Editors' ChoiceEpilepsy

Ketogenic bugs as epilepsy drugs

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Science Translational Medicine  20 Jun 2018:
Vol. 10, Issue 446, eaau0471
DOI: 10.1126/scitranslmed.aau0471

Abstract

The gut microbiome mediates the beneficial effects of a ketogenic diet on epileptic seizures through modulation of GABA/glutamate ratios in the hippocampus.

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that originally found prominence as a treatment for pediatric epilepsy and is now also being used as part of therapy for cancer, Alzheimer’s disease, metabolic syndrome, and autism spectrum disorders. However, the underlying mechanisms of the KD on neurological function are still not entirely clear.

Olson et al. used a mouse model of refractory epilepsy to investigate the antiepileptic mechanisms of the KD. The authors first showed that the KD rapidly (within 4 days) altered the gut microbiota, specifically by increasing Akkermansia muciniphila and Parabecteroides. The KD increased seizure threshold to electrical stimulation; however, when KD-fed mice were treated with antibiotics to reduce intestinal bacteria, the seizure threshold returned to control levels. Similarly, in germ-free mice without a gut microbiota, KD did not modulate seizure threshold. Antibiotic-treated mice could have seizure protection restored by feeding with A. muciniphila and Parabecteroides, but not with either bacteria alone or with other bacteria. Administering A. muciniphila and Parabecteroides to mice fed with a normal diet provided a degree of protection against seizures, suggesting that the gut microbiota changes were responsible for the therapeutic effects produced by the KD, rather than the restriction of carbohydrates or the production of ketones. The authors then replicated these findings in a genetic mouse model of temporal lobe epilepsy, demonstrating a significant effect of the gut microbiota on seizure susceptibility in epilepsy of multiple etiologies. Metabolomic analysis showed that both KD and A. muciniphila–and Parabacteroides-fed mice had an increased ratio of γ-aminobutyric acid (an inhibitory neurotransmitter) to glutamate (an excitatory neurotransmitter associated with seizure activity when in excess), specifically in the hippocampus, a brain region strongly associated with the propagation of seizures.

Though there’s much still to be learned about how the gut microbiota interacts with diet to affect our health, the authors’ work reveals a potentially important role for the gut microbiota in the antiepileptic effects of the KD—suggesting that perhaps finding better drugs might include fostering better bugs. Future studies can now explore whether microbe-based treatments can be safely and effectively applied as therapies to prevent or reduce seizure burden in epilepsy.

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