A mouse’s microbiome may cause its brain to leak

Your gut has much more to do with your brain than just the influence it has when you’re passing by the donut shop. Since our guts take in all the fuel we need from the outside world, and our brains are necessary for navigating the outside world, the two need some way to communicate with each other. This method of communication between the gut and brain is called the “gut-brain axis^[1].”

In the 1970s^[2], the molecular mechanism through which the gut and brain communicated was beginning to be understood. Several proteins and peptides (which are made out of the same building blocks as protein, but are smaller) were discovered, that were both produced by and affected the gut and brain. But a problem arose: communication between the brain and gut largely involved big molecules like proteins and peptides. How could such large molecules get across the blood-brain barrier (BBB)?

In order to answer this question, we first need to understand what the BBB is and what its function is. The BBB exists to make sure that compounds in the blood don’t necessarily enter the brain, and that your brain keeps whatever nutrients it needs. You can check out the details in Figure 1. There, you can see that the BBB keeps out large molecules, while being a little more loose about certain types of smaller molecules, while also selectively letting other molecules in.

Figure 1: What is the blood-brain barrier?

The BBB is mainly made up of endothelial cells (the kind of cells that line the inside of blood vessels) that are tightly knit together by “tight junctions,” which are composed of several types of proteins. The purpose of tight junctions is to make sure substances don’t accidently slip in between cells. Two of the proteins which make up tight junctions are claudin and occludin, which are discussed later in the review.

Since the BBB is made up of cells that are tightly-woven together, it is very hard for larger molecules to pass from the bloodstream into the brain. If they do get through, they do so either selectively through transporters or because the BBB is damaged, leaky, or otherwise compromised in some way.

Why does the BBB exist? Well, the brain is a pretty important organ, and so it’s wise to be selective about what gets into and out of the brain. For instance, if you get an infection, the BBB will hopefully stop the infection from reaching the brain^[3]. But the BBB also plays a major role in the developing brain as well. One way it does so is by helping to regulate the environment of the growing brain^[4] to create an optimum environment for development. It also helps protect the growing brain from toxic outside influences, such as bacteria colonizing the gut of newborns, during the so-called critical period of brain development^[5]. In summary, if your brain is a club, the BBB is like the bouncer: it does its best to stick to the list of approved molecules, and doesn’t hesitate to bar entry to the less desirable clubgoers.

Like bouncers, the BBB also has to be trained. The authors of this study hypothesized that gut microbiota (the bacteria that normally live in our gut and usually don’t cause any problems, and in fact can help us) may play a role in this training. The gut microbiome is known to contribute to other areas of mammalian development, such as gut development^[6] (including aspects of how it functions as a barrier) and even other aspects of brain development^[7]. So it’s not a far leap to suspect that the gut microbiome may influence the BBB as well. The authors of this paper set out to test exactly this hypothesis in mice.

Gut bacteria have been observed to influence brain development, as well as influencing gut integrity. This inspired researchers to examine whether or not gut bacteria can also influence the integrity of the blood-brain barrier (BBB), which selectively allows molecules in and out of the brain.