Integrative Analysis of Transcriptomics and Metabolomics Reveals the Effects of Western-Style Diets on Spleen Function

The spleen is essential for immunity, mediating host defense against pathogens and regulating immunological homeostasis. Western-style diets commonly cause the aggregation of body fat and the emergence of obesity. This state might lead to damage to the spleen's functions. However, the effects of Western-style diets on gene expression and metabolic regulation in the spleen have not yet been fully explored. In this study, <i>C57BL/6</i> mice were fed either a high-fat diet (HFD) or standard chow (CHFD) for 10 weeks starting at 8 weeks old. Weekly weights were recorded, and spleens were weighed at 18 weeks. The results showed that HFD mice had significantly higher body weights from 12 weeks (<i>p</i> < 0.05) and a higher splenic index at 18 weeks (<i>p</i> < 0.01). HE staining revealed disrupted spleen structures and infarcted areas in the HFD group. Transcriptome sequencing highlighted immune-related pathways, including inflammatory response and interleukin-6 production. Among the differentially expressed genes (DEGs), <i>PCK1</i>, <i>ALDH9A1</i>, and <i>ALDH7A1</i> were significantly upregulated in the HFD group, whereas <i>PLA2G2F</i> and <i>PLA2G4F</i> exhibited significant downregulation. <i>APOB</i> emerged as a key hub gene in PPI analysis. Metabolomics analysis identified significantly different metabolites (SDMs), including Rifamycins, 7-Ketodeoxycholic Acid, Folinic Acid, and Lotaustralin, as key biomarkers for an HFD, while 1-Methylnicotinamide and Prostaglandin E1 were significant for CHFD. KEGG enrichment linked glycerophospholipid and arachidonic acid metabolism to both transcriptome and metabolome results. The joint analysis of transcriptome and metabolome data revealed that <i>SLC22A8</i> was negatively correlated with Biliverdin and 1-methylnicotinamide, and <i>MCPT1</i> was inversely correlated with 7-Ketodeoxycholic Acid. These findings offer insights into the molecular mechanisms and metabolites that influence spleen immunity and systemic immune homeostasis.