“Understanding how our brain is constantly receiving signals through our gut, as well as the microbiome living there, is of great importance for all aspects of our physiology”, says Irish neuroscientist Professor John Cryan.
John Cryan is the principal investigator in the APC Microbiome Ireland research institute and a member of the Federation of European Neuroscience Societies. According to his groundbreaking work, the gut influences our brain including stress and our emotions.
Your work gravitates around the interaction between the brain, gut and microbiome (the microorganisms in a particular environment). What is the tie between them?
John Cryan: As I work in the neuroscience department of a medical school, I know from experience that in medicine we tend to compartmentalise the body; neuroscientists are trained to predominantly focus on what happens above the neck.
The work that we do now, which is looking at signals between the gut and the brain, disrupts that, and people may think it is totally new.
Nonetheless, Hippocrates already stated: “All disease begins in the gut”. And people researching areas such as satiety (the satisfied feeling of being full after eating) have been working on gut-brain signalling for hundreds of years already. But what is new is the understanding that the gut-brain signalling could also be relevant to a variety of other brain-related conditions, also in terms of modulating (altering or stimulating) the brain in different ways.
Understanding how our brain is constantly receiving signals through our gut is of great importance. These are sent and received through a variety of ways. What is quite new as well is that we realised in the last two decades that the microbiome in the gut is really important for gut-brain signalling as it is for all aspects of our physiology. So, understanding that we now have a microbiome gut-brain axis has been one of the hallmarks of my research.
The gut-brain signalling occurs through direct neurolinks: we have nerves, most notably the vagus nerve (the longest nerve of the autonomic nervous system in the human body), that send signals from the gut to the brain. We also have our enteric nervous system, which is also often referred to as “our second brain”. The enteric nervous system is really important for maintaining homeostasis in the gut, for digestion, for motility and other functions. But it also is a very important part of our signalling to the brain.
What is often forgotten, even by neuroscientists, is that there are more nerve cells in our gut than there are in our spinal cord. We also know that the microbes in the gut are similar to little factories producing various weird and wonderful chemicals that our bodies wouldn’t make otherwise. And factories are dependent on the quality of the workers and the raw materials which come from one’s diet.
Why is the communication between the gut and the brain important for the body?
John Cryan: This communication is really important for what we call interoception. Interoception sounds like a Christopher Nolan movie, but it actually reflects how we feel and how our internal systems communicate with our brain to sense how we are doing. Gut signals are very much part of that interoceptive process.
Next to informing us about our satiation – if we’re full or hungry, and survival mechanisms around that – gut signals tell us if we’re feeling bloated or if we’re feeling dysphoria, which will be communicated through these visceral signals. We can know if there are pain processes, if we have abdominal pain or other discomfort, or if we have immunological problems.
However, we need to frame microbiome signals from an evolutionary perspective, and really understand that the microbes were there first. We do not have microbes communicating to the brain all of a sudden, but rather the brain has evolved in the presence of microbial signals.
We’re slowly discovering what they are – under baseline normal conditions – and how they are influencing core circuits in the brain, driving and shaping our behaviour.
Did you find evidence that microbiome in the gut influence our behaviour and emotions? And how do other scientists respond to this?
John Cryan: I have spent my career being a bit evangelical in trying to convince very sceptical researchers that we should be looking below the neck when trying to understand emotions. But how could I get evidence that the state of microbes could be relevant to the brain and to behaviour? For that, one would need to look to other areas of our engineering or biology. And if you want to see if something is important, you take it out and see what happens.
So, a number of years ago we benefited from having a germ-free facility at the APC Microbiome Ireland Institute in Cork. Mice, which essentially grow up in a bubble and lack any real human translation, have allowed us to answer the fundamental question: “Is the microbiome influential?” The results were outstanding.
One of the most startling was that the animals develop clear social deficits in adulthood, especially male animals. So we started to think that we might need microbes in our gut for normal social interactions and social behaviours.
Now, all of the sudden, the brain gut connection became popular. More and more studies and data are coming out with evidence in this domain – I am pleased to hear people beginning to realise that there is a reason I focus on the gut.
Another really important finding for us was back in 2011 when we published a paper showing that a lactobacillus strain of bacteria was able to dampen down the stress response and have behavioural effects. We were able to block this when we cut the vagus nerve. This vagus nerve finding proved that it affects our emotions. I think key mechanistic findings like this are helping to drive the field forward.
We have been met before with scepticism in the early days of Psychoneuroimmunology, where the concept of the immune system affecting the brain was going against their dogma. Now it is widely accepted. Neuroscientists may find it complex because the microbiome requires collaborating with microbiologists and other gastroenterologists, immunologists – people outside our discipline.
From a mechanistic, physical perspective, how much do we know and how much have we deciphered out of the gut–brain connection?
John Cryan: The gut–brain axis primarily aids us in supporting our entire system. We need our brains to be able to understand what is happening in all of our organs so that they can actually deploy the right resources. That is a very fundamental physiology principle.
The other interesting discovery we have made has been the relationship between the microbiome and social behaviour. As mentioned, some years ago, we showed that germ-free mice have social deficits. That implied that for normal social behaviour, we need to have microbes in our gut.
We started coming up with ideas that maybe from an evolutionary perspective: that microbes are actually being passed on from one person to the other and that might be good for microbial fitness, which might be driving some of this from a puppeteering perspective. We were using the analogy of Pinocchio at the time to try and understand that.
I published a paper on how the microbiome is “the brain’s Geppetto”. Later, I collaborated with an evolutionary microbiologist, then at Vanderbilt University.
After sharing some of these ideas with him, he told me that I was completely wrong. I had forgotten to take into account the fact that the microbes were there first. So there has never been a time where our brains have existed without microbial signals. And we have co-evolved with these friends, who are supporting us with social benefits. Once you start framing it under an evolutionary framework, it becomes very powerful in terms of our understanding of what’s going on.
One example that I find really intriguing is that if you look at human breast milk, it is about 20 times more complex than cow’s milk or other mammalian milk in terms of the sugars. Why would evolution give us these really complex sugars? The infant cannot break down these sugars, as it has no capacity to do so. These milk oligosaccharides are broken down by the microbes into chemicals. Among them is sialic acid, a key building block for brain development. So, the microbes are harnessing the best benefit from human breast milk to support brain development.
What circumstances influence the development of our microbiome?
John Cryan: For the most part, we’re thought to be sterile in utero. We get our microbes as a kind of a birthday present from our mothers from the day we were born, which sets in chain a whole programming of our immune system. Many factors can alter this trajectory in early life and researchers are studying the impact of such perturbations.
Firstly, the mode of delivery at birth. If you’re born by C-section, you don’t get the mother’s microbes in the same way. You get the microbes from the skin and the hospital environment instead. We have been studying C-section a lot as a model system for looking at early life microbial disturbances. The second area is mode of nutrition: whether you’re breastfed or bottle fed, there are big differences in the microbial composition there.
Thirdly: the exposure to antibiotics. Fourthly: the environment we grow up in, the environment we live in. Whether we live in green areas and if we get exposed to a pet. Having a dog, for example, has been shown to be quite good for the microbiome. As we get older, diet and nutrition play a huge role in our microbial composition. Host genetics play a role, which we shouldn’t neglect. Then, social interaction. A paper published in Nature showed that the family you live with start to share microbes as well.
How does this interaction apply to stress and to psychiatric and immune-related disorders?
John Cryan: 15 years ago or so we researched animals that were were subjected to early life stress and early life trauma. We could detect the adverse childhood events in their microbiome in adulthood that showed a signature of stress that persisted. This fact coupled with the knowledge that germ-free animals have an increased stress response. And I mentioned already that giving a lactobacillus decreased the stress response overall, so there’s a very clear relationship between stress and the microbiome.
More recently, we’ve moved our studies to humans. We have very good and ethical ways of stressing people in the lab. We are bringing people in to do a public speaking test and we are able to show if they’ve taken a specific bacterial strain of bifidobacteria that we were dampening down the stress response as acute stress response. We measure skin conductance; we take immune and psychological measures.
Nonetheless, all of this is related to acute stress, which is interesting, but my research is focused more on disorders related to chronic stress or traumatic stress. So we had to come up with a way of ethically, chronically stressing individuals. And this is one of the advantages of being an educator: I was able to subject our students to exams and measure their profiles during this period.
We found that if they took on a specific strain of bacteria, they had a reduction in their stress response as well, or if they had been born by C-section, which means they had an early life disturbance of their microbiome, that they had an exaggerated stress response during this exam period.
We’re now actively working on trying to see if we can develop a nutritional support mechanism that is going to impact the effects of stress. So we ramped up fibre, the building blocks for microbes, and fermented foods, which are grosely under-utilised in the European diet.
We were able to show that if we fed them microbes and nourished the microbes with such a diet, we are able to dampen down the effects of stress in a small population. We monitored 42 individuals for one month and we were able to observe changes in how these individuals perceived stress.
We coined a new term for these strategies that target the microbiome for mental health benefits: psychobiotics.
We’re now studying the changes in the microbiome over time in social anxiety disorder, but also major depressive disorders. The goal is to develop interventions that could counter some of the effects and can have a beneficial effect. Alongside Scott C. Anderson and Ted Dinan, I co-authored “The Psychobiotic Revolution” to try and get the public interested. It has been published in Spanish, Polish, and Chinese as well as English.
We are at the beginning of a new way of thinking about mental health management and preventative mental health management through targeting the microbes in the gut. This is turning mental health psychiatry upside down, looking at it from a whole different below-the-neck perspective.
Tony Hannan‘s group in Australia for example has been doing very nice work. They looked at Huntington’s Disease and showed that the onset of Huntington’s is also gated by diet and the microbiome overall. So neurology is really beginning to understand that this is important.
How can we keep our microbiome healthy and by doing so, our brain as well?
John Cryan: There are inter-individual differences and what might work for one might not work for the other, but one thing our microbes like is diversity. So having a diverse diet, full of fermented foods and fibres is always a good start. Polyphenols are key chemicals, present in foods, which give them lots of colour. You find them in nuts, red wine and dark chocolate, but equally in grape juice and onions. Polyphenols have also been shown to be beneficial for microbes.
We can try and minimise exposure to foods and substances we know have a negative effect on our microbiome, such as processed foods, artificial sweeteners in particular, emulsifiers. Also trying to minimise C-section rates in the Western world would be good. Stress is bad for our microbiome, jet lag as well, and as I previously mentioned, having a pet, especially a dog, is good for your microbiome.
What groundbreaking findings are you expecting in the near future?
John Cryan: Currently, I would like to see a few things breakthrough-wise moving forward. One is technology that is beginning to take off that can enable the sampling and measurement of the microbiome in situ and understand what’s going on. There is a lot of innovation in smart pills and various other biosensors that you basically swallow and you can communicate out. There are also innovations in smart toilets where people can use a mass spectrometer to measure their excrements. I think that is going to be extremely important.
Also, understanding the role of the microbiome in normal, everyday behaviour is going to be crucial to understand the contribution of the microbiome “out in the wild” in human everyday work. If we can get to that, we’ll also understand better how to target it in disease.
