Background: Prematurity increases the risk of neonatal mortality and long-term health issues, such as obesity and cardiovascular disease. Breastfeeding benefits preterm infants by reducing necrotizing enterocolitis, improving cognition, and supporting early growth, although the mechanisms underlying these benefits are unclear. Objective: Within the exposome-framework, the combined influence of breast milk nutritional, microbiological, and toxicological components on preterm infant growth during hospitalization was explored.
Methods: In the single-center prospective observational LACTACOL cohort (NCT01493063), weight and body composition were assessed on 137 exclusively breastfed preterm infants (28-34 weeks), with discharge-weight and fat-free mass (FFM) Z-scores as growth indicators. An omic-scale characterization of breast milk's nutritional, microbiological, and toxicological composition combined with an exploratory multivariate random forest analysis helped identify predictive components of both growth indicators.
Results: Combined endogenous and exogenous breast milk compartments predicted discharge weight and FFM Z-scores with 34% and 42% accuracy, respectively, driven by the nutriome (24%). Key regulators of weight gain included choline-containing lipid species enriched in lauric, linoleic, and/or oleic acids and under sphingolipid and phosphatidylcholine forms; as well as carnitine and glucogenic amino acids. Exposome (contribution 19%) and microbiome (12%) components, such as dioxin-like, polychlorinated biphenyls, and bacteria (Enterobacter, Corynebacterium), were strong predictors of FFM, alongside bioactive lipids as sphingolipids and phospholipids enriched in nervonic and oleic acids, or eicosapentanoic acid and its oxylipin.
Conclusions: These findings deepen our understanding of breast milk components’ benefits for preterm infant early growth and emphasize the potential importance of bioactive lipids, in promoting infant healthy growth and long-term outcomes.
The data of nutriome-exposome-micorbiome of preterm milk are synthetized in this dataset English (2025-03-20).

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