Marilen Benner

SUMMARY AND DISCUSSION 229 8 UTI itself is a risk factor for PE, which is hypothesized to originate from an increase in the systemic inflammatory burden (109-111). In Chapter 7 , we investigate in how far antibiotic intervention in pregnant mice causes changes in systemic, as well as local (placenta) immunity. We observed that while the medication did not affect reproductive success, microbial manipulation translated to altered immunology of the mother, reaching as far as the placenta. We based our microbial intervention on the combination of antibiotics published by Tormo-Badia et al., who showed lasting immunological effects in offspring of non-obese diabetic mice treated with antibiotics (112). The authors observed a reduced diversity of intestinal microbiota and limited activation of T cells in the pups. Altered immunity of the offspring might not only result from their own altered microbial profile, but from treatment effects on the fetal prenatal environment such as demonstrated by our results. The presented data illustrate that the effect of gestational antibiotics on the offspring need to be studied in light of the treatment’s effect on maternal immunity. Unfortunately, low bacterial yield upon sequencing of placental microbiota prohibited us to draw conclusions on exact species composition, or a treatment-induced switch in frequencies or abundance. However, few samples in which detection was possible, indicate a shift in placental species distribution. It is tempting to speculate that this indicates altered prenatal microbial exposure. Could microbial priming of the developing child occur in utero, with possible lifelong effect on the offspring? Various studies have linked the gestational use of antibiotics to an increased risk for the child to develop asthma, atopic dermatitis, and allergic disease and increased childhood hospitalization of the offspring (113-116). While the possible confounding effect of other underlying causes of disease, linking maternal and fetal health, needs to be kept in mind (117), murine studies could also confirm the link in antibiotic intervention studies (118- 120). Still, the causative relationship and etiology of disease needs to be elucidated. Systemic immune adaptations of the mother, immune modulation reaching the baby, direct effects of (metabolites of) the microbial intervention, effects passed on during breastfeeding, a shift in microbial prenatal exposure; the list of possible medication-related impact on the offspring is long. Neither route probably impacts childhood health exclusively. The need to treat pregnant women with antibiotics will persist in order to save mother and child of an acute threat. It remains to be revealed how gestational antibiotics are linked to long-term effects on immunity. Our study points out that effects due to an altered uterine environment have to be considered as a part of this investigation. GENERAL CONCLUSION AND FUTURE PERSPECTIVES Healthy pregnancy depends on a broad variety anatomic, endocrine, metabolic, and immunologic adaptations, which orchestrate local immunity (Figure 1). The findings discussed in this thesis point out that uterine immunity is highly dynamic, and is affected by even more factors than