The microbiota-brain connection in neurological diseases: the ubiquitous short-chain fatty acids

The connection between the gut and brain forms a sophisticated two-way communication system where compounds produced by intestinal bacteria, especially short-chain fatty acids, play essential roles in brain-related disease processes. Evidence across multiple neurological disorders reveals convergent pathophysiological pathways involving SCFAs, which modulate neurological function via histone deacetylase inhibition, G-protein coupled receptor activation, and blood-brain barrier regulation. Clinical investigations demonstrate disorder-specific signatures: reduced butyrate-producing bacteria correlate with Parkinson's disease progression; Alzheimer's disease exhibits significant reductions in key SCFAs; and diminished butyrate production disrupts immunoregulatory homeostasis in multiple sclerosis. Additionally, neurodevelopmental disorders like autism show distinctive microbiome alterations affecting both gut and brain function. Beyond SCFAs, microbiota influence neural communication through immune modulation, neurotransmitter production, and vagus nerve signaling. Interventional studies targeting the microbiome through precision probiotics, prebiotics, and fecal microbiota transplantation demonstrate preliminary efficacy, particularly in Parkinson's disease and autism. Methodological heterogeneity and challenges establishing causality remain significant limitations. Future priorities include longitudinal characterization of microbiome dynamics preceding symptom onset, development of personalized therapeutics, and implementation of predictive computational models. Progress in these domains could transform microbiome-based approaches from experimental interventions to precision medicine applications in neurological disease management.