Prenatal antibiotic exposure and the origins offspring asthma susceptibility. (ORIGIN)

• Applicant: Dr. Melanie Lynn Conrad
• Subject Area: Gynaecology and Obstetrics ; Reproductive Medicine, Urology
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260349368

Asthma is the most common chronic inflammatory disease of childhood, with approximately 4 million children affected in Germany. Though allergic asthma undoubtedly has a genetic component, a dramatic increase in incidence over the past decades indicates that the environment also plays a fundamental role in disease susceptibility. Research shows that taking antibiotics during pregnancy is associated with increased risk for asthma development in children and it is estimated that 25% of pregnant women take antibiotics. If prenatal antibiotic exposure has even a small effect on childhood asthma susceptibility, this high frequency of antibiotic usage could substantially influence public health. Since it is still unknown how antibiotics taken during pregnancy influence fetal/neonatal development and childhood asthma susceptibility, it is increasingly important to study the mechanisms involved in these processes. To examine these mechanisms, we recently designed the first proof-of-concept mouse model demonstrating that treatment of pregnant mice with antibiotics increased offspring asthma severity in a dose dependent manner. Using this model, we also observed that that antibiotic treatment was associated with increased bacterial load and decreased bacterial diversity in the maternal intestine, a phenomenon that was passed on to the developing pups in early life. Our goal is to use our new model to investigate the mechanisms of how antibiotic treatment during pregnancy influences offspring asthma risk. To investigate this, our proposal will address four specific aims:1) How does antibiotic use during pregnancy alter circulating metabolites and immune mediators in the mothers?2) Assess how maternal antibiotic use influences placental, fetal and neonatal development. 3) Use fostering experiments to determine the pre- versus postnatal contribution of maternal antibiotic use during pregnancy to offspring asthma susceptibility.4) Examine if co-administration of microbial metabolites such as short chain fatty acids during maternal antibiotic treatment protects against a severe offspring asthma phenotype. We hypothesize that antibiotic use during pregnancy changes the amounts of circulating maternal immune molecules and bacterially produced metabolites. We propose that these molecules affect the establishment of the placenta, leading to fetal growth restriction and deceleration of fetal lung development. Additionally, we suggest that the trafficking of these mediators across the placenta directly influences fetal development. Finally, we argue that changes to the gut microbiome in early life, combined with alterations in maternal breast milk constituents, drive neonatal immune system development towards a less tolerant phenotype. In adult animals, this would result in an over sensitized inflammation response, contributing to the severe asthma symptoms observed in offspring from antibiotic treated pregnant mothers.

• DFG Programme: Research Grants