Marilen Benner

GESTATIONAL ANTIBIOTICS AFFECT IMMUNITY 189 7 INTRODUCTION Any medication during pregnancy demands careful consideration, however treatment is essential when infections need to be controlled to ensure safe progression of the pregnancy. In western society, antibiotics for systemic use are amongst the most frequently prescribed drugs during gestation (1). Most commonly, gestational respiratory tract infections or urinary tract infections (UTI) require systemic anti-infectious medical intervention (2-4). If left untreated, 20-40% of asymptomatic UTI advance to acute UTI, which can lead to premature labor in up to half of the women affected (5). Antibiotic intervention has been shown to reduce complications of UTI such as preterm birth and/or low birth weight (6). Approximately 1 in 5 pregnancies is exposed to antimicrobial treatment nowadays (1, 7). While this can safeguard pregnancy, microbial intervention during pregnancy is known to have long term effects on the offspring as well. Gestational use of antibiotics is associated with an increased risk for the offspring to develop non communicable diseases like asthma, obesity, and even increased susceptibility to infections (8-10). In general, antibiotic prescriptions require rational and critical use, not only to limit the selection towards drug-resistant pathogens (11). Awareness of how the natural microbiomes’ contribution to physiology increases, and a diverse microbiome is key to healthy immunity (12-14). Systemic antibiotics drastically reduce the diversity of the gut microbiome and, depending on the compound and its target, impact on bacterial taxa can last for years (15, 16). This interference through broad-spectrum microbial modulation resulted, among others, in colonic infiltration of innate inflammatory cells in mice (17). In addition, antibiotics treatment skewed T cells towards an activated T helper (Th) 1 profile, together with a reduced proportion of FOXP3 + CD4 + regulatory T cells (Treg) (17). After antibiotic treatment, a general increase in pro-inflammatory transcriptional and cellular responses was observed, such as an activation of dendritic cells and upregulation of genes of pro-inflammatory cytokines interleukin 6 (IL-6), IL-8 and CXCL2 (18). The adverse effects of this inflammatory state might be limited in young adults (>65 years age) (18) but it is unsure if this holds true for pregnant women. Pregnancy relies on tightly regulated immunity to allow trophoblast invasion and prevent infection, while excessive inflammation of the prenatal environment has to be avoided as well (19-27). Especially at the direct fetal environment, dysregulated immunity can cause pregnancy complications, such as preeclampsia (PE) and preterm birth, with long-term consequences on the offspring’s development (28-30). As such, antibiotic-mediated changes of immunity can endanger prenatal development. Based on this, we questioned in this study whether gestational antibiotic use translates to maternal immune adaptations with possible impact on reproductive health. We here evaluated immunity of different maternal immunological compartments, including the placenta, using a murine model of gestational microbial modification.