Nose-to-brain axis: mechanistic links between nasal microbiome dysbiosis, neuroinflammation, and brain disorders.

The nasal microbiome has emerged as a previously underrecognized modulator of neuroinflammation and central nervous system (CNS) homeostasis. Beyond its role in respiratory host defense, this microbial niche is anatomically positioned to directly influence brain physiology through olfactory neuronal pathways, systemic immune signaling, and inter-organ communication within the gut-lung-brain axis. Accumulating evidence indicates that nasal microbiome dysbiosis contributes to blood-brain barrier (BBB) dysfunction, microglial activation, and propagation of neurotoxic protein aggregates, processes implicated in neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and major depressive disorder. This review synthesizes experimental and clinical studies elucidating key mechanisms by which nasal microbial imbalance may impact CNS pathology, including microbial translocation along olfactory neurons, release of pathogen-associated molecular patterns and inflammatory mediators, extracellular vesicle-mediated signaling, and peripheral immune crosstalk. We further highlight clinical observations linking nasal microbiome signatures with olfactory dysfunction, cognitive decline, and altered inflammatory profiles, particularly in systemic conditions such as sepsis. Despite rapid advances in this field, significant knowledge gaps persist, including the limited availability of longitudinal human cohorts capable of establishing causality, incomplete mechanistic validation in translational models, and insufficient characterization of how environmental exposures and aging reshape the nasal microbiome-brain interface. By integrating current evidence and defining these unmet needs, this review positions the nasal microbiome as a promising source of diagnostic biomarkers and a therapeutic target for modulating neuroinflammation and mitigating neurodegenerative progression.