Maternal immune activation perturbs intestinal niche through microbial glycerophospholipids and drives offspring behavioral abnormalities.

Cell Rep 2026

Chang H, Zhu X, Shen C, Xu X, Ni Y et al.

Abstract

Maternal immune activation (MIA) contributes to neurodevelopmental deficits in offspring, yet the prenatal mechanisms remain elusive. Here, using a mouse MIA model induced by prenatal exposure to Toxoplasma gondii soluble tachyzoite antigen (STAg), we reveal that maternal gut dysbiosis, characterized by increased Firmicutes and Actinobacteria, drives offspring behavioral deficits. This dysbiosis disrupts intestinal barrier integrity and induces metabolic and inflammatory dysregulation, characterized by elevated M1 macrophages and IL-6, alongside a pronounced accumulation of the glycerophospholipid metabolite 1-oleoyl-2-myristoyl-sn-glycero-3-phosphocholine (OMPC), resulting in adverse outcomes including placental inflammation, fetal neuroinflammation, and behavioral abnormalities in offspring. Mechanistically, OMPC binds to Tnfrsf25 on macrophages, activating JAK1/STAT3/IL-6 signaling. Crucially, maternal probiotic supplementation with Lactobacillus rhamnosus GG (LGG) restores gut-immune homeostasis, attenuates placental inflammation and fetal neuroinflammation, and rescues offspring behavioral impairments. Collectively, our findings define OMPC/JAK1/STAT3/IL-6 signaling as a pathogenic hub in MIA and nominate LGG as a prenatal prophylactic strategy to mitigate neurodevelopmental disorders.

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