The gut-brain connection

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Historically, we had a very top-down view of intelligence from the perspective of how we make decisions, or how we know, sense, and integrate information that leads to behavioural or physiological adaptations. We thought that there is this very clever brain that’s getting information from our environment, and that leads to physiological changes, and some of those will involve the intestine. So the brain will tell the intestine to do things.

But we’ve also known now for a long time that when you look at the nerves that connect the brain with the gut, most of the information goes from the gut to the brain. So 70% of the fibres or the connections between the two will go from the gut to the brain. Anatomically, that almost tells you that there has to be very extensive crosstalk; maybe there’s more going from the gut to the brain than from the brain to the gut.

Integrating internal information

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’s the decision maker?

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.

The intelligent gut

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We’re learning now as a community is that pleasant signals can also come from the gastrointestinal tract. These signals may ask us to eat more, for example, of something that is nutritious, and they can even make us happy. It’s not just about the gut telling us to stop eating because we’ve eaten too much and we don’t feel well. It can also send reward signals back to the reward centres in the brain, and that can actually stimulate further eating. So it’s complex, it’s interesting and we still know very little about it.

Historically, the nervous system of the gut, or the “second brain” as it’s now known, had been kind of neglected. The idea was that it was doing these lowly functions, just keeping our guts contracting and not doing anything particularly interesting. That changed.

There’s a lot of interest now in understanding what kind of nerve cells we find there, what they do, how they differ and even how they look. We don’t know that much about this. A few landmark papers in recent years have begun to parse this diversity, to try to make sense of the logic of their connections and the functions they perform beyond their known roles in digestion and peristalsis of the food along the tract.

Gut cells, fruit flies and reproduction

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.

Zinc sensors in the gut

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.

Translating findings to human problems

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.

Diversity in the scientific community

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If we have learned something from biology, it’s that diversity leads to robustness and resilience. It is really important that we capture that diversity of traits as widely as we can. Of course, that means having males, females and minorities that are not currently represented in our scientific landscape to ensure the robustness, resilience and quality of our community.

I sometimes struggle to understand why people are resilient to this idea of understanding diversity better. I think it’s good to catalogue it, and it’s useful to understand all these differences and also how plastic they are. It’s all about trade-offs, and it’s all about plasticity; trait A is not always trait A, and trait A is not always useful. It will be useful in a particular environment, but in another environment, we will need trait B. If we have all these traits and we have all this plasticity as a community, we’ll be best placed to tackle future challenges. To me, that obviously includes increasing representation of women and many other underrepresented minorities in our community.

Discover more about

the guts

Miguel-Aliaga, I., Redhai, S., Pilgrim, C., et al. (2020). An intestinal zinc sensor regulates food intake and developmental growth. Nature, 580, 263–268.

Miguel-Aliaga, I., Jasper, H., & Lemaitre, B. (2018). Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster. Genetics, 210(2), 357–396.