What inflammation is really doing to your brain and body, plus 5 ways to protect yourself with Prof Ed Bullmore

Could inflammation be causing low mood, anxiety, depression, or even affecting your risk of dementia? 

Emerging science suggests that inflammation in the body may change how the brain works. In this episode, Ed Bullmore, a Professor of Psychiatry at King's College London and a leading voice in brain research, explores why feeling low, emotionally flat, foggy or exhausted may not always be “all in your head”.

Ed explores emerging science suggesting that inflammation in the body may alter how the brain works. He explains how inflammation can influence the brain and discusses why obesity, gut health, gum disease, menopause, ageing and stress may all play a role. He also examines why medicine has traditionally separated physical and mental health, and what this may mean for understanding the root causes of low mood.

If your mood, energy and brain health are shaped by more than what’s happening in your mind, what might your body be trying to tell you?

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Jonathan: Ed, can my brain be affected if another part of my body is inflamed?

Ed: Yes.

Jonathan: Am I more likely to experience depression if my body has inflammation?

Ed: Yes.

Jonathan: Are more people than ever visiting their doctor with mental health issues like anxiety, depression, and stress?

Ed: Yes.

Jonathan: Is someone's risk of depression mostly due to their genes? Yes and no. If you have inflammation in your body, can you always tell?

Ed: No.

Jonathan: Did we evolve to sometimes feel depressed? 

Ed: Probably. 

Jonathan: And finally, what's the biggest myth that you often hear about depression? 

Ed: It's all in the mind. 

Jonathan: I was brought up with a very traditional British attitude towards emotions. I was supposed to have a stiff upper lip, stay calm and carry on, and absolutely, no matter what, never talk about my emotions. And I suspect there's quite a lot of listeners who are probably brought up in that same way. And I've realized over the last sort of three or four years that this hasn't always been helping me. As well as doing this podcast, I'm the CEO of a startup. It's immensely stressful, and I find that trying to be a good husband and father is also really hard. And I think I have built this way of behaving over the last decade to pretend that everything is fine on the outside, while often on the inside I'm feeling very low, you know, sometimes really empty, you know, struggling to sort of keep going. And I understand that there are, like, millions of people who, like me, you know, are affected by low mood or anxiety or depression. You know, sometimes they might call it stress. And that many people continue to feel that even talking about that is a stigma, like something that you shouldn't do. And you've spent many years researching mood and mental health in the brain. What is mental health, and maybe how does that tie into some of what I've been talking about?

Ed: I think, you know, when we were brought up, and actually still, there's a very strong traditional view that mental health and physical health are completely poles apart. Mind and body have got nothing to do with each other. It's perfectly okay to go to your GP with a cough or a broken arm or some kind of physical complaint. But it's perceived quite differently, or has been, to fess up to some of the issues that you've just mentioned. Anxiety, depression, other mental health symptoms have, you know, traditionally been shrouded in secrecy, shame, and stigma. And I think that's partly because they've been regarded as completely separate from physical health. And one of the things that has intrigued me over the last ten, fifteen years particularly, is that the evidence is all pointing in a different direction. If you look at it scientifically and forget what you were taught growing up or what views you inherited from your parents. If you just looked at the scientific literature now, you would not come to the conclusion that physical and mental health were completely separate. There's all sorts of evidence indicating that they are linked, and particularly through the immune system. And that accounts for the connections between bodily inflammation and, let's say, increased risk of depression that we touched on earlier. So the scientific landscape has shifted, but a lot of people's habitual ways of thinking about these things haven't yet changed.

Jonathan: You know, so many of us might say, "Oh, you know, I feel really stressed," or, "I feel, you know, really anxious." Probably far fewer of us would say, "I feel depressed," or at least with like the sort of sense of the clinical depression. "I feel a bit depressed," but then it might be so different. Can you help us to understand what that is and, like, how common this is?

Ed: I don't particularly like that phrase, actually, mental health. I don't like the idea that we can think about health as entirely of the mind or entirely of the body. That split between mind and body goes back a long, long way. I mean, you know, you can find traces of it in the Bible. It comes through the Western philosophical tradition with Descartes. It gets embedded into the way that we think about scientific medicine, and that's carried on, you know, in the medical tradition ever since. So that's an ancient idea. It's got very, very deep roots. And the way the medical profession has been organized since at least kind of like the turn of the nineteenth, twentieth century, is to split out the doctors that look after the mind from the doctors that look after the body. I'm a psychiatrist, so I'm trained in the specialization of the mind. So the disorders that we were taught about and primarily treated are things like psychotic disorders. So that would be quite severe mental illness with symptoms of delusions, losing touch with reality, hallucinations, seeing things or hearing things that aren't really there. And that can come in a variety of different forms. Schizophrenia is one. Bipolar disorder is another. And then there's depression, which can range from mildly off-color or blue all the way through to severe hopelessness, a sort of nihilistic sense that really nothing is worth doing or maybe even that nothing is really real. Depression can merge into psychosis at the extreme end. Addiction, obsessive compulsive disorder. And then there are a whole other group of disorders, for example, attention deficit hyperactivity disorder, ADHD, that, you know, are sometimes categorized as neurodevelopmental rather than mental illness, but they contribute to a lot of problems for people, not just in childhood and adolescence, but into early adult life. So there's a whole catalog of psychiatric disorders. I mean, the American Psychiatric Association publishes periodically a manual, a diagnostic manual called DSM, which has been increasing in size ever since the 1950s when the first edition was published. It's become a thicker and thicker volume, as if we're discovering more and more different psychiatric disorders.

Jonathan: And are we discovering more and more psychiatric disorders—

Ed: No.

Jonathan: —or are we just getting better at recognizing them?

Ed: I think we're putting more and more labels on things, on behaviors and experiences, but have we discovered new diseases in the same way that, let's say, you know, going back 100 years, there was a kind of flurry of activity with people discovering all sorts of new infectious diseases or what caused infectious diseases, cholera, tuberculosis, syphilis, and so on. You know, there was a period in the history of medicine where there was a real surge of new discoveries about diseases, but most of what we're talking about in psychiatry doesn't really stack up as a disease. It's more like a sort of descriptive syndrome. If you wanted to have a formal diagnosis of depression, let's say, or bipolar disorder or schizophrenia, that would mean basically walking through a checklist of symptoms. And if you tick off the right combination of symptoms, you end up in a particular diagnostic category. But unlike the way that disease is diagnosed in the rest of medicine, in psychiatry, it's just enough to have the right list of symptoms for a particular diagnosis. It's not historically been important to understand the cause, the root cause. And I think that is the direction that we have to see things move in future scientifically. And I think as we get close to understanding the causes of depression or anxiety, we'll discover that actually you can be depressed for many different reasons. Sometimes there's going to be a significant genetic contribution. Sometimes there'll be environmental factors playing into it. Sometimes it's going to be a combination. And really the future of psychiatry, I would say, is going to take a much more causal approach to understanding what's going on. And the treatments that we offer people are going to be much more focused on what we think is the root cause of their symptoms rather than, as we currently do, offering a sort of one size fits all treatment. Anybody that comes to their GP and says a few things about how they're feeling low during the day or how they're having difficulty sleeping or a little bit of anxiety, that will usually be enough to trigger a prescription of an antidepressant drug, which is offered to patients more or less across the board without any deep understanding of what might have caused the symptoms in any particular case.

Jonathan: So sort of like you're treating the symptom. I'm thinking about this, you know, like I've got a cut on my arm, you put a plaster on it to deal with the cut. But if there's something underneath that's actually causing this—

Ed: Yeah.

Jonathan: —to keep happening—

Ed: Yeah.

Jonathan: —you're not really treating—

Ed: Yeah.

Jonathan: —the underlying—

Ed: Right.

Jonathan: —cause of this. Is that, am I understanding that right, Ed?

Ed: If you had, let's say, malaria in the nineteenth century, you would have been diagnosed as fever, tropical fever maybe. You're feeling hot. You go and see your GP. He tells you you've got fever and then treats the fever. And there are treatments that will lower the temperature of the body in the short term, but they're not treating the cause. And the big breakthrough in infectious disease was recognizing that a lot of people can have fever, but there might be a lot of difference between people in terms of why they've got fever. What is the germ? What is the root cause? And once you understand the root cause, then you can offer a treatment that tackles the cause, which is how we got to antibiotics and vaccines, and why infectious disease, at least for many of us in the West, is much less of a problem than it was historically. But in psychiatry, we're still more or less in the space of treating fever rather than treating specific bacterial infections. How can you really be effective in terms of treatment or prevention if you don't understand what's causing the problem in the first place? And then if you think about, you know, let's say depression, what are the causes of depression? If you look at the current psychiatric manual that I was talking about earlier, and you read the criteria for a diagnosis of depression, you can have all sorts of symptoms. You can sleep too much, you can sleep too little, you can put on weight, you can gain weight, you can be hyperactive, you can be slow in your behavior. All of those are symptoms of depression. So you can see just by that checklist that you're going to end up with a very heterogeneous group of people who might have quite different experiences of illness, but they're all lumped under the same diagnosis. The only exclusion criterion is that you can't have a diagnosis of major depressive disorder if there's a physical bodily cause for it or if there's any kind of, you know, background physical illness. So if I had rheumatoid arthritis, for example, which is, you know, a bodily inflammatory disorder with pain in my joints, and I went to my GP, my general practitioner, primary care physician, and said I've got the pain, I've got these arthritic joints, and I'm feeling depressed. At the moment, people would say, "Well, that's comorbid depression." That's some kind of like you're feeling depressed perhaps because you realize that you've got this systemic autoimmune problem. It might get worse over time. Maybe you've seen other people with rheumatoid arthritis who become progressively disabled. You know that, and you're predicting a gloomy future for yourself, and that's why you're feeling depressed as well as having the joint pain. That's the traditional way of dealing with it, to separate the mental symptoms of depression and fatigue and brain fog, which are extremely common among people with all sorts of bodily inflammatory disorders from the physical problem and the physical treatment.

Jonathan: Just struck by this conversation, you said that in the medical profession, we sort of split doctors very early in their career between doctors of the body and doctors of the brain, which is a really funny thing to do when the brain is part of the body.

Ed: And we split the doctors into doctors of the mind, doctors of the brain, and doctors of various other bits of the body. It's, I would say, administratively convenient for the medical profession to organize itself in that way. But it doesn't really address the reality of illness. Because I think anybody who's been through any kind of illness episode, I mean, it's not necessarily severe, will know that the experiences are seamless mental and physical symptoms usually. I mean, in my book, The Inflamed Mind, I talk about my experience with periodontitis, right, gum disease, and going to a dentist with pain in my jaw and feeling quite low. And the dentist did a root canal treatment, fiddled about in the sort of infected cavity left by the removed tooth. And I went home and felt really quite glum, and my first thought about that was along traditional lines that, you know, I had a problem in my mouth. This tooth had been infected, and I'd gone and got treatment for it, and I was feeling depressed because that experience had made me realize quite literally that I was getting long in the tooth. It had given me a sort of foresight of my own mortality, and that's why I was gloomy. And then I thought, well, no, actually, maybe it's not that. Maybe the infection in my mouth and the dentist fiddling about there and kind of aggravating the local inflammation has triggered a release of proteins called cytokines, which are like, you can think of as inflammatory hormones from my tooth circulating through the body, getting into my brain, and just biasing the way I think about things into a more depressive perspective. That's an experience of illness where you've got a local problem in your body, in this case my tooth, and you've got a psychological sort of reflection of that, feeling depressed. And usually we say those are two separate things.

Jonathan: You're saying actually there's inflammation in your tooth and then indeed the dentist sort of treating it, you know? Yeah. We all know when we go to the dentist, if they do anything like that, it's painful at the time, right? You're actually saying that is triggering a set of chemicals and the cytokines—

Ed: Yeah.

Jonathan: —as part of that—

Ed: Yeah.

Jonathan: —that actually cause your mood to change for you to feel lower mood, maybe even depressed as a direct result—

Ed: Yeah.

Jonathan: —of this physical thing.

Ed: Yeah. I think one key thing that, you know, it's worth just emphasizing at the outset is the immune system is a whole body system, you know? So even if you've got inflammation in your tooth or in your thumb, even if you can kind of point to the bit of your body that feels most inflamed or looks most inflamed, that isn't the limit of the body's inflammatory response. Almost always, when you've got a local hotspot of inflammation, you're going to have a systemic response as part of it. So you will have increased levels of these hormones, cytokines, which, you know, stimulate immune cells in other parts of the body. They will be in increased concentration in people with local inflammation. You know, the levels of immune cells, the white blood cells in the circulation will also change as a result of local inflammation. So I think that's one thing that is important for people to understand is that inflammation is almost always systemic. It almost always involves the whole body to some degree.

Jonathan: I think that's fascinating, and I think it links back, as you said, to your book, The Inflamed Mind, which talks a lot about these links between sort of the inflammation that you have in your body and your mind and particularly depression there. In fact, I'm thinking about this. I'm thinking that my dad is nearly 80, and he still thinks that being tired is mental weakness that should be overcome and has—

Ed: Right.

Jonathan: —like no relationship—

Ed: Yeah.

Jonathan: —in fact, to anything you can do. He'd be like, "Ed, this is nonsense. If you just have the right mental attitude, you can ignore all of this. Like, this is completely separate."

Ed: Well, whatever the cause of fatigue or depression, I mean, I think it is important often to kind of cope with it as productively as you can, which I suppose would be in line with your dad's advice. But I think we should also just give ourselves a break and recognize that if people are coping with persistent fatigue, struggling to think clearly about things, feeling quite gloomy or tearful at times, it's not just that they lack moral fiber or that they should pull up their socks or, you know, all of the sort of more traditional ways of kind of encouraging people to sort of just power through these symptoms. They will have physical causes.

Jonathan: You already mentioned the fact that sort of inflammation is happening and it's a sort of whole body thing. Could you just explain in very simple terms what is inflammation and, you know, you gave us an example of your sore tooth, but why in general is it happening in the body?

Ed: Inflammation really is the first line of the immune system defense against attack. As soon as you're born, you are exposed to what is actually quite a hostile environment biologically. There are all sorts of germs, bacteria, viruses, other sorts of risks that you're exposed to as a very young child, and you need to be defended against that, and it's the immune system that provides that defense. And particularly there's a part of the immune system, it's called the innate immune system, meaning that it's kind of fully wired, it's fully programmed at birth. You're born with this, and it's the innate immune system's response to the infections that you first encounter as a child that causes inflammation. That innate immune system, that innate responsivity to being attacked from outside often by a germ of some kind, is hugely important. But also inflammation can cause disease. It's a bit of a double-edged sword. Sometimes the immune system can get a bit carried away, you might say. It can misidentify parts of the body as if they were infectious agents. This is the story for autoimmune disease, for example, arthritis, many other kinds of joint disease. Good example of an autoimmune disease where the immune system has mistakenly identified some part of the body as if it was a hostile agent and has started attacking the body, which causes persistent inflammation.

Jonathan: And so persistent inflammation means rather than like I've had a cut, something happens—

Ed: Yeah.

Jonathan: —my immune system is involved and it swells and then it treats it, it sort of continues ongoing, you know, even though in fact my cut has healed over and I don't need it anymore?

Ed: Exactly. If I had an infected cut in my hand, as you say, it would get inflamed, so it would get swollen, it would go red, it would feel tender. That is all indicating that the immune system is piling into that area and trying to kind of kill off the bacteria that are causing the wound to be infected. And if the immune system is successful and it can kill off the bacteria and eliminate the problem, then the inflammation fades away and you think, great, the immune system's all good. But if the immune system mistakenly identifies some particular protein in your joints as a problem and starts attacking your joints, it's never really going to go away because the immune system can't kind of eliminate your joints in the same way that it could kill off the bacteria that are causing the infection in your hand. There's never going to be a decisive victory for the immune system once it starts attacking the body itself.

Jonathan: Could you help link that to the brain now? Like, inflammation seems to come up over and over again—

Ed: Yeah.

Jonathan: —on these podcasts. It's fascinating. But it's never really been linked to sort of the brain and your mood and things like that. So what happens? How does something that's going on in my joint or my arteries or whatever lead to something happening in my brain?

Ed: When I was at medical school, which was in the 1980s, one of the things we were taught, as a matter of fact, is that the brain is somehow protected from the immune system. The jargon for it was the brain is immune-privileged. It sort of sits outside the immune system, and that was supposed to be because it was protected by this thing called the blood-brain barrier.

Jonathan: Sounds like a handy thing to have. What does it do?

Ed: To be honest, it doesn't really exist. But what we were taught at medical school is that there was something like a Berlin Wall around the brain that meant that blood cells and proteins that were circulating in the bloodstream couldn't get across the blood-brain barrier and into the brain. So let's go back to the example of rheumatoid arthritis. The idea that somebody with rheumatoid arthritis and all sorts of inflammatory activity going on in the body and circulating in the blood, that that could have anything to do with mood, that was kind of ruled out straight away because how could it have an effect on mood if it didn't have an effect on the brain, and it couldn't have an effect on the brain because of the blood-brain barrier? That was what we were taught, and actually, I think that is still current teaching in a lot of medical schools. The brain is sort of sealed off from the rest of the body or at least from the rest of the immune system.

Jonathan: And it's not true?

Ed: No, it's not true. So, you know, I was talking about cytokines, these kind of like inflammatory hormones that are triggered whenever you have a local inflammation anywhere in the body. Those proteins we used to think couldn't get across the blood-brain barrier, but now we know that they can by various different routes. In fact, the white blood cells, the cells of the immune system, can also get across the blood-brain barrier.

Jonathan: So this whole idea that none of the, that, like, your blood can't get into your brain—

Ed: Yeah.

Jonathan: —and none of the components of the blood—

Ed: Yeah.

Jonathan: —can get into your brain—

Ed: Yeah.

Jonathan: —which I have definitely been told—

Ed: Yeah, yeah.

Jonathan: —this just isn't true.

Ed: No. It's not like a wide-open door, but nor is it a Berlin Wall. It's a filtered portal. So protein cells can get in and, you know, that is very likely how somebody with a physical disease like arthritis, again, and those kind of hormones circulating in the blood, the circulation carries those inflammatory hormones to the brain, and they can get into the brain and trigger changes in neuronal activity, in nerve cell, in the activity of the nerve cells in the brain.

Jonathan: So I've got this inflammation. It's created these hormones that you called cytokines.

Ed: Yeah.

Jonathan: They are in fact slipping through the Berlin Wall, you know, late at night or, you know, under the barbed wire or whatever, getting into my brain.

Ed: Yeah.

Jonathan: How does that then cause me to be depressed or anxious or whatever?

Ed: We think of the brain as important in perceiving the outside world in vision, hearing, smell, and so on, picking up signals from outside. But there are also parts of the brain that are specialized at kind of tuning into the bodily environment. They're called interoceptive systems in the brain. So they're focused on perception of the internal state of the body rather than the external state of the world around us. And those systems are quite responsive to inflammatory changes in the body generally. You're going to ask me, how does that cause mood changes? How does a conscious sense of gloominess about the world around us, how does that arise from the activity of nerve cells? But what we can see quite clearly from, let's say, brain imaging studies, is that if you change the inflammatory state of the body, you will change the functional activity of the brain in brain circuits or brain networks that we know are important for mood and for mood disorders.

Jonathan: You're saying the science is really quite clear now that if I have this raised inflammation in the rest of my body, it sends hormones into my brain, and those literally lead to changes in parts of my brain that are directly related to my mood.

Ed: Exactly. And the other thing I would say is that if you look at animals, and you make animals inflamed, a technique that's experimentally been much used in trying to unpick all of this in detail, if you make an animal inflamed, it changes its behavior. It can't tell you it's feeling gloomy about the future, but if you look at the way it's behaving, a mouse that becomes inflamed will be less exploratory. It'll be less mobile. It'll be less interactive with other mice. There's a whole sort of suite of behavioral changes that you can trigger in animals with inflammation that look a lot like some of the things that we experience as humans and call depression. The thing to remember about the immune system is basically its only job is to try and keep us alive. And if it helps us to stay alive, even after we've been infected or injured or suffered some kind of cause of inflammation, if it helps us to survive, to change our behavior, change our sleeping patterns, change the amount that we eat, perhaps change the extent to which that we interact with, you know, our family or the wider social group that we're part of. If those changes help us survive, then they will be selected by natural selection. They'll have evolved as part of the immune system's repertoire of response to help the animal or the human get through the trauma or injury, which might otherwise be life-threatening.

Jonathan: So Ed, I'm listening to this, and the other thing I'm thinking about is it feels like there's been this explosion of rates of mental health issues over the last few decades. And, you know, anxiety is one of those things that people report enormous increases. Is there, like, a big increase in these issues of mental health over the last 20 or so years? And then how do we understand this? Because you're saying there's this mechanism that, like, your body is inflamed, this leads to these mental health issues. So does that mean that also that the inflammation has been rising? What's actually going on from your perspective?

Ed: We are facing what looks like a wave of increased incidents and severity of mental health problems. Some people would say that's just because the current generation's a bit softer. Or maybe instead of kind of bottling this up and trying to cope with it, people are more vocal about it and open about it. Or maybe that practitioners are getting a little bit more liberal in making these diagnoses.

Jonathan: And Ed, what about sort of anxiety and depression? 'Cause I definitely feel like we're all just a lot more anxious than we were when I was growing up.

Ed: Yeah. Well, we're definitely talking more about it. Perhaps not as startling as some of the other areas that I've already mentioned. But I think, yes, there is certainly increasing demand for services.

Jonathan: If I go back to this idea you're sharing that these mental health issues are being driven by inflammation in my body, presuming that means that we're having more inflammation, more of this longterm inflammation in our body than our ancestors used to have, what's causing this brain inflammation?

Ed: One, you know, important nuance here is that there's a difference between having a syndrome and having a disease. At the moment, we're talking about depression as a syndrome, and I would think that over time what we will discover is that there are a number of different pathways to becoming depressed, in the same way that there are a number of different infections that can cause fever. Some of those people with depression are going to have an important inflammatory or immune component. We think it's probably about thirty percent or so of people with severe depression have got a significant inflammatory component to it, and then there are all those other people that have got inflammatory disease in the body, like rheumatoid arthritis, who will have depressive symptoms that we can't currently diagnose as a major depressive disorder because of the curious diagnostic system that we've inherited in psychiatry. If you go to your primary care physician and you say, "I'm feeling low, I'm gloomy about the future, I'm not sleeping very well," and the other symptoms of depression, within a few minutes, they will have prescribed an antidepressant and/or a course of cognitive behavioral therapy, and you'll be out the door and back on the street, as it were. What doesn't happen very often is people taking a moment to think, okay, so you've got these depressive symptoms. Are there relevant inflammatory or other physical problems that we should be thinking about as a sort of three hundred and sixty degree approach to investigation and treatment of your issues? GPs don't routinely screen for inflammation when they're consulted by people with depressive symptoms.

Jonathan: And could we talk about those now? And I think some of these you mentioned in the book. And the first one to me is a huge surprise, obesity.

Ed: The more obesity, the more inflammation. If you do epidemiological research or large-scale population research, there's a lot of evidence for a pretty robust association between obesity and depression. People with depression are more likely to be obese. People with obesity are more likely to be depressed. We've known that for ages. But the way that we've usually interpreted it, the way we've traditionally interpreted it, is to say maybe people with obesity are depressed because they don't like the way they look or they feel ashamed about their appearance. So that's a kind of psychological sort of overlay on the physical problem of obesity. The new concept is just that this very robust association between obesity and depression is driven by a causal process. You know, the accumulation of fat tissue and the immune cells in the fat causes release of these inflammatory hormones, which changes the way the brain operates in a way that makes people feel depressed.

Jonathan: That actually switched me almost naturally, I think, onto the second one, the microbiome. Lots of people listening to this podcast obviously are ZOE members and have used it and sort of adjusted their diet and one of the things that people tend to be most surprised by, and I was most surprised by, is the way in which your mood can shift, like your energy and things like this very fast, like much sooner than you then see in like some of maybe like some of the blood work that might take three or...

Ed: Mm.

Jonathan: ...or longer months. How does that tie into this story you're talking about, and is there any role for the microbiome in here? Do we know?

Ed: Oh yeah, definitely. I think what I was taught at medical school is what everybody was taught at medical school and what everybody is still taught at medical school to a large extent, and that matters because that fixes the medical mindset. And what we were taught about diet and mood was nothing. And what we have seen progressively since then is people becoming aware that inside our gut we have a large and complex sort of collection of bacteria, some of which are potentially dangerous. And if you change the composition of the microbiome, you are going to elicit an immune response in the gut. You know, if you look where in the body the immune system is concentrated, a lot of it is in the gut, and that makes perfect sense because the gut is arguably our most vulnerable frontier, and it has to be vulnerable by design because the gut is intended to kind of extract nutrients out of what we eat. The gut wall is permeable. If you change the composition of the microbiome and hostile bacteria become more abundant, there is going to be an immune response.

Jonathan: So do you, like, the fact that we have worse microbiomes in the past could be something that helps to explain the fact that mental health is worse, and then the other way around, that if we had better microbiomes, that could potentially reduce these symptoms of mental health?

Ed: I think so, in some people. Okay, again, I don't want to kind of imagine there is a panacea and that everybody needs to have, you know, fecal transplants or some kind of radical treatment for the microbiome, and that's going to make depression go away. But there will be cases where you can see that there is a change in the microbiome and that there will be dietary or other interventions that can shift things into a healthier direction, and that should trigger less of an immune response in the gut, and that should give a better sense of mental health, but probably also better brain health as well.

Jonathan: Amazing. Let me move on to the next one, and I feel it was triggered by your little story at the beginning. Tooth decay.

Ed: Yeah.

Jonathan: That seems like it can't be very important.

Ed: Oh, it's very important. The mouth, the teeth, the gums are obviously the province of dentists. Dentists and doctors hardly talk to each other. Doctors very rarely look inside a patient's mouth. My mouth is part of my body. How have we got used to the idea that, you know, I go and see a doctor in, you know, my general practice clinic for a bodily symptom, and I go and see a completely different kind of practitioner when I've got a problem in my mouth, and they don't talk to each other? You know, my dental records are invisible to my medical practitioner and vice versa to a large extent. A problem that a lot of people have, particularly adults, is gum disease, which is a low-grade infection, which can cause inflammation that's quite, you know, difficult to eradicate. In the mouth, inflammation is systemic. If I've got a local inflammation in my wisdom tooth here, that is going to be causing release of cytokines. I would be able to detect that as a source of inflammation in a blood test, and that I think can contribute to brain and mind problems.

Jonathan: And so Ed, is there a real link between, like, people with gum disease having higher levels of depression and things like this?

Ed: Yes, and also I should say I'm not 100% sure how solid this evidence is, but I've always thought it's very interesting and it needs to be further investigated, the links between dental inflammation and brain aging, and whether, you know, gum disease is contributory to risk of dementia. Sounds slightly outlandish when you first think about it, and we've talked mostly about the psychiatric disorders of, let's say, children, adolescents, and adults. But I think we need to also think hard about the role of inflammation in brain aging and how inflammation in the brain can accelerate dementia.

Jonathan: And there is a clear link between raised gum disease and more risk of dementia?

Ed: There is an epidemiological association, yeah.

Jonathan: What about menopause and post-menopause?

Ed: There is some evidence that going through menopause changes the inflammatory state. People have talked about menopause being a risk for inflammation, and certainly going through the menopause is often a crisis or can be a crisis in mental health for some women. I would say this is another area where we've traditionally sort of not taken a very integrated approach to understanding what's going on. So a woman who is feeling depressed around the time of menopause or after menopause might often be told, "Well, you know, you're just reflecting on your loss of reproductivity." But I think there are important endocrine and immune changes around the time of menopause that we should be thinking about as contributory to the mental health symptoms that arise then.

Jonathan: One of the things I'm really interested by is the way in which you say the traditional way that doctors thought about this is almost let me explain this away. Like, something's happened, like you've put on lots of weight or you're going through menopause or you're sick or whatever. Therefore, it's logical that you would feel depressed about things, therefore that explains it.

Ed: Yeah.

Jonathan: Whereas it feels like you're saying, well, in all of those cases you can see there are these really big changes in hormones in your body, your inflammation levels are really high. And actually that could be the cause, and therefore if you were to be able to treat the underlying inflammation but not change the rest of it, then actually suddenly those mental health situations might fall away without the change in the situation that you're sort of claiming is the logical argument. Which is a pretty radically different way of thinking about this.

Ed: It is from the point of view of the medical profession, yeah. You know, I think from the point of view of most patients, it's not that radical. I think if you talk to a lot of people who are going through the menopause or who are obese or have arthritis, if you actually talk to people about what they're experiencing, as I said earlier, they will usually have a kind of more or less seamless experience of both physical and mental symptoms. The idea that the bodily illness can have something to do with the brain, I mean, how on earth has that come to seem like a radical idea? You know, really, I just don't understand it.

Jonathan: Can I come on to aging now? Which also was a big surprise to me.

Ed: We tend to get more inflamed as we get older. Our brains as we grow older, they lose processing capacity, basically. They lose nerve cells. Cognitive capacity falls off as you get older, working memory. So there are these normal background changes in the brain, and there is also a tendency over time for the immune system to become more inflamed as people grow older.

Jonathan: You're saying aging in general leads to brain changes—

Ed: Yeah.

Jonathan: —and increases the risk of things like dementia and Alzheimer's and things like that.

Ed: Yeah.

Jonathan: If I have a high degree of inflammation in my body—

Ed: Yeah.

Jonathan: —then actually that's going to accelerate the rate at which those changes happen—

Ed: Yeah.

Jonathan: —and therefore increases my risk of Alzheimer's and things like this?

Ed: Yes. I mean, that's broadly correct. But I think it's not so much that inflammation causes Alzheimer's disease so much as inflammation could accelerate the rate of progression of Alzheimer's disease.

Jonathan: Should I think about it a bit like I might have a genetic risk—

Ed: Yeah.

Jonathan: —of heart disease? If I eat a terrible diet and, you know, sort of bacon for breakfast every morning—

Ed: Yeah.

Jonathan: —I've got a really high chance of it. If I eat really well and I'm exercising—

Ed: Yeah.

Jonathan: —and all these sorts of things, then actually I might, you know, be fine and live to be 95.

Ed: Yes. That's roughly right. Obviously, there's a major focus on trying to find new treatments for, let's just focus on Alzheimer's disease and, you know, other causes of dementia as well. And the treatment that is currently out there is pretty minimal. But when you actually look at the brains of people with Alzheimer's disease, what you can see is that these amyloid deposits, you know, these abnormal proteins that are kind of like the diagnostic hallmark of Alzheimer's disease, they are recognized by the immune system as if they were hostile or alien agents. So they trigger an immune response, an inflammatory response in the brain. And if you can damp that down, you can protect the nerve cells and you can slow down the rate of nerve cell loss, and therefore slow down the rate of cognitive impairment that ultimately ends in a state of dementia.

Jonathan: So if we could reduce this inflammation—

Ed: Yeah.

Jonathan: —and the effect of this inflammation on your brain—

Ed: Yeah.

Jonathan: —then we could really slow down the rate at which you develop dementia, Alzheimer's, whatever.

Ed: Yes.

Jonathan: What are the lifestyle factors that are most important for affecting brain inflammation that, you know, we could change?

Ed: So physical exercise, particularly if it's sustained, is anti-inflammatory, and it has beneficial effects on mood. If you look at trials and large-scale observational evidence, it's pretty clear that there is an association between physical activity, physical fitness, and levels of mental health. It's also pretty clear that there is an association between physical fitness and inflammation. People have done randomized trials of physical training, physical fitness, and have demonstrated moderately effective shifts in mood equivalent to what you'd see with antidepressant drugs.

Jonathan: My doctor could prescribe me exercise or antidepressants, and they have about the same level of impact.

Ed: Yeah, they do. It's always important just to bear in mind that a lot of the evidence we're talking about is kind of like aggregated over thousands of people. But if I was struggling with symptoms of depression and anxiety, that is one thing I would definitely do. What is beneficial seems to be from the data that we see at the moment is a sort of sustained regime of physical health maintenance. And I don't think that necessarily needs to be kind of like going to the gym and doing something extreme. It just needs to be making sure that you kind of stay active every day.

Jonathan: So could walking every day, like, can that count as exercise or does it have to be...

Ed: Yeah, definitely. It can. Yeah. I just count my steps every day and just make sure that I'm doing ten thousand or thereabouts.

Jonathan: What about diet?

Ed: There's a pretty good association between a so-called Mediterranean diet and both inflammation and depression. There's also some associations between ultra-processed foods and both inflammation and depression.

Jonathan: And I'm guessing the Mediterranean diet is good, but the ultra-processed food not so good.

Ed: Yeah. I think what's interesting about those three things, ultra-processed food, physical fitness, mobility, and Mediterranean diet, is that there's a lot of data accumulated, particularly over the last five years or so, to show that in all three of those cases, there's an association with both inflammation and mental health symptoms. I mean, the most parsimonious explanation for that is that there is a causal relationship between diet, the state of the microbiome, inflammatory response, and that's why dietary changes can shift mood.

Jonathan: One thing we haven't really touched on at all is stress in our lives. So, you know, we talked about many other factors, some of which we can change, some we can't. How much does that matter and what can we do to improve things?

Ed: People think of stress, particularly social stress, as if it was only detected by the mind. But what we can see, you can see this in animals, for example, if you stress an animal, it elicits an immune response. And this goes back to what the immune system is there for. The immune system is there to keep us alive under hostile conditions, and those hostile conditions could be a bacterial infection or it could be some kind of psychosocial stress. Perhaps particularly in the first few years of life, you know, one of the things that we really know in psychiatry, and we've known this for a long, long time, is that if you're exposed to stress as a child, that has very long-term adverse consequences, or often has very long-term adverse consequences for your mental health in decades to come. Why is that? You know, I think a really interesting idea that needs further investigation is that if you're exposed to stress, and I'm talking things like abuse, neglect, extreme poverty, loss of a parent in the first few years of life, those are major threats to the survival of that child. They elicit an immune response, and the immune system has a memory. We haven't really talked about that, but I mean, that's why vaccination works. You know, you can expose the immune system to a stress and it will remember that for decades. And I suspect that how the immune system responds to stress and particularly how the immune system remembers the stress it was exposed to as a child, I think is going to be really important for us.

Jonathan: If you were advising a patient actionable advice, things that you could choose to do, you know, whether that's talking therapy on one side and all the stuff that people in wellness are so keen on about meditation and yoga, what would you say across those sorts of things?

Ed: If you'd asked me 15 or so years ago, what do I think about the potential benefits of yoga for mental health? I would have thought that was a bit woo-woo. Now I think I'm much more liberal in what I can imagine could really work. New ideas that have come out of the science of the immune system, the brain, and the mind over the last 10, 15 years, they do allow us to think quite differently about what might work and why. The interventions you're talking about, lifestyle changes, activity, diet, yoga, meditation, there's not really much downside to any of that. I don't see any reason why you wouldn't want to give it a go. And certainly for the exercise and dietary things, I think there's pretty good evidence that if it's effective, it might be through the immune system.

Jonathan: What does the science say about talking therapy?

Ed: Well, they're moderately effective on average, let's say cognitive behavioral therapy, which is a sort of default for mild to moderate depression and anxiety. There is an effect that has been evidenced in trials. Psychotherapy looks like it works for some people.

Jonathan: One final question. So if someone is listening to this podcast and it's really resonated with them, maybe they've been feeling consistently low or emotionally flat or, like, really anxious, where would you suggest they start?

Ed: The official answer to that is they should start by consulting their primary care physician or general practitioner. People really shouldn't feel shy or ashamed to seek medical attention. Then, and this is easier said than done, try to get into a conversation with your primary care physician about your mental health symptoms as part of your broader physical health. So in other words, try and get the medical profession to think more about you as an individual with both mental and physical symptoms, rather than allowing the medical profession to compartmentalize you into different kinds of problems that need different specialist input.

Jonathan: Ed, thank you so much. I would like to do a quick summing up and just correct me if I get anything wrong, please. The thing that I go to first of all is this amazing idea that when I have inflammation elsewhere in my body, it actually changes the part of my brain that controls my mood. And you describe that there are these hormones like these cytokines that might be caused by this inflammation somewhere else, and actually those get through into my brain. And so this idea that my mind and my body are two completely separate things just isn't true. That there has been a surge of mental health issues over the last few years, and that one of the reasons why somehow we don't talk about this in the same conversation as we talk about maybe the ultra-processed food or the obesity epidemic or any of the rest of it, is that the medical profession is broken up into people who think about the body, people who think about the mind, and people who think about the mouth. And they're like three completely separate groups that never talk to each other.

Ed: Yeah.

Jonathan: And you sort of said, "It's sort of mad. That's not the way the body is. It's just an accident of history." I was really struck. There are a number of factors that can drive depression and mental health that I wouldn't have thought about. So you, for example, describe living with obesity, that just leads to much higher levels of inflammation in your body that leads to higher depression. Talked about the microbiome, like the evidence is earlier, but again, seems like lots of reasons with so much of the immune system being focused on managing the microbiome to think this is directly linking through to mood. Gum disease. You said if you have higher levels of gum disease, that is actually linked to higher levels of dementia and Alzheimer's. So there's this direct link between sort of this inflammation around your teeth and this terrible brain disease. Perimenopause and menopause. You said that often changes levels of inflammation, and it's a time of many mood issues for a lot of women. And again, you could jump to it's something that's all in the mind, but actually very often it could be to do with something that we know. We've done a lot of menopause-related studies at ZOE. These huge changes in your metabolism and all of these sorts of things. And last but not least, aging. Naturally, your brain changes. As you're aging, your risk of dementia goes up. If you have this higher inflammation, this can sort of accelerate your rate. So if you're aging and you've got high inflammation, this is a really big risk for then getting Alzheimer's. But the good news is you're not all stuck with whatever sort of your genes gave you. There's things you can do. You started with exercise. You said the evidence for this improving mental health is really strong, and you don't have to be pounding away in the gym. Even just walking every day, like doing more movement can have a real impact, but it's something you want to do regularly. That the evidence for a good diet, you talked about a Mediterranean diet, which is very similar to what we talk about a lot across this show, can improve mood, and your hypothesis is probably the microbiome is a central part of what shapes this for the reasons you've talked about. And similarly, we're just starting to see ultra-processed food is bad. We know that ultra-processed food increases inflammation, so I think that also helps to explain. A bit depressing that this is about 70% of our diet across the Western world now. And last but not least, we talked a little bit about stress and yoga and meditation. And so you said 15 years ago, you'd have thought it was wishful thinking, woo-woo, you know, a bit mad. But you're starting to think that it might be possible that things like yoga and meditation could really impact your mood for the reasons that we think about the mind and the body are in fact one thing.

Ed: That's right. That's a very good summary.