AUTHOR=Ottaviano Emerenziana , Marsiglia Matteo Domenico , Ceccarani Camilla , Ancona Silvia , Triva Francesca , La Briola Francesca , Bergamoni Stefania , Teutonico Federica , Pompili Alice , Viganò Ilaria , Ricci Emilia , Vignoli Aglaia , Borghi Elisa 

TITLE=Tuberous sclerosis complex, epilepsy, and the microbiota-gut-brain axis: a pilot study of shared and divergent microbial signatures

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 19 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1655456

DOI=10.3389/fnins.2025.1655456

ISSN=1662-453X

ABSTRACT=ObjectiveTuberous sclerosis complex (TSC) presents with a broad clinical spectrum. While some individuals exhibit mild symptoms, most experience seizures and neuropsychiatric comorbidities. Emerging evidence suggests that both genetic and environmental factors, including gut microbiota, may influence epilepsy susceptibility. The microbiota–gut–brain axis (MGBA) is a key communication pathway through which intestinal microbes impact the central nervous system. Although the role of the MGBA in the pathogenesis of neurological diseases, particularly seizures, has been explored in both animal models and humans, data specific to TSC are lacking.MethodsIn this exploratory study, we assessed whether individuals with TSC (n = 15) display a distinct gut microbial signature using V3–V4 16S rRNA sequencing. Their profiles were compared with two control groups: 18 children with epilepsy (EPI) and 12 age- and sex-matched healthy controls (HC). Stool short-chain fatty acid (SCFA) levels and dietary intake were also evaluated.ResultsNo significant differences were observed among the three groups in dietary intake, SCFA and branched-chain fatty acid (BCFA) levels, or alpha-diversity. Beta-diversity analysis showed a non-significant trend toward clustering of TSC and EPI samples, indicating a shared microbial profile distinct from HC. Taxonomic analysis revealed a reduction in Firmicutes—particularly the Ruminococcaceae family and the genus Gemmiger—in both TSC and EPI groups, consistent with epilepsy-associated dysbiosis. Notably, the TSC group showed a specific enrichment in Akkermansiaceae, a feature also reported in other neurodevelopmental disorders such as CDKL5 deficiency disorder and cerebral palsy.SignificanceThese preliminary findings suggest that gut microbiota alterations may contribute to neuroinflammatory processes linked to epileptogenesis and comorbidities in TSC. Further studies are needed to validate these results and explore microbiota-based therapeutic strategies aimed at improving outcomes and quality of life for individuals with TSC and their caregivers.