Here find a review of what is known of the ways in which age-related changes in the gut microbiome can contribute to the chronic inflammation of aging and development of neurodegenerative conditions. The ability to accurately map the composition of the gut microbiome by sequencing microbial DNA, in particular species-specific variations in the 16S rRNA gene, has produced a vast and growing body of data. Researchers have linked specific microbial populations to specific age-related conditions, and shown that the balance of populations shifts with age to favor those that provoke the immune system at the expense of those producing beneficial metabolites. This is the first step on the road to creating interventions capable of the lasting restoration of a more youthful gut microbiome, a goal that we know is possible because it can be achieved via fecal microbiota transplantation from a young donor to an old recipient, and approach that improves health and slows aging in animal studies.
Neurodegenerative diseases (NDs) represent a major global health challenge in aging populations, with their incidence continuing to rise worldwide. Although substantial progress has been made in elucidating the clinical features and molecular underpinnings of these disorders, the precise mechanisms driving neurodegeneration remain incompletely understood. This review examines the increasing significance of the gut-brain-immune triad in the pathogenesis of NDs, with particular attention to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It explores how disruptions in gut microbiota composition and function influence neuroinflammation, blood-brain barrier integrity, and immune modulation through microbial-derived metabolites, including short-chain fatty acids, lipopolysaccharides, and bacterial amyloids.
In both Alzheimer's and Parkinson's diseases, a reduced abundance of short-chain fatty acid-producing bacterial taxa has been consistently associated with heightened pro-inflammatory signaling, thereby facilitating disease progression. Although detailed mechanistic understanding remains limited, experimental evidence - primarily from rodent models - indicates that microbial metabolites derived from a dysbiotic gut may initiate or aggravate central nervous system dysfunctions, such as neuroinflammation, synaptic dysregulation, neuronal degeneration, and disruptions in neurotransmitter signaling via vagal, humoral, and immune-mediated pathways.
The review further highlights how gut microbiota alterations in amyotrophic lateral sclerosis and multiple sclerosis contribute to dysregulated T cell polarization, glial cell activation, and central nervous system inflammation, implicating microbial factors in disease pathophysiology. A major limitation in the field remains the difficulty of establishing causality, as clinical manifestations often arise after extended preclinical phases - lasting years or decades - during which aging, dietary patterns, pharmacological exposures, environmental factors, and comorbidities collectively modulate the gut microbiome. Finally, the review discusses how microbial influences on host epigenetic regulation may offer innovative avenues for modulating neuroimmune dynamics, underscoring the therapeutic potential of targeted microbiome-based interventions in neurodegenerative diseases.
Link: http://dx.doi.org/10.14218/JTG.2025.00027
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