Balanced Energy-Protein Supplementation Radically Modifies Multi-Matrix, Multi-Omics Profiles in Mother-Infant Dyads in Rural Burkina Faso: a Randomized Controlled Trial

Balanced energy-protein (BEP) supplementation during pregnancy improves birth and growth outcomes, but its biological mechanisms remain unclear. In 309 mother-infant dyads from the MISAME-III trial in rural Burkina Faso, we integrated metabolomics, proteomics, metagenomics and milk composition profiling across maternal, milk, and infant compartment. Prenatal BEP was associated with sustained infant growth benefits through 12 months, whereas postnatal BEP increased milk B vitamins and altered lipid composition without measurable growth benefits. BEP supplementation was associated with coordinated metabolic and proteomic responses across maternal, milk and infant compartment, particularly involving glycan biosynthesis, lipid metabolism and protein turnover. Mediation analysis identified 432 molecular mediators, with milk IgA emerging as the most consistent mediator, although it accounted for only ~3% of the total effect on infant head circumference. Inter-omics networks revealed stronger maternal-infant metabolomic connectivity than milk-infant connectivity, supporting a prominent role for prenatal programming in driving BEP-associated growth benefits. ClinicalTrial.gov: NCT03533712.