Hepcidin mediates hypoferremia and reduces the growth potential of bacteria in the immediate post-natal period in human neonates

Abstract

Septicemia is a leading cause of death among neonates in low-income settings, a situation that is deteriorating due to high levels of antimicrobial resistance. Novel interventions are urgently needed. Iron stimulates the growth of most bacteria and hypoferremia induced by the acute phase response is a key element of innate immunity. Cord blood, which has high levels of hemoglobin, iron and transferrin saturation, has hitherto been used as a proxy for the iron status of neonates. We investigated hepcidin-mediated redistribution of iron in the immediate post-natal period and tested the effect of the observed hypoferremia on the growth of pathogens frequently associated with neonatal sepsis. Healthy, vaginally delivered neonates were enrolled in a cohort study at a single center in rural Gambia (N = 120). Cord blood and two further blood samples up to 96 hours of age were analyzed for markers of iron metabolism. Samples pooled by transferrin saturation were used to conduct ex-vivo growth assays with Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli and Klebsiella pneumonia. A profound reduction in transferrin saturation occurred within the first 12 h of life, from high mean levels in cord blood (47.6% (95% CI 43.7–51.5%)) to levels at the lower end of the normal reference range by 24 h of age (24.4% (21.2–27.6%)). These levels remained suppressed to 48 h of age with some recovery by 96 h. Reductions in serum iron were associated with high hepcidin and IL-6 levels. Ex-vivo growth of all sentinel pathogens was strongly associated with serum transferrin saturation. These results suggest the possibility that the hypoferremia could be augmented (e.g. by mini-hepcidins) as a novel therapeutic option that would not be vulnerable to antimicrobial resistance. Trial registration: The original trial in which this study was nested is registered at ISRCTN, number 93854442.

Hepcidin, Serum Iron, and Transferrin Saturation in Full-Term and Premature Infants during the First Month of Life: A State-of-the-Art Review of Existing Evidence in Humans

“…This study reported a much higher cord blood hepcidin value (67.9 ng/mL; 95% CI: 59.3, 76.5 ng/mL), as Supplemental Figure 1A shows. In addition, this study also recorded higher hepcidin concentrations in venous samples collected at 72 h (92.9 ng/mL; 95% CI: 83.3, 102.3 ng/mL) ( 46 ) than in those collected by Prentice et al ( 99 ) at 77 h (55.6 ng/mL; 95% CI: 47.1, 65.5 ng/mL).…”

“… Standardized hepcidin over the neonatal period. (A) Full-term neonates: α shows the weighted mean (95% CI) for all studies seen in Supplemental Figure 1A; β, χ, and ε show Prentice et al ( 99 ); δ shows Kulik-Rechberger et al ( 46 ). (B) Preterm neonates: α shows the weighted mean (95% CI) for all studies seen in Supplemental Figure 1B; β shows Uijterschout et al ( 100 ).…”

“… Transferrin saturation over the neonatal period. (A) Full-term neonates: α shows the weighted mean (95% CI) for all studies seen in Supplemental Figure 2A; β, γ, and δ show Prentice et al ( 99 ); χ shows Al-Tawil et al ( 102 ); ε shows Balogh et al ( 94 ); ϕ shows Andersson et al ( 103 ); η shows Milman et al ( 39 ); ι shows Kitajima et al ( 104 ); φ shows Yamada and Leone ( 105 ). (B) Preterm neonates: α shows the weighted mean (95% CI) for all studies seen in Supplemental Figure 2B; β shows Lackmann et al ( 106 ); χ shows Celik et al ( 107 ); δ shows Yamada and Leone ( 105 ); ε shows Kitajima et al ( 104 ).…”

“…When all the data are reviewed together ( Figure 3A ), hepcidin increases from within the first 2–11 h of life ( 99 ) and then continues to increase ≤82 h postdelivery. At all times the hepcidin concentrations are much higher than those recorded in adults.…”

“…At all times the hepcidin concentrations are much higher than those recorded in adults. This excess hepcidin production may provide a quick, comprehensive, and relatively long-lasting (0–3 d) hypoferremic response to aid protection during this vulnerable period ( 99 ). After the first few days, TSAT gradually increases as do serum iron concentrations, eventually reaching a plateau at ∼1 mo of age.…”