The gut-brain connection

This makes sense if you think that this integration, this kind of decision-making, needs to consider not only external information but also internal information. Where does this internal information come from? The gastrointestinal tract is a good place; it’s exposed to nutrients, microbiota and potentially the stuff that’s circulating in our bloodstream. So it’s a good place to make decisions, at least concerning our internal state.

The gut cells will be exposed to this complex information, such as what we’ve eaten or what we haven’t eaten, or the activity of the bugs within our intestine. What are they up to? What are they metabolising? Why are they transforming? And the gut cells are also exposed to things such as our internal state, for example, at the level of reproduction.

We have an article coming out where we found that the nerve cells of our gut sense whether females are having babies or not, and if they are, they change and that will change how they fire. The gut cells can integrate all this information and feed that back to the brain for the brain to change things.

Who makes the decision? Who triggers whatever behavioural adaptation or physiological adaptation is going to ensue? I would argue that in some cases that integration has been made at the level of the gut cells. That’s what one can describe as gut intelligence.

We’re only beginning to learn about these mechanisms. If you consider what we are sensing, historically, as far as the gastrointestinal tract is concerned, we tended to think of it in the context of food intake. For example, we tended to think the gut was stopping us: we’ve eaten too much; we’re full. We don’t feel well; would you stop eating? We uded to think that the gut was sending these signals back to the brain, which it does. And we used to think that was its only role.

Our entry point into all this was actually fruit flies, so Drosophila. The reason for that was that their gastrointestinal tract is relatively complex, but it’s a much simpler digestive system to work with. They also have nerve cells in the gut. But we can actually map or characterise all these different cells and what each cell does. So that’s what we’ve been doing over the years, and we realised that they do pretty interesting stuff.

For example, we’ve learned that there’s a particular subset of these nerve cells that integrate, that actually learn that the female fly is reproducing. These nerve cells are normally quiet. They’re not firing; they’re not doing anything. They’re just there, in males and in females. Then, when the fly reproduces – so when the fly has mated, and it begins to make loads of eggs – these nerve cells are awakened and begin to fire. This firing changes how the stomach-like organ in the fly contracts, and this in turn increases food intake.

What we think is happening is that these neurons relay this reproductive information through the digestive system, though the nervous system, so that the female fly increases food intake during reproduction. That makes sense because female flies, like us when we make babies, have additional nutritional needs. If we increase food intake, it helps with the developing progeny, with the developing baby.

But the interesting thing is that it’s only a subset of neurons that do this specifically in mated females. They exist in males, and they exist in females. They are silent, and then they awaken or begin to function during reproduction. So plasticity extends beyond the gut itself and beyond stem cells; it even encompasses the nerve cells that populate this intestine.

The advantage of flies is that you can use the system to explore in an unbiased manner what the nerve cells or what the gut cells may be sensing. We’ve done that through so-called genetic screens. We basically remove genes one at a time from specific gut cells and see what happens. The easiest way to go about it is just to see how the fly develops, whether it develops faster or whether it develops more slowly. We can also do this in different environments and in different nutritional conditions. So we did this, for example, with a rich diet versus a poor diet or nutrient scarcity to see which genes matter and for what.

In doing this, we made an unexpected finding. We realised that metals are really important, and we found a zinc sensor. We thought that it was all about the gut sensing sugars and protein and fat. It turns out that the gut also senses metals. And this metal sensing is really important for food intake. Metal sensing actually relays a signal back to the brain that makes a fly eat. Now we wonder whether we should stop considering metals as building blocks, and whether we should consider them as something a little more instructive with potential roles in food intake, regulation and energy balance.

We found this zinc sensor that regulates food intake in flies. The zinc sensor does not exist in us; this gene, or a similar one to the one found in flies, is not present in humans. We thought that this was interesting because in fact the zinc sensor is only present in flies and mosquitoes.

Mosquitoes can be a problem, for example, in the context of malaria as vectors of human disease. We thought the zinc sensor was interesting from this perspective because it is only present in the intestinal lining. So any drug that targets it should be able to access it quite readily. You could think of a drug that a mosquito ingests, and it immediately hits this gene in the intestinal lining. If we knock it out, so if we get rid of it in mosquitoes, the mosquitoes die. So potentially, a finding made in flies can be translated to mosquitoes to eventually affect humans.

That is a more indirect and potentially equally useful way to translate findings. We mustn’t be too prescriptive about what we regard as a translation, and what we regard as useful science, because the utility of science can come from very different and unexpected directions. The recent Nobel Prize on CRISPR is a very good example of this.