151 - Early Antibiotic Exposure Affects the Immune Adaptation to Pregnancy and the Course of Pregnancy

Publication Number: 151.5040

Stefanie Dietz-Ziegler, Heidelberg University, Medical Faculty, Department of Neonatology, Heidelberg, Baden-Wurttemberg, Germany; Jessica D.. Ruehle, Heidelberg University, Medical Faculty, Department of Neonatology, Heidelberg, Baden-Wurttemberg, Germany; Janine Hebel, Childrens University Hospital Tübingen, Tuebingen, Baden-Wurttemberg, Germany; christian F. Poets, Tübingen University Hospital, Tuebingen, Baden-Wurttemberg, Germany; Christian Gille, Heidelberg University, Heidelberg, Baden-Wurttemberg, Germany; Natascha Köstlin-Gille, University Hospital Tübingen, Tübingen, Baden-Wurttemberg, Germany

Background: Miscarriages are by far the most common pregnancy complication and often the cause of unwanted childlessness. During pregnancy, maternal immune cells are in close contact with cells of the semi-allogeneic fetus. To prevent the fetus from being rejected by maternal immune cells, the immune system must be carefully regulated without compromising its ability to fight off pathogens. Although it has been known for some time that the intestinal microbiome plays a crucial role in health maintenance and disease development, and that many of these effects are mediated through its interaction with the immune system, almost nothing is known on how the intestinal microbiome influences the immune adaptation to pregnancy.

Objective: We aimed to investigate if a microbiome-modulation with antibiotics influences the immune adaptation to pregnancy and the course of pregnancy.

Design/Methods: We used a murine abortion model in which female CBA/J mice are mated with male DBA/2J mice, resulting in a spontaneous miscarriage rate of approximately 25%. We exposed CBA/J mice to a specific antibiotic regimen beginning already perinatally and continuing until mating (early antibiotic exposure, EAE). We then analyzed microbiome composition, immune cell composition and abortion rates at pregnancy day 10.5 compared to animals not exposed to antibiotics.

Results: EAE led to significant changes in the microbiome as assessed by qPCR with decreased abundance of Firmicutes, α-Proteobacteria and Fusobacteria, but increased abundance of Bacteroidetes in animals with EAE, leading to a decreased Firmicutes to Bacteroidetes ratio. Moreover, we found an altered immunological adaptation to a pregnancy with increased proportions of myeloid cells - especially myeloid-derived suppressor cells (MDSC) – and decreased proportions of T cells in pregnant mice with EAE in comparison to control animals. Within the population of T cells, the proportion of CD4+ T helper cells and CD8+ cytotoxic T cells was increased in mice with EAE, while the proportion of double-negative (DN) T cells was significantly reduced. These microbiome-mediated immunological alterations in the animals with EAE were associated with a reduced miscarriage rate.

Conclusion(s): The findings of our study demonstrate that microbiome-modulation can impact immune adaptation to pregnancy and pregnancy success. Thus, the intestinal microbiome could be a target for the development of new immunomodulatory therapies of pregnancy complications.