Gut microbiota and neurodevelopmental plasticity: implications for typical and atypical development

Gut microbiota signals are increasingly recognized as critical regulators of brain function, plasticity, and behavior. Alterations of intestinal microbial composition, particularly during early development, may have long-lasting effects on the host immune and metabolic functions. However, its impact on postnatal neurodevelopment remains unclear. Here, we investigated how antibiotic (ABX)-induced microbial manipulation affects postnatal neuroplasticity and whether microbiota-targeted interventions can restore brain function in a context of atypical development. In juvenile mice, early-life ABX treatment altered gut microbial composition and impaired ocular dominance plasticity (ODP) in the visual cortex. Transcriptomic and miRNome analyses revealed extensive changes in genes linked to extracellular matrix remodeling and myelination, both crucial for experience-dependent plasticity. Remarkably, fecal transplantation (FT) from young donors restored ODP in adult mice, demonstrating the microbiota causal role in regulating neuroplasticity.Beyond physiological neurodevelopment, we also explored the role of gut microbiota in Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD), a severe neurodevelopmental condition often associated with gastrointestinal dysfunctions. Microbiota profiling in two CDKL5 knockout (KO) mouse models revealed significant alterations in the gut microbiota composition, particularly during juvenile stages. ABX-driven microbiota manipulation in CDD mice led to improved visual cortical responses, reduced hyperactivity, and normalized microglial morphology. Furthermore, FT from CDD mice to WT recipients successfully transferred both visual deficits and behavioral abnormalities, confirming the microbiota role in modulating neurological symptoms.Together, these findings highlight the gut microbiota as a key regulator of neurodevelopment and plasticity, with implications for therapeutic interventions in neurodevelopmental disorders and aging-related cognitive decline.