Gut Microbiota, Neuroinflammation, and Autonomic Dysfunction in Neurodegenerative Diseases: A Systematic Review of Mechanistic and Translational Evidence

Abstract

Neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, multiple system atrophy, and amyotrophic lateral sclerosis, are increasingly recognized as complex conditions arising from interactions among the gut microbiota, immune system, and autonomic nervous system. Growing evidence indicates that disruption of the intestinal microbial ecosystem may contribute to neuroinflammatory processes, autonomic impairment, and progressive neurodegeneration through the microbiota-gut-brain axis, although the underlying mechanisms and their translational implications remain incompletely understood. This systematic review was conducted in accordance with the PRISMA 2020 guidelines to comprehensively evaluate the evidence linking gut microbiota dysbiosis with neuroinflammation and autonomic dysfunction across neurodegenerative diseases. A systematic search of PubMed/MEDLINE, Scopus, Web of Science, EMBASE, EBSCOhost, CINAHL, PsycINFO, CENTRAL, Google Scholar, and major grey literature sources yielded 2,769 records. After duplicate removal and eligibility screening, 62 full-text reports underwent detailed assessment, of which 11 studies met the predefined eligibility criteria and were included in the qualitative synthesis. The evidence encompassed human observational, animal experimental, and in vitro approaches, with several studies integrating complementary clinical, microbiome, and experimental methodologies. Most included studies focused on Parkinson’s disease and multiple system atrophy. Across studies, microbial dysbiosis was characterized by reduced abundance of short-chain fatty acid (SCFA)-producing bacteria alongside increased representation of pro-inflammatory microbial taxa. These microbial alterations were associated with disruption of intestinal barrier integrity, activation of inflammatory signaling pathways, microglial activation, elevated pro-inflammatory cytokine production, α-synuclein aggregation, and autonomic manifestations such as gastrointestinal dysmotility and cardiovascular autonomic dysfunction. Experimental studies provided biological support for the microbiota-gut-brain axis, whereas clinical investigations consistently demonstrated associations without establishing causality. Overall, current evidence suggests that gut microbial dysbiosis is closely associated with neuroinflammation and autonomic dysfunction in neurodegenerative diseases and may represent a promising avenue for biomarker discovery and therapeutic intervention. Nevertheless, the available literature is constrained by methodological heterogeneity, limited sample sizes, and the predominance of observational and preclinical studies. Future large-scale longitudinal investigations and rigorously designed randomized controlled trials are required to determine causal relationships and define the clinical utility of microbiome-targeted strategies.