Differential modulation of gestational immunity by fatty acids: tissue-specific immune remodeling and clinical implications

Pregnancy necessitates dynamic maternal metabolic adaptations where fatty acids (FAs) serve dual roles as energy substrates and immunomodulators. However, the effects of specific FAs on gestational immunity and pregnancy outcomes remain elusive. In the present study, we administered saturated palmitic acid (PA), monounsaturated oleic acid (OA), polyunsaturated arachidonic acid (AA), or vehicle solutions daily to pregnant mice (gestational day 0.5 [GD0.5]-7.5) and performed comprehensive immune profiling at GD13.5. Mendelian randomization (MR) analysis was employed to evaluate translational relevance in human pregnancies. AA increased embryo resorption rates and decreased both embryonic and placental weights, aligning with MR evidence linking elevated maternal circulating AA to miscarriage risk. Decidual AA exposure amplified pro-inflammatory macrophages (CD11c+), cytotoxic natural killer (NK) cells (NKp46+, IFN-γ+), and cytotoxic T lymphocytes (CTLs, TNF-α+), contrasting OA-driven expansion of M2-like macrophages (CD206+) and pregnancy-protective NK cells (B220+CD11c+). Systemically, AA polarized Th1/CTL dominance (IFN-γ+CD8+) and Ly-6Chigh monocyte retention, whereas OA enhanced Th2 responses and Ly-6Clow monocyte maturation. Paradoxically, AA up-regulated ULN tolerogenic dendritic cells (DCs) and IL-10 expressing regulatory B cells, suggesting tissue-specific lipid sensing. PA activated splenic IFN-γ+ NKs but spared decidual/ULN tolerance. In summary, distinct FAs differentially program gestational immunity in a tissue-specific manner: OA enforces systemic tolerance, while AA drives localized inflammation despite compensatory ULN immunosuppression. These findings advocate personalized FA interventions to optimize pregnancy outcomes.