From intestinal barrier sensing to glial immune programming: a barrier-immune-glia relay in microbiota-associated neurodegeneration.

The gut microbiota contributes to host homeostasis through metabolic, immunological, neural, and barrier-related pathways, and its role in the onset and progression of neurodegenerative diseases has received increasing attention. Patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis often exhibit alterations in gut microbial composition, microbial metabolic function, and peripheral inflammatory phenotypes. However, existing clinical evidence is derived predominantly from cross-sectional studies, and the direction of causality between microbiota alterations and disease pathology remains to be established. This review uses a "barrier-immune-glial relay" framework to systematically summarize the potential mechanisms through which gut microbiota-associated signals influence immune homeostasis in the central nervous system. First, alterations in microbial composition, short-chain fatty acids, bile acids, tryptophan derivatives, and lipopolysaccharide may act on the intestinal epithelial barrier, enteric nervous system, and intestinal mucosal immune cells, thereby affecting local immune tolerance and inflammatory responses. Second, intestinal macrophages, dendritic cells, innate lymphoid cells, T cells, and B cells may translate local microbial signals into circulating metabolites, inflammatory mediators, and immune cell-associated signals, which may in turn influence blood-brain barrier function and the central immune microenvironment. Furthermore, microglia and astrocytes, as key integrators within the central nervous system, can respond to gut-derived metabolites and peripheral immune signals. Their interaction network may determine whether neuroinflammation, synaptic injury, and neurodegenerative pathology are amplified or constrained. This review also evaluates the levels of evidence supporting these mechanisms in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Although these disorders may share mechanistic nodes, including barrier impairment, immunometabolic dysregulation, and glial responses, their core pathologies, immune contexts, and temporal disease trajectories differ substantially. Finally, we propose that establishing a verifiable causal chain linking "microbial functional genes-metabolites-barrier and immune remodeling-glial cell states-neuropathology-clinical phenotypes" will provide a basis for biomarker development and precision interventions in neurodegenerative diseases.