Comprehensive multi-omics analysis reveals the core role of glycerophospholipid metabolism in the influence of short-chain fatty acids on the development of sepsis.

Sepsis is a systemic inflammatory response syndrome caused by infection, which has a high morbidity and mortality. Short-chain fatty acids (SCFAs) have been proved to improve the outcome of sepsis by regulating immunity and metabolism, but its specific mechanism is not clear. This study employed a multi-omics strategy integrating murine models, untargeted metabolomics, human transcriptomics (GSE185263, GSE54514), single-cell RNA sequencing (GSE167363), and Mendelian randomization to investigate SCFAs’ role in sepsis. Cecal ligation and puncture (CLP) was performed in C57BL/6 mice (n = 60). Transcriptomic analysis identified 76 differentially expressed genes between septic and healthy subjects. Machine learning (SVM-RFE and LASSO regression) prioritized five SCFA-associated hub genes (CASP5, GPR84, MMP9, MPO, PRTN3), with molecular docking revealing two potential modulators. Single-cell profiling localized these targets to monocytes, while immune infiltration analysis confirmed SCFA-mediated immunomodulation. Murine metabolomics identified glycerophospholipid (GPL) metabolism as the most significantly altered pathway under SCFAs intervention. Mendelian randomization established causal relationships between GPL pathway genes and sepsis incidence/28-day mortality. Collectively, the study provide novel mechanistic and translational insights into the therapeutic targeting of short-chain fatty acids in sepsis.