Gut Microbial Metabolism as a Dynamic Interface in Neurodegenerative Diseases

Gut microbial metabolites serve as functional mediators of gut–brain communication, linking microbial alterations to neurodegenerative pathology. How metabolite profiles shift during disease progression and interact with host genetic susceptibility remains poorly characterized. This review centers on Alzheimer’s disease (AD) as the primary model, with Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) included for cross-disease comparison. Across the AD continuum, microbial metabolic remodeling features reduced protective metabolites and elevated inflammation-related metabolites. Short-chain fatty acids (SCFAs), particularly butyrate, and indole-derived metabolites are altered from early cognitive impairment to clinical dementia. Trimethylamine N-oxide (TMAO), kynurenine intermediates and abnormal bile acid profiles accumulate and drive neuroinflammatory and metabolic disturbances. Mechanistically, metabolic shifts affect AD pathology through three interrelated pathways. Tryptophan-derived metabolites regulate immune homeostasis via aryl hydrocarbon receptor (AhR) signaling. SCFAs modulate epigenetic processes linked to Aβ and tau lesions. Intestinal and blood-brain barrier damage allows peripheral metabolic and inflammatory signals to reach the central nervous system. APOE4 alters lipid metabolism and systemic inflammation to modify individual metabolic susceptibility. Shared metabolic abnormalities including SCFA loss and barrier damage exist in PD and ALS, alongside disease-specific metabolic changes. Existing data support associations among host factors, the microbiome, and metabolite profiles, but longitudinal target-engagement studies remain limited.