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While a role for the microbiome in regulating adult prefrontal cortex (PFC) myelination is known, its effects on early\u2010life myelin formation, growth, and integrity remain unclear. Using a cross\u2010species approach in germ\u2010free (GF) mice and zebrafish, we examined how the microbiota influences early myelination and neural development. Multi\u2010system, multi\u2010level analyses showed that the microbiota impacts glial maturation and myelination across species. In GF mice, we observed sex\u2010 and age\u2010dependent alterations in pathways linked to neuronal activity and myelination, with myelin\u2010related transcriptomic changes correlating with functional shifts in neurotransmission\u2010 and metabolism\u2010related metabolites over time. Myelin growth and integrity were also affected in a sex\u2010 and time\u2010dependent manner. As microglia regulate neuronal activity and engulf myelin, we examined microbiota\u2013microglia 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\u2010mediated modulation of neuronal activity, myelination, and glial maturation in early life, providing a foundation for future studies into these mechanisms.<\/jats:p>","DOI":"10.1002\/advs.202515671","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T03:55:53Z","timestamp":1768794953000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Microbiota Shapes Central Nervous System Myelination in Early Life"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6974-6770","authenticated-orcid":false,"given":"Caoimhe M. 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