An immune-cell signature of bacterial sepsis (Patient PBMCs)

Abstract

Inflammatory bowel disease (IBD) and Sepsis are both characterised by immune dysregulation. Notably, IBD is a factor in the increase in septic infections. However, these two conditions' shared molecular and pathophysiological mechanisms remain unclear. We used 'limma' and 'WGCNA' analyses to identify common DEGs between these two conditions. Single-cell RNA sequencing further assessed immune cell heterogeneity. We used machine learning algorithms to construct and identify diagnostic markers for Sepsis, which we then validated using receiver operating characteristic curve (ROC) analysis. A mouse model of IBD combined with Sepsis was constructed, and real-time PCR and western blot validated the expression of BCL2A1 and CEBPB. It was found that 58 shared DEGs identified in both IBD and Sepsis were highly enriched in immune and inflammation-related pathways. Single-cell analysis revealed that CD14⁺ monocytes (or IL1B⁺ macrophages) primarily express these hub genes. Both conditions significantly increased the proportion of this cell type compared to healthy controls. Finally, BCL2A1 and CEBPB were identified as potential biomarkers that have strong diagnostic potential. Furthermore, we confirmed that levels of BCL2A1 and CEBPB were elevated in mice with IBD complicated by Sepsis through real-time PCR and observed that IBD exacerbates the progression of Sepsis. We conclude that IL1B⁺ macrophages expressing high levels of these hub genes play a key role in the immune dysregulation associated with both IBD and Sepsis. The overlapping gene expression and pathway alterations in these cells indicate shared common molecular mechanisms, suggesting new strategies for targeted therapeutic interventions.