Temporal intervention of yeast β-glucan and ellagic acid drives low-inflammatory trained immunity phenotype

Trained immunity enhances the host innate immune response; however, prolonged stimulation or metabolic stress conditions such as a Western diet readily provoke persistent inflammation. In this study, we established a temporal intervention strategy in Western diet-fed mice by alternating yeast β-glucan and ellagic acid to generate repeated cycles of inflammatory activation and resolution, and evaluated whether this co-intervention could support a trained-immunity-associated phenotype while limiting inflammatory burden. Compared with single interventions, the temporal β-glucan-ellagic acid regimen induced coordinated lipid metabolic remodeling centered on sphingolipid and glycerophospholipid pathways, enhanced oxidative phosphorylation, and increased the expression of genes involved in amino acid and cofactor metabolism. These changes were accompanied by enrichment of Akkermansiaceae and Dubosiella, two taxa associated with barrier support and energy metabolism. At the phenotypic level, temporally coordinated intervention increased H3K4me3, p300, PGC-1α, and p-mTOR, elevated IL-10, and reduced NLRP3 expression, attenuated hepatic injury, and supported a low-inflammatory, energy metabolism-associated trained-immunity-like phenotype. The work provides mechanistic clues and a practical framework for rhythm-based immunometabolic intervention.