Maternal diet shapes neonatal microbiome ontogenesis and neurometabolic resilience

Maternal diet high in saturated fatty acids (SFA) promote infant gut dysbiosis and impairs metabolic and neurocognitive outcomes; however, the protective potential of maternal polyunsaturated fatty acids (PUFA), particularly omega-3 (n3), remains unclear. This study examined how maternal diets enriched in SFA (20% milk fat), omega-6 (n6; 20% corn oil), or omega-3 (n3; 19% olive oil + 1% fish oil) influence neonatal metabolism, neurodevelopment, the gut microbiome, the gut-blood-brain metabolomes, and the brain lipidome in C57BL/6 mice. The offspring were exposed to these diets only during gestation and lactation and then maintained on a Western-style diet for 10 weeks. Compared to SFA, maternal PUFA-rich diets induced distinct and persistent microbiome signatures and reshaped the gut and systemic metabolomic profiles into adulthood. The offspring of n3-fed dams displayed higher lean-to-fat mass ratios, improved ileal morphology, and enhanced gut epithelial integrity. Chronic low-grade inflammation (MCP-1) along the gut-blood-brain axis was markedly reduced in n3 offspring. Moreover, maternal n3 intake enhanced synaptic plasticity, suppressed neuroinflammation, and enriched brain lipids and metabolites associated with membrane integrity, neuronal signaling, and anti-inflammatory pathways. Overall, maternal omega-3 intake confers long-term neuroprotective effects by modulating brain lipid remodeling and the gut-brain-immune axis.