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

• Published in: Scientific reports Vol. 15; no. 1; pp. 29164 - 19
• Main Authors: Tian, Yunfen, Sun, Meisha, Luo, Lan, Lou, Fen, Zhou, Peng, Chen, Jiejuan, Lv, Hongdan, Zhang, Fangxiang, Zhang, Mazhong, Wang, Bin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.08.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/140; 631/154/152; 631/154/555; 631/250/254; 631/80/304; 692/4017; 692/53; 692/699/375/1367; Animal models; Animals; Binomial distribution; Bioinformatics; Cecum; Chromatography; Disease Models, Animal; Fatty acids; Fatty Acids, Volatile - metabolism; Gas flow; Gelatinase B; Gene Expression Profiling; Genes; Glycerophospholipid metabolism; Glycerophospholipids - metabolism; Humanities and Social Sciences; Humans; Immune system; Immunomodulation; Inflammation; Laboratory animals; Lymphocytes; Machine learning; Male; Mendelian Randomization Analysis; Metabolism; Metabolites; Metabolomics; Metabolomics - methods; Mice; Mice, Inbred C57BL; Monocytes; Morbidity; Mortality; Multi-omics; multidisciplinary; Multiomics; Pathogenesis; Science; Science (multidisciplinary); Sepsis; Sepsis - genetics; Sepsis - metabolism; Short chain fatty acids; Systemic inflammatory response syndrome; Therapeutic targets; Transcriptome; Transcriptomics; Beijing China; China; Sepsis; Glycerophospholipid metabolism; Short chain fatty acids; Multi-omics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-025-13322-7

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.