Gut microbiota dynamics and its impact on the efficacy of ACTH therapy in infantile epileptic spasms syndrome

Background: Infantile epileptic spasms syndrome (IESS) is a severe early-life epileptic encephalopathy with diverse etiologies, yet its precise pathogenesis remains unclear. The gut-brain axis has emerged as a key modulator of neurodevelopment and seizure susceptibility, and although gut microbiota dysbiosis has been implicated in various epilepsy syndromes, its role in IESS, particularly in relation to treatment response, remains unexplored. This preliminary study therefore investigated gut microbiota composition in pediatric IESS and its potential as a biomarker of response to adrenocorticotropic hormone (ACTH) therapy. Methods: Eighteen patients with IESS were enrolled. Two age-matched control groups were established: a focal epilepsy (FE) group and a healthy (H) group. The 18 patients with IESS were subsequently categorized into two groups based on therapeutic response: ACTH-effective and ACTH-ineffective. Fecal samples were collected before and after ACTH treatment and subjected to 16S ribosomal DNA sequencing, followed by bioinformatics analyses. Results: Gut microbiota α-diversity was significantly lower in the IESS group than in the FE group, and β-diversity significantly differed among the IESS, FE, and H groups. Proteobacteria and Actinobacteria exhibited significantly higher relative abundances in the IESS group, while Ruminococcaceae was significantly lower than in the FE and H groups. The IESS group had significantly higher Veillonellaceae abundance but significantly lower Lachnospiraceae and Faecalibacterium abundances compared with the H group. Intestinal microbiota network structure was weaker in IESS than in the FE and H groups. Before ACTH treatment, the ACTH-ineffective subgroup exhibited significantly lower actinomycetes and bifidobacteria abundances, downregulated amino acid metabolism pathways, and weaker network aggregation than the effective subgroup. After treatment, the IESS group displayed enhanced network aggregation, significantly decreased Bacillus abundance, and downregulated retinol metabolism. Additionally, Corynebacteriales and Enterobacteriaceae were enriched before treatment, while Intestinibacter was enriched after treatment. Conclusion: Gut microbiota profiles in children with IESS suggested a potential association with response to ACTH therapy. These preliminary findings, while requiring validation in larger independent cohorts, highlight a potential role for the gut microbiota in the pathophysiology of IESS and underscore the need for further multi-omic investigations to elucidate underlying mechanisms.