The Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurodegenerative Disorders: Convergent Mechanisms and Translational Prospects

Abstract

Background: The gut microbiome exerts a profound influence on central nervous system (CNS) function through interconnected neural, immune, endocrine, and metabolic pathways. This “microbiota gut brain axis” has emerged as a compelling frontier in neuropsychiatric and neurodegenerative research. In this review, we integrate evidence across four high-burden conditions major depressive disorder, anxiety disorders, autism spectrum disorder (ASD), and Parkinson’s disease (PD) to delineate convergent and disorder-specific microbiome mechanisms, evaluate interventional modalities, and chart a translational roadmap. Scope and Methods: We synthesize human cohorts, controlled trials, and mechanistic preclinical studies published during the past decade, with emphasis on multi-omics (metagenomics, metabolomics, metatranscriptomics) and host-microbe interaction modeling. Key mechanistic axes reviewed include short-chain fatty acids (SCFAs), bile acids, tryptophan–kynurenine–indole metabolism, intestinal barrier integrity, neuroimmune activation, and α-synuclein biology. Intervention strategies—diet, probiotics/synbiotics, postbiotics, and fecal microbiota transplantation (FMT) are evaluated in light of efficacy, safety, biomarker engagement, and durability. Key Findings: Across depression and anxiety, dysbiosis is consistently characterized by depletion of SCFA-producing taxa and altered neurotransmitter-precursor pathways, correlating with inflammatory and metabolic dysregulation. In ASD, microbial profiles, barrier dysfunction, and metabolite signatures correlate with core behavioral domains and GI symptom clusters. Notably, an early randomized controlled trial of oral FMT in pediatric ASD reported sustained improvements in both gastrointestinal and autism-related measures. In PD, prodromal gastrointestinal dysfunction, microbial shifts, and α-synuclein aggregation implicate a “gut-first” trajectory in subsets of patients, with microbial metabolites and endotoxins plausibly driving neurodegenerative cascades. Conclusions and Outlook: The microbiome emerges as a promising, modifiable nexus connecting gut and brain in psychiatric, developmental, and neurodegenerative contexts. Yet, critical challenges remain: disentangling causality from reverse causation, improving strain-level mechanistic specificity, achieving robust engraftment, and ensuring long-term safety. We propose a next-generation trial framework combining stratification by microbial function, a priori mechanistic endpoints, adaptive designs, and integrated metabolomic/neuroimmune readouts. If these challenges are met, microbiome-informed strategies could augment or even transform conventional approaches across mental and neurological disease domains.