Beta-hydroxybutyrate reverses cognitive impairment and neuroinflammation in mouse sepsis-associated encephalopathy by modulating `NF-κB` signaling.

Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, contributing to increased mortality and long-term cognitive deficits. It is characterized by profound neuroinflammation, neuronal damage, and often blood-brain barrier (BBB) disruption, yet effective treatments remain elusive. Understanding the underlying mechanisms and identifying neuroprotective agents is critical. β-hydroxybutyrate (BHB), a ketone body, has emerged as a molecule with potential neuroprotective and anti-inflammatory properties, making it a candidate for mitigating SAE pathology.

Researchers established a mouse model of SAE using cecal ligation and puncture (CLP). Cognitive impairment was assessed via the Barnes maze. Neuronal survival was evaluated using Nissl staining, while microglial activation and pro-inflammatory cytokine levels were measured by immunofluorescence staining and RT-qPCR, respectively. Serum metabolites and cerebral gene expression were compared across control, SAE, and SAE mice treated with BHB. Metabolomics and transcriptomics analyses were performed to identify altered pathways, followed by Western blot for protein-level validation.

β-hydroxybutyrate (BHB) administration markedly reversed CLP-induced cognitive impairment in SAE mice. It significantly attenuated neuronal loss and histopathological damage within the hippocampus. This neuroprotection was accompanied by a notable reduction in pro-inflammatory cytokine production 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. Consistent with these multi-omics findings, protein-level validation by Western blot confirmed that BHB suppressed SAE-induced activation of NF-κB.

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.