Peanut Oral Immunotherapy Response Linked to Gut Immune in Children

A new study found that multi-omics profiling of immune cells revealed molecular drivers of peanut oral immunotherapy responsiveness linked to gastrointestinal mechanisms.¹

“Taken together, our findings suggest a critical imbalance of robust Treg responses and B cell suppression on the one hand and the dominance of innate immune signaling and metabolic stress on the other as [a] potential mechanism of incomplete desensitization,” wrote study investigator Aleix Arnau-Soler, PhD, a postdoctoral scientist at Max-Delbrück-Center’s pediatric allergy clinic, and colleagues.¹

The US Food & Drug Administration approved oral immunotherapy for peanuts (Palforzia, formerly AR101) in January 2020.² Although oral immunotherapy helps desensitize patients to their peanut allergy, 15% to 30% of patients do not respond and are at significant risk of anaphylaxis with the treatment.¹

Investigators conducted a placebo-controlled trial to identify molecular drivers of the responsiveness of oral immunotherapy for peanuts.¹ The team assessed this via multi-omics profiling in immune cells, analyzing immunoglobulins, cytokines, transcriptome, and DNA methylome profiles before and after treatment in both peanut-stimulated and unstimulated peripheral blood mononuclear cells in children with a peanut allergy.

“Unlike other studies focusing on allergen-specific T cells using CD154-based approaches, they addressed the transcriptome and methylome profiling of whole PBMC bulks, yielding more granular high-level insights into the functional biology of peanut OIT,” wrote Annette Kuehn, PhD, from Luxembourg Institute of Health, and Thomas Eiwegger, MD, from the University of Toronto, in an accompanying editorial.³ “This poses risks and chances in re-visiting more general questions with new state-of-the-art transcriptomic methods by using ‘older’ methods of allergen-specific stimulation, which are less rigid than those performed more recently in this context.”

The study included 49 children (29 boys, 20 girls; mean age, 7 years) with a challenge-proven peanut allergy.¹ In total, 27 participants received peanut, and 22 received a placebo; 11 on placebo later switched to peanut. For 14 months, participants in the active arm underwent dose escalation up to the target dose of 125–250 mg of peanut protein, which was then maintained for an additional 2 months.

The study found that complete responders, who tolerated 4500 mg of peanut protein (15 – 30 peanuts), presented lower pre-treatment peanut-specific IgE and Th2 cytokine production (IL-4, IL-5) compared to incomplete responders who tolerated ≤ 1000 mg of peanut protein.¹

Investigators identified 184 differentially expressed genes and 1001 differentially methylated genes.¹ These genes were linked to innate immune cells (ILC3s), adaptive immune cells CD8αα subset of CD8+ T cells), γδ T cells, and exosomes. These findings demonstrate the important role gastrointestinal immune regulation plays in the success of oral immunotherapy.

“Using deep immune phenotyping of PBMC from peanut-allergic patients, gastrointestinal symptoms were associated with gut-migratory immune signatures—marked by Th2, memory regulatory T cells (Tregs) and CD8+ T cell responses—via chemotactic navigation and CD196/CCR6 upregulation, further emphasizing the importance of gut tissue inflammation,” Kuehn and Eiwegger wrote.³

The team also observed more changes in DNA methylation than RNA expression linked to a stronger oral immunotherapy response.

“This may be due to methylation changes detected for genes not expressed in [peripheral blood mononuclear cells],” Arnau-Soler and colleagues explained.¹

The study found that patients receiving peanut oral immunotherapy had a much lower activity of immunoglobulin genes than those receiving a placebo.¹ The finding suggests that oral immunotherapy changes how B cells function.

Among patients who responded fully to oral immunotherapy, functional networks showed a stronger regulatory T-cell activity and suppression of B-cell responses.¹ However, among incomplete responders, innate immune signaling (NLRP1, HIF-1 signaling pathway) and signs of metabolic stress (hypoxia, glycolysis) dominated the networks.

“The data from Arnau-Soler et al. is highly relevant in pointing toward changes of gut-associated immunity in successful peanut [oral immunotherapy],” Kuehn and Eiwegger concluded.³ “A limitation is that those findings are confirmed at the protein and single-cell level. In the future, it will be required to combine different OMIC approaches exploring both innate and adaptive targets, considering gut immune homeostasis when investigating immunological changes during [oral immunotherapy].”

References

1. Arnau-Soler A, Ashley SE, Ghauri A, et al. Understanding the Variability of Peanut-Oral Immunotherapy Responses by Multi-Omics Profiling of Immune Cells. Allergy. Published online July 22, 2025. doi:10.1111/all.16627

2. Oral Immunotherapy (OIT) in Practice | Food Allergy Research & Education. Food Allergy Research & Education. https://www.foodallergy.org/resources/oral-immunotherapy-oit-practice

3. Kuehn A, Eiwegger T. Oral Immunotherapy of Peanut Allergy: A Critical Role for Gut-Associated Immunity. Allergy. Published online August 1, 2025. doi:10.1111/all.16657