Elucidating the Pathophysiology and Diagnostic Biomarkers of Sepsis-Associated Encephalopathy: A Multiomics Approach

Sepsis-associated encephalopathy (SAE) is a diffuse neurological injury that results from severe sepsis, and its underlying pathophysiological mechanisms remain largely unknown. This study aimed to elucidate the pathological basis of SAE and identify potential diagnostic biomarkers by integrating analyses of the intestinal microbiome, plasma metabolomics, and circulating microRNAs (miRNAs). We analyzed data from 50 patients who were divided into SAE or non-SAE groups. The results revealed significant differences in microbial composition between these groups, with a marked decrease in Bacteroides abundance and an increase in Enterococcus abundance in SAE patients. Compared with non-SAE patients, SAE patients presented notable alterations in LysoPC 18:3, linoleic acid, and miRNA PC-3p-535_63045 levels. Multiomics association analysis revealed positive correlations between Enterococcus and LysoPC 18:3, whereas Bacteroides and PC-3p-535_63045 were negatively correlated with linoleic acid. Gene prediction analysis indicated that PC-3p-535_63045 was enriched in PIK3R1, and a KEGG pathway analysis underscored the role of the PI3K‒Akt signaling pathway. PC-3p-535_63045 exhibited strong diagnostic performance, with an AUC of 0.850 (specificity of 0.867, sensitivity of 0.800). Comparative ROC analysis revealed no significant difference between PC-3p-535_63045 alone and the multiomics model. The integrated results from multiomics LASSO regression and random forest analyses suggest that PC-3p-535_63045 is a promising biomarker for the diagnosis of SAE. In conclusion, our multiomics analysis revealed a significant association among Bacteroides, PC-3p-535_63045, and linoleic acid, which suggests that the PI3K-Akt signaling pathway may play an important role in SAE progression. These findings deepen our understanding of the pathophysiological mechanisms underlying SAE and may ultimately enhance diagnostic and predictive capabilities for this condition.