How the gut protects the brain

The gut is well known for being the first line of defence against infection, but it seems it also protects our most important organ – the brain.

According to surprising new research, antibodies that defend the perimeter of the brain are normally found in, and trained by, our gut.

“This finding opens a new area of neuroimmunology, showing that gut-educated antibody-producing cells inhabit and defend regions that surround the central nervous system,” says Dorian McGavern from the National Institutes of Health, US, co-author of a paper in the journal Nature.

The work brought together researchers from the NIS and the University of Cambridge, UK. They found that special IgA antibodies were present in the outer meninges – membranes that cover the brain and spinal cord – of both mice and humans.

“This finding was completely unexpected,” says McGavern. “Prior to our study, IgA cells had not been shown to reside in the dura mater – the outer meninge – under steady state conditions.”

The researchers first found these cells in mice then confirmed that IgA was also present in human cells they collected from the meninges during surgery.

They used DNA sequencing to identify the origin of these IgA cells and found that, out of millions of IgA sequences, they most closely matched a very specific gut IgA that occurred in the intestine.

Understandably, the gut microbiome helps gut IgA learn to defend against infections that may enter our stomach and intestine, but these two IgA share an origin, which means brain IgA cells share the same training ground.

“It’s truly remarkable that in such a small piece of intestine we would see this large an overlap with cells in the meninges,” McGavern says. “These data provide more compelling evidence that the brain is protected by immune cells that are educated in the gut.”

IgA is usually is found in nostrils, lungs and intestines, as it protects mucous surfaces that are likely to come in contact with something from outside of the body. However, the brain isn’t as close to an orifice as the nostrils and stomach, so bacteria can only get there via the bloodstream, which is why this finding is such a surprise.

“But actually, it makes perfect sense: even a minor breach of the intestinal barrier will allow bugs to enter the bloodstream, with devastating consequences if they’re able to spread into the brain,” says Cambridge’s Menna Clatworthy.

“Seeding the meninges with antibody-producing cells that are selected to recognise gut microbes ensures defence against the most likely invaders.”

The team was able to confirm that the gut microbiome influenced brain IgA by testing mice that had no gut bacteria. These mice did not have cells that produced IgA near the brain, potentially because the gut IgA cells could not learn how to recognise harmful gut bacteria.

When they removed protective plasma from the meninges, microbes were able to spread to the brain via the bloodstream because brain IgA was not present to catch and destroy them.

When they replaced the gut bacteria of the mice, brain IgA was produced again, which shows a very strong correlation between the gut microbiome and brain defence.

They further tested this defence system by infecting mice with a harmful fungus that is known to be trapped by IgA, just like a bacterium. Mice with the correct IgA cells survived, but mice without the cells were unable to prevent infection.

“By simply removing the IgA cells from the meninges, and without affecting any other immune cells, this fungus went from being a controlled pathogen to causing a fatal brain infection,” says McGavern. “This clearly shows the importance of the local immune response.”