Interweaving microglial senescence and gut microbiome dynamics in Alzheimer's disease – Mechanisms and therapeutic frontiers

Feb 26, 2026Molecular and cellular neurosciences

Links between aging brain immune cells and gut bacteria in Alzheimer's disease: causes and treatment possibilities

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Abstract

Alzheimer's disease may be influenced by microglial senescence and gut microbiota dysbiosis.

Microglia that have aged may lose their ability to clear harmful substances, leading to increased neuronal damage.
Gut dysbiosis, marked by fewer beneficial bacteria and more harmful species, can heighten systemic inflammation and weaken protective barriers in the body.
Microbial substances can affect microglial behavior through connections between the gut and brain, potentially worsening Alzheimer's disease.
Targeting the aging of microglia and gut health may offer new therapeutic strategies for Alzheimer's disease.
Precision medicine approaches could improve treatment by using microbiome profiling and genetic analysis.

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Alzheimer's disease (AD), a prevalent neurodegenerative disorder characterized by cognitive impairment and neuronal degeneration, is increasingly recognized as being driven not only by the traditional amyloid-beta and tau pathologies but also by persistent neuroinflammation and systemic immune dysregulation. Emerging evidence implicates microglia senescence and gut microbiota dysbiosis is critical contributors to the neuroinflammatory landscape. Senescent microglia marked by reduced phagocytic ability and a pro-inflammatory secretory profile, are unable to clear pathogenic stimuli, thereby intensifying neuronal damage. Simultaneously, gut dysbiosis, characterized by a reduction in beneficial bacteria and an increase in endotoxin-producing species, elevates systemic inflammation and compromises the intestinal and blood brain barrier. Microbial metabolites, such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS), affect microglial activation through the gut-brain axis, primarily via the TLR4/NF-κB and NLRP3 inflammasome pathways, thus promoting microglial senescence and exacerbating AD pathology. Therapeutic approaches that target these interacting pathways are rejuvenation of microglia with senolytics and stimulation of TREM2; regulation of gut microbiota with probiotics, prebiotics, lifestyle modification, dietary intervention; and fecal microbiota transplantation. Precision medicine approaches incorporating microbiome profiling and immunogenetic analysis will enhance these treatments. This review combines mechanistic insight into microglial aging and gut-brain interaction, emphasizes their synergistic role in AD pathogenesis, and delineates integrated therapeutic strategies. Dissection of the gut-microglia axis can reveal novel targets for early intervention to counteract neuroinflammation, improve cognitive function, and slow disease progression in AD.

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Interweaving microglial senescence and gut microbiome dynamics in Alzheimer's disease – Mechanisms and therapeutic frontiers

Abstract

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