Ketogenic diet and epilepsy: protective role of intestinal microbiota

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The ketogenic diet is effective against forms of epilepsy that are resistant to conventional treatment. It is said to act via certain bacteria of the intestinal microbiota, which themselves regulate the balance between excitation and inhibition in specific brain areas.

 

The ketogenic diet is low in carbohydrates but high in fats, and produces beneficial results in some diseases, including epilepsy that is refractory to the usual treatments. A team from the University of California (USA) has discovered a mechanism in which the intestinal microbiota is considered central to the effectiveness of this type of diet in the prevention of seizures. 

Two protective bacterial groups

The researchers first studied the effects of a 2-week ketogenic diet (fat:protein ratio of 6:1) in a mouse model of epilepsy refractory to the treatments usually administered. Compared to control mice, the electrical threshold at which seizures were triggered in mice given a fat overdose was raised by 50%, suggesting that the ketogenic diet has a protective effect against epilepsy. Generally less rich in bacteria from the fourth day of diet, their intestinal microbiota however showed a clear increase in Akkermansia muciniphila and Parabacteroides–groups presumed to be protective–at the end of the 2 weeks of the diet.

Successful gavage and transplant

On the other hand, the beneficial effect of the ketogenic diet on seizures was nonexistent in mice raised in a sterile environment or treated with antibiotics, thus suggesting that the gastrointestinal microbiota was involved in triggering seizures. The protective effect was able to be restored by oral gavage of mice with a combination of A. muciniphila and two species of Parabacteroides for two weeks. Furthermore, the protective effect proved transferable as transplants of the intestinal microbiota of mice on a ketogenic diet conferred a protective effect on mice treated with antibiotics then fed normally. These results, which were reproduced in another murine model closer to human epilepsy, suggest that the ketogenic diet may provide protection against epilepsy  via  the A. muciniphila and Parabacteroides bacteria present in the intestinal microbiota.

An inhibitory balance in the brain

The authors showed that these two bacterial groups regulate the ratio of two neurotransmitters in mouse hippocampus: GABA* (inhibitory) and glutamate (excitatory). This modulation takes place in the colon via a decrease in gamma-glutamylation activity** of the essential amino acids used by the brain to synthesize GABA and glutamate. A. muciniphila may promote the growth of Parabacteroides by metabolizing components derived from the ketogenic diet, which in return would lead to the growth of A. muciniphila (hence the overabundance of these bacteria during the diet). This bacterial collaboration reduces gamma-glutamylation. The ratio of GABA to glutamate is then increased, resulting in a predominant inhibitory effect–and therefore a raised epileptogenic threshold. The impact of the intestinal microbiota on neurotransmission has to be further explored before any clinical application can be developed. These results may nevertheless already provide a physiological explanation for the increased risk of seizures during the prolonged intake of some antibiotics such as metronidazole.

 

* GABA = gamma-aminobutyric acid, the main inhibitory neurotransmitter of the central nervous system

**Addition of a glutathione group in the gamma position

 

Sources:

CA Olson et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell. 2018 Jun 14;173(7):1728-1741.e13