Genetic research has focused on identifying linkages between polymorphisms and phenotypic traits to explain variations in complex biologies. However, the magnitude of these linkages has not been particularly high. Conversely, the ability of developmental plasticity to generate biological variation from one genotype is well understood, while interest has emerged in the clinical significance of epigenetic processes, particularly those influenced by the external environment. Environmental cues in early development may induce responses that provide adaptive advantage later in life. The benefit of such responses depends on the fidelity of the prediction of the future environment. Life history and physiological changes mediated through epigenetic processes then follow, determining the later phenotype. Developmental mismatch, leading to disease, can arise from discordance between the fetal environment, which is relatively constant across generations, and the postnatal nutritional environment, which can change drastically within and between generations.
Metabolic disorders represent the outcome of an individual living in an energetically inappropriate environment. Experimental and clinical evidence suggests that individual capacity to live in a given energetic environment is influenced by developmental factors acting through epigenetic mechanisms. Epigenetic biomarkers may be able to identify risk of developmental mismatch and thus offer the opportunity for nutritional or other intervention.

Factors influencing the establishment of the intestinal microbiota in infancy
Ingegerd Adlerberth, Sweden

The establishment of the intestinal microbiota commences at birth and new bacteria establish in succession during the first years of life until an adult-type highly complex microbiota has been achieved. The first bacteria to establish in the neonatal gut are usually aerobic or facultatively anaerobic bacteria, like enterobacteria, enterococci and staphylococci. During their growth they consume the oxygen and change the intestinal milieu making it suitable for the proliferation of anaerobic bacteria. Bifidobacterium, Clostridium and Bacteroides are among the first anaerobes establishing in the microbiota. As more oxygen-sensitive species establish and the complexity of the microbiota increases, the population sizes of aerobic and facultative bacteria decline. This phenomenon is thought to result from oxygen depletion, substrate competition and the accumulation of toxic metabolites. A wide range of factors influence the intestinal microbiota and its establishment, including delivery and feeding mode, antibiotic treatment, and contacts with parents, siblings, and hospital staff. Differences in colonization pattern can be observed between vaginally and sectio-delivered infants, and between infants in industrialized and developing countries, reflecting the importance of maternal microbiota and the environment as sources of colonizing bacteria. This article describes the intestinal colonization pattern in human infants, and reviews factors affecting this process.

Genetically determined variation in polyunsaturated fatty acid metabolism may result in different dietary requirements
Berthold Koletzko, Germany

Tissue availability of polyunsaturated fatty acids (PUFA) is of major relevance for health, and it depends both on dietary intake and metabolic turnover. We found close associations between variants in the human genes of delta-5 and delta-6 desaturase, FADS1 and FADS2, and serum phospholipid contents of PUFA and long-chain PUFA (LC-PUFA). Polymorphisms and reconstructed haplotypes of FADS1 and the upstream region of FADS2 showed strong associations with levels of the n-6 LC-PUFA arachidonic acid (20:4n-6). Carriers of the less common polymorphisms and their respective haplotypes also had a lower prevalence of allergic rhinitis and atopic eczema. Our data demonstrate for the first time that the fatty acid composition of serum phospholipids is genetically controlled by the FADS1 FADS2 gene cluster. The investigated single nucleotide polymorphisms (SNPs) in this cluster explain 28% of the variance of arachidonic acid and up to 12% of its precursor acids. Based on this genetic variation, individuals may require different amounts of dietary PUFA or LC-PUFA to achieve comparable biological effects. We strongly recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing biological effects of PUFA and LC-PUFA, which should enhanced sensitivity and precision of such studies.

Metabolic Profiling
Gerard Berry, USA

The concept of chemical individuality was introduced by Garrod in 1908. Inheritance of Mendelian traits including disease states has finally reached a new level of understanding based on the modern principles of gene expression coupled with new insight into the metabolism of RNA species and protein. Over 300 different perturbations in metabolite profiles with their identifying alteration(s) in protein and/or gene structure and/or function have been identified in the past 100 years. With the realization in 1953, that the sentinel disease, phenylketonuria (PKU), can be effectively treated by nutritional manipulation tailored to the needs of each individual, we have essentially entered a new phase in metabolic medicine, namely, that of nutritional therapeutics. The infant destined for a lifetime of cognitive and motoric handicaps may be rescued by the implementation of a nutritional prescription in early development. Patients with inherited defects that impact on intermediary metabolism need to receive nutritional therapy on an individualized basis. Metabolic profiling, i.e., the array of small molecules or analytes, as well as large macromolecules, measured with precision in body fluids or tissues, can be used to devise a nutritional therapeutic plan, as well as serve as endpoints to evaluate the biochemical efficacy of intervention.

Newborn screening of metabolic disorders: Recent progress and future developments
Piero Rinaldo, USA

Tandem mass spectrometry has been the main driver behind a significant expansion of newborn screening programs. The ability to detect more than 40 conditions by a single test underscores the need to better understand the clinical and laboratory characteristics of the conditions being tested, and the complexity of pattern recognition and differential diagnosis of one or more elevated markers. The panel of conditions recommended by the American College of Medical Genetics, 20 primary conditions and 22 secondary targets, has been adopted as the standard of care in the vast majority of US states.
The evolution of newborn screening is far from being idle, as a large number of infectious, genetic, and metabolic conditions are currently under investigation at variable stages of test development and clinical validation. In the US, a formal process with oversight by the Advisory Committee on Heritable Disorders and Genetic Diseases in Newborn and Children has been established for nomination and evidence-based review of new candidate conditions. If approved, these conditions could be added to the uniform panel and consequently pave the way to large scale implementation.

The scope of the Problem: the Phenotype of Human Obesity
Allan Walker, USA

The fetal intestinal immune system is structurally intact from a very early gestational age. At birth, the neonate is challenged with an extraordinary and variable bacterial challenge. This mucosal and bacterial interface is the site of critical symbiotic and potentially pathogenic interactions. Neonatal inflammatory reactions are often exaggerated, creating a situation in a newly colonized gut whereby homeostasis must be actively achieved. Fortunately, the neonate is armed with a multitude of protective mechanisms by which to ensure a productive microbiota in the setting of an intact mucosal surface. The intestinal epithelium orchestrates complex interactions and signaling through a variety of intrinsic and extrinsic stimuli. Chief among these is the immunomodulatory capacity of breast milk which is increasingly implicated in the achievement of intestinal and immunologic health via a multitude of mechanisms. Additionally, developmental expression of enzymes, pattern recognition, downstream signaling and dendritic cell interaction all contribute to intestinal homeostasis. Current research is uncovering the molecular mechanisms behind many of these mechanisms. These strategies lend insight into the establishment of tolerance so critical to neonatal health. In a clinic context of increasing food allergy and inflammatory bowel disease, elucidating this machinery is increasingly pertinent. Future research should explore these molecular interactions more closely for their potential therapeutic applications.

Gut microbiota and insulin resistance, Recent evidence and a lesson learned from antibiotic treatments
Jason Chou, Switzerland

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Individual Epigenetic Variation: When, Why, and So What?
Robert Waterland, USA

Epigenetics provides a potential explanation for how environmental factors modify the risk for common diseases among individuals. Interindividual variation in DNA methylation patterns and epigenetic regulation has been reported at specific genomic regions including transposable elements, genomically imprinted genes and the ‘inactive’ X chromosomes in females. We currently have a very poor understanding of the factors that contribute to interindividual epigenetic variation. In particular, it is important to understand when during the life cycle epigenetic variation arises, why epigenetic regulation varies among individuals, and whether epigenetic interindividuality affects susceptibility to diet-related chronic disease. In this review we will summarize current progress toward answering these questions.

Interaction of Early Infant Feeding, Heredity and Other Environmental Factors as Determinants in the Development of Allergy and Sensitisation
Erkki Savilahti, Finland

The role of early infant nutrition in the development of allergic symptoms and allergic sensitisation has been disputed for 70 years. Interaction between genetic factors and infant feeding has been limited to studies looking for that between parental heredity for allergy, and length of breast-feeding as well as looking some qualities of breast-milk in a few studies. In the 10 original studies comparing the development of allergic symptoms among children, in whom breastfeeding duration was used as a risk factor separately among those with either positive or negative parental heredity for atopy, no definite answer could be found. The effect of early feeding even was changed in both heredity negative and positive groups when looking at symptoms at age 2 and 5 years. Out of 9 possible combinations, 6 combinations were present in the studies, none in more than 2 studies. For sensitization, long BF was a risk in 3 out of 5 reports if family history of allergy was positive and in 2, if negative. Low levels of soluble CD14 and cow’s milk specific IgA antibodies in breast-milk may increase infants’ risk to develop allergy.

Personalized Care of Pediatric Cancer Patients
Ching Lau, USA

One of the great success stories of clinical oncology is the improvement of the cure rates of pediatric acute lymphoblastic leukemia (ALL) from around 10% in the 1960s to nearly 90% today. The primary factor responsible for this remarkable improvement is the personalization of treatment, with stratification of patients based on both disease and host characteristics in order to optimize therapy. While age, WBC, and immunophenotype provide a rudimentary system for classification of ALL, molecular factors are playing an increasingly important role in further individualization of ALL therapy. Such risk-based stratification strategies are also increasingly being used in the treatment of children with solid tumors. In addition, genomic technologies are now being used to identify new molecular markers or signatures for both diagnostic and prognostic purposes. Recently we reported the analysis of pediatric osteosarcoma by expression profiling in an attempt to identify a molecular signature that could predict chemoresistance of a tumor before treatment is initiated. We identified a 45 -gene signature that discriminates between good and poor responders to chemotherapy in osteosarcoma. Using this classifier, we can predict with 100% accuracy the chemoresponse of osteosarcoma patients prior to the initiation of treatment. These encouraging results suggest that the genomic approach will revolutionize the diagnosis and prognostication of pediatric cancer patients and improve their outcome through predictive, personalized care.

Personalizing Nutrient Intakes of Formula-Fed Infants – Breast Milk as a Model
Bo Lonnerdal, USA

Human Milk Oligosaccharides: Evolution, Structures and Bioselectivivity as Substrates for Intestinal Bacteria
Bruce German, USA

Human milk contains a high concentration and diversity of soluble oligosaccharides, carbohydrate polymers formed from a relatively small number of different monosaccharides. Novel methods combining liquid chromatography with high resolution mass spectrometry have identified approximately 200 unique structures of oligosaccharide complexes varying from 3 to 22 sugars. Structures and diversity of oligosaccharides follow the general pattern of mammalian and primate evolution though the concentration and diversity of homo sapiens is striking. There is also considerable diversity among different human mothers in the structures of oligosaccharides. Milks from randomly selected mothers contain as few as 23 and as many as 130 different oligosaccharides. The functional implications of this diversity is not yet known. Despite the role of milk to serve as a sole source of nutrition for infant mammals, the majority of the oligosaccharides in milk are not digestible by human infants. This apparent paradox raises the obvious questions about the functions of these oligosaccharides and how their diverse molecular structures affect their functions. The nutritional function that is most frequently attributed to milk oligosaccharides is to serve as prebiotics—a form of indigestible carbohydrate that is selectively fermented by desirable gut microflora. This function was tested by purifying human milk oligosaccharides and providing these as the sole carbon source to various intestinal bacteria. Indeed, the selectively of even the entire complex mixture of oligosaccharides pooled from dozens of human milk samples is remarkable. Even among a variety of Bifidobacteria only Bifidobacteria longum biovar infantis was able to grow extensively on HMO as sole carbon source. The genomic sequence of this strain revealed approximately 100 genes that are unique to infantis, including a variety of co-regulated glycosidases, relative to other Bifidobacteria, implying a co-evolution of human milk oligosaccharides and the genetic capability of select intestinal bacteria to utilize them. The goal of ongoing research is to assign specific functions to the combined oligosaccharide – bacteria – host interactions that emerged from this evolutionary pressure.

Opportunities for Improving the Health and Nutrition of the Human Infant by Probiotics
Seppo Salminen, Finland

The newborn is first colonized by microbes at birth. The colonizing bacteria originate mainly from the mother’s gut, vaginal tract and skin. It has been suggested that prior to birth the foetus is microbiologically sterile. The origin of the microbiota and its further development depend on genetics, mode of delivery, early feeding strategies and the hygienic conditions around the child. The indigenous microbiota of an infant gastrointestinal tract is modulated through contact and interaction with the microbiota of the parents and the infant’s immediate environment. Bacteria are present in the environment of the infant prior to delivery and after delivery and breast-feeding continues to enhance the original inoculum by specific lactic acid bacteria and bifidobacteria enabling the infant gut microbiota to be dominated by bifidobacteria. These bacteria set the basis for gut microbiota development and modulation along with breastfeeding and the environmental exposures. Modifying this exposure can take place by probiotic bacteria when breast-feeding is not possible. Thus, incorporating specific probiotics selected for the infant gut microbiota development may form a beneficial possibility for future infant feeding purposes.
Probiotics are live microbial food components which, when ingested in adequate amounts, have a scientifically demonstrated effect on human health. Many current probiotics have documented health promoting effects and most of the effects have been demonstrated in infants and children, may be via an effect on the relatively simple gut microbiota in infants. For improving infant nutrition gut microbiota development has to be considered along with the means to influence the process through dietary intervention with specific probiotics. The target in infants is to modify the gut microbiota to resemble that of the healthy breast-fed infant and to counteract deviations or aberrancies present in infants at risk of specific diseases. This forms the basis for healthy individual gut microbiota which promotes the health and well-being of the infant. Thus, providing specific selected probiotics to the mother to balance the intestinal microbiota during pregnancy and to the infant after birth.

Do we Need Personalized Recommendations for Infants at Risk of Developing Disease?
Olle Hernell, Sweden

Current nutrition recommendations, which are directed towards populations, are based on estimated average nutrient requirements for a target population and intend to meet the needs of most individuals within that population. They also aim at preventing common diseases such as obesity, diabetes and cardiovascular disease. For infants with specific genetic polymorphisms, e.g. some inborn errors of metabolism adherence to current recommendations will cause disease symptoms and they need personalized nutrition recommendations. Some other monogenic polymorphisms, e.g. adult hypolactasia are common, but with varying prevalence between ethnic groups and within populations. Ages at onset as well as the degree of the resulting lactose intolerance also vary, making population-based as well as personalized recommendations difficult. The tolerable intake is best set by each individual based on symptoms. For polygenetic diseases such as celiac disease, type 1 diabetes and allergic disease current knowledge is insufficient to suggest personalized recommendations aiming at primary prevention for all high risk infants, although it may be justified to provide such recommendations on an individual level should the parents ask for them. New technologies such as nutrigenetics and nutrigenomics are promising tools with which current nutrition recommendations possibly can be refined and the potential of individualized nutrition be explored. It seems likely that in the future it will be possible to offer more subgroups within a population personalized recommendations.