Multi-omics profiling reveals microbiota–gut–brain axis dysregulation in an LPS-induced model of sepsis-associated encephalopathy

Abstract

Background Sepsis-associated encephalopathy (SAE) is a common complication of sepsis. Its underlying mechanisms remain incompletely understood, and effective treatments are still lacking. Recent studies have shown that the microbiota-gut-brain axis may play a key role in the pathogenesis of SAE, but its potential mechanisms have not yet been clarified. Methods In this study, we used a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model and systematically characterized microbiota–gut–brain axis-associated alterations using multi-omics profiling combined with histopathology, behavioral assessment, and blood–brain barrier integrity assays. Results Our results showed that LPS exposure induced intestinal inflammation and barrier disruption, neurovascular dysfunction, anxiety-like behavior, and impaired cognitive function in zebrafish. Gut microbiota profiling revealed marked compositional alterations, accompanied by widespread metabolic disturbances in intestinal and brain tissues. Brain transcriptomic analysis showed that the differentially expressed genes were closely associated with the PI3K-Akt signaling pathway, cell adhesion, and autophagy-related pathways. Cross-omics association analyses suggested potential associations among gut microbial dysbiosis, metabolic disturbances, and brain molecular responses. Conclusion These findings suggest that disruption of the microbiota–gut–brain axis may contribute to LPS-induced SAE-like neurobehavioral abnormalities and provide a basis for further mechanistic and therapeutic studies.