Gut Microbiota Signatures in Tuberous Sclerosis Complex and Epilepsy: A Pilot Study

Emerenziana Ottaviano¹Matteo Domenico Marsiglia¹Camilla Ceccarani²Silvia Ancona¹Francesca Triva¹Francesca Labriola³Stefania Bergamoni⁴Federica Teutonico⁴Alice Pompili¹Ilaria Viganò³Emilia Ricci³Aglaia Vignoli^1*Elisa Borghi¹

• ¹University of Milan, Milan, Italy
• ²Istituto di Ricerca Genetica e Biomedica Consiglio Nazionale delle Ricerche Sede di Milano, Milan, Italy
• ³Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, Milan, Italy
• ⁴Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy

ABSTRACT Objective-Tuberous 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. Methods-In 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. Results-No 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. Significance-These 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.