INTRODUCTION
Exposure and adaptation to extra-uterine life represents a substantial challenge for homeostatic physiological systems of neonates. Paramount amongst these are modifications within immune function which must facilitate acquisition of a symbiotic microbiome whilst protecting against pathogen challenge. Infection is a significant cause of morbidity and mortality in neonates1-3 but current understanding of the functional capacity of the neonatal immune system in the first few weeks of life remains limited. Substantial differences are observed between neonatal and adult immune function. CXCL8 (IL-8) is the major effector chemokine of neonatal T cells whilst production of IFN-γ is markedly suppressed and a reduction in NK cell numbers is observed4.
Elegant multi-dimensional analyses have revealed that profound changes in immune cell numbers, phenotype and proteome are observed within the first week of life and presage initiation of a stereotypic differentiation pathway. This profile is seen in both preterm and term infants and as such appears to represent a response to multiple environmental cues, predominantly microbial, that are received after birth5. Dynamic alterations in the interferon and complement pathways, as well as neutrophil-associated signaling, are particularly prominent6. However, less is known regarding neonatal immune function and the potential impact of nutritional intake on immune homeostasis.
An important consideration in relation to neonatal immune function is the relative setpoint of immune regulation in the early postnatal period. A range of factors act to limit alloreactive immune responses during pregnancy and avoid immunological rejection of the fetus. This includes an increase in both maternal and fetal-derived regulatory T cells (Tregs)7,8 together with preferential differentiation of fetal CD4+ cells towards Treg phenotype9 mediated through increased ‘tolerogenic’ dendritic cell activity10. It is likely that this balance towards relative immune suppression continues into neonatal life but the profile of this, and its relative dependence on the postnatal environment, remain unclear.
The perinatal establishment of the gut microbiome is likely to be a dominant regulator of neonatal immune development. Indeed, colonization with specific commensal bacteria can enhance the development of Treg responses11, whilst dysbiosis disturbs stereotypic immune development and promotes T cell activation5. Vertical transmission of maternal microbiota is the initial, and potentially most important, determinant of the neonatal microbiome. In this regard it is notable that the mode of delivery is a critical factor and its influence on childhood microbiome extends for at least 7 years12. The influence of microbiome composition on long term health outcomes is an area of considerable interest and atypical colonization has been associated with a range of conditions including impaired immune function and increased risk of allergy13.
The importance of nutrition as a determinant of the profile of neonatal immunity has been poorly investigated. The natural nutrition for neonates is from breastmilk which contains a range of complex nutrients as well as antimicrobial proteins. Breastmilk also contains bacteria and maternal cells, and as such it is not surprising that exposure to either breastmilk or formula milk significantly influences the composition of the gut microbiome14.
Differential microbiome composition is likely to act as an indirect influence on how nutrition can modify the neonatal immune profile but there may also be a direct effect from exposure to maternal cells and antigenic proteins within milk. We analyzed how immune phenotype and function evolve between birth and 3 weeks of age in a cohort of healthy neonates born by caesarean section. Our aim was to determine prospective changes in the neonatal adaptive immune response in relation to source of nutrition and neonatal gut microbiome with a specific focus on regulatory T cells.