Innate Immunity and Microbial Recognition in Reproduction: From Barrier Defense to Maternal-Fetal Tolerance

Reproduction requires the innate immune system to perform two opposing tasks simultaneously: prevent microbial invasion while preserving tolerance to sperm, the semi-allogeneic embryo, and the developing fetus. This review proposes a unified barrier defense-tolerance framework to explain how reproductive success depends on the coordinated integration of epithelial and mucus barriers, antimicrobial peptides, complement, tissue-resident innate immune cells, pattern-recognition receptor signaling, microbial ecology, and endocrine-metabolic regulation across the female and male reproductive tracts and the maternal-fetal interface. We summarize how Toll-like receptors, NOD-like receptors, RIG-I-like receptors, and cGAS-STING pathways shape early reproductive events, including gamete quality control, sperm transit, implantation, placentation, and antiviral defense, and how tightly constrained physiological inflammation supports tissue remodeling, whereas excessive or unresolved activation contributes to infertility, recurrent pregnancy loss, preeclampsia, fetal growth restriction, and preterm birth. We further examine microbiota-host interactions in reproduction, emphasizing that evidence is strongest for cervicovaginal communities, while endometrial, placental, and male genital microbiota findings require more cautious interpretation because of low-biomass sampling, contamination risk, and limited reproducibility. Beyond local microbial niches, gut-derived metabolites emerge as important regulators of immune tone and barrier function in reproductive tissues. We also discuss downstream effector mechanisms, including inflammasomes, regulated cell death, extracellular vesicles, and soluble innate mediators, and evaluate their translational relevance for biomarker development and targeted intervention. Overall, reproductive disorders are best viewed as systems-level outcomes of disturbed interactions among host barriers, innate sensing thresholds, microbial signals, and metabolic context, providing a conceptual basis for future multi-omics and mechanism-driven reproductive immunology.