Temporal Trained Immunity by β-Glucan Alleviates LPS-induced Pathological Inflammation

• Insoluble yeast β-glucan directs protective or pathological trained immunity via metabolic reprogramming. • Protective trained immunity relies on energy metabolism and glycolipid pathways. • Pathological trained immunity features amplified immune signaling with suppressed metabolism. Immune stimulation can imprint lasting immune memory, while the host metabolic milieu dictates the functional polarity of trained immunity. In this study, mice were administered high–molecular weight β-glucan at three temporal frequencies (high, medium, and low). Centered on metabolomics and integrated with microbiome, transcriptome, and immunophenotypic analyses, we investigated how β-glucan orchestrates the temporal remodeling of LPS-induced acute inflammatory metabolic networks and immune responses from a metabolism-driven perspective. The results revealed that β-glucan rewired inflammation primarily through energy-dependent metabolic programs, in which lipid metabolism initiated endogenous anti-inflammatory mechanisms, and butyrate-producing taxa provided synergistic support for serotonin and lipid metabolism. High-frequency training predominantly activated metabolic responses related to immune signaling, phagocytic function, and antioxidant defenses, yet partially suppressed certain defense and repair pathways. In contrast, medium-frequency training represented a critical metabolic–immune inflection point, rapidly inducing arachidonic acid, linoleic acid, and taurine metabolism, promoting the expression of Caspase-3, HMGB1, and regulatory T-cell–related genes, and sustaining energy availability and removal of damaged cells through enhanced oxidative phosphorylation pathways. Temporal cadence governed the balance between protective and pathological outcomes of trained immunity by coupling metabolic reprogramming with the interplay between energy metabolism and immune memory.