From gut education to central infiltration: microbiota-driven immune trafficking along the gut-brain axis

The classical paradigm of central nervous system (CNS) immune privilege has evolved toward recognizing a dynamic, multi-organ neuroimmune axis. In recent years, the gastrointestinal tract has been widely recognized as a major immune reservoir, where rather than functioning as a localized physical barrier, the gastrointestinal mucosa acts as a vital educational center that instructs systemic immune responses. Within the gut-associated lymphoid tissue, dietary inputs, microbial metabolites, and commensal colonization imprint intestinal adaptive and innate immune cells with distinct functional phenotypes and migratory signatures. Through coordinated molecular mechanisms, these gut-educated immune cells egress from the mucosa to reach distant sites, with the CNS representing a critical destination. In experimental models, under homeostatic conditions, gut-derived signals direct the physiological seeding of central border zones and parenchyma, where specialized populations maintain baseline tissue surveillance, reinforce barrier integrity, and calibrate neurodevelopmental behaviors. Conversely, pathobiont expansion, loss of short-chain fatty acid-producing commensals, and mucosal barrier disruption predominantly promote pathogenic gut priming, transforming gut-resident cells into autoreactive or pro-inflammatory effectors that breach central neurovascular borders. Once inside the CNS, these gut immune cells can contribute to neurodegeneration, ischemic injury, and neuroinflammatory pathology. However, this migration is not always destructive; specific gut-educated populations are simultaneously deployed to central boundaries to execute anti-inflammatory and counter-regulatory protection. By tracing this microbiota-driven intestinal priming to central infiltration, we highlight shared homing mechanisms identified mainly in preclinical models (mouse models, germ-free and photoconvertible animals), while outlining translational challenges in establishing their role in human neuroinflammatory pathology.