Abstract
BACKGROUND: The ketogenic diet (KD) is a high fat, sufficient protein, and low carbohydrate dietary therapy for drug-resistant epilepsy. The underlying mechanisms of action of the KD remain unclear. In mice, the microbiota is necessary for the anti-seizure effect and specific microbes influence circulatory levels of metabolites that are linked to seizure reduction. However, it remains unclear which changes are linked to seizure reduction in patients with epilepsy. METHODS: We analysed the serum metabolome of children with drug-resistant epilepsy (n = 14) before and after three months on KD. Metabolomic changes were correlated to the gut microbiome and treatment outcome, i.e., seizure reduction. FINDINGS: In this prospective observational study, we uncovered associations between microbial species and serum metabolites that correlated with seizure reduction. Plasmalogens were most strongly linked to seizure reduction and had significant positive correlations with several gut microbes (e.g., Faecalibacterium prausnitzii, Alistipes communis, Alistipes shahii, and Christensenella minuta) while significant negative correlations were found for five strains of Escherichia coli. Infant-type Bifidobacteria correlated negatively with other metabolites associated with seizure reduction. INTERPRETATION: The microbes and metabolites identified here may contribute to the therapeutic effect of the KD in children with drug-resistant epilepsy. Several of these metabolites (e.g., plasmalogens) play important roles in neurobiology and may influence seizures. Based on our findings, anti-seizure therapeutic strategies could be developed involving the targeted manipulation of the gut microbiota and/or its metabolites. FUNDING: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Sunnerdahls Handikappfond, Stockholm County Council Research Funds, and Linnea & Josef Carlssons Foundation.