Often termed the ‘lost organ’ the human gut contains trillions of microbes. A rich, diverse gut microbiota is considered to promote health, whereas a microbiota with reduced diversity is associated with gut inflammation and disease. Many factors affect gut microbes including host genetics, injury, diet, infection and antibiotics; the use of the latter being associated with the increased risk of obesity, cancer, asthma and diabetes in children.

The development of gut microbiota begins before the infant is born with maternal factors such as infection and birth-mode. Then at birth microbial gut colonization begins, continually developing for about 3 years, until the microbiota becomes more stable and adult-like. The gut microbiota in children under 3 years of age fluctuates and is more impressionable to environmental factors than the adult microbiota. During this time children experience significant developmental changes that influence their health status and gut microbiome. Children also suffer more infectious diseases and associated antibiotic usage, than adults. Studies indicate that most, but not all, bacterial species recover during the 6 months post-antibiotic treatment and that specific early-life exposures to antibiotics, caesarean section and formula feeding disrupts gut microbiome establishment.

It has been suggested there is an early-life ‘critical window’ of development during which the microbiota is disrupted beyond repair favouring susceptibility to future health issues. A major concern is permanent loss of beneficial bacteria after repeated early life infections and associated antibiotics, with cumulative effects increasing susceptibility to emerging health issues and infections.

For some people, coronavirus (COVID-19) can cause symptoms that last weeks or months after the infection has gone. This has been called post-COVID-19 syndrome or "long COVID". Common symptoms include fatigue, shortness of breath, chest pain or tightness, difficulty sleeping, joint pain, problems with memory and concentration ('brain fog'). Little is known about what causes long COVID and very little about how to treat long COVID. This project aims, in a first instance, to investigate risks and determinants that make an individual more likely to have long COVID, and then to understand the health consequences of long COVID. This is of critical public health importance in helping to treat, prevent and mitigate consequences of long COVID.

There are key transitions that often occur when adolescents become adults, such as leaving full-time education, starting a full-time job, living with a partner, or becoming a parent. In previous generations, when these transitions happen early or happen close together, they have been shown to be related to poorer health and related behaviours, for example, weight gain or increased smoking. However, there is little evidence available on what typical transition patterns look like for today’s young people, which patterns are the most harmful to health, or the reasons that these patterns cause poorer health (for example, is weight gain in those who have made lots of these transitions early in life explained more by the extra stress or by lack of time to eat healthily or exercise). Using data from two recent UK birth cohorts, and sophisticated methods of analysis, we will try to answer these questions. Where possible, we will see if findings differ for sex, ethnic minority, and LGBTQ+ groups. This information can help us understand the best way to support young people moving from adolescence to young adulthood, to help optimise their health later in life.

Molar-incisor Hypomineralisation (MIH) is a tooth condition specifically affecting the enamel (outer layer of the tooth) of one or more of the child’s first adult molars (back teeth) and in some cases the incisors (front teeth). MIH affected teeth appear discoloured, and vary in presentation; cream, yellow or brown. Teeth are commonly very sensitive, painful and in severe cases crumbly. Furthermore, affected teeth often have a poor prognosis and are more susceptible to dental decay meaning the teeth are often extracted before adulthood. It is usually diagnosed when the adult molars and incisors erupt in the mouth at around 6-7 years of age. In some cases, it can also affect the primary teeth, which is known as hypominersalised second primary molars (HSPM) and is seen around 2-3 years of age.

MIH has a high prevalence; approximately 13.1% globally (95% CI 11.8-14.5%) and 15.9% in the UK (95% CI 14.5-17.1%). The literature suggests MIH is caused by disturbances during tooth development. This is influenced by genetics and environmental factors, particularly during pregnancy, time of birth and in the first few years of life. Some of the environmental factors investigated include breastfeeding, environmental toxins (dioxins and Bisphenol A), problems occurring at birth and childhood illnesses. However, the literature concludes that the aetiology of MIH is unclear. Currently, there is little research on maternal factors and MIH, particularly the common environmental risk factors; maternal smoking (7 studies – the most recent suggesting a significant association) and alcohol consumption (2 studies), both in which the strength of evidence is weak and conflicting. Furthermore, much of the research conducted is retrospective and therefore prone common biases such as recall bias. There is a need for high-quality prospective studies. Other studies suggest that maternal smoking and alcohol consumption are associated with offspring HSPM. The embryological development of the second primary molars and first permanent molars are similar, and therefore may share the same environmental influences.

We propose to conduct a prospective study looking at the association between common maternal pregnancy characteristics and MIH. These include maternal smoking, alcohol consumption and body mass index (BMI). We will assess for the presence of residual confounding by including a negative parental exposure control. This involves comparing the confounder adjusted associations of maternal pregnancy exposures with the offspring outcome of interest to similarly adjusted associations of the same characteristics (negative controls) in the father. Similarly, we will use offspring dental trauma as a negative control outcome. Triangulating results from conventional multivariable regression, negative exposure controls and negative outcome controls provides scope to improve causal understanding.

Substantial differences exist between the immune reponses made by males and females that critically impact health and survival. Typically, females make stronger immune responses to vaccines and infections and achieve superior outcomes throughout life. For example, females achieve the same levels of neutralizing antibodies from half the dose of influenza vaccine as males from the full dose. However, this more exuberant immune response leads to greater susceptibility to immunopathology and autoimmune diseases and more adverse events from immunizations. To complicate matters, there are exceptions; as fetuses, females have a 2-fold greater susceptibility to mother-to-child transmission of both HIV and HCV infection, and to IFN-I-resistant viruses. To better understand the mechanisms responsible for these complex observations, we propose to compare the epigenetic and hormonal responses in males and females to immunization and vaccination in early life. We hypothesize that life-long immune sex differences are established early through the interplay of host genetics, sex-specific steroid biosynthesis, epigenetics and the environment, and that early-life epigenetic changes in response to sex-specific steroid modulation and infection and immunization play a dominant role in this process.

Experiences of childhood maltreatment is suggested as an important risk factor for the development of delinquent behaviour. Heightened sensation-seeking is related to the development of delinquency. Moreover, sensation-seeking, or biological correlates of sensation-seeking, are suggested as factors linking childhood maltreatment to delinquency. More specifically, it is hypothesized that epigenetic correlates of sensation-seeking might function as a mechanism for translating environmental signals into biological changes that may subsequently lead to maladaptive behavior development. In this study we will try to identify the epigenetic correlates of sensation-seeking in children and investigate whether these epigenetic correlates are influenced by earlier experiences of childhood maltreatment and may impact subsequent development of delinquency in early adolescence.

Systematic reviews and meta-analyses using aggregate data have indicated an increased risk of childhood asthma for women undergoing caesarean section, but the results were subject to moderate heterogeneity, potential residual confounding and publication bias1-4. We aim to use the EU child cohort network to re-examine the associations with different types of delivery using IPD MA to produce a more reliable pooled meta-analytic estimate. Potential mediators such as respiratory tract infections and allergic sensitization will be examined for the associations between different types of mode of delivery and asthma.

Hand preference is only weakly determined by genetics. Consequently, environment likely plays a role by modifying the expression of certain genes during early development. In this study, we will ask to what extent DNA methylation, a well-known regulator of genes, is associated with hand preference in ALSPAC children and their parents beyond known genetic associations.