The ketogenic diet is known to successfully treat epilepsy for many people. In a recent study, researchers determine how the ketogenic diet alters the gut microbiota and if this mediates the anti-seizure effects.
The ketogenic diet is a low-carbohydrate, high-fat diet that puts the body into a metabolic state called ketosis. During ketosis, the body is starved of carbohydrates and is forced to generate ketone bodies from the breakdown of fat for energy. The ketogenic diet is popular for weight loss, and although the diet’s benefits in healthy people are controversial, the ketogenic diet has long been used to successfully treat epilepsy. However, it is unknown how adopting the ketogenic diet actually affects brain activity to prevent seizures.
The gut microbiota is involved in metabolic and neurological pathways
The gut microbiota is an essential component for human health, and diet is an important factor for determining the composition of the gut microbiota. The gut microbiota is involved in metabolic and neurological pathways, so it is possible that the ketogenic diet alters the gut microbiota in a way that alters these pathways to treat epilepsy.
In a study published in Cell, the authors were interested in determining how the ketogenic diet alters the gut microbiota, and if this change in the gut microbiota mediates the anti-seizure effects. The authors used a mouse model of refractory epilepsy, a type of epilepsy where medicine is not able to control seizures, to investigate the mechanism that the ketogenic diet prevents seizures.
Ketogenic diet increased the abundance of bacterial species in the gut
First, the authors showed that, in only four days, the ketogenic diet altered the gut microbiota by increasing abundance of the bacterial species Akkermansia muciniphila and Parabecteroides. Then, the authors demonstrated that the ketogenic diet increased the seizure threshold of the mice after electrical stimulation, but when the mice were treated with antibiotics that diminish gut microbiota, the seizure threshold to electrical stimulation returned to control levels. Further, in mice lacking gut microbiota all together, the ketogenic diet had no effect on seizure threshold.
Specific bacterial species provided some protection against seizures
The researchers went on to see if they could identify which bacterial species were important for seizure protection. In antibiotic-treated mice, the addition of Akkermansia muciniphila and Parabecteroides bacterial species together could restore the increased seizure threshold seen in mice fed the ketogenic diet.
Further, in mice fed a normal diet, the addition of Akkermansia muciniphila and Parabecteroides bacterial species provided some protection against seizures, demonstrating that these bacterial species are important in mediating the therapeutic effect of the ketogenic diet, rather than carbohydrate restriction and ketone production.
Researchers also tested a mouse model of temporal lobe epilepsy and saw the same results, demonstrating that gut microbiota can improve seizures of different types of epilepsy.
Gut microbiota affect levels of neurotransmitters in the brain to prevent seizures
Researchers looked at the brains of epileptic mice that were fed the Akkermansia muciniphila and Parabecteroides bacterial species. They found that there was an increase in inhibitory neurotransmitters and a reduction of excitatory neurotransmitters associated with seizure activity. These changes in neurotransmitter levels occurred in the hippocampus, a brain region that is known to initiate seizures. This suggests that maintaining a “normal” excitatory or inhibitory neurotransmitter ratio could be critical for preventing seizures and a therapeutic avenue that should be pursued.
Scientists are continuing to learn about the critical role gut microbiota plays on human health. Here, researchers determined that the ketogenic diet alters the gut microbiota to produce antiepileptic effects. Further research is required to determine whether some cases of epilepsy are due to altered gut microbiota, and if microbe-based therapeutics can be effectively and safely used.
Written by Mallory Wiggans
Reference: Olsen, C.A., Vuong, H.E. Yano, J.M., Liang, Q.Y., Nusbaum, D.J. & Hsiao, E.Y. (2018). The gut microbiota mediates the anti-seizure effects of ketogenic diet. Cell 173, 1728-1741.