Tuberous Sclerosis Complex, Epilepsy, and the Microbiota-Gut-Brain Axis: A Pilot Study of Shared and Divergent Microbial Signatures

Tuberous sclerosis complex (TSC) is a rare genetic disorder often associated with epilepsy and neurodevelopmental comorbidities. Despite known pathogenic variants in TSC1 and TSC2, the broad clinical variability suggests additional modulatory factors. Recent evidence implicates the microbiota-gut-brain axis (MGBA) in the pathogenesis of epilepsy, particularly in drug-resistant forms.This pilot study explored the gut microbiota composition in individuals with TSC to investigate its potential role in epilepsy severity. We enrolled 15 TSC patients, 12 healthy controls (HC), and 18 individuals with non-TSC epilepsy (EPI). Dietary intake was assessed via 3-day food diaries. Fecal samples were analyzed using 16S rRNA sequencing, and microbial metabolites (short- and branched-chain fatty acids) were quantified.No significant differences were found in alpha-diversity across groups. Beta-diversity analysis showed a trend toward clustering between TSC and HC. Taxonomic profiling revealed a significant reduction in Firmicutes in both TSC and EPI groups compared to HC, leading to a decreased Firmicutes/Bacteroidota ratio. The reduction was mainly driven by decreased abundance of beneficial genera such as Gemmiger, Blautia_A, and Faecalibacterium, known for anti-inflammatory properties and butyrate production.Despite these compositional changes, SCFA and BCFA levels were similar across groups, suggesting potential functional compensation. However, the depletion of butyrate-producing bacteria could indicate a disrupted MGBA, potentially contributing to epileptogenesis and clinical variability in TSC.These findings support a link between gut dysbiosis and epilepsy in TSC, warranting larger studies to confirm the role of the gut microbiota as a biomarker and therapeutic target in this population.