Project description:Gut microbiota play an important role in regulating individual health. It is also increasingly apparent that changes in maternal gut microbiota result can render her offspring more susceptible to diseases later in life. Such bacterial induced changes likely originate in the womb. As the placenta is the primary communication organ between mother and conceptus, it is vulnerable to in utero environmental changes, including those associated with maternal gut microbiota. The placenta also relays nutritional and other factors, including serotonin, to the developing fetal brain that help guide development of this organ. Thus, placental disruptions can influence the placenta-brain axis and subsequently neurobehavioral programming with potential long-term consequences. One mechanism by which changes in maternal gut microbiota might effect the placenta are through alterations in bacterial short chained fatty acids (SCFA). The hypothesis, thus, tested in the current studies is that absence of a maternal gut microbiota, as occurs in germ-free (GF) mice, would impact bacterial SCFA in her fecal samples and in the fetal placenta and brain. Secondarily, we tested whether transcriptomic changes would be evident in the placenta and fetal brain from conceptuses derived from GF relative to multi-pathogen free (MPF) pregnant females.
Project description:Immune tolerance at the maternal-fetal interface is required for fetal development. Excessive maternal interferon gamma (IFNγ) and interleukin-17 (IL-17) is linked to pregnancy complications, but the regulation of maternal IFNγ and IL-17 at the maternal-fetal interface (MFI) is poorly understood. Here we demonstrate a gut-placenta immune axis in pregnant mice in which the absence or perturbation of gut microbiota dysregulates maternal IFNγ and IL-17 responses at the MFI, resulting in fetal resorption. Microbiota-dependent tryptophan derivatives suppress IFNγ+ and IL-17+ T cells at the MFI by priming myeloid-derived suppressor cells (MDSCs) and gut-derived RORγt+ Tregs, respectively. The tryptophan derivative indole-3-carbinol, or tryptophan-metabolizing Lactobacillus murinus, rebalances the T cell response at the MFI and reduces fetal resorption in germ-free mice. Furthermore, MDSCs, RORγt+ Tregs, and microbiota-dependent tryptophan derivatives are dysregulated at the MFI in human recurrent miscarriage cases. Together, our findings identify microbiota-dependent immune tolerance mechanisms that promote fetal development.