**An agenda for research into nutrients in paediatrics**

Food and nutrition has been central to human culture, philosophy and science since the beginning of civilisation. However the building blocks of food and nutrition, the nutrients, remained unknown until the late 19th century. Over the next 100 years advances in physics, chemistry and physiology led to rapid developments in our knowledge, first with development of an understanding of energy and the macronutrients, followed by the minerals and vitamins. The first vitamins to be explored scientifically were thiamine, vitamin D and C and in 1935 ascorbic acid was synthesised, beginning the 20th century rapid development of knowledge of nutrients[1].

Recommendations for intakes of nutrients were first made before chemical characterisation had begun in earnest and the long road to the establishment of formal nutrient recommendations has been described by Harper[2,3]. Recommendations on the intake of limes containing vitamin C to prevent scurvy began in the British Navy at the end of the 18th century. Since then times of crisis, mainly warfare, have stimulated further research into nutrients and improving the nutritional status (and hence fighting ability) of the population. Early recommendations for intakes were focussed on adult males, and children were simply not considered. After World War One and the onset of the Great Depression, the League of Nations established several commissions to investigate the provision of adequate nutrition for populations and the establishment of nutrient intake recommendations. In the 1930s the special needs of children and nursing mothers were considered for the first time in the recommendations of the British Committee on Nutrition [4]. This was followed by the reports of the League of Nations that included recommendations for nutrients during periods of growth that were extrapolations of adult requirements of the known macro and micronutrients[3]. In 1941 the Food and Nutrition Board of the National Academy of Sciences was established and the first edition of the Recommended Dietary Allowances was published. When commenting on this, Nutrition Reviews noted that the RDAs "emphasize once more the truth of the opinion that the dietary requirements can be met by a well-chosen diet of natural foods[5]." Since that time there have been numerous variations of the RDAs published by national and international organisations under a variety of titles. The cost of development and the size of documentation has grown exponentially and current volumes of the US Dietary Reference Intakes occupy a whole shelf[6].

Setting nutrient requirements for children has required different approaches to setting the values for adults and it is only in the last 50 years that extra effort has been placed on establishing children's nutrient requirements. Nutrients cannot be simply extrapolated on the basis of weight from adults, but must provide for higher metabolic rates and energy expenditure, and growth and development. In the history of nutrients protein was regarded as the key to infant and child health. Low levels of protein were associated with poor growth and malnutrition (kwashiorkor) in children. Although growth is a major consideration for children, it only requires a small proportion of the total energy and protein requirements. In 1957 Hegsted concluded that "growth was a minor determinant of protein or other nutrient needs after the first months of life. The amount of new tissue protein deposited per day in growing children or during the adolescent growth spurt is very small compared with the total maintenance requirement of protein. This distinguishes humans and other primate species from common laboratory and domestic species[7]." More recently the role of early life protein intake in the laying the basis for later obesity through influencing insulin-like growth factor 1 (IGF-1) levels has been a focus of research[8,9]. There are important lessons to be learned from the exploration of protein needs of infants and children and the requirements follow a U-shaped curve. But it is even more complex as in real life there increased requirements associated with response to illness, injury and periods of rapid growth.

The establishment of iron requirements for infants and children and the development of interventions to overcome deficiencies has proved to be complex. Iron deficiency has been associated with poor growth, reduced cognitive development and ill health [10]. Yet breastmilk contains only a low level of iron, albeit in a readily bioavailable form [11]. Lactoferrin is important for transporting iron within the body, but is protective against infection by making iron unavailable to micro-organisms that require iron for growth[12]. All infant feeding guidelines recommend the introduction of complementary foods at around 6 months of age which provide increased amounts of iron. Recent attempts to increase iron supplies for children in developing countries by genetically modifying foods have not been entirely successful as they have resulted in increased rates of infection, including malaria[13-15]. This has led to a re-evaluation of how some nutrient requirements are set and deficiencies are met.

The current agenda for paediatric nutrients research will occupy nutritionists, biochemists, paediatricians and epidemiologists for many years ahead. Some of the immediate needs to be answered are to define the interactions and outcomes of nutrient levels with future health and disease beyond childhood, epigenetics and nutrients, interactions of nutrients with the human microbiome, sustainability and climate change, ethnicity gene interactions with nutrients.

The developmental origins of health and disease (DOHAD) hypothesis has added new emphasis to early life nutrition. How nutrition and growth influence later chronic disease has been the subject of many observational studies[16-18]. Future developments will probably rely on animal, perhaps primate models and the use of laboratory studies, as longer term prospective human studies are not feasible. The implications for setting of nutrient requirements may be far reaching – no longer is deficiency or short term growth the criteria, but long term life-course outcomes must be considered.

In recent years there has been considerable interest in the human microbiome and long term health outcomes following the initiative of the National Institutes of Health to sponsor research in this field[19]. It is well known that in the human body microbial cells outnumber human cells at least ten-fold. But what is not known is how they influence nutrient requirements, particularly in early life when the stable microbiome is being finalised. Malnutrition has an effect on the establishment of a stable microbiome[20]. Dysfunction of the microbiome has been linked to disorders as diverse as obesity, under-nutrition, diabetes and gastro-intestinal cancer[21-23]. It can be anticipated that nutrient- microbiome interaction will become an important area for nutrient research.

For infants the gold standard of nutrition and for nutrients is breastmilk. Many of the nutrients contained in breastmilk are in relatively low concentrations, but in highly bioavailable forms[24]. In the development of infant formula nutrients such as iron have to be included in greater concentrations than in breastmilk to adjust for the bioavailability[25]. Breastmilk is the most sustainable of infant foods in an era where resources, climate change and sustainability are paramount. A recent report of the Institute of Medicine explored current and emerging knowledge on nutrients in the light of the increasing environmental constraints on the food system[26]. This will continue to be an important area of research as climate affects different aspects of nutrition, for example bioavailablity. All of these emerging issues meant that it is likely that there will be further special issues of "Nutrients" devoted to paediatric concerns.

In this 'Nutrients' special collection we present a range of paediatric papers. The first section of reviews contains papers on two important topics. UNICEF estimates that more than 500000 children die every year of diarrhoeal disease, and most could be prevented or treated with relatively simple interventions[27]. The recent Global Burden of Disease study also confirms the continuing burden of mortality and morbidity form diarrhoeal disease in children[28]. The systematic review by Lamberti and colleagues confirms the value of zinc supplementation in the management of diarrhoea and endorses the current WHO recommendations.

Six of the papers relate to breastfeeding and there are several more on early infancy reflecting the importance of breastfeeding in early nutrition and in influencing life course nutrition. The paper by Imai et al joins a large number of observational studies that show an association between early nutrition and growth and later obesity. In this study infant feeding method and the early introduction of solids are associated with a higher BMI. The ethical impossibility of randomised controlled trials of breastfeeding and obesity means that we have to rely on the weight of observational studies and recognise that residual confounding may persist. Other papers document the optimal nutrients provided by breastmilk, supporting the continued promotion of breastfeeding. There are two papers that document the provision of nutrients from supplements in children, an area that will need continuing study to ensure that supplement use is appropriate. The special issue concludes with several papers on methodology in nutrient and body composition research.

The papers selected for this special collection illustrate the breadth of paediatric research, but there are still many scientific challenges remaining. There is still great potential for improvement in the health of children through nutrition and understanding of nutrient requirements, metabolism and social context is important to realising these potential health gains.

Dr. Mi Kyung Lee BSc MA PhD and Prof Colin Binns MBBS MPH PhD *Guest Editors* 
