PROFILE- Neonatal nutrition – shaping the future

16 March 2012

There is overwhelming evidence that early life nutrition determines later health outcomes. Across every population ever studied, rates of cardiovascular disease, stroke and Type 2 diabetes have all been strongly associated with growth in the fetus and newborn. Inappropriate early life weight gain (either too fast or too slow) seems to 'programme' later life health status, exerting effects in a continuous manner across a range of weights many would not consider particularly abnormal.

This phenomenon does not simply affect abnormally small or large babies – it is relevant for every newborn baby and their nutrition in early life. Estimates suggest that the increased risk of developing cardiovascular disease from being born weighing just 2.5kg (approximately 5lb) compared to 3.5kg (8lb) is equivalent to that of being a lifelong smoker.

Nutrition in early life deserves to be seen as a key public health priority. Increased investment in research and development will allow us to translate scientific knowledge into shaping healthier lives. Unlike almost any other area of medicine, neonatal nutrition will determine health and disease for the entire lifespan – the potential benefits are unrivalled. This is then a global issue – the adverse health costs of failing to provide appropriate early nutrition are vast.

Optimal nutrition is equally vital for the 10% of babies born prematurely, including over 6,000 extremely premature in the UK every year. For these, nutrition not only determines their long-term health status, it also affects the risk of serious disease in early life.

Our work is focused on this vulnerable group and encompasses two key areas. Firstly, we aim to improve our understanding of the complex relationships between nutrition, gut function and serious disease such as sepsis and necrotising enterocolitis (NEC), a serious gut complication of premature babies. Together sepsis and NEC are responsible for about 25% of all deaths in premature babies and seriously increase risks of poor cognition and health in later life. Secondly, we are exploring the relationships between patterns of early growth and later life outcomes (such as obesity and insulin resistance), and in particular the epigenetic mechanisms by which early life events may determine later disease.

The human gut plays host to billions and billions of bacteria, with more than a thousand different species. In fact, we consist of more non-human than human cells, each with their own functional DNA. This is termed the human microbiome. Bacterial cells 'talk' to our cells, and exert essential nutritional, immunological and metabolic effects. Animals co-evolved with these microorganisms – without them we would die. Whilst there is much public (and commercial) interest in taking supplements of so-called healthy bacteria (probiotics), the science is complex, especially in newborn babies. It is not simply the presence or absence of individual species that is important: it is the relationships between them that determine health or disease.

Premature babies are born into, and cared for in, relatively sterile environments. Milk feeding takes time to be established, many are exposed to multiple antibiotics and all come into contact with microbes that are different to that of a healthy breast fed newborn baby. Our work has shown significant differences in the premature baby microbiome and how this relates to key diseases.

We observed a relatively paucity of the healthy bacteria normally seen in newborn babies, a more limited diversity of species and an over abundance of more pathogenic bacteria. In addition, we have shown that babies who developed sepsis or NEC had patterns of gut colonisation that were distinct from more healthy premature babies. Work is now examining how nutritional interventions, especially certain key immunonutrients, and enterally administered supplemental probiotics affect the microbial community in the gastrointestinal tract of newborn babies.

We have long known the importance of promoting breast milk for premature babies, and how it reduces key morbidities like NEC, but recent studies have also suggested that supplemental probiotics may decrease the risk of NEC and death by a staggering 50%. Immunonutrients are also important: lactoferrin, a major protein in mammalian milk, reduces the risk of infections through a bewildering array of processes. As a key component of the innate immune system in mammals it is highly conserved, with bovine lactoferrin showing a high degree of homology with human lactoferrin. Preliminary trials have suggested that supplemental bovine lactoferrin may half the risk of sepsis in premature babies.

We aim to conduct further research into the efficacy and mechanistic evaluation of these interventions, which spans the research areas of basic science through to large-scale confirmatory studies. This requires collaborative research networks both nationally and internationally, links we are developing through the UK NIHR and partners, and across Europe under the auspices of groups such as the European Society for Paediatric Research. This work is not without its challenges – our current studies will involve thousands of infants cared for in excess of 30 major neonatal centres in the UK alone, whilst further work will require collaborations between neonatal clinicians across Europe and beyond.

Decreasing the risk of death and serious early morbidities such as sepsis and NEC will rightly been seen by many, and especially parents, as a key priority of neonatal nutrition, but it remains equally important that our research retains a life-course perspective – children are our future. Our second major area of interest, then, is the long-term effects of early nutritional interventions and growth, and how this may programme childhood obesity and other key maturity-onset diseases such as diabetes and cardiovascular disease. Studies have followed children born preterm into late adolescence, and assessed a range of metabolic outcomes.

We, and others, have demonstrated relationships between early life growth and later bone density, obesity, cognition and insulin resistance. We want to understand how this happens. How do our genes 'memorise' early life events? Why does neonatal nutrition affect your risk of dying from a heart attack when you are 65? Epigenetics examines how the fixed sequence of our DNA may be affected by nutritional and other exposures, and how, in turn, this may affect gene expression.

DNA methylation is the most explored epigenetic mechanism, and our studies are amongst the first to explore associations with neonatal growth and nutrition in adolescent children who were born prematurely. Epigenetics may be important to our understanding of how to optimise early growth in infants, but requires the creation and careful tracking of cohorts over several decades. This requires government and funding bodies to take a long-term perspective of neonatal nutrition, which is needed if we are to grasp the very real opportunity of shaping healthier lives.

Dr Nicholas D Embleton- Consultant Neonatal Paediatrician
Newcastle Hospitals NHS
Newcastle University
www.ncl.ac.uk/biomedicine/research/groups/profile/nicholas.embleton
nicholas.embleton@ncl.ac.uk