The balance of microbial populations making up the gut microbiome changes with age in ways that are detrimental to health. Microbes generating necessary metabolites diminish in number, while microbes that provoke chronic inflammation grow in number. Further, researchers have established that is a tendency towards a distinctly different gut microbiome composition in some age-related conditions, such as Alzheimer's disease. Whether this difference over and above the more usual age-related changes acts to contribute directly to Alzheimer's disease, or is a side-effect of a dysregulated immune system or other aspect of aged metabolism, remains to be concretely determined. Here, researchers focus on microglia, the innate immune cells of the brain. Dysfunctional, inflammatory microglia are thought to be involved in neurodegenerative conditions, and one can argue for a connection to the gut microbiome.
Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. For decades, research into AD has been dominated by the amyloid cascade hypothesis. However, amyloid-beta (Aβ) clearance alone slows progression by only 35%. This compels increasing attention to peripheral factors in AD pathophysiology, redirecting the field from a brain-centric, amyloid-focused model toward a systemic perspective that emphasizes peripheral-central interactions.
It is now increasingly recognized that chronic, low-grade systemic inflammation, a condition often termed "inflammaging," acts as a critical driver of neuroinflammation and accelerates neurodegenerative processes. Within this framework, the gastrointestinal tract, which harbors the body's largest immune cell population and the vast metabolic capacity of the gut microbiome, emerges as a pivotal hub for originating peripheral signals that shape brain health and disease. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.
Link: https://doi.org/10.3389/fragi.2025.1704047
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