Gut microbiota promote immune tolerance at the maternal-fetal interface

Immune tolerance at the maternal-fetal interface is required for fetal development. Excessive maternal interferon gamma (IFN?) and interleukin-17 (IL-17) is linked to pregnancy complications, but the regulation of maternal IFN? 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 IFN? and IL-17 responses at the MFI, resulting in fetal resorption. Microbiota-dependent tryptophan derivatives suppress IFN?+ and IL-17+ T cells at the MFI by priming myeloid-derived suppressor cells (MDSCs) and gut-derived ROR?t+ 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, ROR?t+ 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. Overall design: scRNA-seq of CD45+ cells from blood, placenta, and uterus of E16.5 pregnant SPF and germ-free mice