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.