Using Your Nervous System to Enhance Your Immune System | Huberman Lab Essentials

Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, we are discussing the immune system. And we are also discussing how the nervous system can be used to activate and control the immune system. The first topic we have to attack is the question of what is the immune system and how does it work? I'd like to just take a moment and do a sort of brief immune system 101. Really simple. Cover the basic elements of the immune system, so that everyone listening or watching this can get a clear sense of how the immune system functions and what its basic parts are. It's actually really simple because it is truly elegant in design. You have three main layers of defense for your health. And the first of those three is a physical barrier that we call your skin. And that might seem kind of obvious, but everything about you is contained in this compartment that is boundary by your skin. If you've ever had a cut, you essentially have a breach of the boundary that is your immune system. Still in category one, your body and your external surface, you have openings to that surface. So, what are those openings? Well, let's start at the top and work our way down. A primary site of potential infection are your eyes. You have your ears, you have your nostrils, you have your mouth. Okay, those are going to be the primary sites by which things can get into your system, and you need to put things into your system, you need to drink and eat, and you need to get light into your system, that's why you have those openings. And then, of course, along the back of your throat, all the way down to your stomach and your digestive system, and through your intestines and out your rectum, you have a tube that you are basically a series of tubes. I've said that before in this podcast, and this is one such tube by which you extract nutrients from the outside environment. But, all along that tube, including your nose and your mouth, it's lined with mucus. And while mucus might seem kind of gross to some of you, the more you learn about mucus, the more you realize that mucus is really, really cool. Because mucus essentially acts as a filter, as a trap for bacteria and viruses, and it has certain ways of scrubbing or killing those bacteria and viruses. Now, inevitably, bacteria, viruses, and parasitic infections are going to make their way into our body. But, whether or not they are killed off or whether or not they take over and cause us harm is going to be determined by layers two and three. So, layers two and three are the so-called innate immune system and the adaptive immune system. So, the innate immune system is what I would call the second layer of defense. It's very fast. So, this innate immune system is this rapid response. When something enters our system and our body doesn't recognize it, it's something that's either a bacteria, virus, or parasite. And the innate immune system involves the release of particular cells that are waiting, dormant, ready to attack whatever this invader is. And some of these cell types you've heard of before. The most typical one are the are the so-called white blood cells. So, the white blood cells will actively go to the site of invasion and will start to encapsulate or try and um surround that given invader. The other names of these different cell types are things like neutrophils, macrophages, natural killer cells. They're just a few of the many types of immune cells. They work in concert with two other assistants. And those assistants are called the complement proteins. Complement proteins exist in the blood and what they do is they travel to sites where there's an invasion and they mark certain things for being engulfed and eaten. So, they sort of put a a an eat me tag on it. And then there are the cells that are either damaged from the injury or from the parasite or are suffering because of the bacteria or the virus itself. And the cells of your body will also release an alarm signal, which is not an eat me signal, but a help me signal. And those help me signals come in the form what we call cytokines. And the cytokines are things like interleukin 1, interleukin 6, tumor necrosis factor alpha. The interleukin are shouting out help me. The complement proteins are coming in and saying eat eat this and tagging the the invader with an eat me signal. And then the killer cells and the white blood cells are doing the job of of trying to kill off that thing. That's the innate immune system. So, that your skin and your mucus lining plus your innate immune system are a beautiful two-layered set of defenses against various kinds of invaders and infections. And then there's the third type, which is the adaptive immune system. And you'll notice that leading up until now I haven't said the word antibody at all. And that's because it is the job not of the skin or the mucus or the microbiome or the innate immune system to produce antibodies that can recognize specific invaders, but rather it is the job of the adaptive immune system to create antibodies against bacteria, viruses, and even parasites, and even physical um intruders to your system. So, the adaptive immune system has this incredible ability to show up at the site of invasion or infection or inflammation. And what it does is it actually attaches to and creates a sort of a an imprint of the shape of whatever invader happens to be there. And then, using that imprint in concert with some other cells, creates antibodies that are specific to recognize that invader should the body ever have that invader inside of it again. Now, that's why it's called the adaptive immune system. And in many ways, it creates a memory of a prior infection so that these antibodies can be made anytime that same invader comes back again. All right? And so, this is the basis of what we call immunity. Now, there are a lot more details to the adaptive immune system, but I just want to emphasize a a few points that might be relevant. Um first of all, the name of the antibodies that are created sometimes come in the form of IgM and IgG, things of that sort. This isn't a full deep dive immunology class, but IG stands for immunoglobulin, okay? So, the immunoglobulins are part of the adaptive immune response in in creating antibodies. If you hear IgM, the IgM is the first of the adaptive immune responses, and it tends to come on earlier. So, if somebody is immunopositive for IgM for a particular type of viral or bacterial invader, that means that it was a fairly recent infection. Later, one creates the adaptive immune system, I should say, creates an IgG, which is the more stable form of the specific antibody that's going to recognize a given invader. So, IgG tends to come up a little bit later. So, just to recap, something gets into your system, then there's the innate response, which is a more general response of trying to contain and combat the infection or invader, and then the adaptive response is the one that generates the antibodies first, the IgM response, the immunoglobulin M response, and then the immunoglobulin G response, IgG response. So, how do we keep these three barriers or these three defense systems to infection tuned up? One of the key ways we can do that is to keep that mucus lining in really good shape. And what does that mean? Well, the the mucus lining needs to turn over quite often, and it needs to be the correct chemistry to be a trap for the bad stuff, and for it to be permeable to the good stuff, to the nutrients that we need. And it is now very clear from hundreds, if not thousands, of studies that the best way to do that is to maintain a healthy, so-called microbiome. The microbiome being these little bacterial organisms that are good for us, that live all along our mucus pathways, and even in our eyes. Now, just to be really clear, it's not just about the gut microbiome. We actually have a a microbiome in our eyes, we have one that's specific to our mouth, we have a nasal-specific microbiome, there's one all along the gut, and the species of microbiota that live all along the digestive tract differ from the mouth to the throat to the stomach, intestines, and to the rectum. It's well established that there are healthy microbiota that live all along that length, and that they differ along that length. This is a reminder that whenever possible, unless eating or speaking, you want to be nasal breathing, not breathing through your mouth. Your nose is a much better filter for viruses and bacteria than is your mouth. And so, be a nose breather, not a mouth breather, you will combat more of the infections that you are constantly confronted with. The other way to try and keep out bad things and to avoid getting sick is the advice that your mother and certainly my mother gave me, which is to not touch your eyes after touching other people or touching other surfaces. And the reason to avoid doing that is the eyes are a primary entry point for a lot of bacteria and viruses. And then the third way to keep a healthy line of defense for your entire mucus tract is to enhance the proliferation of good gut microbiota. The best way to enhance the quality of your gut microbiome and the mucus lining that serves as this protective layer all along your body is to ingest two to four servings a day of fermented foods, low sugar fermented foods. It helps reduce the activity of certain cytokines. When people have a healthy gut microbiome, there are fewer cells in the body being infected from outside infections and therefore less of a reason for cells to be crying out help because they are thriving, not suffering. Things like sauerkraut, things like natto, if if you can access that, kimchi, pickles, again low sugar sources are going to be the sources that are going to be most effective for this. Next, I'd like to talk about what's called sickness behavior. Sickness behavior is a suite of responses that we tend to all undergo when we are feeling sick. The main thing about sickness behavior is that it tends to involve a slowing of our usual levels of activity. People start to feel lethargic or they feel like the activities that previously they could do with relative ease are very difficult for them or somewhat overwhelming. The other thing you start to see is that people and animals, by the way, stop grooming. They stop taking care of themselves. Not necessarily stop showering, although oftentimes that's the case, but they will stop uh doing their hair. They'll stop putting on makeup. Uh uh you know, depending on whether or not they did that before, they might stop. Animals will stop licking and grooming themselves. People will stop taking care of their cosmetic appearance. Now, it's not just because they don't care how they look when they're sick, it's because there's this overall suppression of certain kinds of activities and an enhancement of other kinds of activities. And this is really important. Sickness behavior is actually a motivated state. It's a state that's designed to accomplish certain things. One of the other features of sickness behavior, in addition to being lethargic, loss of grooming, will be a loss of appetite. Right? Oftentimes, people who have a great appetite normally just won't feel hungry at all. When we have that, we can be kind of irritable, we don't want to do certain things, and we just want to be left alone. things are harder. How? Why? Well, there's a known pathway, which is the so-called vagus nerve, that connects the body and the brain, signals to particular brain sites to engage this category of motivational state that we call sickness behavior. The vagus nerve is a very extensive nerve pathway. It's the 10th cranial nerve, comes out of the back of the the brainstem, heads into the body, and and branches out extensively to innervate or connect to many of our organs, including our lungs, our heart, our gut, etc. And all of those organs are able also to send neural signals back up to the brain. We sometimes hear the vagus as the route to calming ourselves down. Unfortunately, that's more or less a myth that I don't know how it got propagated. There have now been many studies of the vagus in various contexts, including in sickness behavior, and it's very clear that the vagus nerve is the fast pathway by which an infection in the body is signaled to the brain to a particular location in the brain called the hypothalamus, which harbors a lot of different types of neurons. Neurons, for instance, in the preoptic area that increase body temperature and fever. Right? That's one of the most important things is to increase body temperature in order to It's the body's attempt to kill off this invader because many viruses and many bacteria don't survive well at elevated heat. That's the function of a fever. It also sends input to areas of the brain that change your perception of the outside world. One of the most uh obvious of these, obvious once I tell it to you, is photophobia. Right? I love bright sunshine. I love bright lights when I want to be alert. But most people, when they are sick, when there's an inflammation response in the body, they feel like bright lights are kind of aversive. They get a well-described, kind of classical photophobia. And that's mediated by a pathway that goes from your eye to an area of your thalamus called the anterior nucleus of the of the thalamus. Then from there up to the outer lining of the brain, which is the meninges, just over the on the outside of the brain where the brain starts to interface with some of the other uh connective tissues. We can actually create a photophobia and a headache when one is ill. And the last element I'd like to talk about is the rest. There's something that gets triggered from the body to the brain to the hypothalamus. And there are nuclei there that promote the desire to sleep even during the daytime, what would normally be the active phase of your circadian cycle. Now, that is really interesting because what's happening here is you've got multiple pathways that are saying avoid light, reduce your amount of behavior, heat up, all the things that are making you sick. This is sickness behavior and it's going from your your body to your mind to to make you do the right thing. Now, there's also a slow pathway that's purely mediated by the blood, so-called humoral factors, not because they're funny, but humoral factors are factors of the blood. As you have an effect an infection for many hours or days, the amount of IL-6 and IL-1 and tumor necrosis factor and other inflammatory cytokines is starting to increase such that the total amount in your circulation gets high enough and is communicated to the brain. And it tends to enter the brain through a particular type of tissue that's really interesting called choroid, c h o r o i d. The choroid starts releasing and responding to these cytokines uh inflammatory cytokines, and then the brain actually starts to experience all sorts of changes in terms of inflammation to neurons, your memory tends to get poor, your cognition tends to get poor. These are transient things most often. These eventually these things will pass, but this is deep into sickness when you're really feeling lousy. You can't read, you can't watch a movie, you can't do anything. So, if you ever get sick and you just can't be bothered by anything, it's probably because you've had that fast response from the body and you've also had this slower response where you literally have a set of tissues in your brain that are sending out these these inflammatory signals and now your whole brain is starting to cope or is trying to cope with this infection. So, you've got a slow pathway and a fast pathway. That all sounds really terrible. So, now I'd like to talk about what you can do to reduce the probability of getting sick and there are actually things that one can do as you start to get sick and once you're sick to accelerate the healing process by flipping the equation. Up until now we've been talking about how the body activates certain areas in the brain to create sickness behavior that's very much like depression. You're probably all familiar with this from any time you've had a cold or a flu or something really lousy or an injury. Now let's flip the equation and ask what can we do with our nervous system in order to enhance the function of our immune system in order to be able to heal and recover from illness and injury more quickly. We all know what we should do. We should all hydrate, drink some water, and go to sleep. Right? That's what we're all we are all told. But there are actually things that you can actively do in order to get your immune system to deploy a more robust response at that early phase of potential infection. Let's focus first on the rest component. Yes, of course we are all told that we should take a hot shower and go to sleep, you know, and get 9 or 10 hours of sleep. But there's an interesting way of looking at sleep specifically for its role in enhancing the immune system. During sleep and in particular during sleep that's associated with the early stage of any kind of viral or bacterial infection, the so-called glymphatic system is much more active than it would be normally. What's the glymphatic system? The glymphatic system with a G is a system in the brain by which debris that accumulates throughout the day, but in particular debris that accumulates under conditions of neuroinflammation and inflammation of the body is cleared out or is washed out of the brain. And the activity of this glymphatic system is extremely important for the recovery from infection of any kind. There is a way that you can increase the activity of your glymphatic system under normal circumstances. Because of the mechanics of the glymphatic system, it turns out that if you elevate your heels by about 12 degrees, it doesn't have to be exactly 12, as you sleep by putting maybe a rolled pillow or two pillows underneath your feet, by having the head below your legs, it seems that there's more glymphatic washout or clearance during sleep. So, I would say if you're not feeling well, yes, take the hot shower. Yes, uh get into bed and go to sleep, but elevate your feet to try and increase the activity of the glymphatic system. Some might even consider that if you have to be awake, that you might want to be awake with your feet elevated above your head. Now, that might not be practical for the workplace, um but it might be practical for a short nap during the day or or something of that sort. Next, I'd like to do an in-depth analysis of a study that has achieved some prominence out there, not just in the scientific literature, but on the internet, because it relates to how particular types of breathing can impact the immune system and the ability to combat infection. The title of this paper is voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. This is a paper that was published in PNAS, which is the Proceedings of the National Academy of Sciences USA. It's a very prestigious journal, and I just want to describe the basic contour of the study. I'll explain the findings, and then I want to go in-depth and explain the mechanistic basis for these findings and the protocol that we can all export from these findings. So, here we go. So, first of all, a couple of terms so that everybody is on the same page. The sympathetic nervous system is one division of our nervous system. It's a set of neurons down the middle of our spinal cord and in our brain that generally lead to a heightened state of arousal and alertness. It's associated with epinephrine release in the brain and adrenaline release in the body. It's the so-called fight or flight system when it's really active, but it's the system that's active when we are wide awake. And we already talked about the innate immune system. That's that first line of defense after the skin barrier, of course, whereby some infection comes into the body and there's this rapid response of increasing inflammation. And that's also about the time that you first feel lousy. So, when you start to feel like, "Oh, I think I've got something. I don't feel right. A headache. I feel nauseous. I'm heating up. I I don't feel good." That's That's the the innate immune system kicking in. So, what they did in this study, they injected people with E. coli. It's a bacteria, which makes people all people feel terrible. These people voluntarily signed up for this study. However, some of the subjects in this study performed a behavioral protocol that can best be described as cyclic hyperventilation. So, they're comparing controls that do just sort of a basic meditation versus people that do this intense breathing followed by some breath holds. In the intervention group, the breathing group, plasma levels of anti-inflammatory cytokine IL-10, so this is a cytokine that is lowers inflammation, increased after endotoxin administration. And that was triggered by an increase in epinephrine and adrenaline. So, in other words, doing a particular pattern of breathing allowed an anti-inflammatory cytokine to be turned on. And they discovered that levels of pro-inflammatory TNF alpha, tumor necrosis factor alpha, IL-6, interleukin 6, and interleukin 8, which you should all be familiar with now, as pro-inflammatory cytokines were lower in the intervention group. Finally, flu-like symptoms were lower in the intervention group. So, this is an amazing finding, right? These are human subjects. One is One group of subjects is doing this breathing protocol. The other group of subjects is just meditating. They both Both sets of subjects have been in injected with E. coli, so you know everyone's getting the same amount placed into their system. How in the world does this work? Why does this work? First of all, what is this magical pattern of breathing? Some of you may recognize this as so-called Wim Hof breathing. The breathing that is so-called Wim Hof breathing is very similar, not exactly the same, but very similar to tumo breathing as it's been described historically. In the science and physiology community, we refer to it as cyclic hyperventilation, which just means repeated deep breaths in and out, and then there are these retentions. So, I'm because I'm here in the hot seat anyway, I might as well demonstrate it for you so you know what this looks like. It involves 20 to 30 deep inhales and and then exhales through the mouth followed by a exhale of all one's air and a breath hold. That's the retention. And then at some point, 15 to 60 seconds later, repeating the 25 or 30 breaths and then again a breath hold with lungs empty. Okay, I'm not going to do the whole thing right now, but it it goes something like this. Okay, so let's assume I did that for 30 30 breaths. I can already feel myself um perspiring a little bit. You're heating up. That's the release of adrenaline. It's caused by that breathing pattern and then exhaling all of one's air, no speaking in between like I'm doing. And then sitting lungs empty until one feels the impulse to breathe and then repeating for several rounds, two or three or even four rounds. Basically, this study looked at people doing cyclic hyperventilation with retention, three rounds of 25 to 30 breaths followed by exhale hold in between of various duration, but in general 15 to 60 seconds is typical. So, what's going on here? How is the breathing leading to these shifts in or I should say reduction in inflammatory cytokines and an increase in the liberation of these anti-inflammatory cytokines? This is beyond the scope of this discussion, but that it's actually the release of epinephrine, aka adrenaline, that's causing this reduction in inflammation. And that's actually supported by something that you've probably experienced before, which is if you've ever worked worked worked worked worked really hard or you've been care a caretaker for somebody else or studying for exams and people around you are getting sick and you're just powering through it and you're not getting sick, but then you stop, you turn in your final exam, you you stop taking care of somebody else or you finally stop and rest or you go on vacation and then you get sick. Well, you've just experienced the effect that adrenaline, epinephrine, can have in activating your immune system by way of the nervous system in order to keep fighting and combating infection. And that brings us to a larger theme, which is that stress and combating infection or a wound is not one unique system. It's the same stress system that you use to combat psychological stress. So, when you're very very stressed, at least in the short term, because you release so much adrenaline and epinephrine, you're actually better able to combat infections and you reduce inflammation and the whole feeling lousy response, right? Remember, reduced flu-like symptoms here. So, this pattern of breathing is actually a very useful tool. And I confess, I use this pattern of breathing anytime I am at the initial stages of of getting some sort of bug. If I feel like I've been running myself ragged or if I somehow, for whatever reason, have a tickle in my throat or I have that kind of sensation in my nose like I might have um it may might have caught a bug of some sort, I will do this pattern of breathing. I've been doing it consistently gosh, for the last 4 years or or more. Um you know, now this is just anecdotal uh reports, but I find that it allows me indeed to either have those early symptoms disappear or it allows me to just kind of push through and and harder longer. I don't suggest people continue to push through exposure to infections. Obviously, you don't want to infect other people. Um nor do you want to crash and suddenly get get a massive uh illness of some sort because you stop doing this breathing. But, I do think it's a useful tool. It's a purely behavioral intervention that has been shown here and now there additional studies on the way to enhance the function of your immune system and to reduce inflammation. And this is to me one of the most concrete examples of a zero cost tool that bridges the activation of the nervous system through breathing with the immune system by way of releasing adrenaline and thereby reducing the terrible effects or feelings of lousiness from a in this case, an E. coli infection. There's one last very interesting feature of this study that I want to emphasize. And that was that they actually measured the so-called catecholamine concentrations. Catecholamines are things like dopamine, epinephrine, norepinephrine. These are chemicals in your nervous system and body that promote states of alertness. Uh dopamine, of course, part of the reward and motivation pathways. They explored the levels of these molecules in blood, in plasma during and after this breathing protocol. And as interesting, as I mentioned before, epinephrine showed robust increases compared to the control group. Norepinephrine significant increases occurred in the in the breathing group, but um in the cyclic hyperventilation retention breathing group, of course. Um but less so. Um and dopamine levels actually um dropped somewhat. But this is very interesting because there's a new and emerging literature largely from Aisa, A Y S A Rolls Lab uh in Israel. What her laboratory has shown is that motivational state and mindset has a powerful impact on various aspects of the immune system that were thought to be independent of the brain and mind and thinking. They explored the well-established psychological phenomenon that when cancer patients or very ill people or people who are suffering from very debilitating injuries when they had or report when people had or reported a sense of hope, their rates of recovery were much higher. All right, sounds very subjective. But what is a sense of hope? A sense of hope is a sense of the future. A sense of the future is tightly associated with the dopamine system. And so what they've discovered and through other studies from other groups have discovered is that stimulation of the dopamine pathway either simply by thinking about a future ideally a positive future, but thinking about a positive future leads to activation of the so-called mesolimbic reward pathway and could reduce the size of tumors, could accelerate wound healing, could greatly accelerate the passage from a state of illness to a state of health and well-being. It's because this reward pathway and the fact that it's related to a sense of the future seems to liberate entire systems within the body that make inflammatory cytokines go down and anti-inflammatory cytokines go up. Exactly as was demonstrated in the beautiful PNAS study where breathing cyclic hyperventilation was used to increase epinephrine, increase norepinephrine, and to augment the catecholamine system. So, I think that the the bridges between these studies are really relevant. There is a very exciting article published from Chufu Ma's lab at Harvard Medical School and the title of the article is a neuroanatomical basis for electroacupuncture to drive the vagal adrenal axis. When Chufu's lab looked at stimulation of the body with so-called electroacupuncture, so this is these are needles where a small bit of electrical current, low level of electrical current, is passed into the the needle and therefore into the body, they located sites on the body that can increase inflammation by way of releasing inflammatory cytokines. These areas included the the abdomen and they found areas on the body such as the lower limbs, the hind limbs in this case that can stimulate the vagal adrenal reflex and can lead to reduced inflammation. And what was really interesting is that they figured out that it was activation of nerve endings that resided in the fascia. The fascia is a a really thick sheath of tissue that surrounds muscle. And so what they discovered is there's a specific population of neurons, those neurons have a name as they often do in science. Name isn't important, but if you want to look it up, it's the proc R2 neurons, p r o k R2 neurons. And they send a connection deep into the limb fascial tissue. And then they send another wire up into the spinal cord into a region of the hindbrain in the back of your brain kind of near your neck called the medulla in the medulla oblongata. That neuron also has a name called the DMZ, doesn't matter. And that neuron connects to the adrenal gland to release our good old friends the catecholamines norepinephrine, epinephrine, and dopamine or norepinephrine, epinephrine, and and dopamine. So, what is all this saying? This is saying that activation of the deep fascial tissue causes a chain of neural reactions that leads eventually to the release of norepinephrine, norepinephrine, epinephrine, and dopamine. And once again, lowers inflammation very much like the breathing study that we talked about earlier in the pattern of cyclic hyperventilation with retention leading to reductions in inflammation. Okay, so thus far we've been discussing how one can prevent getting sick or when one starts to feel ill, how one might be able to shorten the course of that infection by ramping up the activity of the immune system. But what about when you're already experiencing symptoms? There are many ways to address that at the symptom level. You're probably aware of all the over-the-counter medications, many of which focus on the epinephrine system. You know, things that are of the pseudoephedrine variety prevent or reduce congestion because of the way that they cause release of epinephrine and some of the effects on dilating the bronchioles and dilating the nasal passages and so forth. I'm not going to speak to whether or not those are good or bad choices. They do have a couple of effects that are not so great for the course of treating the underlying cause, which are first of all, they can cause dehydration. So, you have to make sure that you're hydrating well both fluids and electrolytes. And they also can interfere with sleep. There is an interesting alternative choice, and when I say alternative, I do mean alternative. The choice that I'm referring to is spirulina, which is actually a form of algae. There are some really nice studies and some data and also an understanding of the mechanism by which spirulina can have potent effects in reducing what's called rhinitis, which is a fancy word for congestion of the nose and and inflammation of the nose. These looked at humans, so this is not a mouse study. This is a study on humans. Both sexes, so males and females. In one case, looking at 100 plus subjects, 129 subjects. The other, 65 subjects. So, decent number of subjects, randomized trial, double blind. Both cases saw significant decreases in nasal obstruction, improved ability to smell, improved sleep, uh daily working, cytokine inflammatory cytokines were reduced as well. Reduction in nasal itching, all the stuff that you'd like like to experience, I could imagine, after taking 2 g, 2 g, not milligrams, but 2 g of spirulina. Once again, we've covered a lot of information. Today, we learned about the immune system, the adaptive immune system, the innate immune system, and the nervous system and how those interact. And throughout, we discussed protocols that can allow you to tap into this relationship between the nervous system and immune system and hopefully avoid and/or shorten the course of any illnesses, injuries, or inflammation that you might encounter.