162 - Fecal Extracellular Vesicles Modulate T-cell Responses During Healthy Pregnancy and Preeclampsia

Publication Number: 162.5042

Stefanie Dietz-Ziegler, Heidelberg University, Medical Faculty, Department of Neonatology, Heidelberg, Baden-Wurttemberg, Germany; Samantha Kewitz, University of Tübingen, Tübingen, 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: Pregnancy is an exceptional immunological situation in which a semi-allogeneic organism must be tolerated by the mother's immune system. To make this possible, specific adaptation processes take place, in particular profound changes in the T helper cell response. The intestinal microbiome contributes significantly to health, but in case of pathological changes – a so called dysbiosis - it can also be involved in the development of diseases. So far, little is known about whether and how the intestinal microbiome influences immune adaptation to pregnancy. Bacterial extracellular vesicles (BEVs), which are released by bacteria of the intestinal microbiome, can overcome the intestinal barrier and exert systemic immunomodulatory effects.

Objective: We investigated whether BEVs influence T-cell homeostasis during pregnancy.

Design/Methods: We collected stool samples from non-pregnant women, women with recurrent spontaneous abortions (RSA), healthy pregnant women and pregnant women with preeclampsia (PE). We established a protocol for isolating BEVs from preserved stool samples and investigated their composition and their effect on T cells in an in vitro model.

Results: We found that BEVs were taken up by T cells in a time dependent manner and modulated the T cell phenotype. BEVs from control subjects, women with RSA, healthy pregnant women and women with PE showed differences in their bacterial origin. In vitro, BEVs from the stool of pregnant women changed the T helper cell phenotype towards a regulatory profile favorable for pregnancy with induction of Th2 cells and suppression of Th17 cells compared to BEVs from the stool of non-pregnant controls. Furthermore, BEVs from non-pregnant controls and healthy pregnant women differentially modulated the proteome content of T-cells. While BEVs from patients with RSA had no different effects on the T helper cell composition than fecal BEVs from control subjects, BEVs from the stool of patients with preeclampsia induced a proinflammatory T helper cell phenotype with reduced Th2 cells and reduced regulatory T cells as well as increased Th17 cells.

Conclusion(s): We show in vitro that the intestinal microbiome can profoundly influence immune adaptation to pregnancy via BEVs. BEVs of the intestinal microbiome could be a promising approach for the development of microbiome-targeted preventive or therapeutic strategies directed at immunological pregnancy complications.