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

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 recent Frontiers in Cellular Neuroscience The researchers investigated the effect of age-related composition of the gut microbiome and its metabolites on age-related diseases caused by dysfunctional macrophages in the brain.

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

Background

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. Typically, the CNS is marginally affected by transient brain macrophage activation. However, aging causes persistent activation of brain macrophages and chronic systemic inflammation, which in turn leads to behavioral, physiological, and cognitive dysfunction.

The systematic identification of gut microbial metabolites that enter the brain and affect 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 adult mouse brain. These cells are derived from primitive myeloid progenitors that maintain their population in the brain through self-renewal.

Microglia are involved in various neurological functions from development to homeostasis and several CNS pathologies. In addition, these cells regulate neuronal cell apoptosis, myelination, and synaptogenesis by immediately responding to nerve injury and pathogenic invasion. These properties strongly suggest that microglia could lead to CNS disorders, particularly during neurodevelopment and neurodegeneration.

Along with morphological and genetic changes, activated microglia also produce pro-inflammatory cytokines that amplify 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 cell damage in the CNS, elevated levels of these cytokines can damage neurons. and glial cells. Therefore, chronically activated microglia or an imbalance in cytokine release leads to the development or progression of neurodegenerative disease.

The activation of microglia in an age-dependent manner has been well defined in many studies. Aging also causes an increase in microglial major histocompatibility complex II (MHC II) expression and an increase in pro-inflammatory cytokines. Similar conditions have also been observed in the human brains of AD patients.

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

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

Non-parenchymal CNS-associated macrophages (CAMs) include perivascular, meningeal, and choroid plexus macrophages, all of which are part of the innate immune cells of the brain. These cells influence cerebral inflammation, which is also influenced by metabolites released from gut microbes.

Influence of the gut microbiome and its metabolites on CNS macrophages

The gut microbiome influences the functions of CNS macrophages. In vivo experiments in a germ-free (GF) mouse model revealed that the microbiome plays an important role in the development and maturation of microglia, in addition to influencing the functioning of the adult brain.

In addition to the morphological influence, the microbiome also influences the transcriptomic profile of microglia in GF mice through the downregulation of several genes associated with cellular activation and triggering of immune responses.

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

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

Several neurological diseases, including AD, have been linked to microglial dysfunction due to gut microbiome dysbiosis. One of the primary symptoms of AD is the accumulation of amyloid-beta (Aβ) plaques, which are influenced by the gut microbiome. Cell adhesion molecules (CAMs) in GF mice revealed a lack of appropriate responses to immunostimulants.

The gut microbiome significantly influences CNS macrophages from the developmental stage to adulthood. In addition, gut microbiome metabolites influence macrophage-mediated inflammatory responses in the CNS. Several studies suggest that brain macrophages play a key role as a mediator between the gut microbiome and CNS disorders.

Decreased metabolic activity of gut bacteria is associated with age, which reduces the production of short-chain fatty acids (SCFA). In addition, low levels of SCFAs 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 concentrations associated with cardiovascular disease, arteriosclerosis, AD, and cancer. Aging causes TMAO levels to increase in humans.

Conclusions

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

Link to journal:

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

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