The Gut–Liver–Brain Axis in Neurodegeneration: Unraveling Metabolic–Immune Crosstalk from Peripheral Sensing to Central Vulnerability

Neurodegenerative diseases (NDs) have traditionally been regarded as brain-centered disorders driven primarily by the accumulation of pathological proteins. However, increasing evidence indicates that systemic metabolic dysfunction, chronic inflammation, intestinal dysbiosis, hepatic abnormalities, and barrier impairment may substantially influence disease susceptibility and progression. This review integrates current evidence on the gut–liver–brain axis (GLBA) and proposes Systemic Metabolic–Immune Reprogramming (SMIR) as a systems-level framework for understanding how peripheral disturbances may be translated into central nervous system vulnerability. Within this model, the gut generates microbial and metabolic signals, the liver functions as a metabolic–immune integrator that senses, transforms, buffers, or amplifies these signals, and the brain represents a downstream vulnerable organ in which persistent systemic disturbances reshape neuroimmune states and neuronal homeostasis. Particular emphasis is placed on the sequential and bidirectional interactions among intestinal barrier dysfunction, hepatic metabolic–immune activation, systemic inflammatory remodeling, blood–brain barrier vulnerability, and central neuroimmune dysregulation. Key molecular mediators include short-chain fatty acids, bile acids, tryptophan–kynurenine metabolites, trimethylamine N-oxide, ceramides, hepatokines, complement components, extracellular vesicles, and inflammatory cytokines, together with signaling pathways involving TLRs, FXR/TGR5, NLRP3, mitochondrial stress, and cGAS–STING. We further discuss how microglial and astrocytic metabolic reprogramming, mitochondrial dysfunction, ferroptosis, and impaired proteostasis may connect systemic metabolic stress with neuronal injury. Disease-specific manifestations of this framework are examined in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple system atrophy, highlighting both shared systemic mechanisms and distinct patterns of organ susceptibility. Emerging approaches, including longitudinal multi-omics, spatial transcriptomics, metabolomics, extracellular-vesicle profiling, organoid models, and artificial intelligence-assisted integration, may enable reconstruction of inter-organ communication networks and identification of disease-specific SMIR signatures. Therapeutically, this framework supports a shift from isolated downstream targets toward coordinated modulation of microbiome composition, hepatic metabolism, immune activity, barrier integrity, nutrition, and CNS pathology. Although causal relationships remain to be established, the GLBA–SMIR perspective provides a testable conceptual foundation for earlier diagnosis, patient stratification, precision nutrition, and multi-system intervention in neurodegenerative diseases.