Spermidine Deficiency Drives Food Allergy by Shutting Down Mast Cell Autophagy

Food allergy affects roughly 8% of children and 5% of adults globally, with prevalence rising 3.5-fold over two decades. Yet disease-modifying therapies remain scarce because the metabolic underpinnings of allergic sensitization and effector responses are poorly understood. This study from China Agricultural University asked whether polyamine metabolism — and specifically the polyamine spermidine, already celebrated in longevity research for its autophagy-inducing properties — plays a causal role in food allergy pathogenesis.

Using a well-validated peanut allergy model in BALB/c mice (n = 8–10 per group), the investigators sensitized animals five times with peanut protein plus aluminum hydroxide adjuvant, then challenged orally. Allergic mice showed dramatically elevated clinical allergy scores, reduced core body temperature (a proxy for anaphylaxis), high allergen-specific IgE, elevated IgG1/IgG2a ratios, and a strongly Th2-skewed cytokine profile (elevated IL-4 and IL-33, reduced IFN-γ). Jejunal spermidine levels measured by HPLC-MS were significantly reduced in allergic animals while putrescine and spermine remained stable, pinpointing a spermidine-specific metabolic shift. SAT1 mRNA was significantly elevated in peripheral blood, jejunum, and lung tissue of allergic mice, a finding corroborated by reanalysis of the public peanut allergy transcriptomic dataset GSE17595. SAT1 upregulation was also confirmed in whey protein- and shrimp-allergic mouse models, indicating a conserved feature across food allergen types.

To test causality, mice received daily oral gavage of spermidine at 10 mg/kg (selected from a dose-response experiment comparing 5, 10, and 20 mg/kg). Spermidine-supplemented mice showed markedly attenuated clinical scores, preserved body temperature, reduced allergen-specific IgE, lower IgG1/IgG2a ratios, decreased IL-4 and IL-33, increased IFN-γ and IL-2, and lower serum histamine and mast cell protease-1 (MMCP-1). Jejunal histology confirmed preserved villus architecture with reduced epithelial shedding and neutrophil infiltration. In a parallel arm, systemic Sat1 knockdown via intravenous siRNA delivery (verified by qPCR) phenocopied spermidine supplementation: reduced allergy scores, decreased IgE, reversed Th2 cytokine polarization, and restored jejunal spermidine levels — all without detectable systemic toxicity.

Mechanistic dissection focused on mast cells, the primary effectors of IgE-mediated allergic reactions. SAT1 was markedly upregulated in mast cells from allergic mice and in IgE/antigen-stimulated bone marrow-derived mast cells (BMMCs) in vitro. SAT1 overexpression promoted degranulation (measured by beta-hexosaminidase release and histamine secretion), while SAT1 knockdown suppressed it. Critically, autophagic flux — assessed by LC3-II accumulation, p62 degradation, and transmission electron microscopy — was significantly impaired in allergic mast cells, and this impairment was rescued by spermidine or SAT1 knockdown. Using RNA immunoprecipitation and co-immunoprecipitation assays, the team identified the lncRNA Cdk19os as a direct SAT1-binding partner. SAT1-Cdk19os interaction suppressed transcription of Atg5 and Atg7, two autophagy-essential genes. Cdk19os knockdown mimicked SAT1 overexpression, worsening allergy; Cdk19os overexpression rescued autophagy and attenuated degranulation. The autophagy inducer rapamycin further confirmed that pharmacological autophagy activation ameliorated allergic responses in vivo.

These findings establish a SAT1→spermidine depletion→Cdk19os→Atg5/Atg7 suppression→impaired autophagy→mast cell hyperdegranulation axis as a novel metabolic-immunological driver of food allergy. For the longevity field, this is significant: spermidine is already known to extend lifespan in model organisms and to support autophagy as an anti-aging mechanism, and this study reveals it also constrains a major allergic inflammatory pathway. The work is conducted entirely in murine models, and translation to humans requires clinical investigation, but it opens a compelling case for dietary spermidine — found naturally in wheat germ, aged cheese, and mushrooms — as a functional food intervention for allergy prevention.