The aging gut–glia–immune axis in alzheimer’s disease: microbiome-derived mediators of neuroinflammation and therapeutic innovation

Jan 12, 2026GeroScience

How Changes in Gut Support Cells and Immunity with Age May Influence Brain Inflammation and Treatment in Alzheimer's Disease

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Abstract

Alzheimer's disease is linked to gut microbiome changes that may worsen neurodegeneration.

Aging is the strongest risk factor for Alzheimer's disease, associated with chronic inflammation and oxidative stress.
The gut-glia-immune axis connects microbiome alterations to glial dysfunction, impacting neuronal health.
Microbial metabolites regulate brain immune responses and glial activity, influencing Alzheimer's progression.
Age-related changes in the microbiome can disrupt glial balance, increase neuroinflammation, and hinder amyloid clearance.
Therapeutic strategies targeting the microbiome, like probiotics and fecal microbiota transplantation, may help alleviate cognitive decline.

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Alzheimer's disease (AD), the most common cause of dementia in the aging population, is marked by amyloid-beta (Aβ) plaques, tau tangles, and progressive neuronal degeneration, placing heavy clinical and socioeconomic burdens on healthcare worldwide. Aging remains the strongest risk factor, with chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and impaired proteostasis creating a vulnerable brain environment that accelerates AD onset and progression. Recent evidence highlights the gut-glia-immune axis as a critical pathway linking age-related microbiome changes to glial dysfunction. Microbial metabolites, such as short-chain fatty acids and tryptophan derivatives, regulate microglial maturation, astrocytic activity, and neuroimmune signaling. However, age-associated dysbiosis disrupts glial homeostasis, amplifies neuroinflammation, and impairs amyloid clearance, thereby worsening neurodegeneration. Preclinical models including germ-free mice and fecal microbiota transplantation along with clinical studies of elderly AD patients, provide compelling evidence of microbiome-driven modulation of disease. From a therapeutic perspective, microbiome-targeted interventions including probiotics, prebiotics, synbiotics, and microbiota-directed small molecules offer promising strategies to restore glial balance, reduce inflammation, and protect cognitive function. This review highlights the therapeutic potential of probiotics, synbiotics, and fecal microbiota transplantation for mitigating neuroinflammation and cognitive decline in Alzheimer's disease. However, given the multifactorial nature of neurodegenerative disorders, these strategies are unlikely to be universally effective and must be tailored to individual patient profiles.

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The aging gut–glia–immune axis in alzheimer’s disease: microbiome-derived mediators of neuroinflammation and therapeutic innovation

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