Lipidomics reveals dysregulated lipid profiles in lipopolysaccharide administration-induced cognitive impairments

Sepsis-associated encephalopathy is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology of septic encephalopathy underlying cerebral metabolism, cognition, learning, and memory capabilities is poorly understood. In this study, LC/MS-MS-based metabolomics was used to investigate the cognitive deficit mechanism underlying bacterial lipopolysaccharide (LPS)-induced sepsis-associated encephalopathy. Mice were randomly divided into the vehicle (control), LPS, and LPS + minocycline (LPS+Mino) groups. Minocycline was administered 30 min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed starting from day 6 with open field, fear conditioning tests, and T-maze, respectively. LPS-induced sepsis caused a profound alteration of the lipid profile in multiple brain regions. Analyses of lipid profiles revealed that the lipidome was differentially affected among the different brain areas in the LPS-induced septic brain. Following the injection of LPS, more lipid categories were impacted in the cerebral cortex. And glycerophospholipids contributed to a large proportion of those significantly modified lipids in the nucleus accumbens (NAc) and hippocampus. Furthermore, the length and unsaturation of fatty acids were also differentially affected in the LPS-induced septic brain. After being treated with minocycline, the dysregulated lipidomic profiles can be partially reversed, demonstrating the critical roles of dysregulated lipidome in sepsis-associated encephalopathy. Collectively, our results show that sepsis-associated encephalopathy differentially reprograms the lipidomic metabolism among the brain areas, which may underlie its cognitive deficits.