Immune profiling the blood and the gut microbiome: Advanced population- and patient-based stratification for tackling the allergy epidemic

The global burden of allergic diseases is on the rise, calling for improved diagnostic, treatment and prevention strategies. To tackle this crisis and to promote novel solutions, a multitude of contributing factors requires consideration, ranging from a deeper understanding of the underlying disease mechanisms to a deeper understanding of the disease etiology. Both intrinsic, such as genetic predisposition, and extrinsic factors, such as environmental exposures and lifestyle, play significant roles in epithelial barrier disruption and shifts of the immune balance from tolerance to T helper 2 (Th2) immunity against usually harmless antigens. At the site of epithelial barrier disturbance, alterations in the microbiome composition and function, known as dysbiosis, emerged as further contributors to the development of allergic conditions. Taking into account those aspects, the primary objective of this PhD thesis was to investigate IgE-mediated allergies and explore innovative strategies for the categorization of entire populations as well as specific patient subgroups. The ultimate aim is to enhance patient care and well-being through these advancements.
To establish a first knowledge base on allergies in Luxembourg, we examined an adult, cross-sectional population-based cohort (Study 1). This work employed a new integrated approach, using blood IgE signatures, as well as health and lifestyle determinates. We revealed important insights into the identification of high-risk individuals, facilitating potential targeted interventions and preventive measures. We saw a high burden in the youngest population, mostly with pollen allergies and related food allergies. Especially in food allergy, clinical heterogeneity is a well-recognized challenge, with wide variations observed for reaction thresholds, severity, and organs involved. A review of current literature identified gaps in peanut allergy diagnosis as a model for severe and persistent food allergies (Study 2). Current diagnostic measures have limitations in accurately predicting clinical reactivity, underscoring the need for advancements in this field to improve patient care and outcomes. Relating to this knowledge gap, we aimed to better stratify patients based on novel complex blood immune patterns (Study 3). Integrating immune cell changes during oral food challenge with clinical outcomes, patients with variable clinical reactivity differed based on unique immune cell profiles. Our results pointed even to immune patterns involving into reactions of the gastrointestinal tract, with the great potential as a predictive marker. Finally, in a novel field of patient classification, fecal immune factors were explored in food-allergic patients (Study 4). We succeeded to correlate clinical outcomes of established peanut allergy with characteristics of the gut microbiome and so far underexplored fecal markers, elevated IgE and Th17 cytokines. This innovative approach offers promising prospects for personalized management and treatment of allergic conditions, as well as an early disease marker potentially aiding in prevention.
In conclusion, the findings of this PhD thesis provide important insights into the development of population-based and personalized approaches, paving the way for targeted interventions, improved diagnostic measures, and enhanced patient care in the field of allergic diseases.