THE BRAIN IMMUNE GUT CONNECTION
Microbiome’s impact on brain, gut and immune system.
Taken from videos of Kiran Krishnan
Bacteria have been here well before we were so at the cellular level, the bacteria cell has existed on Earth well before human cells. When you look at cellular communication, which is a fundamental part of the functioning human system, the rules between how cells communicate were written by bacteria and we incorporated those rules into our systems. In fact, every one of our cells with the exception of our red blood cells, has ancient pleiotropic bacteria in them. The Mitochondria, the powerhouse of the cell, is really an ancient bacteria. The human cell really came about from two microbial cells merging into one and creating a new kind of cellular structure that eventually became the human type of cellular function. So bacteria wrote all of the rules around how our systems work. And what we come to understand from advanced studies is that it still is the case. Most of the communication within different parts of our body, whether it's the gut communicating with our brain or the brain communicating with our immune system or our brain communicating with our heart, all of the different connections in our body are for the most part facilitated by microbes. We’ve outsourced most of the mechanics of being human to microbes. In part because we don’t have enough genetic capability to do any of the things we need to do.
During the human genome project the scientists were anticipating when they were mapping out the entire human genome was for virtually every disease we know about there would be a gene associated with it. If you have Heart Disease it's because you have the Heart Disease Gene that something is wrong with the gene or virtually every condition has gene dysfunction. And that most of our functionalities are metabolic capabilities and are coded for through our own DNA. So they anticipated that humans would have somewhere between 150,000 -200,000 functional genes. But when they mapped the human genome, the number of functional genes, were only around 22,000. Then the big question came — With just 22,000 genes how is it that we do all of these sophisticated things? That created a massive gap after the human genome project. And is actually part of what kicked off the human microbiome project. Now 22,000 genes to somebody who is not familiar with science might sound like a lot, but an earthworm has somewhere around 30,000 genes. A rice plant has somewhere around 32,000 genes. So we’re less sophisticated and less cool than an earthworm so how is it that we’re top of the food chain, top of the evolutionary ladder? The reason is that we have 2.5 million microbial functional microbial genes in our system. So most of the coding to become and function as a human, comes from microbes. That's the part that's so important to understand. Our microbial ecosystem in our body, on our body, and even around us, codes for and facilitates most of the cellular functions that are required to be and act and function as a human. That's a very important message for people to get because we cannot overstate the importance of understanding the microbiome and its role in the function of your brain, the function of your immune system, the function of your gut, and every other part of your body as well. The rulebooks are written by bacteria.
How does the gut microbiome impact our brain function?
We continue to see the prevalence rate of anxiety, depression, and mood disorders increasing every year. And arguably over the last 2 years during the pandemic, it’s gotten much worse than it has been. Also, look at neurodegenerative conditions like Alzheimer’s, Parkinson, Dementia, that continues to elevate and increase. When you look at psychiatric practice, the practice of psychiatric medicine has not really changed in 50 years.
In the last few years, what we come to find out is that most conditions in the brain are driven by inflammation. Whether it's a neuro degenerative condition, whether it's a mood disorder like anxiety, depression, anorexia, any of those things, are driven by inflammation. And there's a couple of major sources of that inflammation. In fact, the gut microbiome is either going to be the most important supportive component to the brain or it becomes the most toxic aspect of what damages your brain. That's the really interesting aspect of the microbiome. You've got this ecosystem in your gut and the rest of your body does all of these functions for you; really critical functions that you could not exist without them. But if that ecosystem starts to go awry not only does that microbiome not support it, it becomes actually quite damaging to the body. There's a spectrum there and what we don't want is to make our microbiome abusive to our body. That's what happens in the brain too. The gut and the brain are connected quite intimately.
There are three major ways in which the gut is directly connected to and influences the brain:
- One way they're connected is through the neurological pathway. When we look at the neurological connection, the brain is part of the central nervous system, and it's the largest density of neurons. And then it's connected through the Vagus nerve to the nervous system and the nervous system is basically this really dense neurological network that surrounds your entire digestive tract. So the gut and the brain are directly connected neurologically. The microbes in your gut have full access to this entire nervous system, which means they can do things like produce your transmitters and send it up directly to the brain through the Vagus nerve which affects how you feel and affects your decision making and so on.
- The second way that they're connected is to the immunological pathway. We now know that the brain has its own lymphatic circulation. We know there are active immune cells all over the brain called microglial cells and we know that the brain's immune response is affected by what happens in the gut. If there's inflammation in the gut there's going to be inflammation in the brain. If there's leaking in the gut there's going to be leaking in the brain so there's a direct immunological connection between the largest component of the immune system which is in the gut, to the immune system in the brain as well.
- The third is through the circulatory system. Through blood circulation because the microbes in the gut can produce things called post biotics. Post biotics are compounds that the microbes produce from fermenting foods that we take in, and they break it down and they convert the food to other things. And some of those things are highly influential compounds on the brain and those make it to the brain through the circulation, as we absorb those compounds into our circulation from the gut, they can make their way to the brain. This includes things like hormones - serotonin, dopamine, and so on. It also includes things like Gabba and BDNF and all of these things that affect the brain, also things like short chain fatty acids.
The gut and the brain are in constant communication with each other and constantly influencing one another. And it's important to mention it's a bi-directional, meaning it goes both ways. The brain can also influence what's happening in the gut as the gut influences what happens in the brain. When you look at those connections that's where the evidence for where some of these diseases and conditions stem from start to become very clear.
What will be some of the symptoms or conditions people might experience as a result of gut microbiome imbalance?
To begin with, the homeostatic condition. Let's assume you've got a healthy microbiome. What are some of the things it's doing for the brain that's really important for the brain?
- The brain from an energy perspective, pound for pound requires more energy than any other part of your body. The brain has massive energetic demands. Most of that energy comes, obviously from sugar and fat metabolism. In the case of fat, it's ketones for the most part. In terms of sugar, the brain can break down glucose and fructose, through its mitochondria, in all of the cells in the brain. So in order for the brain to be able to produce enough energy just for basic functionality, the mitochondria, which is a powerhouse in the brain cells, have to be functioning at optimum level. And in order for the mitochondria to function optimally what the cells in the brain need to be able to do is remove damage and dying mitochondria and replace it with new mitochondria, so your energies are constantly being reworked and revamped because one of the side effects of the mitochondria working hard and producing energy is that over time they get choked up by things like reactive oxygen species, and so on. As the mitochondria are dying and becoming less efficient they should be removed and replaced with brand new mitochondria so the brain can continue producing the energy needed to function as the brain. The number one signal to enhance this changing of the mitochondria, a process called mitophagy, is derived from the gut. Microbes in the gut take in nutrients like polyphenols so these are active ingredients from plants and they convert them to compounds like uroliths. Uroliths are the main signal to trigger our cells, including our brain cells, to change out its mitochondria and replace damaged mitochondria with new mitochondria.
- Some of the very important sources of anti-inflammatory compounds in the brain, short chain fatty acids, come from the gut microbiome, including other omega three fatty acids like EPA which is known to have anti-inflammatory effects. The microbiome produces a lot of those compounds to help the brain with any sort of inflammation build up in the brain. Also a number of the neurotransmitters, things like BDNF and Gabba that help your brain relax so you can go to sleep, help your brain regrow brain tissue. All of those things are all produced by the microbiome. All of those control mechanisms are centered in the microbiome which is thought to be kind of a central command center for everything that's happening in the body.
So, that's when things are good and happy. Now let's say you've had a course of antibiotics or you've had poor lifestyle choices or you live in an area where you get lots of exposure to pesticides, herbicides, you're drinking water is full of chloride, and fluorine and all of these things that all hurt your microbiome. Maybe you eat a lot of processed and packaged foods that have antimicrobials in them. So you're hurting your microbiome constantly and now you're creating what we previously called gut dysbiosis which is this imbalance of good and bad bacteria in your gut. One of the first things that occurs when you start to get an imbalance of good and bad bacteria is you start to get more leaky gut. The lining of the gut actually becomes more and more permeable to things leaking past that shouldn't be entering into circulation from the digestive tract. That's one of the first consequences of early onset of dysbiosis. When that starts to happen, one of the predominant things that ends up leaking through is something called LPs which is an endotoxin. This is a toxin that's made in the gut lining of the digestive tract by bacteria that live there normally, If it stays in the digestive tract it's totally fine. It doesn't cause a problem at all. But if it's allowed to leak through in the leaky gut into circulation, it becomes a significant issue. In circulation this endotoxin triggers massive inflammatory responses when your immune system runs into it. One of the things that's been shown about this endotoxin is it's highly pervasive in being able to move up the Vagus nerve. If it moves up the Vagus nerve one of the places that it likes to lodge itself is in the brainstem, an area called the Dorsal Vagal Complex. One of the first things that occurs when it launches itself in part of the brainstem, is it triggers an inflammatory response in the brainstem, and it starts disrupting the signals from the brain to the gut and from the gut to the brain. One of the first things individuals will notice as that starts to happen is a slowing down of the bowels, constipation, or a sub-chronic constipation starts to ensue. You don't go to the bathroom as frequently, you feel stuff and full more often, it's harder for your bowels to empty. Even smaller meals make you feel kind of bloated and full and you feel full. It takes longer for the stool to transit, and you end up with this constant constipation type of issue. The other thing that occurs is your level of satiety. When you're eating food it really dramatically increases how long it takes you to feel satiated because the signals from the gut that tell your brain to stop producing hunger hormones, have to come from the microbiome, and those signals get lost if this connection between the gut and the brain is disrupted. Some of the earliest things people feel is slowing down with the metabolism, weight gain, and then slowing down to the bowel movement and constipation.
If this endotoxin starts to move through the circulatory system and gets in the brain, one of the things that it does is interfere with serotonin and dopamine binding. When it interferes with serotonin and dopamine binding, one of the first things is you start to feel anxious. You start to feel less tolerant of stressors, you start to feel harder and harder to satisfy yourself. So people become obsessed. They either start eating a lot of things or obsessing over things like binge watching Netflix, for example. Cannot get enough of things because you're trying to stoke that dopamine response. The ability to feel satisfied as easily as you were before when you were maybe younger and it was less of a condition for you. That also interferes with sleep cycling so now you've got more inflammation going on in the brain so your ability to calm down and sleep also gets compromised, your ability to feel happiness decreases quite a bit, and then you start to feel very tired all the time. Remember, the gut is responsible for helping the brain, keep its energy demands in tip top shape so now you start to feel tired and slower cognitive function memory loss. Those are the most common things you start to see as a gut becomes dysfunctional and it starts impacting the brain. These are symptoms that are very common clinically and people suffer with them subtle enough to where they don't get an official diagnosis so people just kind of get lost in the medical system because certainly allopathic medicine doesn't really focus on this aspect of it.
All of that inflammation starts from the gut and it starts from these endotoxins in the gut, making their way up and lodging themselves in the brain. The development of type two diabetes, through something called central insulin resistance where now your brain can no longer read your blood sugar levels, even if your pancreas is working fine, your brain doesn't have the ability to read sugar levels because the LPS and endotoxin from the gut migrates and makes its way into the hypothalamus where it creates an inflammatory response, and that inflammatory response disrupts how the hypothalamus functions and starts creating neurodegeneration in the hypothalamus. The presence of those endotoxins in the brain triggers constant chronic inflammatory responses in the brain, which leads to neurodegeneration so you're actually eating away your own brain tissue over time. All these things that we experience, that we feel are normal, or maybe a factor of life, like tiredness, slower cognition, memory loss, inability to recall things fast enough, constipation, and other changes. We see it as kind of a normal factor of either “Oh we're just getting older and I'm getting more tired. I'm working too much.” and all those may be factors. We Band Aid those things with things like trying to drink more coffee and taking more laxatives and doing things that band aid. What we're not seeing is that those are the early signs and symptoms of the much more serious problems that are coming up. One example. The first symptom that people suffer from Parkinson's disease, which is a very scary condition, is constipation. Constipation is the first symptom of Parkinson's. Why? Because the inflammation that eventually destroys the neuronal connections in the brain. Start in the gut and the entire nervous system right. Then moves up. One of the second most common symptoms, before it affects the brain completely, is loss of smell. Then it moves up and it's as it's moving up that it impacts the olfactory nerve. And then as you get less and less a-tune and acute with your ability to smell. That's another early sign that it's moving up into the brain and the next step is causing significant dysfunction of the brain right so it's so important to pay attention to these early signs and note they're not necessarily a normal part of functionality. They are a sign of the early stages of inflammation in the brain that's been driven by the gut.
The first aspect of inflammation in the gut and the brain comes from the leak in the gut, and those endotoxins leaking in getting to the brain and triggering inflammation there. The second part of inflammation in the brain comes from external stressors. When we experience an external stressor, it could be a short bout of stress. For example, a work person that you're having an argument with and have some issues with, it's creating stress. We all feel that blood circulation, dilation of your vessels, increased heart rate, and all that. What happens in that process, when you're experiencing that external stress, is your HPA axis, your hypothalamus pituitary adrenal axis is triggered. The HPA axis leads to the release of cortisol. What's so interesting about this is that cortisol response in the brain actually uses the gut as a gateway to figure out what the next step is. What happens is you get an external stressor, you get a triggering of the HPA axis, a release of cortisol, that release of cortisol is actually realized by the immune system and the immune system in the gut has one of two options. It's either going to shut down the inflammation that the cortisol is triggering and make it so that it's all over, cortisol levels come back down. You're not heightened and stressed anymore and you go back to a normal state. Or, if your gut microbiome is messed up what tends to happen is when the cortisol signal comes into the gut it amplifies immune activation in the gut, and then the gut actually sends signals to amplify immune response in the brain, and trigger microglial cells in the brain. So when you have a dysbiotic gut the signals from external stressors will actually get amplified through the gut and create an activation of macrophages of microglial cells in the brain to trigger more inflammatory processes in the brain. External stressors that lead to significant brain inflammation and eventually neuronal damage from that gets deep wade through the gut microbiome. The gut microbiome can either stop the cycle or enhance the cycle. A dysfunctional gut microbiome enhances the cycle. When the cycles enhance you've got more inflammation going on in the brain and you actually become more sensitive to external stressors. Then the next stressor doesn't have to be as intense as the first to trigger that cortisol release again. And when the cortisol gets released again, it triggers more inflammation to the gut, and then makes you even more sensitive to the next stressor so it becomes a continuous cycle of constantly having a problem managing stressors and constantly triggering inflammation not only through the gut, but into the brain eventually. Those are the two main routes for significant chronic inflammation in the brain. It's leaky gut and also, external stress induced inflammatory pathways in the brain. All of those are anchored in the gut microbiome.
If you have a faulty microbiome, it actually can create this negative plasticity, where the stress becomes anchored and becomes more sensitized so it takes less and less amount of stress for you to trigger the same response There's an important amino acid called tryptophan that we all get in our diet and why tryptophan is especially important is because it's the precursor to making serotonin, which is our happy hormone and then melatonin, which is a hormone for sleep and relaxation. In your body, your tryptophan that comes into your diet can get converted to serotonin and then melatonin so it's super important. It's important for you to feel happy, relax and sleep. Now, when you have a dysbiotic gut microbiome that is taking a stress response from the brain through cortisol, what tends to happen is the microbiome shifts. The metabolism of tryptophan instead of converting tryptophan to serotonin and melatonin, it converts it to something called kynurenine, and then another fatty acid. That pathway is actually neurotoxic. Not only does it not make you happy and sleep, it is actually quite toxic to your neurological system. The same compound that tryptophan could become a happy hormone, sleep hormone, or it can become a neuro toxic base of what is going on in your gut microbiome and your gut microbiome decides which pathway tryptophan are going to go in. If you imagine that your gut microbiome is messed up it's dysbiotic and causing inflammation, you have continuous stress coming in from the outside world, more and more of this kind of neurotoxic metabolism is being facilitated, then it becomes harder and harder for you to deal with stress because of the inflammation in the brain and the continuous targeting of your HPA axis. Now what may happen after that is you may go into adrenal fatigue because you're constantly producing cortisol and other stress hormones, because everything around you is triggering that response because your gut is channeling that response to the inflammatory pathway, rather than the inflammatory-happy-hormone-sleep pathway.
It's mind boggling when you think about how the gateway is really the gut. On how we deal with the world around us, but it's also quite telling because the gut is the best example of an adaptation to our environment. If you left your neighborhood and went to live another country, over time, your microbiome would change based on the environment. Which means that some of your functionality will change as well. And so through the course of evolution we've outsourced stress management and the sympathetic parasympathetic response of flight or fight response to our gut microbiome because presumably our gut microbiome has adapted to the environment we're in. In some environments, you have to be highly attuned and heightened to certain types of stressors that may actually kill you. In other environments, it's a different kind of stressor and your gut microbiome is supposed to be able to gauge that for you. So you can adapt to different environments but we know without a shadow of a doubt that external stressors have a huge negative impact on the function and the longevity of your brain, but all of that is guided through the microbiome.
What are some of the things people can do to optimize the microbiome?
We're not yet at the point where we know everything about the gut microbiome. However, with the recent studies that have come out in the past decade, the most important is to practice diversity for our microbiome. We're designed to be with the environment and the environment molds us as well. The more diverse your gut microbiome is, the healthier it is, the less leakiness you have in the gut, and the more protection you have.
The Interesting fact is that for millennia we humans used to take care of our gut flora daily without realizing it. All year round every culture of the world consumed billions of probiotics microbes boosted by prebiotics - non soluble fiiber that is food for the probiotics coming from a variety of colorful vegetables and fruits, nuts, seeds - with fermented foods. This routine dramatically increases diversity. The more different groups of bacteria you feed, the more you start to increase the diversity of your microbiome because there's a whole number of sets of organisms in your microbiome that only proliferate when food is in constantly coming in.
The second thing you can do for diversity of the microbiome is to do some fasting. Do some sort of intermittent fasting - a simple 16-8 hour window. All feeding should happen within an eight hour window between about noonish and 8pm, and then fast mostly from 8pm onwards till about lunchtime the next day.
The third thing is engaging with the environment as much as you can and exercise. Studies are pretty clear. If you are outdoors, if you spend a good amount of time outdoors, in natural environments, like going on hikes, sitting on the beach, walking through the woods, all those kinds of things. It actually dramatically enhances the diversity of the microbiome over time. So you want to be prescriptive and specific about going out and spending some time in nature.
Get a dog. Studies show that households that have dogs actually have a better, more robust microbiome in all of the inhabitants of the household because the dogs go and bring all these microbes into the house and diversify the microbes in the home, which then diversifies your microbiome. Not cleaning and sterilizing most of your home. Studies show people who use chlorine based sanitizers on many surfaces of the home tend to have lower diversity in the microbiome and also tend to have higher incidence rates of allergies, asthma, and so on.
To be continued on the next installation of the blog.
In the meantime we leave you with an effective way to manage daily stress: