GUT MICROBIOME DYSBIOSIS AND NEURODEGENERATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF MECHANISTIC AND CLINICAL EVIDENCE FROM THE GUT–BRAIN AXIS

Abstract

Background: Converging lines of evidence now position the gut–brain axis as a biologically plausible and clinically consequential contributor to the pathogenesis of several neurodegenerative diseases, notably Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). Despite this momentum, the quality, internal consistency, and translational strength of the available mechanistic and clinical evidence have not been subjected to rigorous systematic appraisal. Objectives: We set out to (i) systematically review and quantitatively synthesize published evidence linking gut microbiome composition to neurodegeneration; (ii) map and critically evaluate the principal mechanistic pathways involved; (iii) assess the therapeutic efficacy of gut-targeted interventions, with particular attention to fecal microbiota transplantation (FMT); and (iv) grade overall evidence certainty using the GRADE framework. Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science for studies published from January 2015 through December 2025, following PRISMA 2020 reporting standards. Eligible study types included RCTs, prospective cohort studies, Mendelian randomization analyses, mechanistic experimental studies, and existing meta-analyses. Of 4,218 records initially identified, addmet all inclusion criteria. Risk of bias was evaluated using Cochrane RoB 2.0 for trials and the Newcastle-Ottawa Scale for observational designs. Results: All three disease contexts showed reproducible, though partially overlapping, patterns of dysbiosis. In PD, depletion of butyrate-producing Prevotellaceae and Lachnospiraceae was the most consistent finding; in AD, elevated plasma trimethylamine N-oxide (TMAO) and reduced alpha-diversity predominated; in MS, loss of Faecalibacterium prausnitzii coupled with Akkermansia enrichment was replicated across 11 independent cohorts. Four mechanistic pathways emerged as primary conduits: vagal propagation of alpha-synuclein, SCFA-mediated microglial homeostasis, TMAO-driven amyloid-beta aggregation, and LPS-induced neuroinflammation. The pooled FMT meta-analysis (k=4 RCTs; n=167) yielded a standardized mean difference of −4.8 MDS-UPDRS III points (95% CI: −8.2 to −1.4; p=0.008; I²=61%) in favor of active treatment. Mendelian randomization provided causal evidence for six bacterial taxa in MS susceptibility. GRADE certainty ratings ranged from very low for AD mechanistic data to moderate for MS epidemiological findings. Conclusions: This review establishes that gut microbiome dysbiosis is not a peripheral correlate but an active participant in neurodegenerative pathology across three distinct clinical syndromes. FMT reaches statistical significance for PD motor improvement, though effect sizes sit at the lower margin of clinical importance and heterogeneity remains substantial. Standardized multi-center trials, serial pre-symptomatic microbiome sampling, and validated non-invasive gut–brain biomarkers are the priorities that will determine whether this axis yields durable advances in neurological therapeutics.