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Sepsis is a leading cause of perinatal mortality worldwide. Breast milk (BM) feeding is protective against neonatal sepsis, but the molecular mechanisms remain unexplained. Despite various supplementations with potential bioactive components from BM formula feeding cannot protect from sepsis. S100-alarmins are important immunoregulators in newborns preventing excessive inflammation. At high concentrations, the S100A8/A9 protein complex also has antimicrobial properties due to its metal ion chelation capacity. To assess whether BM contains S100-alarmins that might mediate the sepsis-protective effect of BM 97 human BM samples stratified for gestational age, mode of delivery and sampling after birth were collected and analyzed. S100A8/A9 levels were massively elevated after birth ( p  < 0.0005). They slowly decreased during the first month of life, then reaching levels comparable to normal values in adult serum. The concentration of S100A8/A9 in BM was significantly higher after term compared with preterm birth (extremely preterm,  p  < 0.005; moderate preterm,  p  < 0.05) and after vaginal delivery compared with cesarean section ( p  < 0.0005). In newborn  s100a9 −/−   mice, enterally supplied S100-alarmins could be retrieved systemically in the plasma. To explore the antimicrobial activity against common causal pathogens of neonatal sepsis, purified S100-alarmins and unmodified as well as S100A8/A9-depleted BM were used in growth inhibition tests. The high amount of S100A8/A9 proved to be an important mediator of the antimicrobial activity of BM, especially inhibiting the growth of manganese (Mn) sensitive bacteria such as  Staphylococcus aureus  ( p  < 0.00005) and group B streptococci ( p  < 0.005). Depletion of S100A8/A9 significantly reduced this effect ( p  < 0.05, respectively). The growth of  Escherichia coli  was also inhibited by BM ( p  < 0.00005) as well as by S100A8/A9 in culture assays ( p  < 0.05). But its growth in BM remained unaffected by the removal of S100A8/A9 and was neither dependent on Mn suggesting that the antimicrobial effects of S100A8/A9 in BM are primarily mediated by its Mn chelating capacity. In summary, the enteral supply of bioavailable, antimicrobially active amounts of S100-alarmins might be a promising option to protect newborns at high risk from infections and sepsis.

High Amounts of S100-Alarmins Confer Antimicrobial Activity on Human Breast Milk Targeting Pathogens Relevant in Neonatal Sepsis