Ketogenic diet linked to gut microbes and seizure reduction in epileptic children

New study finds specific gut bacteria and metabolites, like plasmalogens, may play a key role in the ketogenic diet’s anti-seizure effects for drug-resistant epilepsy.

Study: Association between seizure reduction during ketogenic diet treatment of epilepsy and changes in circulatory metabolites and gut microbiota composition. Image Credit: New Africa/Shutterstock.com

In a recent study published in the eBioMedicine, a group of researchers investigated the associations between gut microbiota, serum metabolome, and seizure reduction in children with drug-resistant epilepsy (neurological disorder) following three months on a ketogenic diet (KD) (a high fat, sufficient protein, and low carbohydrate diet).

Background 

Epilepsy is impacting over 50 million individuals globally, with nearly one-third of patients remaining drug-resistant despite numerous antiseizure medications (ASMs). Pharmaco-resistant epilepsy is characterized by the inability to achieve seizure freedom after adequate trials of two suitable ASMs.

The KD dietary therapy is a recognized treatment for children with pharmaco-resistant epilepsy, resulting in over 50% of participants experiencing a significant reduction in seizures.

While KD induces various systemic metabolic changes, including elevated ketone levels, the precise mechanisms behind its anti-seizure effects remain unclear, necessitating further research.

About the study 

The research was carried out at the Neuropediatric Department of Astrid Lindgren Children’s Hospital, Karolinska Hospital, involving children diagnosed with epilepsy who were treated at the Epilepsy Outpatient Clinic.

Due to their resistance to anti-seizure medications, a KD was initiated for eligible participants aged 2 to 17 years with pharmaco-resistant epilepsy. Exclusion criteria included recent antibiotic or probiotic use. A total of 14 patients met the inclusion criteria. The efficacy of the KD was evaluated by tracking changes in seizure frequency, which were recorded daily by parents or caregivers on seizure calendars. 

Baseline seizure frequency was compared to that recorded three months after commencing the diet, and participants were categorised as responders or non-responders based on a 50% seizure reduction threshold.

Each child’s KD was customized by a specialized dietitian, with a stepwise increase in the fat-to-carbohydrate and protein ratio, typically reaching the optimal ratio within 3 to 6 weeks.

Blood samples were collected pre- and post-KD for glucose and beta-hydroxybutyrate analysis, alongside serum and fecal samples for metabolomic and microbiome studies. Ethical approval was secured, and informed consent was obtained from guardians and, when possible, the children. 

Study results 

The study cohort comprised 14 children diagnosed with epilepsy, including nine girls and five boys, with a median age of 8.0 years at the initiation of the KD. Epilepsy onset occurred at a median age of 0.6 years, with 10 of the 14 participants experiencing symptoms before their first birthday.

Seizure types and aetiologies were classified according to the International League Against Epilepsy (ILAE) guidelines, revealing that most children exhibited multiple seizure types, with a median of 2.0 kinds per patient.

The predominant seizure types were generalized tonic-clonic seizures and focal seizures with impaired awareness. Prior to the KD, participants had trialed a median of six ASMs. At the onset of the diet, the number of concomitant ASMs varied from one to four, with a median of two.

The most frequently used ASMs included valproic acid and clobazam. While the goal was to maintain stable ASM dosages for the initial three months of the KD, some adjustments were necessary due to adverse effects, including reductions in doses of topiramate and valproate for a few children.

At the three-month mark on the KD, the mean ratio of fats to carbohydrates and proteins was 3.5 (±SD 0.4), ranging between 3:1 and 4:1. Half of the participants (seven children) were classified as responders, demonstrating a seizure reduction of 50% or more.

The median level of beta-hydroxybutyrate (β-OHB) among responders was 5.2 mmol/L, compared to 4.9 mmol/L in non-responders, which was not statistically significant. 

The analysis of metabolomic profiles highlighted significant changes related to dietary treatment. Variance was largely attributed to the dietary intervention, with notable differences between responders and non-responders.

A total of 995 metabolites were detected, with 345 showing significant changes attributed to the KD. Among these, ketone bodies such as 3-hydroxybutyrate and acetoacetate increased significantly, while glucose levels decreased as expected. Additionally, metabolic pathway analyses revealed eight significantly altered pathways, primarily involving fatty acids. 

Conclusions

To summarize, this investigation reveals significant alterations in metabolites, including lipid pathways and vitamins, linked to gut microbiota and seizure response. Notably, four plasmalogens correlated positively with seizure reduction, while propionate and thymol sulfate were identified as beneficial metabolites.

Conversely, certain diacylglycerols and gamma-glutamyl amino acids showed negative correlations with seizure frequency.

Four gut microbial species, especially from the genus Alistipes, positively correlated with beneficial metabolites, while specific strains of Escherichia coli and infant-type Bifidobacteria negatively impacted seizure reduction, highlighting the importance of gut microbiota balance during KD in epilepsy treatment.