Unveiling the Synapses: Gut Microbiota and Neurodegenerative Disorders Through the Gut–Brain Axis

The microbiota–gut–brain axis (GBA) is a bidirectional communication system integrating neural, endocrine, immune, and metabolic pathways to coordinate gastrointestinal and central nervous system (CNS) function. As the majority of human microbes reside in the gastrointestinal tract, their metabolic activity and immunomodulatory roles are essential for systemic homeostasis, cognitive processes, mood regulation, and neuroprotection. Increasing evidence highlights the vagus nerve as a primary conduit of microbiota–brain signaling, with germ-free mice demonstrating reduced vagal tone that is restored following microbial colonization. Key microbial metabolites—including short-chain fatty acids (SCFAs), bile acids, indoles, and neurotransmitter precursors—activate vagal afferents, regulate neuroimmune responses, and influence microglial maturation and synaptic function. Disruption of microbial community structure, or dysbiosis, is now recognized as a contributing factor in numerous neurological and psychiatric disorders. Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) exhibit distinct microbial alterations, chronic neuroinflammation, and impaired gut and blood–brain barrier integrity. PD patients, for example, consistently show increased Enterobacteriaceae and reduced Prevotellaceae. Dysbiosis also contributes to mood disorders by disrupting microbial production of GABA, serotonin, and tryptophan metabolites. Although microbial biomarkers vary across studies due to disease heterogeneity, integrative multi-omics approaches have begun identifying shared metabolic patterns and therapeutic targets. Microbiota-derived metabolites such as butyrate show neuroprotective and anti-inflammatory effects, while fecal microbiota transplantation (FMT), prebiotics, probiotics, and next-generation probiotics (NGPs) are emerging as promising modulators of the GBA. Advances in metagenomics, metabolomics, and machine-learning–based patient profiling further support the development of personalized, microbiome-driven interventions for neurological disorders.