The Microbiota Shapes Central Nervous System Myelination in Early Life

ABSTRACT Maturation of the gut microbiota coincides with neurodevelopmental processes such as myelination, essential for efficient neural signal transmission. While a role for the microbiome in regulating adult prefrontal cortex (PFC) myelination is known, its effects on early‐life myelin formation, growth, and integrity remain unclear. Using a cross‐species approach in germ‐free (GF) mice and zebrafish, we examined how the microbiota influences early myelination and neural development. Multi‐system, multi‐level analyses showed that the microbiota impacts glial maturation and myelination across species. In GF mice, we observed sex‐ and age‐dependent alterations in pathways linked to neuronal activity and myelination, with myelin‐related transcriptomic changes correlating with functional shifts in neurotransmission‐ and metabolism‐related metabolites over time. Myelin growth and integrity were also affected in a sex‐ and time‐dependent manner. As microglia regulate neuronal activity and engulf myelin, we examined microbiota–microglia interactions and found altered expression of genes involved in microglia maturation and synaptic pruning in both species. In zebrafish larvae, the microbiota influenced the spatial distribution of microglia and oligodendrocytes within the brain and spinal cord. These findings reveal conserved microbiota‐mediated modulation of neuronal activity, myelination, and glial maturation in early life, providing a foundation for future studies into these mechanisms.