Breastfeeding Tied to Lower Infant Inflammation via Lipid‑Metabolism Pathways

A new analysis from the Barwon Infant Study paints a clearer mechanistic picture of how breastfeeding might protect infants from early-life inflammation. Using data from nearly 900 infants in southeastern Australia, the researchers examined links among breastfeeding, infection burden, inflammation (measured by glycoprotein acetyls, or GlycA), and plasma metabolomic and lipidomic profiles.

At both 6 and 12 months, infants who were breastfed (versus not) had lower levels of GlycA, indicating reduced systemic inflammation. At 12 months, breastfeeding was also associated with fewer parent‑reported infections and fewer general practitioner visits for infections. Breastfeeding status correlated with widespread alterations in blood metabolite and lipid profiles: at 6 months, 66 % of assessed metabolomic biomarkers and 89 % of lipid species showed associations with breastfeeding; at 12 months the associations were fewer but remained notable.

To explore causality, the team used mediation analyses to estimate how much of the effect of breastfeeding on inflammation is transmitted via metabolic changes. At 6 months, 82 metabolomic biomarkers and 241 lipid species were estimated to mediate the breastfeeding → lower GlycA link, with median proportions of mediation around 36 %. At 12 months, mediation was also evident. Among lipids, ether lipids—particularly plasmalogens (a subclass of alkenyl phosphatidylethanolamines)—emerged as especially potent mediators. The authors constructed a “plasmalogen score” and found that it mediated an estimated 162 % of the total effect of breastfeeding on GlycA at 6 months and 75 % at 12 months—suggesting that plasmalogen-related pathways may not just mediate but could dominate the anti‑inflammatory impact of breastfeeding.

The authors also explored reverse mediation: whether lower inflammation mediated the effect of breastfeeding on certain metabolites or lipids. They found modest evidence for this directionality, but its magnitude was generally smaller and involved different sets of biomarkers than the forward pathway. Moreover, when considering infection burden, some DHA‑carrying ether lipids also mediated the protective effect of breastfeeding on reducing total infection counts by 12 months.

These findings suggest that the beneficial anti‑inflammatory effects of breastfeeding arise not only from reduced exposure to pathogens, but also from restructuring of lipid metabolism—especially boosting plasmalogen levels, which are known to have antioxidant and membrane‑modulating properties. Because infant formula lacks ether lipids found in human milk, these results point to potentially actionable lipid metabolic pathways that could be targeted in supplemental or alternative feeding strategies.

While cross‑sectional mediation limits causal inference over time, and the binary breastfeeding measure cannot capture feeding intensity or exclusivity, the study’s integration of rich omics data in a well-characterized infancy cohort makes a compelling advance in understanding how early nutrition may set inflammatory trajectories for later health.