Background: Oral immunotherapy is a promising treatment for peanut allergy inducing desensitization in most patients. However, 15-30% of patients do not respond, and a significant risk of anaphylaxis due to treatment remains.

Objective: This study aims to identify molecular differences between strong and weak treatment responders by investigating a comprehensive spectrum of omics profiles in immune cells.

Methods: We analysed immunoglobulins, cytokines, transcriptome and DNA methylome profiles in both peanut-stimulated and unstimulated immune cells isolated from 38 peanut-allergic children before and after oral immunotherapy.

Results: Our study identified 184 differentially expressed genes and 1001 differentially methylated genes associated with the strength of the oral immunotherapy response. Transcriptome and methylome profiling highlighted gut-resident innate (ILC3) and adaptive (CD8αα subset of CD8+ T cells) immune cells as essential players. Functional enrichment analyses additionally pointed to exosomes and gd T cells in promoting peanut desensitization. Overall, our findings emphasize the essential role of regulatory processes within the gastrointestinal tract in oral immunotherapy responsiveness. Furthermore, we confirm that lower pre-treatment cytokine production (IL-4, IL-5) and peanut-specific serum IgE are associated with therapeutic success.

Conclusion: Our multi-omics approach underscores the importance of gastrointestinal immune mechanisms underlying the variation in peanut oral immunotherapy responses and offers potential biomarkers for improving treatment strategies.