The gut-placental axis: microbial signals remodeling maternal-fetal immune tolerance

Abstract

Pregnancy represents a unique immunological challenge requiring the establishment and maintenance of maternal-fetal immune tolerance. Emerging evidence demonstrates that the gut microbiota serves as a critical regulator of placental immune responses through systemic immune remodeling, constituting what is now recognized as the gut-placental immune axis. This narrative review examines the molecular pathways through which intestinal signals reach the maternal-fetal interface, encompassing short-chain fatty acids, tryptophan derivatives and their aryl hydrocarbon receptor (AhR) ligands, secondary bile acids, microbe-associated molecular patterns, bacterial extracellular vesicles, and placental exosomes. These signals collectively regulate key immune cell populations, including myeloid-derived suppressor cells, regulatory T cell subsets such as RORγt+ peripherally derived regulatory T cell (pTreg), Th17/Treg balance, macrophage polarization, and uterine natural killer (NK) cell function. We critically address the placental microbiome controversy, emphasizing that molecular signal transmission rather than live microbial colonization represents the prevailing paradigm for gut-placental communication. This paradigm shift redirects the research focus from identifying bacterial species to characterizing bioactive metabolites and microbe-associated molecular patterns. Furthermore, we elucidate how gut dysbiosis drives pathological cascades in major pregnancy complications, including preeclampsia, gestational diabetes mellitus, recurrent pregnancy loss, preterm birth, and fetal growth restriction. Finally, we evaluate clinical translation prospects encompassing probiotics, dietary fiber interventions, postbiotic metabolite supplementation, and engineered extracellular vesicle therapies, while acknowledging persistent challenges in establishing causal relationships, addressing individual heterogeneity, and ensuring long-term safety. This conceptual framework advances mechanistic understanding of microbiota-immune-placenta interactions and provides a foundation for developing microbiota-informed strategies to predict and prevent adverse pregnancy outcomes. Throughout, we explicitly distinguish human associative evidence from animal causal evidence.