Connections Between the Gut Microbiome and Microglial Dysfunction in the Aging Brain

Inflammatory behavior of the innate immune cells known as microglia is strongly implicated in age-related neurodegeneration. Some microglia are senescent, others just overactive, but the result is chronic inflammation in brain tissue. This situation can be improved in animal models by clearing microglia, but while the means of doing this are readily available, existing drugs that could be repurposed to treat neurodegenerative conditions, such as the senolytic combination of dasatinib and quercetin, or the CSF1R inhibitor PLX3397, clinical trials are yet to run. Researchers here note the connection between the age-related changes of the gut microbiome, which encourage inflammation, and the inflammatory behavior of microglia. Intervening to restore a more youthful gut microbiome is another line of work that is a practical possibility, with several methods demonstrated in animal studies and easily applied to humans, such as flagellin immunization or fecal microbiota transplantation, but yet to reach clinical trials.

Microglia are a group of neuroglia that account for 5-15% of total brain cells. As the resident-macrophage cells, microglia function as the main immune defense in the central nervous system (CNS). To sustain brain homeostasis, microglia continually surveille the brain microenvironment through their connections with neighboring cells and factors. During aging, microglia switch from resting state to activated state and contribute to the development of neurogenerative diseases. Activated microglia produce pro-inflammatory cytokines, and participate in regulating blood-brain barrier (BBB) integrity and synaptic plasticity in aged brain.

Recent studies suggested that the alterations of gut microbiota in the aged are associated with neurodegenerative diseases. Gut-brain axis indicates the complicated connections between gut and brain, which is crucial for microglial maturation and function. These findings pave a new way in attenuating and even reversing cognitive aging through microbiota-microglia axis intervention. In this review, we will review the composition of gut microbiota in aged individuals, depict the changes of microglia associated with aging and discuss neuroinflammation in the aged brain. We then summarize the mechanism of microbiota in regulating microglial function in the aged brain and highlight the role of microbiota-microglia connections in neurodegenerative diseases. This knowledge may enrich our understanding of the crosstalk between aging-related cognitive decline and the microbiota-microglia axis, facilitating the discovery of novel targets in restoring aging-related cognitive decline.


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