Glycerophospholipid Metabolism Mediates Trained Immunity In Periodontitis

Trained immunity heterogeneity in periodontitis patients and its metabolic underpinnings remain unclear. This study integrates multi-omics and Mendelian randomization to define glycerophospholipid metabolism as a mediator of trained immunity, identifying therapeutic targets for inflammatory diseases. Peripheral blood monocytes from 100 periodontitis patients (aged 35-59 years, 45% female) were analyzed for trained immunity responses (ethics approval K2023018, from January 2023 to December 2024). Untargeted metabolomics, Mendelian randomization, and single-cell RNA sequencing with scMetabolism analysis linked circulating metabolites to disease causality and mapped metabolic-immune interactions. In vitro models explored Porphyromonas gingivalis and lysophosphatidylcholine effects on monocyte immune memory. Periodontitis patients exhibited 3.4-fold higher IL-1β secretion in high-trained immunity responders versus low responders (P<0.05), with metabolomics identifying 119 differentially abundant metabolites enriched in glycerophospholipid metabolism (KEGG P<0.01), and Mendelian randomization analysis revealed causal associations between periodontitis risk and nine metabolites (e.g., 1-stearoyl-2-docosahexaenoyl-GPE, OR=1.035, P<0.01), enriched in glycerophospholipid metabolism. Single-cell transcriptomic analysis revealed positive correlations between glycerophospholipid metabolism activity and IL1B expression. P. gingivalis culture supernatant and lysophosphatidylcholine effectively induced trained immunity in THP-1 monocytes, with IL-1β secretion increasing upon secondary LPS challenge (P<0.01). Glycerophospholipid metabolism drives trained immunity in periodontitis via metabolic-immune crosstalk. Targeting this pathway may mitigate chronic inflammation, offering dual therapeutic potential for oral and systemic diseases.