Gut-brain axis: Ketogenic diet may protect children with epilepsy, study suggests

20 Dec 2023 --- Researchers suggest that ketogenic diets may protect against epileptic seizures through changes in the gut microbiome of children on the diet and microbiome-induced changes in brain gene expression. Transplanting fecal samples of pediatric epilepsy patients on a keto diet into mice helped the mice become more seizure-resistant. 

While the low-carbohydrate, high-fat and protein ketogenic diet is commonly used to address epilepsy in children who don’t respond to anti-seizure medications, the authors note that its use remains low due to difficulties in implementation, compliance with its strict requirements and side effects such as nausea, constipation and fatigue. 

Understanding how a keto diet changes the microbiome could help develop new therapeutic approaches to incorporate these benefits. 

“Narrowing down the functions of the microbes that are beneficial toward seizure protection can potentially lead to new ways to enhance the efficacy of the ketogenic diet or to mimic its beneficial effects,” says the study’s lead author, Gregory Lum, a postdoctoral researcher at the University of California (UCLA), US. 

Microbiome-induced changes 
In collaboration with UCLA’s Ketogenic Diet Therapy Program, the researchers collected fecal samples from ten pediatric epilepsy patients who did not respond to anti-seizure medication and followed a ketogenic diet. They took samples before the children started the diet and after being on it for a month. 

Mice that received transplants taken after being on the diet for a month were more resistant to seizures than those that received pre-ketogenic diet fecal transplants. 

A keto diet is high in fat and protein, while low in carbohydrates.Moreover, the study published in Cell Reports found that the ketogenic diet altered essential microbiome functions related to anaplerosis — a metabolic pathway — fatty acid oxidation and amino acid metabolism in pediatric patients. These changes were preserved when the fecal matter was transplanted into mice. 

The authors explain that microbiota-dependent increases in seizure protection were associated with changes in the transcriptome — a complete set of all the brain’s ribonucleic acid (RNA) molecules. They note that these changes may contribute to seizure protection. 

In recipient mice’s hippocampus and frontal cortex, transcripts were enriched, related to RNA processing, regulation and translation, signaling and cell cycle, cellular stress response and oxidative phosphorylation — reducing oxygen and generating high-energy phosphate. 

Epilepsy seizures 
Around one-third of people with refractory epilepsy do not respond to existing anti-seizure medications. 

All ten pediatric patients suffered from different types and causes of refractory epilepsy and consumed varying ratios of fat to carbohydrate and protein, with different nutritional compositions of the consumed diet. 

The authors emphasize that this highlights the “diversity of epilepsies that resist current anti-seizure medications and the broad range of ketogenic diet interventions that are administered to treat pediatric refractory epilepsy.”

The researchers aimed to understand the underlying molecular mechanisms behind the ketogenic diet’s alterations in the gut microbiome, hoping to find new ways to treat seizures more effectively. They built on previous work by the same lab, which determined that mice — bred to mimic epilepsy — fed a ketogenic diet experienced significantly fewer seizures than mice on a standard diet. 

Previous research also found that epileptic mice fed a ketogenic diet experienced significantly fewer seizures.Although the authors assert that more research is needed, they note that the study holds promise as a step toward finding new microbiome-based therapies for pediatric epilepsy patients. 

Specifically, they note that further research should “define the mechanisms by which the human ketogenic diet-associated microbiome signals across the gut-brain axis to modify seizure risk and to assess further the potential for identifying microbiome-based interventions that could increase the efficacy of ketogenic diet treatment, alleviate dietary side effects and ease clinical implementation.” 

Ketogenic diets 
Earlier this year, China-based researchers suggested that following a ketogenic diet helped treat substance use disorders. At the same time, the strict nature of the diet may lead to an increased risk of malnutrition in this vulnerable population. The study also found changes in the gut microbiome after following the diet, as well as neuroprotection and reducing inflammation. 

Using a rodent model, scientists found that the brains of rats following a high-fat diet for a short time adapted to react to the type of food ingested. They balanced the calorie intake by reducing the amount of food consumed. However, the study argued that continuously eating a high-fat diet would disturb an identified pathway between the brain and the gut. 

Meanwhile, researchers labeled the ketogenic diet as the least nutritious after comparing the nutritional density and environmental footprint of popular diets followed by US adults. Moreover, keto and paleo diets were responsible for the highest carbon emissions. To improve nutrition quality and carbon emissions, the researchers suggested reducing fatty meat intake and exchanging omnivorous diets for the Mediterranean diet. 

By Jolanda van Hal