Microenvironment dysregulation in autism spectrum disorder: Immune, epigenetic, synaptic, and gut-brain mechanisms

Autism spectrum disorder is a common and heterogeneous neurodevelopmental condition. Although its etiologies are diverse, converging evidence suggests that genetic susceptibility and environmental exposures intersect across a limited set of biological pathways. We interpret recent advances through a microenvironment dysregulation perspective that connects immune imbalance, epigenetic regulation, synaptic plasticity, and gut-brain interactions. We distinguish mechanistic evidence from experimental models from predominantly correlative findings in human studies and emphasize that these processes may involve multiple entry points across biological subgroups. We propose that early-life immune challenges can, in some individuals, interact with genetic risk to shape epigenetic programs and neural-immune signaling, with downstream consequences for microglial states and synaptic development, potentially reinforced by gut-brain feedback loops. This integrative view highlights testable hypotheses, convergent mechanistic hubs, and a conceptual basis for subgroup-aware biomarker discovery and mechanism-informed interventions.