Gut–Brain Axis, Microbiome, and Neurodegenerative Diseases: Mechanistic Insights, Therapeutic Targets, and Translational Opportunities

Abstract

The gut–brain axis epitomizes a multifaceted bidirectional neuro-gastrointestinal communication paradigm, wherein the gastrointestinal tract and central nervous system engage through intricately orchestrated neural, endocrine, immunological, and metabolic conduits. A growing corpus of empirical evidence substantiates that perturbations in gut microbial architecture, commonly designated as dysbiosis, exhibit profound associations with both the initiation and trajectory of neurodegenerative pathologies, notably Alzheimer’s disease , Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. Metabolically active derivatives of the intestinal microbiota, encompassing short-chain fatty acids, bile acid conjugates, tryptophan catabolites, and a spectrum of neuroactive transmitters, are indispensable in the preservation of neural homeostasis, the modulation of neuroinflammatory cascades, and the regulation of protein misfolding dynamics that underpin these disorders. The advent of integrative meta-omics methodologies, spanning metagenomics, metatranscriptomics, metaproteomics, and metabolomics, has substantially deepened our mechanistic comprehension of host–microbiota reciprocity, concurrently unveiling prospective biomarkers of diagnostic relevance and putative molecular targets for therapeutic intervention. Innovative microbiome-modulatory strategies designed to reconstitute eubiotic equilibrium, including probiotics, prebiotics, fecal microbiota transplantation, precision dietary paradigms, and engineered microbial consortia, are currently under rigorous preclinical and early clinical scrutiny, yielding promising preliminary outcomes. This review endeavors to consolidate contemporary knowledge on the mechanistic substrata of the gut–brain axis in neurodegeneration, to synthesize disease-specific insights, and to critically appraise emerging therapeutic modalities, with a particular emphasis on translational feasibility and precision medicine applications.