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Periodic Report Summary 1 - EARLYNUTRITION (Long-term effects of early nutrition on later health)

Project Context and Objectives:

Increasing evidence, most recently from the EU FP6 Project EARNEST, but also from many other investigators, demonstrates that early nutrition and lifestyle have long-term effects on later health and the risk of common non-communicable diseases (known as “developmental or metabolic programming”). Because of the increasing public health importance and the trans-generational nature of the problem, obesity and associated disorders are the focus of the project ‘EarlyNutrition’, running from 2012-2017 with a total budget of 11.12 million Euros, including a contribution by the European Commission of 8.96 Million Euros. This project brings together 36 partners from academia, industry and the SME sector from 12 European countries, the USA and Australia forming a strong multi-disciplinary team of international leaders in the field which achieves balance and complementarity.

The EarlyNutrition project explores the three current key hypotheses on likely causes and pathways to prevention of early life origins of obesity (specifically adiposity) and associated disorders. It brings together extraordinary expertise and study populations of 470,000 individuals to investigate:

the fuel mediated ‘in utero’ hypothesis which suggests that intrauterine exposure to an excess of fuels, most notably glucose, causes permanent changes of the fetus that lead to obesity in postnatal life; the accelerated postnatal weight gain hypothesis which proposes an association between rapid weight gain in infancy and an increased risk of later obesity and adverse outcomes; and the mismatch hypothesis which suggests that experiencing a developmental ‘mismatch’ between a sub-optimal perinatal and an obesogenic childhood environment is related to a particular predisposition to obesity and corresponding co-morbidities.

EarlyNutrition will provide the scientific foundations for evidence based recommendations for optimal early nutrition that incorporate long-term health outcomes, with a focus on obesity and related disorders. Evidence is produced from animal and placental studies (Theme 1), prospective cohort studies (Theme 2), and randomised controlled trials in pregnant women and infants (Theme 3). Theme 4 covers scientific strategic integration, recommendation development and dissemination, including systematic reviews and behaviour change approaches. Four target groups are studied: women before pregnancy, pregnant women, infants and young children.

Scientific and technical expertise in placental biology, epigenetics and metabolomics provides understanding at the cellular and molecular level of the relationships between early life nutrition and the risk of later obesity and adiposity. This, in turn will help refine strategies for intervention in early life to prevent obesity. The project’s impact comprises definitive evidence on early nutrition effects on health, enhanced EU and global policies, major economic benefits through obesity prevention and value-added nutritional products, and practical recommendations on optimal nutrition in the four target groups. Wide dissemination is achieved through active engagement with stakeholders.

Project Results:

Within Theme 1, several experimental Workpackages examine the mechanisms behind the programming of obesity and related disorders. First studies in rodent models designed to mimic the parallel lifestyle human intervention studies in obese pregnant women in the EarlyNutrition project have shown that a low glycemic index diet, and increased physical activity achieved by two different methods leads to improved glucose tolerance in obese rodents. Another study which was undertaken in piglets to test the effects and safety of a new infant milk formula containing an optimized amino acid (AA) composition has shown that a 20% reduction in total AA level did not result in adverse growth effects, changes in blood parameters or digestive enzyme activities, neither using the conventional AA composition (C-80) or the new composition (O-80). These data provide evidence that feeding of formula with a 20% reduction in protein but with an optimized AA composition appears safe and does not result in acute growth deficits in a pediatric pig model. In a dedicated workpackage which performs functional analyses on the sequence of metabolic events related to early diet, growth, and later adiposity risk using mass spectrometry-based Targeted Metabolomics and state of the art bioinformatics, a quantitative high-throughput method for determination of polar lipid species from plasma / serum samples was developed and thoroughly validated and is now ready for comprehensive analysis of samples deriving from divers studies in the EarlyNutrition project.

Theme 2 covers a range of Workpackages which investigate mechanisms for early nutrition programming effects through studies of prospective human cohorts followed up in childhood, adolescence and adulthood. First analysis in a Workpackage which brings together data from major cohort studies has shown that independent from multiple socio-demographic and lifestyle-related potential confounding characteristics, a higher maternal pre-pregnancy body mass index, and higher weight gain in first trimester, but not second or third trimester, are associated with an adverse cardio-metabolic profile in the offspring. Continued maternal smoking during pregnancy is associated with an adverse body fat distribution and increased risk of overweight in school-age children, but no associations with other cardio-metabolic risk factors were present. In another Workpackage to examine the mismatch of pre-and postnatal environments and its relation to adiposity and associated disorders in late childhood, first published work suggests an important influence of maternal vitamin D insufficiency during pregnancy on the velocity of postnatal adiposity gain. In addition, it was found that fetal growth deceleration followed by infant growth acceleration may lead to an adverse body fat distribution in childhood.

Within Theme 3, a number of Workpackages are devoted to human intervention trials examining modifiable determinants of early nutrition and lifestyle programming effects. Harmonisation of the protocols for the follow up in three large pregnancy intervention studies (ROLO; LIMIT and UPBEAT), which aimed to lower the glycaemic load and to increase the physical activity of pregnant women was achieved. This will provide possibilities for comparative and integrated evaluation of the results. The planning and preparations of the new intervention studies to examine a novel infant formula nitrogen composition and to test the safety, acceptance and metabolic effects in infants receiving a novel low glycaemic index follow-on formula is well underway.

Theme 4 covers complementary, non-experimental Workpackages on scientific strategic integration, recommendation development, training and dissemination. Two dedicated panels, the International Collaboration and Advisory Committee (ICAC) and the Recommendation Development Panel (RDP) have been successfully established. Moreover, three actions of international collaboration and exchange of scientific knowledge have taken place: an International Research Workshop, a joint trans-atlantic paper and the first cycle of the Brain Mobility Programme was implemented to foster exchange and qualification of new investigators and trans-atlantic cooperation between project partners. Additionally, three internal trainings for project partners were held along with three external research symposia also open for the wider research community. In collaboration with the Early Nutrition Academy (ENA), a very successful e-learning platform involving experts from the EarlyNutrition consortium was implemented (

Potential Impact:

Project EarlyNutrition will lead to a better understanding of the impact of early nutritional programming on health during childhood, adolescence and adults in specific subgroups of the population. Furthermore, research in the project will help to identify the nutritional needs of women of childbearing age in Europe. The results should lead to recommendations on optimized nutrition before and during pregnancy, during the breast feeding period and during the early life of infants, with special reference to later health development of offspring. Most current recommendations for pregnant women, particularly obese women, and for young children do not take into account the long-term health consequences of nutrition. EarlyNutrition will systematically review the evidence, draw conclusions and formulate recommendations on optimized nutrition before and during pregnancy, during the breastfeeding period and childhood with special reference to later health development of offspring. Barriers to change will be explored in research investigating driving forces of consumer preferences and behaviour to ensure the suitability and user-friendliness of the recommendations.

For the scientific community, EarlyNutrition will produce better evidence for the impact of lasting effects of "Early Nutrition Programming" on health, well-being and performance, with a focus on obesity and associated disorders. It will provide further clarification of the causative maternal/offspring exposures, effect sizes, key processes and mechanisms regulating programming, will confirm or refute key concepts related to programming, such as the roles of accelerated foetal and/or infant growth and "mismatch" in the programming of obesity susceptibility, and will define new interventions to reverse the obesity epidemic. It will contribute towards a better understanding of the impact of early nutritional programming on health during infancy, childhood, adolescence and in pregnant women. It will provide further evidence towards identifying the nutritional needs of women in Europe before and during pregnancy, based on a better understanding of the long-term consequences in their offspring. A “database toolkit” and standardized approaches to describe key exposures (including dietary patterns) and outcomes, and harmonized methodologies e.g. for assessing outcomes, sample collection and handling, analytical approaches, data management and evaluation, will improve and enhance future intervention studies and facilitate collaboration as well as comparison of results from different studies and meta-analyses of results.

The wider societal implications of project EarlyNutrition are to strengthen the evidence for effective ways of reducing the susceptibility to obesity and its associated disorders, which could lead to future generations with a reduced propensity to gain excessive amounts of weight. The policy recommendations arising out of the project will therefore contribute to the primary prevention of obesity and its associated disorders, metabolic syndrome, diabetes, cardiovascular disease, asthma and certain cancers. This will help to reverse the increasing rates of obesity seen across all European countries.

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