Dietary shaping of the early life metabolome and its role in healthy lung and brain development

Project Information

DEFEND

Grant agreement ID: 946228

DOI

10.3030/946228

Project closed

EC signature date 29 January 2021

Start date 1 February 2021

End date 31 January 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 952,00

EU contribution

€ 1 499 952,00

Coordinated by

REGION HOVEDSTADEN
Denmark

Periodic Reporting for period 3 - DEFEND (Dietary shaping of the early life metabolome and its role in healthy lung and brain development)

Reporting period: 2024-02-01 to 2025-07-31

Summary of the context and overall objectives of the project

Childhood asthma and behavioral problems related to neurodevelopment such as ADHD and autism spectrum disorders are very common childhood diseases with lack of insight in disease mechanisms and no preventive measures, which is a major unmet medical need that is being addressed in the DEFEND research project. Asthma is the main reason for chronic medication use and hospitalization of young children and have a huge impact on children, affected families and a induce a significant socioeconomic burden. Childhood ADHD and autism are characterized by a varying degree of attention deficit, learning disability and impaired social interactions and communication skills, which may have lifelong negative educational, work, and social consequences for the affected individuals.

In the Danish COPSAC mother-child cohort it was shown that pregnancy supplementation with n-3 long-chained polyunsaturated fatty acids (n-3 LCPUFA) and high dose vitamin D reduced the risk of developing and asthma in early childhood and resulted in a higher word production, improved cognitive scores, accelerated gross motor milestone achievement, and reduced the functional impact of emotional and behavioral problems. The protective effect of the high dose vitamin D supplementation during pregnancy on childhood asthma was also seen in the identically designed American VDAART study, where there was a protective effect of maternal intake of n-3 LCPUFA on the child’s risk of asthma. These novel findings may pave the path for utilizing diet supplements during pregnancy for prevention of childhood asthma, ADHD, and autism, but establishing the underlying mechanisms remains to achieve a personalized preventive strategy targeting the diet supplements only to those pregnant women, whose children will benefit from it.

Therefore, the DEFEND research project will use data form the COPSAC and VDAART cohorts resembling more than 1,500 mother-child pairs aiming to understand: 1) how diet and diet supplements in pregnancy and early life shapes the mother’s and child’s metabolic profiles by measuring their blood metabolome, i.e. all small-molecule metabolites, 2) the connection between these metabolic profiles and risk of developing asthma, ADHD, and autism in childhood, and 3) the mechanisms whereby diet and diet supplements can protect young children against developing these common childhood disorders, which is expected to have a significant impact on the children, their families and the society.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have focused on how high dose vitamin D supplementation in pregnancy and blood levels of vitamin D affected the mother’s and child’s metabolic profiles through childhood. We discovered that mother’s vitamin D levels tracked from pregnancy through childhood and low vitamin D levels associated with development of inflammation in childhood, which is a key feature of asthma. We also discovered that a range of diet-related metabolites were transferred from the pregnant mother to the newborn and through childhood. Those metabolites were found associated with risk of infections and asthma in childhood illustrating the importance of maternal diet for offspring respiratory health. Further, we found that high dose vitamin D in pregnancy altered the mother’s metabolic profile and that these changes explained the asthma preventive effect in the children.

The follow-up of our cohorts has shed light on the effects of dietary supplements in pregnancy and diet in early life. We found that fish oil supplementation in pregnancy was in boys associated with earlier achievement of motor milestones, improved cognitive development, and a reduced impact of behavioral problems. Further, the high dose vitamin D supplementation led to improved bone mineralization and fewer bone fractures in childhood and increasing blood levels of vitamin D in early childhood was associated with fewer infections and asthma symptoms.

We also investigated how the maternal and child metabolic profiles were associated with risk of infections and asthma in childhood. These analyses highlighted several metabolic pathways of importance, e.g. steroid metabolites in relation to infections and a lipid class called sphingolipids in relation to asthma. The latter led to the discovery of a new subtype of childhood asthma, which is important as sphingolipids is a potential novel treatment target. Finally, we discovered a new biomarker of exposure to fish and fish oil supplements in pregnancy, which can predict the newborn child’s risk of developing asthma.

Lastly, we have investigated and discovered genetic variants in the mother and child that modified the preventive effect of high dose vitamin D supplementation in pregnancy on risk of childhood asthma. These genetic variants are in known asthma risk genes and genes involved in the vitamin D metabolism, which can be used to select those mothers, whose children will benefit most from vitamin D supplementation during pregnancy.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Hitherto, there are three main findings of the DEFEND project, which may have a large impact on all the many children and families living with asthma. First, the project has firmly established that diet supplements with high dose of vitamin D and fish oil in pregnancy as well as maternal diet in pregnancy and the child’s diet in early life play a large role for the risk of infections, asthma, and several other health outcomes in childhood. Second, the project has shown that there are different preventive effects of diet supplements in pregnancy on childhood asthma dependent on genetic variants in known asthma risk genes and genes involved in the metabolism of vitamin D and fish oil-derived n-3 polyunsaturated fatty acids. These genetic variants can be assessed in pregnant women and thereby target diet supplements to those women, whose children will benefit most from diet supplementations during pregnancy. This novel approach is called personalized precision prevention. Third, the complex analyses of repeated maternal and childhood metabolic profiles have given novel insight into the mechanisms whereby diet and diet supplements can improve offspring respiratory health. This has provided novel biomarkers, which can be utilized to predict a newborn child’s risk of developing asthma. Finally, this has also led to the discovery of a subtype of childhood asthma with early debut, exacerbations, and low lung function, which is characterized by alterations in specific lipids that holds the promise for a novel asthma drug target.

In the second half of the DEFEND project we will be focusing more on neurodevelopmental disorders such as ADHD and autism and expect to generate results that can improve dietary prevention of these disorders. There will be a strong focus on the role of an unhealthy diet in pregnancy and the interplay with socioeconomic status in relation to the child’s risk of developing both asthma, ADHD, and autism. Finally, we expect to do more in dept analyses of the mechanisms underlying asthma and neurodevelopmental delay by integrating complex information on diet, dietary supplements, genetics, genomics, the microbiome, and the metabolic profiles of pregnant mothers and their children. This will hopefully pave the path for developing a personalized precision prevention strategy to achieve a healthy lung and brain development in childhood, which has the potential to have a significant impact on the children, their families, and the society.

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