Protective Effect of Docosahexaenoic Acid Supplementation during Pregnancy against Lipopolysaccharide-Induced Intrauterine Growth Restriction in Fetal Mice

Abstract

Background: Fetal growth restriction (FGR) is a leading cause of perinatal mortality worldwide and is strongly associated with maternal-fetal inflammation. Nutritional interventions that mitigate inflammatory stress during pregnancy may represent a viable strategy to improve fetal outcomes.

Objectives: This study investigated whether maternal docosahexaenoic acid (DHA) supplementation protects against lipopolysaccharide (LPS)-induced FGR in mice and explored the underlying mechanisms involving inflammatory signaling and gut-placenta interactions.

Methods: Institute of Cancer Research mice (6-7 wk old at purchase) were used; pregnant mice were assigned to groups defined by LPS exposure (±) and DHA supplementation (±), resulting in 4 groups: control, DHA, LPS, and DHA+LPS. DHA was administered by gavage throughout gestation (300 mg/kg/d), and LPS was administered intraperitoneally during late gestation (100 μg/kg/d). Primary outcomes included fetal growth parameters and placental development. Secondary outcomes comprised inflammatory markers in placental and jejunal tissues, gut microbiota composition, and intestinal barrier-related proteins. Continuous outcomes were analyzed using 2-way analysis of variance (ANOVA), whereas microbiome outcomes were analyzed using nonparametric tests and permutational multivariate ANOVA.

Results: LPS exposure induced FGR, whereas DHA supplementation significantly attenuated this effect (P < 0.05). DHA suppressed nuclear translocation of nuclear factor-κ B (NF-κB) p65 and reduced proinflammatory cytokines and chemokines, including interleukin (IL)-1β, Il-6, Il-17a, Tnf-α, keratinocyte chemoattractant, and monocyte chemoattractant protein-1, while increasing the anti-inflammatory cytokine Il-10 in placental and jejunal tissues. In addition, DHA enhanced intestinal microbial diversity, increased the abundance of Bifidobacterium, and upregulated tight junction proteins (zonula occludens-1, Claudin-1, and Occludin), consistent with improved intestinal barrier integrity.

Conclusions: In pregnant mice, maternal DHA supplementation mitigated LPS-induced FGR by suppressing NF-κB-mediated inflammatory signaling, modulating gut microbiota composition, and supporting intestinal barrier function, highlighting a potential nutritional strategy to alleviate inflammation-associated adverse pregnancy outcomes.

Keywords: docosahexaenoic acid; fetal growth restriction; gut microbiota-gut–placenta axis; inflammation; lipopolysaccharide.