The gut-lung axis is a critical regulator of systemic immune homeostasis, however, the precise mechanisms linking gut-derived metabolites to distal airway inflammation remain incompletely understood. Here, we show that oral administration of viable Leuconostoc mesenteroides MY2024 engages a metabolite-host enzyme circuit that protects against allergic airway inflammation (AAI). Viable, but not heat-inactivated, MY2024 significantly attenuated ovalbumin (OVA)-induced Th2-driven eosinophilic asthma by suppressing pathogenic M2-like macrophage responses in the lung. Mechanistically, MY2024 increased gut-derived cinnamic acid (CA), which activated a colonic STAT1-SAT1 signaling axis to accelerate systemic spermidine catabolism. Reduced systemic spermidine availability was associated with reduced pulmonary eIF5A hypusination, a metabolic checkpoint known to support alternative macrophage activation. Notably, these protective effects and the associated metabolic reprogramming were preserved in microbiota-depleted mice, highlighting a direct bacterium-to-host metabolic axis. Together, our findings delineate a probiotic-metabolite-host enzyme circuit and identify colonic epithelial SAT1-dependent spermidine catabolism as a potential metabolic checkpoint for regulating type 2 AAI.
PMID: 42414296
