What is already known on this topic
The brain has its own immune cells, including microglia, which act as the first form of active immune defense in the central nervous system (CNS), and CNS-associated macrophages, or CAMs. CAMs reside in the spaces surrounding blood vessels and in the tissues lining the meninges and the choroid plexus, a complex network of capillaries that produces the cerebrospinal fluid. Previous studies have shown that gut microbes can influence some properties of microglia, but the effects of the microbiota on CAMs remain unknown.

What this research adds
Working in mice and brain cells grown in a dish, researchers have found that the microbiota regulates the gene-expression profiles and number of choroid plexus macrophages and, to a lesser extent, perivascular and meningeal macrophages. Infecting germ-free mice with a virus evoked an attenuated immune response of all CAMs. In a mouse model of Alzheimer’s disease, the researchers observed an enhanced uptake of amyloid beta — the main component of the plaques found in the brains of people with Alzheimer’s disease — by perivascular macrophages in germ-free animals.

Conclusions
The findings will help to gain insights into the interplay between the gut microbiota and CAMs in health and disease.

The brain has its own immune cells that protect the organ from disease and injury. Now, a new study shows that gut microbes can regulate the number and function of at least some of these immune cells.

The findings, published in The EMBO Journal, will help to gain insights into the interplay between the gut microbiota and the brain’s immune cells in health and disease.

The immune cells of the central nervous system (CNS) include microglia, which act as the first form of active immune defense, and CNS-associated macrophages, or CAMs. CAMs reside in the spaces surrounding blood vessels and in the tissues lining the meninges and the choroid plexus, a complex network of capillaries that produces the cerebrospinal fluid. 

Previous studies have shown that gut microbes can influence some properties of microglia, but the effects of the microbiota on CAMs remain unknown. 

Daniel Erny at the University of Freiburg and his colleagues used microbiota manipulation approaches, mouse models, and gene expression analyses to characterize CAMs’ cell composition and function.

Immune activity

By comparing microglia and CAMs of germ-free mice with those of control mice, the researchers found that cells from mice grown in the presence of microbes had higher levels of genes associated with immune function.

In microglia from germ-free mice, the team found higher levels of apolipoprotein E, a protein whose microglial expression is known to be reduced during development. This could suggest that microglial cells from germ-free mice are in an immature status.

When the researchers looked at CAMs, they found that the gut microbiota appears to regulate the gene-expression profiles and number of choroid plexus macrophages. Similar effects were observed in perivascular and meningeal macrophages, albeit to a lesser extent.

Attenuated response

To assess the effects of CAMs alterations, the researchers infected germ-free and control mice with lymphocytic choriomeningitis virus, which can cause brain diseases in humans. Then, the team analyzed the expansion of CAMs after four days.

Following viral infection, microglia from control mice increased their density — a reaction that was less prominent in germ-free mice, the researchers found. Further analyses showed that the infection evoked an attenuated immune response of all CAMs from germ-free animals.

Next, the team studied the role of CAMs in a mouse model of Alzheimer’s disease. In the brain of germ-free mice and antibiotic-treated mice, there were fewer depositions of amyloid beta peptide, the main component of the plaques found in the brains of people with Alzheimer’s disease. 

The researchers also observed an enhanced uptake of amyloid beta by perivascular macrophages in germ-free animals, which suggests that the microbiota can regulate the uptake of amyloid beta, thus contributing to disease outcome if clearance of the peptide is impaired.

The findings could help to improve the treatment of neurodegenerative diseases and other inflammatory conditions mediated by the brain’s immune cells, the researchers say.

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Giorgia Guglielmi is a freelance science writer based in Cambridge, Massachusetts. She received a PhD in Biology from the European Molecular Biology Laboratory and a Master’s in Science Writing from the Massachusetts Institute of Technology.