Background: Sepsis-associated encephalopathy (SAE) is defined by neurological impairment resulting from systemic infections. The gut microbiota has been shown to affect the brain via the gut–brain axis (GBA) in SAE. However, the underlying molecular mechanisms are unclear. This research focused on examining the potential mechanisms by which the gut microbiota and the GBA are involved in SAE by integrating multi-omics data.

Methods: An SAE model was established using 7–8-week-old male rats via lipopolysaccharide (LPS) injection combined with caecal ligation and puncture (CLP). The gut microbiota (via 16S rRNA sequencing) and metabolomes were profiled to analyze variations in gut microbiota composition and metabolite abundance in the faeces and hippocampus. Western blot and RT-qPCR analyses were applied to measure the expression of proteins or genes associated with autophagy in the hippocampus.

Results: SAE rat models presented significant differences in gut microbiota composition, characterized by reduced abundances of the genera Butyricimonas, Muribaculaceae, and Bacteroides and increased abundance of the genera Aeromonas and Family_XIII_UCG-00. Integrated analysis of untargeted metabolomics data for the faeces and metabolomics data for the hippocampus revealed that glycerophospholipid metabolism was altered in both the faeces and hippocampus in SAE rat models. Molecular analyses revealed that the activity of hippocampal autophagy pathways was reduced in SAE rat models, in contrast with rats in the non-SAE group and the control group.

Conclusion: Combining multi-omics data with molecular analysis data revealed a potential association among the gut microbiota, host glycerophospholipid metabolism and reduced neuronal autophagy in SAE model rats. The study contributes to a better understanding of the gut microbiota's involvement in SAE.