A recent study published in eBioMedicine has revealed significant associations between gut microbiota, serum metabolites, and the reduction of seizures in children with drug-resistant epilepsy following a ketogenic diet (KD). This high-fat, adequate-protein, and low-carbohydrate diet has been recognized as an effective treatment for children who do not respond to traditional antiseizure medications.
Epilepsy affects over 50 million people worldwide, with approximately one-third of patients unable to achieve seizure control despite multiple medication trials. This condition, known as pharmacoresistant epilepsy, poses significant challenges for management and treatment. The ketogenic diet has emerged as a viable therapeutic option, with studies indicating that over 50% of children on the diet experience notable reductions in seizure frequency.
Despite the known metabolic changes induced by the ketogenic diet, including increased ketone levels, the underlying mechanisms that contribute to its anti-seizure effects are not fully understood, warranting further investigation.
Conducted at the Neuropediatric Department of Astrid Lindgren Children’s Hospital at Karolinska Hospital, the study involved children aged 2 to 17 diagnosed with drug-resistant epilepsy. Fourteen participants were enrolled after meeting specific criteria, including the absence of recent antibiotic or probiotic use. The effectiveness of the diet was assessed by monitoring changes in seizure frequency, which caregivers recorded daily.
The children’s ketogenic diets were tailored by a specialized dietitian, with a gradual increase in the fat-to-carbohydrate and protein ratio, typically achieving optimal levels within three to six weeks. Blood samples were collected before and after the diet to analyze glucose and beta-hydroxybutyrate levels, along with serum and fecal samples for metabolomic and microbiome evaluations. Ethical approval was obtained, and informed consent was secured from guardians, and, when appropriate, from the children themselves.
The study cohort consisted of 14 children, including nine girls and five boys, with a median age of 8 years at the start of the diet. Most participants exhibited multiple seizure types, with generalized tonic-clonic and focal seizures being the most common. Prior to beginning the ketogenic diet, participants had tried a median of six antiseizure medications.
After three months on the ketogenic diet, the mean fat-to-carbohydrate and protein ratio was 3.5, with half of the participants classified as responders, achieving a seizure reduction of 50% or more. Although the median beta-hydroxybutyrate levels were slightly higher in responders (5.2 mmol/L) compared to non-responders (4.9 mmol/L), the difference was not statistically significant.
Metabolomic analysis revealed significant changes in metabolic profiles, with 345 out of 995 detected metabolites showing notable alterations attributed to the ketogenic diet. Key findings included increased levels of ketone bodies, such as 3-hydroxybutyrate and acetoacetate, and a decrease in glucose levels. Additionally, eight metabolic pathways, primarily involving fatty acids, were significantly affected by the dietary intervention.
Conclusions
This study highlights the complex interplay between gut microbiota, metabolites, and seizure response in children undergoing ketogenic diet therapy. Notably, four plasmalogens were positively correlated with seizure reduction, while certain metabolites, such as propionate and thymol sulfate, were identified as beneficial. Conversely, specific diacylglycerols and gamma-glutamyl amino acids were negatively associated with seizure frequency.
The research also identified four gut microbial species linked to positive outcomes, particularly from the genus Alistipes, while certain strains of Escherichia coli and infant-type Bifidobacteria were associated with reduced seizure efficacy. These findings underscore the importance of gut microbiota balance in optimizing the ketogenic diet as a treatment for epilepsy.
This investigation lays the groundwork for further research into the mechanisms behind the ketogenic diet’s effects on epilepsy and the potential role of gut microbiota in enhancing therapeutic outcomes.
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