2025 Liang Chen

By Liang Chen

Chairperson: Professor Klaus Müller, University of Copenhagen, Denmark

Opponent: Professor Harald Renz, Philipps-University, Germany
Opponent: Associate Professor Jon Konradsen, Karolinska Institutet, Sweden

Summary

Background: Asthma and atopic dermatitis (AD) are very prevalent diseases in childhood, which pose significant societal and health challenges and negatively affect quality of life. Asthma is characterized by airway inflammation, hyperresponsiveness, and variable airflow obstruction, which often debuts in early childhood. There are effective treatment options to control symptoms, but no preventive measures. Atopic dermatitis is an inflammatory skin disorder, also often beginning in infancy or childhood and can persist into adulthood. Similar to asthma there are various treatments to alleviate AD symptoms, but currently no preventive measures. Thus, establishing early life biomarkers of asthma and AD and novel preventive measures is of utmost importance, as proactive diagnosis, intervention, and risk factor management could substantially improve long-term health outcomes and quality of life.

Eicosanoids and oxylipins are bioactive lipid mediators derived from polyunsaturated fatty acids and play crucial roles in regulating inflammation, which are core processes in both asthma and AD. In asthma, certain eicosanoids are associated with airway constriction and inflammation, while others exhibit bronchoprotective and anti-inflammatory properties. Similarly, eicosanoids and oxylipins contribute to the inflammatory pathways active in AD, influencing disease severity and symptom expression. These compounds, with their complex and dynamic roles in inflammation, offer a promising area to investigate for understanding early life biological processes that may be implicated in the onset of atopic diseases and could be utilized for predictive and preventive purposes.

Methods: This PhD project is based on a pregnancy RCT of n-3 LCPUFA supplementation and longitudinal clinical data combined with assessments of early life blood oxylipins and urinary eicosanoids from the European COPSAC₂₀₁₀ birth cohort study of 700 mother-child pairs with replication of findings in the American VDAART birth cohort of 881 mother-child pairs. Both genomics, microbiome and immune data were available for integrated analyses.

Aims and objectives: The primary objectives of the thesis are:

1. To investigate the role of early life urinary eicosanoids in the development of childhood asthma and AD, aiming to identify early life biomarkers for risk stratification of children and early disease mechanisms as targets for prevention.
2. To explore the interplay between pregnancy n-3 LCPUFA supplementation and genetic variations in the eicosanoid pathway in relation to the risk of childhood AD, aiming to obtain a precision prevention strategy.
3. To explore the impact of maternal blood levels of oxylipins, focusing on 12-HETE as this oxylipin has been implicated in neonatal alveolar macrophage imprinting, in relation to the risk of asthma and respiratory infections in offspring, aiming to understand early disease mechanisms and obtain a precision prevention strategy.

Included papers: The thesis is based on the following three papers:

1. Urinary eicosanoid levels in early life and risk of atopic disease in childhood. Chen L, et al. J Allergy Clin Immunol. 2024 Sep;154(3):670-678.
2. Prenatal Fish Oil Supplementation, Maternal COX1 Genotype, and Childhood Atopic Dermatitis: A Secondary Analysis of a Randomized Clinical Trial. Chen L, et al. JAMA Dermatol. 2024 Oct 1;160(10):1082-1090.
3. Neonatal alveolar macrophage imprinting assessed by maternal 12-HETE levels associate with childhood respiratory morbidity through airway microbiome and immune alterations and is modified by prenatal n-3 LCPUFA exposure. Chen L, et al. Manuscript in peer review.

Paper I investigates the role of eicosanoids in the development of atopic diseases by analyzing quantitative urinary eicosanoid levels in the first year of life in children from the COPSAC₂₀₁₀ and VDAART cohorts. This study showed that higher levels of thromboxane A2 (TXA2) along with disruptions in other eicosanoid pathways were associated with an increased risk of AD, type-2 inflammation, and wheeze/asthma after multiple test correction across both cohorts. These findings indicate that early life disturbances in the eicosanoid pathways are crucial for understanding the pathophysiology of atopic diseases, particularly AD, where the strongest signals were observed.

Paper II explores the impact of pregnancy n-3 LCPUFA supplementation and maternal COX1 genetic variants on the risk of childhood AD in COPSAC₂₀₁₀. This secondary analysis of our RCT showed that the n-3 LCPUFA supplementation reduced the risk of AD in children, but only in mothers with the COX1 TT genotype, i.e., interaction between the supplement and COX1 genotype. Further, we found that this interaction was driven by alterations of TXA2 metabolites only in the COX1 TT genotype, which provides a potential mechanistic explanation for the observed genotype-dependent protective effect of n-3 LCPUFA supplementation on childhood AD risk. These findings propose a personalized prevention strategy for reducing the burden of childhood AD by genotyping expecting mothers and only providing n-3 LCPUFA supplementation to women carrying the COX1 TT genotype.

Paper III assesses the correlation between maternal pregnancy levels of the 12-HETE oxylipin in relation to offspring risk of asthma and respiratory infections as experimental studies have highlighted a beneficial role of 12-HETE in neonatal alveolar macrophage imprinting, with a deficiency in 12-HETE associated with increased respiratory morbidity in mice. Utilizing data from both COPSAC₂₀₁₀ and VDAART, we demonstrated that undetectable plasma 12-HETE during pregnancy associated with increased risk of childhood asthma and respiratory infections, alongside an altered infant airway microbiota structure, notably higher abundance of Streptococcus, Gemella and Rothia, and an altered infant airway immune profile in COPSAC₂₀₁₀. Further, we observed an interaction between maternal 12-HETE and the n-3 LCPUFA supplementation in COPSAC₂₀₁₀ and dietary n-3 LCPUFA intake in VDAART in relation to offspring respiratory morbidity. Specifically, higher prenatal n-3 LCPUFA exposure reduced risk of asthma and respiratory infections only among mothers with detectable 12-HETE levels. These findings underscore a beneficial role of maternal 12-HETE in offspring respiratory morbidity, possibly acting through the infant airway microbiota and immune system, which can be modified by n3-LCPUFA supplementation in pregnancy.

Conclusion: The findings of this thesis emphasize the significance of pregnancy and early-life metabolic disturbances in the eicosanoid and oxylipin pathways, which in a complex interplay with the infant airway microbiota structure, the infant airway immune profiles, and dietary interventions during pregnancy are influencing the risk of asthma and AD in the offspring. By identifying key eicosanoid and oxylipin biomarkers and their interactions with dietary and genetic factors, the research presented in this thesis provides valuable insights to develop personalized prevention strategies and interventions aimed at reducing the burden of asthma and AD in childhood.