Marilen Benner

GESTATIONAL ANTIBIOTICS AFFECT IMMUNITY 195 7 pregnancy. We additionally investigated placental and amniotic fluid samples, showing that systemic immune features do not represent immunity of gestational tissues. For example, placental CD4 + CD25 + FOXP3 + Treg populations remained unaffected, whereas the percentage of splenic Treg in antibiotic treated mice was reduced. Especially Treg of the fetal-maternal interface are considered critical to maintaining the anti-inflammatory environment necessary during the implantation period and throughout gestation (44). The increase in decidual Treg upon conception is hypothesized to be facilitated locally; through seminal fluid (45), human chorionic gonadrotropin secreted by the blastocyst (46), extravillous trophoblast cells (47), or local immune cells such as decidual macrophages (47). This local induction, independent from systemic immunity, might be connected to the observed lack of antibiotic effect on placental Treg. On the other hand, we detected an increase in the Th2 cell populations in the placentas after antibiotic treatment. Based on the premise that gestational immunity depends on a tightly regulated Th1/Th2 mediated cytokine balance (48), it is tempting to consider this a protective counteraction to prevent from a possible proinflammatory load upon external modifications during gestation. Thus, while the underlying mechanisms of how gestational antibiotics may perturb maternal immunity and fetal development are not yet clear, our results emphasize the need to study parameters of the fetal environment. The observed altered immunological profile upon antibiotics may be linked to side effects that were previously exclusively ascribed to its antimicrobial effect. During pregnancy, any dysregulation of immunity might affect placentation and thus fetal development (21, 49-51). Gestational immune adaptations are highly specialized to enable selective tolerance towards invading fetal cells, immune-competence to overcome pathogenic invasion, and immune-mediated support of establishing vascularization during placenta formation (52-55). Imbalance of immunity is thought to hamper correct placentation and thus contribute to the etiology of preeclampsia (PE) (56, 57). Indeed, prescription of antibiotics during pregnancy is associated with an increased risk of PE, which is also concerning considering that a fairly large proportion of pregnant women are prescribed antibiotics without an indication (58, 59). Still, it is unclear whether infections like UTI themselves, or their treatment is associated with an increased risk of developing PE (60). In case of an infection that requires antibiotic intervention, the involved inflammatory cascade may elicit systemic maternal inflammation and endothelial injury, which could also increase the risk of PE (61-65). Nevertheless, in vitro assays have shown that an alteration of immune responses can also occur independent of altered microbiota as phagocytosis by macrophages was inhibited directly through addition of antibiotics (66). Moreover, the current study shows that also in absence of infection, antibiotics affect the immune balance during pregnancy. In conclusion, either mediated by manipulation of the microbial profile or by direct effects of antibiotics, treatment affects the tightly regulated immunity of pregnancy. The associated