M. Li, H. Deng, L. Ma and M. Sun (2026). The anti-epileptic mechanism of a ketogenic diet regulating the gut microbiota via SIRT2 activation of the PI3K/AKT signaling pathway. Neuroscience letters, 872, 138488. https://doi.org/10.1016/j.neulet.2025.138488

PubMed 41380905

[Abstract]
PURPOSE: Epilepsy (EP) is a disorder caused by sudden abnormal discharges of neurons in the brain. A ketogenic diet (KD) has significant anticonvulsant effects in some epileptic patients, but the signaling pathway remains unclear. This study aims to investigate the mechanisms underlying the anticonvulsant effects of a KD.

METHODS: Acute epilepsy models were induced by kainic acid (KA) and pentylenetetrazol (PTZ), synaptic electrical activity in the hippocampus was measured. The effects of KD on the expression levels of postsynaptic proteins and SIRT2 was determined, as well as the phosphorylation of the PI3K and Akt-S-473 signaling pathways. Metabolomic analysis was used to investigate the effect of KD on the gut microbiota.

RESULTS: The KD inhibited acute seizures and promoted the amplitude of induced inhibitory postsynaptic current (IPSC) transmission and the frequency of spontaneous IPSC transmission in cortical brain regions. KD upregulated the expression of PI3K, activated the phosphorylation of AKT-S-473, and increased SIRT2 expression. Metabolomic analysis indicated shifts in host metabolism, particularly involving Clostridiales(e.g., Blautia and Lachnospiraceae). Based on existing literature, we hypothesize tha KD may support gut barrier function and anti-inflammatory responses.

CONCLUSION: The anti-epileptic effect of KD in the prefrontal cortex is associated with the activation of the PI3K/Akt signaling pathway and an increase in SIRT2 expression. Additionally, our data are consistent with the emerging concept that the anti-seizure effects of KD may also involve modulation of the gut microbiota. This provides valuable insights for the development of new therapeutic interventions.