Age-related changes in microbiome composition affect brain macrophages

Age-related diseases, such as Parkinson’s and Alzheimer’s disease (AD), are affected by changes in the gut microbiome. In addition, several factors, such as aging, affect the composition of the gut microbiome.

In a recent study in Frontiers in Cellular Neuroscience, scientists reviewed the impact of age-related gut microbiome composition and its metabolites on age-related diseases caused by dysfunctional macrophages within the brain.

Study: Age-dependent effects of gut microbiota metabolites on brain-resident macrophages. Image credit: picmedical / Shutterstock.com

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Loss of homeostasis, cognitive decline, as well as metabolic, inflammatory and degenerative diseases are common age-related conditions.

Macrophages and microglia express many families of receptors associated with the degradation of necrotic and aged tissues. Normally, the CNS is marginally affected by the transient activation of brain macrophages. However, aging results in persistent activation of brain macrophages and chronic systemic inflammation, which subsequently leads to behavioral, physiological, and cognitive dysfunction.

Systemic identification of gut microbial metabolites that reach the brain and influence its function, particularly during aging, has become a critical area of ​​research.

Parenchymal and non-parenchymal microglia in aging

Microglia make up about 10% of the CNS in the brain of an adult mouse. These cells are derived from primitive myeloid progenitors, which maintain their population in the brain through self-renewal.

Microglia are involved in various neurological functions ranging from development to homeostasis and various CNS pathologies. In addition, these cells regulate neuronal cell apoptosis, myelination, and synaptogenesis in immediate response to neuronal injury and pathogenic invasion. These properties strongly indicate that microglia could cause CNS disorders, especially during neurodevelopment and neurodegeneration.

Along with morphological and genetic changes, activated microglia also produce proinflammatory cytokines that enhance the inflammatory response. Although the production of proinflammatory cytokines, such as interleukin 1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), prevents further damage to CNS cells, the increased of the levels of these cytokines can damage neurons. and glial cells. Therefore, chronically activated microglia or an imbalance in cytokine release lead to the development or progression of neurodegenerative disease.

Age-dependent activation of microglia has been well defined in many studies. Aging also results in increased expression of microglial major histocompatibility complex II (MHC II) and enhancement of proinflammatory cytokines. Similar conditions have also been observed in the human brain of AD patients.

Non-parenchymal macrophages are found throughout the CNS. These are associated with different strategic niches in the subarachnoid space, choroid plexus (cpM) and pia mater (mM).

Perivascular macrophages (pvM) and mM are derived from embryonic hematopoietic precursors and are constantly renewed. cpM originate from both adult hematopoietic stem cells (HSCs) and embryonic myeloid progenitors.

CNS-associated non-parenchymal macrophages (CAM) include perivascular, meningeal, and choroid plexus macrophages, all of which are part of the brain’s innate immune cells. These cells affect brain inflammation, which is also influenced by metabolites released by gut microbes.

Impact of the gut microbiome and its metabolites on CNS macrophages

Gut microbiome affects CNS macrophage functions. In vivo experiments using a germ-free (GF) mouse model revealed that the microbiome plays an important role in the development and maturation of microglia, as well as influencing the functioning of the adult brain.

In addition to the morphological influence, the microbiome also affects the transcriptomic profile of microglia in GF mice by down-regulating several genes associated with cellular activation and triggering immune responses.

Absence of the gut microbiome alters microbial function to respond to immunostimulants. For example, when GF mice were challenged with lipopolysaccharide (LPS), microglia showed decreased expression of IL-1β, IL-6, and TNF-α, as well as reduced amoeboid morphology.

Microglia are associated with age- and sex-dependent responses to the microbiome. For example, male mice microglia are more sensitive to microbiome loss at the embryonic stage compared to female mice. However, females lacking a microbiome exhibit significant changes in transcriptomic profiles during maturation.

Several neurological diseases, including AD, have been associated with microglial dysfunction due to gut microbiome dysbiosis. One of the main symptoms of AD is the accumulation of beta-amyloid (Aβ) plaques, which are affected by the gut microbiome. Cell adhesion molecules (CAM) in GF mice have revealed a lack of adequate responses to immunostimulants.

The gut microbiome significantly influences CNS macrophages from developmental stage to adulthood. In addition, gut microbiome metabolites affect inflammatory responses in the CNS, which are mediated by macrophages. Several studies have suggested that brain macrophages play a crucial role as a mediator between the gut microbiome and CNS disorders.

Decline in the metabolic activity of gut bacteria has been associated with age, which reduces the production of short-chain fatty acids (SCFA). In addition, low SCFA levels are associated with several neurodegenerative diseases such as AD and Parkinson’s disease.

The gut microbiome also produces choline-derived trimethylamine N-oxide (TMAO). TMAO production is age dependent, with higher TMAO concentration linked to cardiovascular disease, arteriosclerosis, AD and cancer. Aging causes an increase in TMAO levels in humans.

Conclusions

The current study highlighted that metabolites produced in the gut could enter the brain and affect brain macrophages. In the future, multiple metabolomic, metatranscriptomic, metagenomic, and proteomic methods should be used to better understand the therapeutic potential of the gut microbiome and its metabolites.

Journal reference:

  • Hasavci, D. and Blank, T. (2022). Age-dependent effects of gut microbiota metabolites on brain-resident macrophages. Frontiers in Cellular Neuroscience 16. doi:10.3389/fncel.2022.94452

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