(P19-019-25) Multi-Omics Analyses Reveal Protective Effects of Maternal Omega-3 Diet on Neonatal Neurodevelopment via Gut-Brain-Immune Axis Mechanisms

Objectives: Investigate how a maternal omega-3 diet influences offspring neurodevelopment, fecal/serum/brain metabolomes, brain lipidome, and gut microbiome, compared to saturated fat and omega-6 diets, with offspring raised on a western diet from weaning to adulthood.

Methods: C57BL/6 mouse breeders received western diet (WD) with 20% milk fat (saturated fatty acid group; SFA), 20% corn oil (n6), or 19% olive oil + 1% fish oil (n3). Offspring were exposed to these diets during gestation and nursing, then maintained on WD for 10-weeks. Global NMR metabolomics profiled fecal, serum, and brain samples. Brain samples underwent targeted lipidomics for medium-/long-chain fatty acids. These datasets were correlated with gut microbiome arrays. Ileum, serum, and hippocampal cytokines/chemokines were measured by Western blots and ELISA. HMC3 human microglial cells were exposed to mouse serum for neurodevelopmental validation.

Results: PUFA interventions (n3/n6) significantly (p < 0.05) altered gut and systemic metabolites. The n3 group showed enhanced choline derivatives and energy metabolism versus SFA. The n6 group exhibited elevated branched-chain amino acids (isoleucine, valine), TCA cycle metabolites (acetate, citric acid, ethanol), and reduced taurine compared to n3 and SFA groups. Both PUFAs decreased creatine phosphate, inosine, and sn-glycerophosphocholine, but increased serine compared to SFA, while o-phosphocholine was elevated only in n3. Brain lipidomics revealed higher n3/n6 and PUFA/SFA ratios in n3, enriched with oleic, palmitoleic, EPA, DHA, erucic, and nervonic acids. Multi-omics analyses uncovered intricate microbiome-metabolome-lipidome interactions influencing neurodevelopment. The n3 group reduced MCP-1 protein levels along the gut-blood-brain axis. Both PUFAs stimulated BDNF/TrKB signaling in HMC3 cells, whereas n6 induced pro-inflammatory microglial activation.

Conclusions: The study uncovers mechanisms mediating the long-term neuroprotective effects of a maternal omega-3 diet on offspring via brain lipid remodeling and the gut-brain-immune axis.

Funding Sources: Yakult Probiotics Research Laboratory