The Microbiome: The Eyes & Ears of the Immune System | Kiran Krishnan

Sarah: Well, today we are going to be diving into the topic of the microbiome and the immune system. And of course as we all know, the immune system has been on the top of everyone's, in the forefront of everyone's minds in the last year or so. And many of us have heard that, I guess the gut makes up 70% of the immune system. We see that kind of stat thrown around a lot, but I think there's very little understanding as to how that actually works and how relevant really is it that our gut bugs play such a role and how is it that little bugs that aren't even part of us are so key for our immune system. So we're so excited to dive into it. So Kiran, over to you.

Kiran Krishnan: Yeah, absolutely. So let's make sense of some of those things that people have heard, right? Other speakers have mentioned before, 70% of your immune system is in your gut and the microbiome is clearly connected to your immune system, but I think for people to really appreciate that we have to paint a really important picture, so they understand their immune system, right? The immune system is one of the only parts of the body that is continuously adapting. Your heart is your heart. Your brain is your brain. Your lungs are your lungs. And you might be able to make some changes to them by exercising and causing stressors to them and so on, right? So your lungs can get stronger, your heart can get stronger, your brain connections can improve, but they function the way they function and they function within a certain parameter.

Your system is one of the only parts of your body that starts off completely naive and without any capability of functioning and it does so, so that it can adapt to the environment of the host, because depending on where you live, who you live with, your needs are going to be different than someone else's needs in terms of what your immune system is supposed to protect you from. And so the immune system is specifically designed by nature to be adaptive, to be naive, to begin with, and then adaptive by reading and sampling the environment around you.

Now, the immune system cannot do this adaptation and interpretation of the environment around you without the microbiome, the microbiome is what interprets the environmental information for the immune system. So the microbiome are the eyes and ears of the immune system, because at the end of the day, one of the biggest threats that the immune system is supposed to help you with our microbes themselves, viruses, bacteria, amoeba, so on. Those are the things that have killed more humans than anything else in the existence of humans. We have the black plague that killed half of the European population at one shot. It's mind-boggling-

Sarah: Wild.

Kiran Krishnan: ... when you think about these little microbes. They can travel through the earth, even in the 16, 17, and 18 hundreds and especially now, when we have a single connected world, these microbes can travel far, far distances in relatively short amounts of time and really devastate entire population. So the immune system's there to protect us against these things, these epidemics, pandemics and then of course, all the things you come across every day, but the immune system is continuously covered and engaging with microbes, so they're looking... the immune system is looking for microbes while being covered by microbes. So the only way the immune system knows how to understand the world you're in and what it has to protect you against is doing the translation through microbes. So that requires the immune system to sample the world around you, sampling of the environment, sampling of all the things that enter your system becomes extremely important for the immune system to get tutored, to get trained and then adapt to your ecosystem.

The biggest site of sampling occurs in the GI tract because that's of course the biggest site of exposure that you get to the outside world, everything you eat, you drink, you breathe in, everything goes up your nasal passages into your eyes, everything drains down into your throat, then down into your gut. Everything that's in your lungs, you've got something called a mucociliary elevator where all the mucus that builds up in your lungs will move microbes and air particles and all that up and then you end up swallowing it and it goes down into your gut. So most things that enter your body are entering through the gut and so it's no surprise that the vast majority of your immune sampling tissue occurs and exists in your gut. That's the best way that the immune system is going to get to sample the world around you. It just so happens that that's also the largest density of population of microbes within your system as well.

So you've got this overlay of huge amounts of immune sampling tissue, you've got the most critical immune tissues for activating the immune system areas like the Peyer's patches and so on, all of that existing in your gut, and also most of the microbes that live in your system live in your gut. So that's a really important intersection for the function of your immune system.

Matt: That's fascinating. I've been really enjoying this book, The Hidden Half of Nature, which has been blowing my mind. So everything you're talking about is just like fresh on my mind, which is super exciting. So I'm just curious how does our immune system... because our microbiome and all these microbes that inhabit us is vastly outnumbering our actual immune system, so how does our microbiome sample and how does the, being outnumbered, but how does the immune system actually cope with this amount of data?

Kiran Krishnan: Yeah, so that's really fascinating part about it, right? And that actually was a huge area of confusion for immunological scientists for decades upon decades is what is that communication between the immune system and the microbial... and the microbes when the immune system is continuously covered and surrounded by microbes, right? How does it distinguish between good bugs and bad bugs, infectious bugs and noninfectious bugs. So to give people some real perspective on this, let's put some numbers on it and use some analogies that are easier for people to understand. So the ratio for every single serving immune cell that you have in your body that is floating around looking for infectious microbes, you've got 200,000 microbes already living in your system. So let's take any given part of your body. Let's say your lungs, for example, or a small portion of your lungs. That lung tissue is being surveyed by, let's say one immune cell for this analogy and it's covering a surface area that has over 200,000 microbial cells already.

So to put that in perspective, imagine we were at a concert in a stadium and the stadium had 200,000 attendees in the concert and you are the lone security guard in that massive 200,000 people and your job was to find the one person in that 200,000 that has ill intent. And everybody looks about the same. Everyone's a human, everyone has different hair, eye color, and all that, but nonetheless, that person's not wearing something crazy and egregious. So then the only way that lone security guard can actually seek out and find and protect the rest of the crowd against that one, lone individual is of the other 199,999 people were working with the security guard. They were all doing a neighborhood watch. Everyone was radioed into the security guard so that if any one of them saw something unusual or saw something bad, they would radio in and tell you exactly where to go so that you can make it there on time to stop it. And that's exactly what's happening in the microbiome and your immune system as well.

All of the good commensal microbes are radioed in, in a way. And we can talk about how they communicate with their immune system to looking out for changes to the ecosystem. So you've got all of these viruses and bacteria and all that sitting in your lungs and if you have the right kinds, if you have the right types of viruses and bacteria sitting in your lungs, when the influenza virus comes in and starts infecting lung epithelial cells and causing a disruption to that ecosystem, the first things that recognize that are the local microbes in that area, and the local microbes starts sending out signals to alert the immune system that, hey, something's going on here, you need to come and pay attention to it. So that is the basic signaling that occurs.

Now, here's how we take it one more step. So there are microbes that send out certain inflammatory markers to alert the immune system to that location and then there are microbes that will stimulate these T helper cells and regulatory cells that help your immune system learn that that is a target and then that's the thing that you should be paying attention to and then building immunity against for future exposure. So it's tutoring the immune system that not only have we identified a target, this is an important target that you should be aware of and have some sort of memory and immunity, so that the next time the host encounters it, you can deal with it much faster. Now during that process, there are T regulatory cells that prevent the immune system from accidentally attacking other things in that area as well.

In case your immune system accidentally attacks some of the good commensal bacteria or your own tissue or a particle that just came in the air that it might start attacking and creating a sensitivity to, there are these T regulatory cells that are also stimulated and controlled by the microbiome that helps the immune system learn what not to attack, just as much as teaching the immune system what to attack. So all of that is being orchestrated by the microbiome.

Matt: Amazing.

Sarah: Incredible.

Matt: So I think many of us have lived in an overactive community, perhaps in an apartment block or in a neighborhood where people are being super annoying basically. And so I'd love your analogy of explaining that's how these microbes are communicating. So is there a case when these microbes are like some of those annoying neighborhood watches that we are sometimes a part of are over-reactive and this confuses the immune system?

Kiran Krishnan: It can. And in fact, when you've got a dysfunctional microbiome and it depends on where the dysfunction is. You can have a dysbiosis in your lungs. Like if you don't the right type of microbes in your lungs, you've got too much Stuff Oreos, for example, in your lungs, it may create hyper-reactivity to everything that you encounter, or if you have pathogens or opportunistic pathogens in your gut, in your lungs, in other parts of your body, they may actually not want to send the signal to your immune system that something is there. For example, if your neighbor is involved in some sort of criminal activity, you may not know it, but the neighbor is paranoid and he, or she's got some really shady things going on in their apartment. If there is a burglar nearby, he or she may not want to call the police to attract the police anywhere to that area, so they may actually see that something's going wrong and not actually alert the authorities about it because they don't want to bring light on themselves.

So in that case, you could have dysfunctional bacteria that will actually allow pathogens to come in and infect the host because they prefer not to attract the attention of the immune system to that area. Now, that's one mechanism. The other mechanism is there are pathogens, opportunistic pathogens within your system that actually send off lots of confusing signals to the microbiome, sorry to the immune system, thereby trying to distract attention from themselves. So it's almost like if there was all of these cops in the neighborhood and you wanted to burglarize a house, you might actually phone in a false burglary down the road so that all the police are distracted down there and then you can break into this house over here and not have the cops there ready to respond. So there are microbes that do that as well. So they take opportunities in order to evade the immune system, confuse the immune system, and then thereby evading detection and helping themselves. So the most egregious actors are the opportunistic pathogens.

So there are direct pathogens that the moment they come in, they're trying to infect you, they're trying to kill you. Or they're really not trying to kill you, they're just trying to do better for themselves and that in turn is going to kill you, unfortunately. But there are the opportunistic pathogens that can remain within your system for long periods of time and they wait for the right chance to proliferate themselves. That's why they call opportunistic, the right opportunity, the right scenario then they go, "Hey guys, this is the right time for us to start ramping up our numbers because the host immune system is depressed, the microbes that normally fight us in battle against us are depressed and there are lots of infections going on. So our chance of actually success is higher." So those are the ones that really create long-term problems with people's immune systems.

Sarah: Wow. Okay. These little buddies can either be our friends or our foes and that's... I love all the analogies, so thank you for that. Okay. So we've established that in the best case scenario, as far as our immune response goes, our gut bugs can be, I guess, our first responders sending off flares going, "Hey, here's the issue. Come on immune system, let's deal with this quickly." But what if we do not have a healthy microbiome? What is the end result and how does that impact the immune system?

Kiran Krishnan: Yeah. COVID was an amazing example of this. So there's a couple of major consequences that occur if we don't have a healthy microbiome. So when you look at all of the data coming in about the people that had the worst go at COVID with the COVID infection, from SARS-CoV-2, it was people with long-term chronic illnesses, right? And these were all inflammatory type conditions, so obesity, heart disease, hypertension, diabetes, these people had 7, 8, 9 times higher risk of dying from SARS-CoV-2 than an individual same age match without those conditions. So then the question becomes, what is it about heart disease, or what is it about obesity or diabetes that actually makes you much weaker when it comes to your immune system? And there's a couple of aspects to that, which will help answer the question you just asked.

Aspect number one is that these individuals have diabetes, have hypertension, have obesity and all because they are dysbiotic. We know from the myriad of research that's out there that it's dysfunction and dysbiosis within your microbiome that actually creates those conditions. So they have those conditions because of dysbiosis and it's that same dysbiosis that makes them more susceptible to immune dysfunction as well. So it's not the diabetes, it's not the elevated blood sugar levels that somehow compromises the immune system, it's the fact that they are already dysbiotic, so their ability to deal with an infection that comes in is heavily compromised. So that means these individuals have a few different factors. They have, one, more opportunistic pathogens, so more of the types of bugs that are either, A, not going to signal the immune system or, B, always signaling the immune system to confuse the crap out of it. There's this issue of loss signaling, which I'll talk about in a second.

And then the other aspect of it is when your immune system cannot respond in a timely manner, because it's not being alerted appropriately then the pathogen that we're talking about, the pathogen at hand has a much higher chance of really building high numbers. So in the case of COVID, for example, what happened is people who have these chronic conditions and I'll explain why their immune system slow to respond. The virus comes in, it starts replicating and the immune system is not aware that this is happening. So it's replicating, replicating, replicating. They have no symptoms, because remember the symptoms that you feel from the infection come from the immune response to the infection. So that's why you have this long latent period of upwards of two and a half weeks before people show symptoms is because the virus is just happily replicating, building its numbers, killing off your tissue. The immune system is still not aware that it's happening.

Now when the immune system finally detects it, it's a very, very scary response for the immune system because the immune system has to go full bore because the infection is now much bigger than what it would have been if it was responding to it within the first day or two days. Two weeks later, it's a much bigger problem for the immune system. And remember the immune system, the first response in the immune system is called the innate immune response. The innate immune response is a non-specific response. It's not responding to that particular virus. It's responding to something going wrong in this region. So because it's, non-specific, it's really coming and blow torching that entire area. The analogy I give is like you're trying to kill mosquitoes with a blowtorch. You're going to kill the mosquitoes for sure, but you're going to burn the wall and stuff around here too, right?

Sarah: Yeah.

Kiran Krishnan: But that's how the innate immune system works. It's supposed to be the fast acting part of the immune system, it gets there first, often within hours of something coming in, assuming it's getting the right signals, but then it's turning on the blowtorch and it's starting to blow torch things. Now, when it comes in and the virus has been replicating now for 10 days, 12 days, it's got to turn up a much bigger flame on the blowtorch. So not only now, is it slow to respond and there's so much more virus in the system, it's also, the response itself is highly damaging to the host. And so that is what tends to happen. That's how you go from, "Ah I'm feeling fine" You don't feel any symptoms for 10 days, 12 days and then all of a sudden you're on death's doorstep and you're being rushed to the hospital and ventilated and all that crazy stuff. So that's the big difference.

Now, why is it that those individuals' microbiomes did not alert the immune system and the immune system was not able to respond within a shorter period of time. So there's an issue of loss signaling. So remember I mentioned that the microbiome communicates with the immune system through these flares, I use the term flares, but really what they are is inflammatory markers. Because the immune system from day one, one of its innate capabilities is to respond to inflammatory markers. That's how the immune system finds problems and it gets there just like when you damage your skin, you get a cut, the first thing you see is the pain. Of course, that's your neurons telling you damage there, but you see redness developing in that area. That's the inflammation. The reason the inflammation exists is to sequester that area so that any sort of microbes that got in there, it can't spread throughout the body, but then it also triggers the repairing part of the immune system to come to that site of action.

So the immune system responds really well to inflammation. So the microbes have learned that if they want to direct the immune system to that area, they have to shoot off inflammatory markers. And they can do that in two ways. They will either themselves make the inflammatory markers, which is mind-boggling when you think about how microbes can make cytokines and interleukins and markers that our immune system uses to communicate. These microbes are actually producing these, or they can stimulate the cells in the area, your own cells in the area to release these markers. Either way, they're trying to attract the immune system. Now here's what happens with people with dysbiosis and chronic low grade inflammation. These same signals are going on all throughout the body. So the analogy I give for people to understand that is imagine you had a neighborhood with 500 homes and one of those houses catches on fire and that one house that's catching on fire has a fire alarm that goes off. It's very easy for the fire team to figure out, the firefighters to figure out which house it is, get to it, and hopefully put it out.

Imagine in that same scenario, all of the houses in the 500 house neighborhood have fire alarms going out when only one is burning. It becomes very hard for the firefighters to figure out which house is actually on fire until the fire gets so big that they can actually see the smoke from a distance, then they can hone in on it. That's exactly what's happening in these individuals. They've got the same inflammatory signals going on everywhere throughout their body. The immune system is misdirected all the time. So when you have this infection that starts here in the lungs and all of these immune cells that's trying to... all these microbes they're trying to signal that there's a fire going on there, the immune system is distracted by all of the signals throughout the body. So it takes that much longer to actually respond to that site of action. Does that make sense?

Sarah: No, absolutely.

Kiran Krishnan: That's the tie, that's the molecular tie between why is it that if you have hypertension, all of a sudden your immune system doesn't work that well, and your risk for dying from this pandemic viruses is eight times higher. What is that molecular connection? It's because the same dysbiosis that led to hypertension or led to diabetes is the same kind of dysbiosis that actually creates chronic low grade inflammation in the body and that same chronic low grade inflammation is completely confusing the immune system.

Sarah: Urgh. Goodness gracious. Well said, but goodness gracious. Wow. What have we learned so far in the last 18 months say in the scientific literature, what studies have been made as far as the gut, the immune system and response to COVID, what have we learned?

Kiran Krishnan: Okay. One study that actually came out in March of 2020 when all of this kind of started, so this wasn't a COVID specific study, but this study really illustrated the risk that we run as a population in terms of dealing with something that is relatively mild, as far as a pandemic virus. We weren't dealing with like a global Ebola. We were really dealing with a respiratory virus to begin with that really was making certain susceptible populations very, very sick, right? So we were lucky in the sense that it was not a very scary virus, but we have an amazing percentage of our adult population that is highly vulnerable. Many of them wouldn't even know it. You don't have to be extremely ill to have been extremely vulnerable to something like this. So that March, 2020 paper that I saw was the thing that actually made me very concerned because what not... And that was a 10 year study followup from previous studies that were being done on the connection between the gut microbiome and the immune system. And what this study showed that this very, very specific and important immune cell called the dendritic cell. The dendritic cell is really critical in functioning to move the immune system from the blowtorch response to the highly specific response that doesn't damage everything around it.

So that's how the immune system functions. That blowtorch response is first, but that has to be sequestered within a couple of days, and then moved into the highly specific adaptive response where the next set of immune cells that are responding are responding specifically to the infectious agent and they're not blow torching. Now they've come in with very specific tools just to get that agent, so they're not damaging everything around you. That transition from that innate to adaptive immunity requires the function of the dendritic cell. And it's the dendritic cell that's going to go to the site of action, figure out what's causing the infection, gobble it up, and then take it to your lymph nodes to present it to T cells and B cells. So that is such a critical function for your immune system to go from, I'm damaging and destroying the host as I'm trying to control this thing to, okay, we're going to build long-term immunity and we're going to fight this thing very specifically so the host doesn't get damaged. So that dendritic cell is critical.

Now what that study showed in March, 2020, that the dendritic cell cannot operate even in light of infection, of an active infection going on, unless it gets a signal from the microbiome. So it's not that it's confused and it's going to function differently. It literally will sit there and watch the host get infected and host cells die and it will not participate in the fight until it gains a certain signal from the microbiome. It's called the tonal activation of the immune system. And the reason for this and we might think like, wait, why the hell have we handed the keys to our protection to these microbes. The reason is because if we didn't, we wouldn't exist more than a few months from the day we're born.

So what the microbiome does is it helps establish a threshold, a tonal threshold after which the immune system should respond. And the reason for that is we don't want our immune system to respond to everything we come in contact with. If it does, we would constantly be battling colds and flus and fevers and eye allergies and all that. We would literally be dead within months of being born. Our immune system would essentially kill us. And so what the microbes have done is they've set up this threshold level that has taught the immune system that, hey, if you don't see signals above this threshold, just chill out, right? Don't do anything. We got everything below this threshold. Everything is fine below the threshold. If it goes above this, then I'm going to send you a signal and you're going to come and you're going to participate in the fight. So without the right signal from the microbiome, your immune system's just sitting there watching it. And that kind of dysbiosis is so common in our society, which means that we are especially susceptible to infectious agents like a virus that comes in.

And it's not because we don't have the technology to deal with it and so on. It's just because we are inherently unhealthy because we have this significant dysbiosis. So that's one paper that came out right when all of this started that I was like, "Holy crap. We might be in trouble."

Matt: Definitely.

Kiran Krishnan: And then since then there've been a number of studies on the microbiome specific to COVID and what seems very clear now from at least four published studies is that individuals with certain types of dysbiosis in the microbiome had very high risk for hospitalization and death. And the dysbiosis is low diversity in the microbiome, low levels of certain Keystone strains like Faecalibacterium prausnitzii, Bifidobacterium longum, Bifidobacterium animalis. And then people also with high levels of opportunistic organisms, like Candida auris, Candida albicans. These are the types of organisms that are going to sit around and go, "Hey, come on in virus. We really don't care if you're infecting. In fact, this is good for us, you're going to distract the immune system." And so they're not going to help you. They're not helping the immune system figure out that something's there to kill the host.

So they're four studies that have shown that, that deep connection between dysfunction in the microbiome, and then how poorly you responded to the presence of the virus and the risk for hospitalization and death. And then on top of that, what they also found is that people who have the long haulers syndrome, even after they cleared the infection, I mean, there's no more virus in their system they continue to have the same type of dysbiosis in their microbiome. The hypothesis there is that because they continue to be severely dysbiotic, they can't recover properly from the infection. And we can talk about that other really important aspect is that, yes, you'll get an infection, you're all going to get infections. We all are. And hopefully most of us will get those infections under control like we normally do, but then are we appropriately recovering from each of those infections? Because infection control is a dirty game in the body. It causes a lot of disruption. So do we recover from it appropriately? That's the other question.

And we're seeing with COVID that, wow, there's a really good number of the population that does not recover from it and months later are still suffering.

Matt: Urgh, man. Wow. As usual, always my mind is blown.

Sarah: It's like mic drop moments every 30 seconds. And let's just recover from what we're learning.

Matt: So yeah, this ancient system that's in our body has this ancient communication system that is kobold and works together with their immune system and in an elaborate, it's obviously you're making this really easy to understand. I'm like, I get this now, but I know this is far more complex than what you're actually saying. You're giving us the-

Kiran Krishnan: And that's why using analogies becomes so important, right? Because it's so hard to wrap your mind around a lot of this stuff. And when you read the papers and you read through all the kinds of different pathways and signaling and all that, it becomes so complicated, but it really boils down to simple structural functions that the cells at the cellular level have figured out to protect us the big dumb host. We're really kind of just walking around like a structure. We don't know what is going on at the cellular level that is just keeping us upright and functioning day to day. We don't really appreciate and understand that so much, but at the cellular level, they figured this out millions of millions of years ago.

Let me give you one amazing example of communication that for me it just baffles my mind. So take a lung infections in particular because that's been the highlight of the last 18 months and this is true for influenza and any other lung infection. So the first things that notice something's infecting the lungs are, as we said, the microbes in that area, the local indigenous microbes to the area. So they see something coming in and starting to infect them. They want to alert their immune system, but here's what they do. They send out signals, they don't alert the immune system, they actually alert the microbes in your gut that something is happening in the lungs. So the microbes from the lungs are talking to the microbes in the gut. How do they do that? We have no idea, but they're doing that. So they're sending signals from the lungs to the gut telling the gut, because the gut of course is the major sampling site. That's where a lot of immune control occurs, but they're telling the gut that, hey, there's something happening here. Can you recruit the immune system and send them to the lungs?

And then the gut microbes create signals to send immune cells to the lungs from channels through the gut and then those immune cells, finally, when they get there, they'll go back towards the lymph nodes, closer to the gut and start proliferating and selecting the right immune cells that are going to fight whatever that agent is. So that kind of communication is just mind-boggling. We don't know how they do it, and we don't know how they do it so quickly. I mean, it just speaks of this tip of the iceberg scenario that we're in, where we're barely understanding this stuff to begin with.

Matt: Wow. So speaking, that is absolutely incredible and mind blowing and... Yeah. So thank you for enlightening us mere mortals with at least the tip of the iceberg. That's really exciting to get our head around it. So speaking of the gut and low grade inflammation, I find this fascinating because as you're saying, sometimes people are getting COVID or some other infection and they're getting wiped out and it's like, wait a second, they weren't even obese, but there was some form of low grade inflammation going on and so I'm very curious to hear about leaky gut and perhaps the immune response as well.

Kiran Krishnan: Yeah. So in fact, leaky gut, there were a couple of really well done editorials in peer review journals that were published on the role that leaky gut and endotoxemia and the associated inflammation has played in this whole COVID issue. And mind you, all the conditions we speak of that are conditions associated with high risk of mortality and morbidity with COVID are all conditions that are driven by leaky gut. And there's no doubt about that. There's so much research out there showing diabetes, heart disease, obesity, all of those things, senile dementia, Alzheimer's, all of these things are driven by leaky gut. So leaky gut is at the core of creating this chronic low grade inflammation. And the thing is leaky gut can occur in people that look perfectly healthy like you guys. Everyone would look at you and go, they're the picture of health, but if you didn't have a healthy gut, you would be leaky. You would have chronic low grade inflammation and you would never know it until it got so bad that it actually manifested into one of those conditions.

So that chronic low grade inflammation is the scariest thing. That's the soup in which most chronic diseases are created and it's also the biggest risk factor that we run in terms of dysfunction within the immune system. It also becomes the recipe for really egregious immune issues. It's one to be slower to recover from the flu or the cold. It's a whole other thing when your immune system starts attacking your own body. And that auto immune generation is all... they all stems from the same exact root cause.

Matt: Wow. That's incredible. So what can we do? So I go, "All right. I want my neighborhood watch upgraded guys. There's some bad guys here, the cartels somewhere here, can't do that without you." What are we going to do about it?

Kiran Krishnan: Yeah. And that's the best part about all this. Is when we start to learn that all of these risks are driven by dysfunction in the microbiome, the ecosystem within us, it becomes really empowering to me, at least because of my background, what I know that we can change everything, everything can be improved, everything can be helped. Whether what you're talking about is improving your immune response, recovering from an infection that you're still haven't recovered from, improving symptoms like fatigue and frequent colds, flus, allergies, and all that or even dealing with things like auto immune diseases, right? Where your immune system has gone haywire. All of these things respond to a few basic improvements to the microbiome. And this was further validated by all the studies on COVID and the microbiome.

So the first thing is diversity in the microbiome. If you increase your diversity in the microbiome, you change the whole world inside you. You become a completely different person without knowing it. Why is that? Because you've now gained extremely important superpowers that you didn't know you did not have. So the risk-

Matt: My Marvel thing is playing in my brain already. I'm the next character.

Kiran Krishnan: You didn't know you were supposed to be able to fly. You just walk around all day long just on the sidewalk on the ground. Now you can gain the ability to fly on a cellular level. It's super exciting when you think about it, because... I'd like to remind people that the vast majority of our metabolic function, all of the things that are occurring at a cellular level that make us human, allow us to adapt to the world around us and survive and thrive and all that, most of that genetic material that provides the capabilities come from the microbes that live in us. Our own genetic information, which is within ourselves, within our chromosomes only account for somewhere around 10, 15% of all our functionality. Most of our functionality comes from microbes and so when you have a small diversity in microbes in your system, you've got very narrow capabilities, the moment you expand your microbial ecosystem, you've expanded your capabilities, the things that you can do at the cellular level. So that is one of the most important things.

And the 15 plus years of microbiome research, the over, almost a hundred thousand papers that are published, when you look at characteristics of the microbiome that are associated with health, wellness, and longevity disease prevention, all of this stuff, it's always diversity is paramount. In fact, diversity will also dictate how long you live. So there's some really good studies on diversity of the microbiome and longevity. The people who are in their nineties, who are living relatively healthy lives with low rates of chronic illness tend to have the diversity of 30 year olds in the microbiome. People who are in their sixties and seventies who have diversity that is less than those in their thirties will tend to have much higher frequency of chronic illness and all kinds of other medical problems and they just won't live as long. So diversity is paramount. So that's one thing. We can talk about what you can do about diversity.

The second part is there are certain heroes strains within your microbiome that are critically important to not only maintaining the rest of the microbiome, but they do jobs that directly inhibit the formation of disease within us. One of them, I mentioned that was associated with a higher risk for COVID if you have low levels of this microbe is called Faecalibacterium prausnitzii. Faecalibacterium prausnitzii is this superhero bug inside you that combats all kinds of inflammatory damage to the lining of your gut and it plays a really important role in repairing the gut frequently to prevent things like leaky gut. And we now know and hopefully you've known from other things as well, that leaky gut is at the foundation of disease. So if you had some of these heroes strains, you've got high diversity, just those two things alone are enough to completely change the world inside you and change how your microbiome and your immune system communicate and therefore how your immune system functions.

Sarah: Oh, great tips. So diversity, what are the top three tips, top two tips for increasing your diversity?

Kiran Krishnan: So there's probably four or five that are really powerful. So I can go through them. I think the first thing we want to keep in mind is higher diversity in your food intake provides more diversity in your microbiome. So as a species we've evolved, our ancestors ate somewhere around 600 different types of foods on an annual basis. Most people in the modern world eat maybe 20 different types of foods. So the more we can add in terms of variety to the foods that we eat, the more diverse groups of microbes you will feed within the system. Remember the vast majority of food you eat, you don't assimilate as nutrients into your system. Most of it goes into your large bowel and gets fermented in some way or the other. And then they're all of these critical nutrients that we need to function at a basic level that are supposed to be produced by microbes in your system.

I'll give you one really, really important example of that. We talked about recovery from infection. One of the things that occurs during the infectious process is cells, your own cells get heavily damaged, oxidative stress. So your immune system uses things like reactive oxygen species to try to kill viruses, bacteria, or cells that are infected by viruses and so on. So that oxidative damage occurs through all of this tissue in that local area. So now you've got all of this crippled like cells that are just broken and not functioning well, their mitochondria is dysfunction because of all the reactive oxygen species. That's part of what makes you feel really tired and kind of fatigued and that malaise feeling when you're ill. And it's even after you're ill. And then for long haulers, it's even worse. They're feeling like that every single day for the next, how many months.

So one of the things that is really important is mitochondrial biogenesis. So regenerating new mitochondria those cells, so that you can start producing appropriate levels of energy. A critical compound to doing that, to recovering your own mitochondria in cells is a set of compounds called urolithins, and in particular uroltihin A. Urolithin A is a really important compound of regenerating your own mitochondria and getting rid of damaged mitochondria that got damaged in this whole fight. We cannot get any urolithin from any foods that you eat. There isn't a food that's rich in urolithins. The only way to get it is to have the right type of microbes in your large bowel that will take polyphenols that come in from your diet and convert them to your urolithins. So not only is that a really critical aspect of why you should feed yourself diverse types of nutrients, in part because the microbes are going to create compounds out of those nutrients that are really critical for your body to recover from this infection.

So not only does that create diversity in your microbiome, but it also produces a diversity of active compounds that your system needs in order to start recovering from the infection itself. So the first thing of course is, like we mentioned, is eating a diverse... trying to expand the diversity of your diet. Number two is you can do fasting. Intermittent fasting has been shown to be able to increase diversity within your microbiome and it's a little bit counterintuitive. You're like, okay, so feeding the microbiome is good, but then also not feeding. So you're probably like, what the hell is this guy talking about? We go through periods. We were designed to go through periods of being fed and fasted. And in fact, there are microbes that only proliferate when you're not putting food into the system. So when you look at the microbiome and how it deals with food, there are what we call primary digesters, secondary digesters, tertiary digesters.

So the big macro molecules that come in from food are typically broken down by the primary digesters. So they're the ones that have the enzymes and all the capabilities to break down the big proteins, amino acids, and carbohydrates and so on. And then their byproducts go down to feed the secondary fermenters and secondary digesters. So now these primaries are sleeping, they're done, they did their work. They proliferated. They had a good party. They're feeling good. They're resting. Now the secondary layer are the ones that are really proliferating and doing all of these amazing things and breaking down their waste products. And then they produce waste products that feed the next layer. So what tends to occur is that process takes a long time, many, many hours, 10, 11, 12 hours. And if you allow that to happen, you're actually feeding the entire layer of microbes in all of the different sections.

If the primary digesters do their job, and then we go down to the secondary digesters and they're doing their work. If you put more food in at that time, then these guys have to stop what they're doing because the primary digesters have to kick back on again. They're resting after their party gets cut short, they have to wake up again and they have to start digesting the food there. So we keep stifling the full array of metabolic processes if we're always feeding every eight, nine hours. So having some period of time throughout the day, even if it's 12, 13 hours where there's no food coming into the system, it allows us to go through that entire process and allows us to get everything that we should be getting out of food because each step of digestion produces new compounds that are absolutely critical to us. So that's why the not feeding over a period of time becomes important.

The third thing that could be very, very simple is getting outside. Studies show that if you're outside in more natural environments, that the more you interact with the natural environment, whether you go on a hike or the beach or wherever it may be, that tends to increase your diversity within the microbiome. So people that live on farms, for example, or rural areas, you don't even have to be on a farm. You just live in a rural area they tend to have higher degree of diversity in the microbiome than people that live in cities. So being able to go out to a natural environment helps that a lot. Getting a dog increases our diversity quite a bit. They're such wonderful animals. I don't know if you guys have dogs or not. But they're wonderful animals and they bring in a lot of microbes into your ecosystem and they help increase the diversity.

Another really, really important part that maybe we don't talk about enough as it relates to the microbiome is stress management, right? So external stressors can create an inflammatory process in the brain that actually can screw up the diversity of your microbiome. So when you encounter an external stressor, let's say it's something really simple, like something you read online that just makes you stressed and you're arguing with somebody in a thread or something like that about a political thing or whatever it maybe and you're getting stressed. So you're releasing cortisol, epinephrin, norepinephrine, the release of those types of hormones will actually act as a signal for opportunistic organisms to really start proliferating in the system. Remember those dirty little opportunists I talked about earlier. One thing many of those organisms have learned is that when stress hormone levels are high, the host's immune system is depressed. And so because of that change, then they have come to understand that when we detect cortisol is high or epinephrin is high, this is a good time for us to proliferate.

So then they proliferate, they start producing their toxins. They start fighting against your commensal bacteria, and they can create a dysbiosis and a loss of diversity within your microbiome. And in fact stress induced intestinal permeability in a 2015 meta-analysis paper in the Frontiers of Immunology was shown to be the biggest cause of mortality and morbidity worldwide. So we cannot overstate how important it is to start mitigating those external stressors in our lives. Whether it's on your commute to work every day, you get really frustrated with being in traffic. You're really just kind of worked up and angry and everyone that cuts you off, you honk at them, you flip them the bird, you just argue with people across cars or it's the person you're dating, the person you're with causes you stress, your family, whatever it may be, finding a way to deal with that is so critically important because stress drives dysbiosis, loss of diversity, increased leakiness in the gut and significant chronic low grade inflammation. So if people just do those four things to begin with, that's huge. It'll make a massive change in your outcomes.

Sarah: Oh, so important and great practical tips. Thank you, Kiran. I've heard that... Was there some study that was like five family pets is a sweet spot for the microbiome? And had this story, I think it was an immunologist, his wife had a baby and then he had the family lab lik the newborn baby all over to enrich the microbiome. What are your thoughts on some of that? Have you heard about the five pet thing?

Kiran Krishnan: Yeah, I have. And in fact even just a single dog will make a big difference. If you have a diversity of animals that really makes a difference. But another tip, maybe we can throw a number five because the Finnish allergy study really reminds me of that. If you guys aren't familiar with that, what was done was that there was an area of Finland and Finland in general tends to have like a lot of modern countries have very high allergy and asthma rates. So asthma in the US for example, is really considered an epidemic. In the US I think we now have almost 10 million kids that have pretty severe asthma. And then things like peanut allergies, all that's going through the roof. Like in school, I don't know that's true where you are, but in school here, you cannot bring a peanut based cookie to school. You'll get lambasted and stuck in a little kid jail if you did that. Because there are kids that will die from just proximity to it, which is just mind-boggling when you think about it.

So similar problems are happening in Finland. Now, what was interesting about what the Finnish government health authorities noticed is that a town that was very close proximity to Finland in Russia. So geographically, they were very similar, right? Very close by just a few hundred kilometers apart had very low rates of allergies, asthma and so on. So they did this long-term study to try to figure out why is there such a big difference between this rates of allergies and asthma, because geographically they're almost identical places. And what they figured out was that in Finland, people had their doors and windows close more often and they sterilize their environment. So they hyper clean, that smell that chemical smell became, that artificial lemon smell became the association of clean versus in the town in Russia they kept the doors and windows and all that open much more and so they were getting a lot of exposure to outside microbes. But here was the beautiful thing about that.

What they then did was they mandated, the government mandated that a certain number of daycare centers needed to build dirt patches. Just get natural dirt and create a big patch of dirt and it became mandated that the kids had to play in that dirt patch for X amount of time throughout the week, which is... In the US none of that would ever fly. There'll be all these protesting groups about the right to not play in dirt that we'd come up with. Somehow you're destroying our freedoms. But in places like Europe, you can mandate that stuff and people are doing it, but then as it turns out, they started following those kids, the ones that got that specific exposure, the ones that don't, and they see a huge change in the rates of allergies, asthma and immune dysfunctions. So something as simple as that, playing in the dirt has such a huge impact. And even though we're talking about kids, remember I mentioned that our immune system is constantly adapting and evolving, right? So you don't have to be a kid to change how your immune system works.

Kiran Krishnan: At any age almost you can change how your immune system functions and that's the beauty of all of this connection and knowledge that we've come to learn. So maybe number five would be don't necessarily sterilize your home. Most of the surfaces in your home don't need to be sterilized. Keep the windows and doors open as much as you can so you can allow some of the natural microbes in and then maybe play in the dirt.

Sarah: Love it.

Matt: Sounds fun. Speaking of dirt, I'm very curious to hear your thoughts on this, that looking at soil for example, we know that soil has a similar interplay of plants, like in terms of the diversity of microbes in the soil, makes for a healthier plant. I'm curious as to the result in that of the way the types of foods that we eat and the impacts on our microbiome. So if we zoom out and we look at, we've worked out if we've destroyed the diversity of the soil microbiome, plants become unhealthy. And then the way that we eat and particularly maybe the use of certain... overuse of antibiotics, destroying as well our innate diversity of microbiome, and sometimes killing off entire species. What is the impact of all of this? It's interesting when you see these things married, dirt has an incredible power to, obviously we've co-evolved with it and how we're eating these plants contribute to the diversity of my microbiome.

How do we make that connection? Does it matter what we eat? Is it important for us to be eating more organic, for example? And what are some things that can... like antibiotics or anything destroy the diversity of the microbiome?

Kiran Krishnan: Yeah. So antibiotics have a huge impact on your microbiome. Now, antibiotics are needed in certain times. It'll save your life. So definitely no diminishing the importance there, but more often than not, antibiotics are overused, even this... Centers for Disease Control has estimated that at least 50% of antibiotic prescriptions are unnecessary because they're being prescribed for things like viral infections, that it's not really helping with. In fact, there's lots of studies that show that having a course of antibiotics will actually make it harder for you to deal with the flu if you have a course of antibiotics at the same time that you get the flu or even right before getting the flu. So there's all these studies that are followed that.

So we know for sure that even a single course of antibiotics will disrupt your microbiome in a very significant way, and that disruption can be detected up to two years after that course of antibiotics. But here's the thing that's even more profound than that. Let's say one of you had a course of antibiotics. The other person's gut would also be dysbiotic from that antibiotic, even though Sarah didn't take the antibiotic. There was an amazing study done out of Johns Hopkins and published. What they showed was that we really kind of, within the world that we, our little ecosystems that we live in and our households, we have a microbiome cloud where we share microbes quite readily with all the people that are within the home. And it doesn't have to be intimate partners. It can be platonic people as well, roommates and so on. So what they did was they followed individuals that were given a course of antibiotics at a hospital and then they took all these microbiome samples from those individuals before they started the antibiotic and then they took it during the course of antibiotics and then up to six months after.

And of course they found that if you took the antibiotics it created a significant disruption to your microbiome during, and then up to six months after, but then the individuals that lived in the same household who did not take the antibiotics, also saw the same disruption. So not only is it going to impact us if we've had of course antibiotics, it's going to impact the people around us, then not to mention the antibiotics that are in the soil, the antibiotics that are in the animals that we eat and so on. So antibiotics are used willy-nilly all over the place. In the US I know we... there are something like 98 different antibiotics that are approved for use in agriculture. And all of those have a huge impact on your microbiome overall.

We see that with the soil. So your question of does it matter what we eat? And absolutely does. Now, unfortunately, even organic foods, even though they have less pesticides, and it's a better choice to go with organic, it doesn't necessarily mean that they're grown in very rich soil. So organic doesn't look at that part of it. Organic is more so what we're not putting on the plants. So it's much easier for a farm to go from non-organic production to organic production because they're just changing what they're putting on onto the plants, but the soil could still be dead. If you test most of the soil in most of the farmland, certainly in the US, most parts of Europe and all that, the soil is basically dead. I think some estimates are we have around 50 to 60 harvests left in farmland that we have existing today, where once we get to that point, the soil is so dead it cannot support growth of plants.

I did a couple of little experiments myself in my own backyard soil. We took samples of the soil. We looked at it under microscope. There's no life in there at all. It's so crazy and mind boggling when you think about it. Now, we've been doing studies at Montana State University on this very topic. This is a topic I'm very interested in because the roots of plants mimic our gut lining and it's so interesting how plants will select which microbes they want growing on their roots by plants themselves secreting attractant compounds, or antimicrobial compounds. So plants don't want certain types of bacteria. They want other types of bacteria. They have this ability to absorb nutrients in a healthy way if they had the right types of bacteria, assimilating nutrients for them at the root level.

So we've been taking spore based bacteria that we work with and a kind of a fermentation mix and we've been inoculating the soil prior to planting, compared to plants that don't have that inoculation and we're seeing a major difference in the ability of plants not only to grow, to be healthier by all measures that you look at plants, but also their ability of the plants to assimilate nutrients from the soil, in particular things like sulfur and nitrogen and all of these things that are really important to plant growth. So that kind of stuff is being done in biodynamic farming. So you'll start hearing more and more about that. Organic is still relatively small. I think the last estimate I saw was somewhere around 3% of all the farmland is actually organic. So it's pretty small, even less than that is biodynamic, but not biodynamic's whole purpose is to regenerate this life in the soil. So it's about bringing back biodiversity to the soil.

So if we and your audience and all of us out there can support more of the farms and the producers that are moving towards biodynamic, we will alleviate that being a significant problem. The broccoli of today, you might make the right choice and go, "I'm eating broccoli. I'm healthy. That's great for me." Yes. Broccoli is good for you, but the broccoli of today has 50% the nutritional value as broccoli from 30 years ago. It's mind boggling. So it becomes very hard for us to get what we need even in a basic nutritional level just to function in a healthy way. Let alone getting extra of what we need because we live in a very toxigenic world. So our demands for micronutrients and all that are so much higher than they were a few decades ago. So it becomes a really big struggle and I think supplementation and all that becomes really important.

Matt: Amazing.

Sarah: Oh, thanks for that. And I guess it's an encouragement for all of us to look into gardening-

Matt: Grow your own food.

Sarah: ... how you can grow your own food, really tend to the soil and then support farmers that try putting an effort in to do this right and do it properly for the future and for our body. So thank you so much. There's so many questions I could ask you here. I've literally got a library of things that you already said were interesting, but that I want to ask you more about, but we've hit it now and so I'm going to be diligent and wrap up, but thank you so much. It's been such an insightful calling. I'm really excited to publish this and get this out to the world, because it's so needed. Who would have thought these little guys in our bodies were so pivotal for our very survival. And I guess it's a humbling conversation because I think all of us are like, "Oh yeah, I'm good. I'm healthy." And then our gut bugs are like, "Hello. You can't do without us."

Kiran Krishnan: So good as far as... and there's one more message I want to put across to people, not to sound like an alarmist because that doesn't actually help. But I do want to emphasize that we are living right now through a series of mass extinctions that are happening within our own microbiome. So we have evolved over millions of years. Our ancestors went through a lot to put together by accident, of course, this really amazing ecosystem that exists within us that affords us all of the functionalities of being human. But what is really clear is we're losing huge populations of microbes completely, meaning they no longer exist in the human microbiome from generation to generation because of our practices. So we're working with one of our research groups with the hunter gatherer tribes in Papua New Guinea. We work very closely with Dr. [Jehne Walter] who's spent time there, studied their microbiome inside out. We've identified, done all these tests on their microbiomes and they have 50% increased diversity than we do.

There are microbes hundreds upon hundreds of species that exist in their guts that do not at all exist in our microbiomes anymore. We've lost them completely. And they're so critical to certain types of health functions. So part of what we're doing is trying to figure out, can we take some of those microbes and kind of rewild our system back to normal. But the important message there is that if we keep going the way we're going, where we're using lots of anti-microbials, using lots of antibiotics, not eating diversity and not paying attention to diversity, this generation of kids ahead are being born with fewer and fewer microbes it becomes our duty, we are the shepherds of these ecosystems that have been given to us over millions of years of evolution. It's our job to preserve that and pass that on to the next generation.

So the analogy I give people is, imagine if I told you that the next generation of kids would be born without a spleen because of our actions today, right? And then the generation after that, it's going to be born without a spleen and with only one kidney. We would be alarmed and going, what the hell are we doing? It's similar to that, because remember the microbes dictate your functionality and when you're missing certain groups of microbes, you're missing complete functionalities out of your body, which makes you very susceptible to all kinds of things. So this diversity conversation, the right type of soil, the right type of food, the exposures, all of these things we've talked about are so critically important, not just for our health, but really the future of the human race in so many ways and we cannot overstate that.

And it's a problem that we may not appreciate the extent of until it's too late. And that's the part that's really scary for a super nerdy microbiologist like myself. So we should do everything we can and your programs like what you guys offer and the education that you offer to your audience is so powerful in this process that I think that I'm super grateful to be able to come on here and be able to talk to you about it.

Matt: Oh, wow. Thank you so much for that encouragement and I guess what you're saying is it's such a huge wake up call that first, not to get lost, just particularly focusing on one virus, but as that as a dysfunction of not only the planet, but ourselves as well, like our reaction to this virus-

Sarah: A disconnection from the earth.

Matt: A disconnect. And there'll be probably many, and unfortunately, maybe worse viruses that come if we continue to violate these laws of nature that we've inherited from our evolutionary past. So thank you much.

Sarah: So it's time to take our custodianship seriously of these precious microbes.

Kiran Krishnan: Exactly. Yes. It's been given to us. We have to enhance it, improve it, and then pass it on.

Sarah: Yeah. Absolutely. Thank you, Kiran. What an important message.

Matt: If people want to learn more about you, what you're doing, what is the best place that they can follow you and learn more about?

Sarah: Or your probiotics or-

Matt: Yeah. Your probiotic.

Sarah: ... any of the research you're doing.

Kiran Krishnan: Sure. Yeah. I try to post more. I'm horrible at social media as you guys have probably seen, but I try to post a lot more of the talks I do and the research work that we're doing and we're involved in and all that. And Instagram is where I've been trying to be more active. I think I changed my handle recently to Kiran Biome-

Sarah: You did.

Kiran Krishnan: I did, right?

Sarah: I love it. So much easier.

Kiran Krishnan: Because the previous one was horrific.

Sarah: Kiran00 something, something underscore this.

Kiran Krishnan: Exactly. It's so bad. It is so, so bad.

Matt: Like a random password.

Sarah: Yeah. Like a password.

Kiran Krishnan: Certainly. And I think it was a password for something which is also... just shows how bad I am at the technology side of it. But yes, I think it's just Kiran, K-I-R-A-N Biome. So follow me on there or even send me messages. I really try to engage with even individuals on there if they have questions about things, because I think it's so important to share knowledge as much as possible. And then of course, you're welcome to come to our website, microbiomelabs with an S .com and we do post a lot of our webinars, education, research papers, and all that on there as well. So yeah, feel free to jump in any of those places.

Sarah: Wonderful.

Matt: We certainly encourage that. Thank you so much. It's such an important message. And yeah, we don't take this lightly the time that you've shared and the knowledge that you've shared with us. Thank you so much.

Kiran Krishnan: Thank you. It's my pleasure.

Matt: Well, I think the saying goes, cometh the hour, cometh the man.

Sarah: Sorry. What?

Matt: You haven't heard of that saying?

Sarah: No.

Matt: That's a famous saying. Anyway, Kiran, he crushed it.

Sarah: He did.

Matt: I think he packaged something together that the world needs to hear for sure. And as divisive as COVID has been, or the pandemic's been for people on all different sides of the fence we just think that this conversation has not been emphasized and that the microbiome's role, the key role in our immune defense system and how you could say dangerous persistent low grade inflammation is, is just such a... You'd say like a critical missing piece of the puzzle that not many people know about. So man, if you've gotten anything out of this conversation, we would love to hear from you. But I just can't think of a conversation that's really as important as this at the moment. So if you really want to help someone or just obviously equip... The only thing we can do now is just share what we have. We have a limited reach, and now it's sort of up to you guys to take that and to extend it into your network and community.

When we started this, doing this free, it takes a lot of time, effort, resources to put this together and this was always a big part of our vision is that we would be able to take voices like Kiran that has distilled such important information and give it out to the people that need to hear it the most. And so over to you guys, give it a share, give it a like, give us a subscribe. We need help in the algorithm to get this out to as many people as possible, grab the link, put it in your inbox and send it to five people that you think might need to hear it. And I think this talk is the beginning of something huge. So let us know what you thought in the comments. And if you do recognize the saying, unlike Sarah, let me know as well so I'm not just left on the lurch.

Sarah: I think you mean to say, cometh the hour, cometh the human. Because I didn't feel included-

Matt: It's true.

Sarah: ... in that quote.

Matt: So gender inclusive. Cometh the hour, cometh the woman. Cometh the hour, cometh the man. Cometh the hour, cometh the human.

Sarah: It is a good tongue twister for you. Thank you so much for joining us once again. Remember to like, and subscribe and share as much as you can. It really helps get this really, really crucial information out into the world. And if you like social media head on over to Instagram, we're posting a lot there lately. And I think you might get a lot out of it too. So thanks again for joining us and we look forward to seeing you next time.