How the gut microbiota can modulate the predisposition to epileptic seizures

The gut–brain axis

Over the past ten years, neuroscience has shown that the gut microbiota communicates with the brain in both directions, through what we now call the gut–brain axis. It is a complex network, still only partly understood, involving the vagus nerve and the enteric nervous system, hormones, molecules of the immune system such as cytokines and chemokines, and various neurotransmitters.

When the composition of the microbiota is altered — a condition known as dysbiosis — this imbalance can be associated with several diseases of the central nervous system, including multiple sclerosis, Parkinson's disease and Alzheimer's disease.

The scientific question

Some studies had already observed significant differences in the gut microbiota of people with epilepsy compared with that of healthy volunteers. One fundamental question remained open, however: is the altered microbiota merely a consequence of the disease, or can it actively contribute to lowering the seizure threshold?

In other words, can a microbiota associated with epilepsy, on its own, make a healthy brain more susceptible to seizures?

The experiment

To answer this question, the research group used faecal microbiota transplantation (FMT). The microbiota of donor mice made epileptic was transferred to young, healthy recipient mice whose microbiota was still developing.

After the transplant, all recipients received a subclinical dose of pilocarpine, a substance used in experimental models to induce epileptic seizures. The amount used in the study, however, was too low on its own to provoke a seizure.

This allowed the researchers to test whether the transferred microbiota was able to lower the threshold of brain excitability, making the recipients more vulnerable to the effect of pilocarpine.

The results

Even before pilocarpine was administered, the mice that had received the microbiota from epileptic animals showed more abnormal EEG activity than the controls.

After the subclinical dose of pilocarpine, the difference became even clearer: 10 out of 21 mice in the R-EPI group developed status epilepticus, compared with just one out of 13 in the control group.

The «double-hit» hypothesis

These findings fit the so-called double-hit hypothesis: an event that on its own is not enough to cause epilepsy can trigger a cascade of epileptogenic processes when, over time, it combines with a second stimulus.

On the basis of these results, the microbiota alterations associated with epilepsy represent the first «hit» in the recipient mice, while the subclinical dose of pilocarpine constitutes the second. The transplant alone did not cause seizures in the following three weeks, but it made the animals far more susceptible to developing status epilepticus after the second stimulus.

Pilocarpine also acts on inflammatory pathways, in a way not entirely unlike what can happen in conditions such as fever or influenza, which are sometimes associated with the onset of seizures in already predisposed individuals.

For the first time, a microbiota from epileptic donors has been shown to lower the seizure threshold in healthy recipients.

What it means

The study provides the first evidence that microbiota transferred from epileptic donors can lower the seizure threshold in healthy recipients. This result supports the hypothesis that the gut microbiota, through the gut–brain axis, can directly influence brain excitability.

This opens up the possibility of developing integrated therapeutic approaches based on probiotics, prebiotics, microbiota transplantation and nutritional strategies targeting the gut–brain axis. The anticonvulsant effect of the ketogenic diet, already known in some forms of drug-resistant epilepsy, is today also attributed in part to the gut microbiota.

The next challenge will be to understand which microbiota alterations are truly decisive and through which molecular mechanisms they act along the microbiota–gut–brain axis.