Beyond desensitization: the SCFA-Treg-gut microbiota axis as a mechanistic framework for sustained unresponsiveness...

Food allergy is an immune-mediated condition associated with acute reactions, risk of anaphylaxis, and a substantial day-to-day management burden. Oral immunotherapy (OIT) can increase the amount of allergen tolerated during treatment, but this desensitized state commonly depends on continued exposure. Sustained unresponsiveness (SU), also termed remission in some trials, is a stricter operational endpoint in which clinical non-reactivity is retained after a predefined period of treatment withdrawal and is confirmed by oral food challenge. The biological processes that determine whether desensitization develops into SU remain incompletely understood. This narrative review evaluates the gut microbiota-short-chain fatty acid (SCFA)-regulatory T-cell (Treg) axis as a mechanistic framework for this transition. Experimental studies show that microbial SCFAs can influence Treg differentiation and function through histone deacetylase inhibition and metabolite-sensing receptors, while also conditioning epithelial and antigen-presenting-cell programs that favor mucosal tolerance. Human cohort and microbiota-transfer studies support an association between early-life microbial maturation, SCFA-related metabolic capacity, and allergic outcomes, but most causal evidence remains preclinical. Importantly, fecal SCFA concentrations are imperfect surrogates for mucosal exposure, and a randomized trial of oral butyrate added to peanut OIT did not improve SU. These findings argue against treating a single metabolite as a sufficient therapeutic target. Translational development should instead test spatially targeted metabolite delivery, defined microbial therapeutics, and precision prebiotic or synbiotic strategies as adjuncts to antigen-directed therapy. Future trials require harmonized post-withdrawal challenge definitions, longitudinal sampling of microbial function and host immunity, and biomarker-guided patient stratification. The SCFA-Treg-gut microbiota axis is therefore best viewed as a testable, integrative model of durable immune control rather than an established therapeutic pathway to SU.