Microbiota-driven neuroimmune mechanisms in brain disorders: Microglial activation, cytokine signaling, and translational implications.

PMID 41886797 | DOI 10.1016/j.jneuroim.2026.578913 · Journal of neuroimmunology · 2026

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Neuroinflammation is increasingly recognized as a central driver of diverse neurological and neuropsychiatric disorders. Within this framework, the microbiota-gut-brain axis (MGBA) has emerged as a critical modulator of neuroimmune signaling rather than a broad systemic regulator. Microbial-derived metabolites and immune mediators influence central nervous system (CNS) homeostasis by shaping microglial maturation and activation, regulating cytokine signaling networks, including IL-1β, IL-6, and TNF-α and modulating inflammasome pathways, such as NLRP3. These immune mechanisms intersect with blood-brain barrier (BBB) integrity, where dysbiosis-associated inflammation and altered short-chain fatty acid (SCFA) production may compromise tight junction stability and promote peripheral immune infiltration. Through immune-glial crosstalk, microbial signals can amplify or attenuate neuroinflammatory cascades, thereby influencing vulnerability to autoimmune, neurodegenerative, and neurodevelopmental disorders. This review synthesizes current mechanistic evidence linking gut microbial perturbations to CNS immune regulation, emphasizing microglial activation, cytokine-mediated signaling, and BBB immunomodulation as core pathways. By reframing the MGBA through a neuroimmune lens, we highlight emerging therapeutic strategies targeting microbiota-driven inflammatory circuits to advance precision interventions for inflammatory brain disorders.