Analysis of treatment-naïve gut microbiota in children with new-onset epilepsy

Abstract Background Epilepsy has diverse known etiologies. We hypothesized that gut dysbiosis contributes to epilepsy as a susceptibility factor and aimed to analyze the gut microbiota in treatment-naïve children with new-onset epilepsy. Methods Stool samples were collected from 32 children with untreated epilepsy and 40 healthy controls. A subgroup of eight patients provided a second sample ~2–3 years after starting antiepileptic drug therapy. Samples were analyzed using 16S ribosomal ribonucleic acid gene sequencing to compare microbiota diversity and composition. Results Compared with controls, the untreated epilepsy group had lower alpha diversity (Chao1 index, p  = 0.043) and distinct beta diversity clustering ( p  = 0.001). The epilepsy group showed enrichment of Blautia and depletion of Phocaeicola plebeius and Eisenbergiella . After treatment, patients’ microbiota formed a new cluster that differed significantly from both controls and their pretreatment state ( p  = 0.001). Bacterial genes, such as pld and tyrR , were predicted to be reduced in the epilepsy group. Following treatment, the gut microbiota exhibited distinct functional alterations, including increased protein synthesis and reduced expression of stress-response genes, rather than normalization. Conclusion Treatment-naïve new-onset epilepsy involves distinct gut dysbiosis. Antiepileptic drugs induce specific functional reconfiguration. Targeting these adaptations may offer new insights for seizure control. Impact We demonstrate that treatment-naïve children with new-onset epilepsy have distinct gut microbiota dysbiosis, characterized by reduced microbial diversity and altered taxonomic composition. Antiepileptic drugs significantly modify both microbial structure and predicted functional pathways. This is one of the studies with a sufficient sample size, based on an a priori power analysis, to explore gut microbiota in treatment-naïve patients with pediatric epilepsy while controlling for key confounders. It provides baseline evidence for microbiota-epilepsy relationships independent of medication effects. The findings suggest therapeutic potential for microbiota-targeted interventions and highlight the importance of considering both dysbiosis and drug-induced changes in epilepsy management strategies.