From gut to brain: short-term ketogenic diet alleviates status epilepticus-induced cognitive deficits in rats

Cognitive impairment is common in epilepsy. Ketogenic diets (KD) are shown to improve cognitive function in patients with drug-resistant epilepsy over the long term. It is believed that the microbiota-gut-brain axis affects brain function and behavior. However, the effects and mechanisms of short-term KD use on cognition remain unclear. By studying the microbiota-gut-brain axis, we aim to examine the effects of short-term KD use on cognition in an epilepsy rat model.

Rats with epilepsy were fed a KD or a normal diet (ND) for 4 weeks. Following the lithium-pilocarpine-induced status epilepticus (SE), an assessment of cognitive function was performed using the Morris Water Maze (MWM) test. Fecal short-chain fatty acids (SCFAs), serum amino acids, and neurotransmitters were analyzed in accordance with gut microbiota composition.

On the probe trials of the MWM, rats in the KD group showed significantly shorter escape times (P < 0.001) and spent more time in the target quadrant (P < 0.05) compared to rats in the ND group. KD was associated with reduced microbial richness compared to ND, as well as distinct differences in gut microbiota composition across phyla, families, and genera. The KD group had significantly lower levels of fecal SCFAs (P < 0.05 for isobutyric acid and isovaleric acid; P < 0.01 for butyric acid; P < 0.0001 for acetic acid, propionic acid, valeric acid, and caproic acid). Serum amino acids and neurotransmitters also exhibited corresponding alterations. The KD group showed significantly elevated levels of norepinephrine, histamine, and threonine (all P < 0.05), dopamine, 5-hydroxytryptamine, acetylcholine, and serine (all P < 0.01), and glutamate (P < 0.001). Conversely, levels of arginine, phenylalanine, methionine, and asparagine (all P < 0.01), tryptophan, kynurenine, and ornithine (all P < 0.001), and lysine and tyrosine (both P < 0.0001) were significantly reduced.

In epileptic rats, short-term use of the KD may modulate gut microbiota and enhance cognition. Shifts in gut microbiota are associated with changes in neurotransmitters and amino acids. Further investigation is warranted into the microbiota-gut-brain axis as a biomarker for cognitive improvement in epilepsy.