Gut microbiota dysregulation in dementia: Molecular mechanism linking the gut-brain axis to neurodegeneration

Dementia is a progressive neurodegenerative syndrome characterised by cognitive decline, synaptic dysfunction, and neuronal loss. In recent years, growing attention has been given to the role of the gut-brain axis in neurodegenerative disease. Emerging evidence indicates that changes in gut microbiota composition and metabolic activity may affect various systemic processes that contribute to dementia. This review examines the current evidence linking gut microbiota imbalance to dementia through mechanisms involving immune regulation, metabolic signalling, and neuronal stability. Clinical studies have identified distinct microbial changes in patients with cognitive impairment, including decreased microbial diversity and altered abundance of specific bacterial groups. These changes may affect host physiology via several interconnected pathways. Disruption of the intestinal barrier due to dysbiosis can facilitate the translocation of microbial products into the bloodstream, triggering immune activation. Microbial metabolites, such as short-chain fatty acids, bile acids, and tryptophan-derived compounds, can influence metabolic signalling and cellular functions within the nervous system. These pathways have been implicated in processes relevant to dementia, including neuroinflammation, mitochondrial dysfunction, synaptic impairment, and neurovascular alterations. Although most research focuses on Alzheimer's disease, emerging evidence suggests that microbiota-related mechanisms may also be relevant to other dementia types, such as vascular dementia, frontotemporal dementia and dementia with Lewy bodies. Despite these advances, the underlying mechanisms remain underexplored, and further research is needed to investigate molecular pathways and host-microbiome interactions. This knowledge could support the development of novel biomarkers and inform the future development of microbiota-targeted strategies for dementia, although their clinical efficacy and applicability remain to be established.