Decreased Oral Tolerance to Egg Allergen Ovalbumin in Mice Fed an Amino Acid-Based Diet via Triggering Epithelial-Derived IL-33 Release and Suppressing p-Treg Production.

Oral tolerance (OT) to dietary antigens is crucial to preventing food allergy (FA). The generation and maintenance of the OT require constant stimulation with dietary antigens. Infants fed long-term with amino acid-based formulas (AAFs) lack this stimulation, leaving the impact on subsequent OT induction unknown. Herein, we investigated the effects of long-term AAF consumption on OT development by subjecting neonatal mice to an amino acid-based diet (AAD) before introducing the egg allergen ovalbumin. The results showed that the AAD significantly impaired OT generation. Upon an oral allergen challenge, AAD-fed mice exhibited pronounced allergic symptoms, increased OVA-sIgE/sIgG1 levels, and intestinal mast cell activation. These changes were accompanied by increased intestinal IL-33 expression, the expansion of cDC2B and Th2 subsets, and a reduced frequency of peripheral Tregs. Consequently, AAD feeding drives a Th2-dominant response, resisting oral food tolerance induction. This study suggests that the excessive use of AAFs may increase FA susceptibility and broaden our understanding of the immune effects of dietary antigens.