The microbiome’s role in the immune system of the brain

A large body of evidence continues to support the microbiome’s role in interacting with the gut-brain axis.  Researchers in Germany recently investigated this relationship further by studying how host-microbiota can specifically influence the brain immune system of mice.  The researchers studied microglial cells, which are essentially the macrophages of the brain.  They patrol for pathogens, help maintain synaptic function, and play an important role in brain development.  Unlike macrophages that operate in our peripheral immune system, microglia cells operate behind the blood brain barrier and are thus subject to a different standard of biological rules.  Understanding how the microbiome interacts with this unique immune complex will shed light on this unique aspect to our body’s immunity. 

Twenty-four mice were divided into two groups; germ free (GF) mice and mice colonized with specific pathogen free (SPF) bacteria populations.  The researchers first measured microglial gene signatures and surface molecules between both groups.  The GF mice showed a marked contrast to SPF mice in expression of genes linked to microglial cell activation.  Molecular analysis also showed differences in surface protein expression between both groups, namely revealing that the GF mice had phenotypically immature microglial cells.  After these findings, researchers gave antibiotics to SPF mice to wipe out their microbial populations.  After a 4-week antibiotic regiment, the microglial cells were shown to be phenotypical similar to those of the GF mice, demonstrating crucial involvement of host-microbiota.   

Bacterial isolates were also characterized to search for trends in microbiota population versus immune response.  Overall examination concluded that limited complexity in species diversity was correlated with microglial immaturity.  Researchers also demonstrated that recolonizing microbiota populations in mice was able to restore microglial integrity.  Another unique experiment reinforced this finding.  Short-chain fatty acids, metabolic products of bacteria, were mixed in the drinking water of GF mice.  These additives were also shown to rescue the malformed microglia. 

The microbiome is an emerging field, but the immune system of the brain is an evolving topic as well.  The brain and CNS in general used to be considered as immune privileged, meaning antigen introductions do not trigger immune responses.  Although this definition is now considered incorrect, the brain is a unique tissue site with many interesting features, including the blood-brain barrier (mentioned above).  This experiment demonstrates that the microbiome interacts with this distinct physiological immune complex, and elucidating more mechanisms could lead to exciting new discoveries in the future.    

The gut microbiome is critical to making the blood brain barrier impermeable

We have written before about the importance of the microbiome in enforcing gut impermeability.  Evidence is mounting that bacteria are crucial for preventing ‘leaky’, or permeable guts.  Leaky guts allow molecules to pass through them, which can cause many problems, especially for the immune system.  The blood brain barrier (BBB) is equally important, as it prevents toxins and molecules from entering the brain from the blood vessels.  Now, researchers have discovered the microbiome may have an equally important function towards BBB impermeability.  An article was published last week in the journal Science Translational Medicine that has shown the first link between gut bacteria and the BBB.

Researchers raised 2 groups of mice: a control group that was normally reared and had a natural gut microbiome, and a germ-free group of mice that had no gut bacteria at all.  They then tested these mice’s BBB permeability using various techniques.  The normal mice had a normal, impermeable BBB, while the germ-free mice had very permeable BBBs.  This permeability persisted, unchecked, through adulthood in the germ free mice.  However, when the researchers transplanted the microbiomes of normal mice into the guts of the germ-free mice, their BBBs very rapidly ‘tightened’ and became normal.

Gut permeability regulation by bacteria has been related to the presence of short-chained fatty acids (SCFAs), which gut bacteria produce.  The scientists wondered if these SCFAs may also have a role in regulating BBB permeability.  They fed some of the germ-free mice with SCFAs and their BBB permeability decreased and resembled the BBB of normal mice. 

This study demonstrates a new, until now, unknown function of the microbiome: it is critical to creating an impermeable BBB.  The impermeability of the BBB is essential for neuron growth and overall brain function, so this study is another in a long line that shows a healthy gut leads to a healthy brain.