotic exposure has the potential to cause significant collateral damage by perturbing the infant gut microbiota and its developing immune system. Breast milk, conversely, supplies the infant with oligosaccharides that possess unique immune-modulatory (and sometimes antimicrobial) properties beneficial for shaping the development of a normal gut microbiome. Current pediatric guidelines that recommend the use of AMP for GBS prophylaxis and the appropriate duration of breastfeeding are now receiving significant new attention because of their clear impacts upon the health of the infant accrued through changes, deleterious or beneficial, on the development of a healthy microbiome and infant immune system. Co-PIs Victor Nizet and George Liu of this Basic Science Project entitled “The impact of Ampicillin and Breast Milk Oligosaccharides on the Infant Microbiome and Immune Functions” are pediatric physician-scientists large and successful translational research programs built around GBS and related bacterial pathogens, antibiotic therapeutics and host immune responses. This current proposal will apply experimental mouse models in which the labs have long standing expertise to provide key mechanistic insights in this highly novel area of maternal-infant clinical pharmacology. Namely, we will be studying the novel aspects of toxicology or adverse impact of empiric prophylactic antibiotic therapy given to (millions of) mothers during pregnancy, or alternatively, to the infant afterbirth for empiric treatment of suspected sepsis. These antibiotic exposures reduce risk of infection, but simultaneously affect the infant microbiome and metabolome in both the short and long term, likely impacting subsequent immune responses of the infant to infections and vaccinations. Our overarching hypothesis is that AMP, given prophylactically to the mother or empirically to the infant, has a measurable detrimental effect on infants’ gut microbiome and developing immune system, and consequently adversely affect the infant’s subsequent response to bacterial infections and vaccines and the clinical pharmacology of later antibiotic administration. Conversely, we hypothesize that maternal milk oligosaccharides (MMO) provide a benefit to the infant by improving the resilience of the gut microbiome, consequently mitigating the antibiotic adverse effects, and improving subsequent response to GB S infections and pneumococcal and hepatitis B vaccine responses. Successful completion of this Basic Science Project will help determine the benefits and adverse effects of antibiotics and MMOs on the infant microbiome and immune system and further inform the appropriateness of current GBS antibiotic prophylaxis guidelines and recommendations for the length of breastfeeding.