Transcriptomics and metabolomics reveal the protective effect of β-hydroxybutyrate on sepsis associated...

In this study, metabolomics and transcriptomics were applied to reveal the potential mechanisms underlying the protective effects of β-hydroxybutyrate (BHB) on sepsis-associated encephalopathy (SAE).

A mouse SAE model was established. The Barnes maze was used to evaluate cecal ligation and puncture (CLP)-induced cognitive impairment. Neuronal survival, microglial activation, and proinflammatory cytokine levels were assessed using Nissl staining, immunofluorescence staining, and RT-qPCR. Serum metabolites and cerebral genes from control, SAE, and SAE mice treated with BHB were compared. Metabolomics and transcriptomics analysis were performed. Finally, based on the integrated transcriptomic and metabolomic analyses, we identified the target signaling pathway.

Our results demonstrated that β-hydroxybutyrate (BHB) markedly reversed CLP-induced cognitive impairment. BHB administration attenuated neuronal loss and histopathological damage in the hippocampus, accompanied by reduced production of pro-inflammatory cytokines and decreased activation of Iba-1-positive microglia in SAE mice. Metabolomic profiling revealed that SAE induced significant alterations in serum metabolic signatures, with galactose, glycerophosphocholine, taurine, and hypotaurine levels markedly decreased. BHB treatment partially restored these metabolite levels toward normal. Transcriptomic analysis identified significant enrichment of the NF-κB signaling pathway in response to BHB treatment in SAE mice. Correlation analysis further showed that NF-κB-associated inflammatory genes (including VCAM1, TNF, NFKBIA, NFKB1, IL6, IL1B, ICAM1, CXCL family members, CD40, and CCL4/5) were strongly and negatively correlated with galactose, hypotaurine, and taurine levels, whereas glycerophosphocholine exhibited weak or non-significant associations. Consistent with the multi-omics findings, protein-level validation by Western blot confirmed that BHB suppressed SAE-induced activation of the NF-κB pathway in hippocampal tissue.

Overall, this study reveals that BHB exerts neuroprotective effects in SAE through integrated metabolic and transcriptional reprogramming, in which attenuation of NF-κB-mediated inflammatory signaling represents a key mechanistic link between altered serum metabolites and downstream gene expression changes.