Abstract

Hydrogen sulfide (H 2 S), an endogenous gasotransmitter, has garnered increasing attention for its role in modulating immune responses and intestinal barrier function. In this study, diminished jejunal H 2 S levels and expression of its synthesizing enzyme cystathionine gamma-lyase (CSE) in intestinal epithelium were observed in ovalbumin (OVA)-induced food allergic mice. CSE deficiency aggravated OVA-induced food allergy by activating the IL-25/ILC2 axis and enhancing type 2 immune responses, effects that were reversed by exogenous H 2 S supplementation. Furthermore, H 2 S treatment suppressed intestinal epithelial cell-derived IL-25 expression by inhibiting c-Jun. IL-25 neutralization attenuated ILC2-driven type 2 immune responses and alleviated allergic symptoms in OVA-challenged CSE-knockout ( Cse –/– ) mice. Moreover, ILC2 inhibition diminished type 2 cytokine production and disrupted the IL-25 feedback loop, thereby ameliorating food allergy in Cse –/– mice. These findings highlight that intestinal epithelial CSE-derived H 2 S alleviates food allergy via the IL-25/ILC2 axis and serves as a potential therapeutic target for allergic diseases.