Jason Prall: Well, we're back with one of my favorites, Kiran Krishnan, thanks for joining us.

Kiran Krishnan: Hey, Jason, so glad to be here with you. Love this topic so it's really exciting to be able to talk about it.

Jason Prall: Well, it's one of those topics that's very prescient, right? We're all kind of thinking about immunity on some level, right? And I think some of us that live in this sort of health space we're probably constantly thinking about this type of thing. But for most of us that are just going about our days, it's sort of a background thing that we don't normally think about. And recently, it's come to the forefront of, what is it that I should be doing?

I think a lot of us in the health space, especially the people that are consuming this type of content, are already kind of thinking along the lines of how do I improve my health and how do I stay healthy? And yet, there seems to be this kind of confusion right now of what the heck do I do because the advice is so all over the place. What we're dealing with, with this coronavirus? How it works? And it's just all over the place. Nobody really has a conceptual framework, I think, of how to go about their day to day because I mean, I've heard people even in the health space that have come down with a very, very serious infection, right?

Kiran Krishnan: Yeah.

Jason Prall: Supposedly corona, and they're dealing with some pretty severe things. And yet there's a lot of other people that say, "I don't know a single person with this thing."

Kiran Krishnan: Right. Yeah.

Jason Prall: It's such a very, very confusing space. And so, what I really want to dive in today with you is to talk about how the microbiota, since you are a microbiologist and you dig into this stuff to the nth degree, how microbiota play a role? How the immune system really even kind of functions? So, we can hopefully give the audience a little bit of a background about how viruses and bacterial infections work so that we can take actionable steps, both preventatively and perhaps, if we feel like something is coming on.

So I think, with that said, maybe you can just give me a sense for how you are going about the world right now. How is it that somebody like you with a lot of

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resources in the health space to be able to do prevention and even take action if something happens, how are you going about this?

Kiran Krishnan: Yeah. So that's a really important question because you hear it said a lot that we are especially vulnerable to this particular contagion because we have no, the word they use is, we have no immunity against it, right?

Jason Prall: Right.

Kiran Krishnan: What that really means, what they're saying is our immune system has no memory of dealing with this particular virus. But it doesn't at all mean that our immune system is ill-equipped to deal with this virus. This is exactly why our immune system exists, right? It is programmed, designed through millions of years of evolution to deal with this very specific type of contagion and a whole variety of them as well. So, to me, I don't have a whole lot of fear around coming across this particular contagion because in my view, my immune system is functioning the way it's supposed to. It is perfectly capable of handling a contagion like this.

So we can talk through the aspects of the immune system that really kind of handle it. So in my view of going about it, I don't have any desire to purposefully expose myself to it, of course, but I also don't have a fear of getting exposed to it because I feel like I'm doing the things that I need to do to make sure my immune system is functioning even in its most basic capacity the way it's supposed to function. And even at that basic capacity, it can completely and easily handle a contagion like this. This is a reason why you've got estimates of somewhere between 50, maybe 70% of people that come across this are completely asymptomatic, right? Meaning they don't have any idea they were ever in contact with this virus.

Your immune system takes care of it like that. In fact, two of my really close friends had it and had no idea and the only reason why they found out they had it is because I've been doing antibody tests for myself, my family, my friends, like every few weeks, every couple of weeks, just to see have we gotten exposed and where are we with the immune response? A couple of them lit up with IgM antibodies, we'll talk about what IgM means, lit up with IgM antibodies, which indicates an acute infection going on right now. And they had zero symptoms, never did have symptoms, and then there was seroconversion, we'll talk about what that means, to IgG without ever having any sort of noticeable response.

So we'll talk about where the symptomology comes from when you do get an infection like this. How is it that your body can get infected and yet you feel nothing? Right? And what are the mechanisms at play there? And really, why we shouldn't necessarily be afraid of this thing? It is going to cause certain types of people and people with certain underlying conditions or very serious conditions and that's what we have to be really cognizant and protective of. But if you are maintaining just kind of basic immune health with the right eating, resting,

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supplementation and basic micronutrients and your microbiome, your gut is healthy, your body should be able to take care of this pretty easily.

Jason Prall: Well, I think it's really important that you highlight this because we constantly hear this is a novel coronavirus. And it's interesting language because it almost invokes a fear response that this is something new that we've never seen this and oh, my God, what's going to happen? But look, we see novel flu viruses every year. We see novel infectious agents constantly, right? That is, like you said, the point of the immune system.

And if there's something that I really have taken to heart and really grow appreciative more every year is that the human body and mind for that matter is so adaptive. It's mind boggling. We are such an adaptive creature, so I think that hopefully puts us to rest. I think this education around how the immune system works and how it's going to respond to some things does allow the fear to subside, hopefully a little bit because we can understand how the mechanisms are really unfolding.

Kiran Krishnan: Yeah.

Jason Prall: And this is just it, right? I mean, how many of us gets sick with the flu each year and don't know it?

Kiran Krishnan: Yeah.

Jason Prall: How many of us get sick all the time and we don't really know it. And yet, if we were to do these tests, like you're mentioning, we'd see all kinds of things happening, right? Because the body's constantly doing things that we don't really recognize unless we're perhaps hyper tuned in, like some of these monks and things that I've talked to that can sense this stuff, which is wild, but maybe you can start me there.

If somebody is getting exposed to something like this and you have one person that has no symptoms that are recognizable, you have another person that experiences maybe the common things, whether it's a fever or cough, and then you have another person that is just severely impacted. What's the difference there? And how can we make sense of that?

Kiran Krishnan: Yeah, so let's look a little bit then about the immune kinetics when a contagion enters your body. And then we'll kind of talk through the process of how your body deals with it and where symptoms arise. So first, let's break down that the immune system has two really big basic categories. One is called the innate immune system and the innate immune response. And then you shuttle into something called the adaptive immune response.

And really, the differences are the innate immune responders are the quick-acting, quick to the site of action, nonspecific immune reactors, meaning they're

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the ones that are running around and looking for invading pathogens, but they don't have any sort of memory for any specific pathogen, right? They're just looking for any sort of change in the normal homeostasis of what's going on in your body. And I'll explain a little bit about how they detect that change because there's a tremendous complexity to that part of it, right?

So they are the quick actors, they're nonspecific. They basically kind of attack everything with a blowtorch. That's part of their job. And then there are immune actors that quickly try to shuttle those guys away but try to get your adaptive part of the immune system to learn about this contagion, whether it's a previously seen one or new one, so that you have a more robust but less noticeable immune response the next time you see it or throughout the end of the course of that infection, right? So that's the generalities.

One of the analogies I always use between the innate and adaptive, it's like think about a home. If you had a home with thousands of windows all over that bugs could come in and you've got two groups of actors that protect the inside of the home from bugs. One of those groups of actors are really fast. They can move really quickly to any window in the house to respond to a bug approaching in, but the equipment that they use to take care of the bug is a blowtorch, right? That's what they have. That's how they're equipped but they're really fast to get there and they're going to blowtorch everything in that area. They're going to burn the wall a little bit too because of their approach but they're going to definitely kill off the bug.

Then the slower actors are the protectors that have very specific tools for each and every different type of bug that can enter and they can, with surgical precision, go and pluck out those bugs out of the atmosphere and get rid of them from the home. So the ones that respond slower but are highly specific is the adaptive system. The ones that respond early on very quickly is the innate immune response. But the innate immune response does use a blowtorch. And so we'll talk about where symptoms become really bad for people. It's basically, in a way, you're getting too much blowtorch response and you're kind of burning down the house, right?

Jason Prall: That makes sense. That's a good analogy. Sorry to interrupt, I was thinking of another analogy just because I've been doing some painting and I feel like when you go in there and you paint, you've got the paint gun, right, the spray gun. It's just painting everything, right?

Kiran Krishnan: Yeah.

Jason Prall: It gets the job done really quickly but it's kind of sloppy and then you just got to do some cleanup. Then you get in there with the fine toothbrush and you take things off and you really, really clean it up. Right? So it's-

Kiran Krishnan: Yeah, getting-

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Jason Prall: And there's precision with each of them to some degree. There's a level of accuracy or precision, I guess.

Kiran Krishnan: Yeah. And they both have a very specific purpose. The fast actors, if they didn't exist and they didn't respond the way they do, then it gives too much time for a huge number of bugs to enter the home. There's a risk then of the home becoming overwhelmed by bugs. So we need them to react fast, so the moment one enters the space, to go there, react quickly but they are going to react with blowtorch until they get tapped on the shoulder and go, "Hey, the specialist is here, stop blowtorching everything," they're going to keep doing what they do. And so we need that transition as a really important phase.

And this particular virus does something with that transition that I'll explain, which is what makes it really dangerous for certain type of people. So that's the kinetics of how the virus infects that really makes this a unique virus and how it does it too. But again, we are perfectly equipped to handle it.

So when a contagion first comes in, and let's talk about what it comes into. This is a part that's really important for people to understand the complexity of the immune system's job. So anything that enters your body, whether it's through your eyes, your mouth, your nose, even through your skin, your urogenital tract, enters into a mucosal surface. Your mucosal surface inside your body is the largest surface area in your body. It's far larger than what we used to call the largest organ which is the skin.

The skin is somewhere around two to three square meters large. The mucosal surface inside your body is about 400 square meters large, right? So that's a massive surface area. That is somewhere around 4,000 square feet. So imagine a house that is 4,000 square feet is a very large space. Anyone will be happy to live in a 4000-square-foot house. And all of that surface area is the mucosal layer that's folded up and put inside your body.

The reason for the mucosal layers, it acts as the sampling barrier for anything that enters your body. The other part of the mucosal layer is that's also where the vast majority of microbes, including viruses, that live inside your system in a commensal fashion, they all live in that mucosal layer as well. So that's where microbes come in, but that's also where all of the endogenous microbes that live in your system exist. So here's where this problem becomes really complex.

Your mucosal system inside your body contains somewhere around 40 trillion microbes already. These are your commensals that live with you all day and night for the rest of your life, so they're there. Your mucosal system where pathogens, like other viruses and bacteria, they could cause infection, enter into that pool of 40 trillion existing microbes. Now, your immune system has somewhere around 200 million cells whose job it is to survey that mucosal surface area.

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So you've got 200 million cells that are surveying a structure that is as big as a 4000-square-foot home that is already covered with 40 trillion other microbes. There are 200,000 times more microbes in your mucosal surface area than there are immune cells to monitor that area.

So let's give an analogy so that people can really kind of wrap their head around the task of the immune system. Imagine you're at a music festival. We've all been at an outdoor festival, a carnival, at some point, and it's a huge field. And in that space, there are 200,000 people. 200,000 people of all sorts, all different genders, races, ages, colors, heights, and so on. They're all there.

Among those 200,000, there may be four or five that are problematic, that could be dangerous, they might have ill intentions, and you are the lone security guard in that festival. Your job is to identify that potentially dangerous person who looks a lot like everyone else that's there and stop them from doing what they will do or what they may do. So that is the job at hand for the immune system.

If you just imagine, you're in a sea of 200,000 people, you're trying to identify four or five that may be problematic and it's just you. It's a 200,000 to one ratio in the body. So that is just mind boggling, if you think about it. I mean, how does our immune system do this for us? So the only way they can do it and the only way in that analogy I gave you that you could possibly defend the 199,999 people that are perfectly good, healthy people there that aren't causing problem is if all of those people are also on your team and they're looking out for suspicious activity. And everyone has a radio and they're going to radio to you if they notice anything.

It's impossible for you as a lone security person to survey every piece of activity going on in that festival. What you need is a cooperation of all the other attendees to radio to you should they see something unusual. That's a neighborhood watch type of mentality. So the microbiome is the neighborhood watch for the immune system.

Those 40 trillion microbes, they play a really important role in keeping an eye on the homeostatic environment. The moment they see a new virus, bacteria, a parasite, or something else that enters the system that is different than the homeostatic environment that they're used to, they are the ones that alert the immune system to the presence of this new contagion. That is one of the really, really amazing and important relationships between our microbes that live in us and our immune system.

And in fact, think about it. The immune system could never survey your entire surface area inside your body and effectively approach new contagions or even previously seen contagions without that job of the microbiome being the neighborhood watch. Does that analogy make sense?

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Jason Prall: Yeah. And so kind of where my mind goes, and correct me if I'm wrong here, but the effectiveness of the microbiota at helping the immune system is probably going to be dependent on, I would imagine, diversity. Do we have a wide diverse range of microbiota? And of course, sheer numbers, population, right? So, which is when we run tests, you see this a lot. You see the populations are down. You see the diversity's low and this generally indicates poor health.

And that's obviously one of the things we want to do. So that interaction is going to be... I mean, this all of a sudden makes really, really important point of the microbiota and a key target if we want to improve our immune function.

Kiran Krishnan: Absolutely, yeah. It's the underlying basement function of the immune system is relying on the microbiota to signal to it when it senses new things entering the body. So that is a fundamental part of immune system's function. So imagine those in that analogy I gave of a big house with lots and lots of windows and bugs entering through the various windows. Imagine if all of the immune actors, the guy with a blowtorch and the guy that's more precision-responding, if they're all in just one room. And they're not out there with the capability of actually surveying that entire house effectively every second of every day. But instead, they have commensal people sitting around in each room that will signal to them the moment they see a bug entering the system. That's the only effective way our immune system can survey our body and protect us from invading microbes.

Now, here's another really important part of it. And you're absolutely right that one of the fundamentals then there within the microbiome of being a healthy microbiome with regards to support of the immune system is diversity. And the fewer pathogens and opportunistic bacteria you have within your microbiome, the better that function occurs.

Because some of these bacteria, because they are opportunistic or because they are straight direct pathogens, they're not going to signal your immune system. They're not sure whose team they're on. They're kind of sitting around waiting for the system to break down because that's when they tend to take over. So if you have low-

Jason Prall: This would be like biofilms that accumulate fungi that is overgrown yeasts and these types of things that... Now, none of these are bad. In fact, biofilms are often good, but they need to be in certain balance and there's certain things that get tipped over. So that's kind of what you're talking about here.

Kiran Krishnan: Absolutely, yeah. Because it's all about relative abundance. For example, studies have shown that the risk for developing severe lung infections or upper respiratory tract infections will depend on what the microbiome of the lungs look like. And the reason for that is when a contagion like COVID enters into your upper respiratory tract, the first thing that sends out a signal that, "Hey, there's a virus in here" is the microbiota in the lungs. And the microbiota in the lungs actually send signals to the microbiota in the gut.

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And then, the microbiota in the gut transmit that signal to the immune system. And because, remember, the gut contains about 70% or so of all of your immune tissue in the body, so that conversation will cease to occur if the gut microbiota is all of a sudden predominated by opportunistic bacteria, who's actually looking for an opportunity where inflammation occurs, so that it itself can start proliferating.

So if you have a dysbiosis going on in your lungs, after lots of smoking for a while, after just kind of lifestyle choices, loads of antibiotics that you've taken, poor diet and so on, that dysfunctional microbiota in the lungs will not signal to your gut when influenza or COVID or any of the respiratory viruses enter into the system. So that's an important thing. And here's a really important point to put across.

I mentioned that the microbiota is what signals to the immune system the presence of a contagion entering into the ecosystem. The way the microbiota does that is through inflammatory markers. Inflammatory markers are extremely powerful signals, big alarm signals to your immune system to try to direct the immune system to the site of action.

So one of the ways they do this is let's say we're talking about the lungs again, let's say the lung microbiota is healthy. You get a contagion that enters in, whether it's a flu virus, it's a coronavirus, or any other type of respiratory virus, some syncytial virus, once it enters into that system, the microbes detect the presence of a new virus that they are not familiar with. When they detect that presence, they will actually start to produce interferons. And they will start to produce cytokines that trigger an inflammatory response from the cells in that area.

And one of the inflammatory markers they release is something called interleukin-1 beta. The reason why interleukin-1 beta is such a powerful inflammatory marker is because when one cell starts to release it, one of your lung epithelial cells starts to release interleukin-1 beta because it got a signal from the microbes that, "Hey, something is weird in this area," it causes the adjacent cell to release that same inflammatory marker. And then the adjacent cell beyond that to release that same inflammatory marker.

And that inflammatory marker is a big alarm or a smoke signal to the immune system that say, "Hey, there's something going on over there in the lungs." That's when the blowtorch actors come in and start kind of blowtorching the area to kill anything that may be invading the system. So inflammation is what your microbiome and the early responders in your immune system use to signal subsequent immune responses. And that's really important to keep in mind because if your body has chronic inflammation, those signals get lost.

So imagine, think about it this way, again, go back to analogy. If you're in a town and there are thousands of homes in the town, and you've got one or two fire trucks that survey and put out the fires in the various homes. The fire trucks are

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stationed in one area or maybe they're driving around to a certain degree and then when there is a fire in a home and a loud alarm and smoke goes off from that home, the fire trucks have an idea of where to go. But if there are alarms going on all over that town, and some of it is due to a fire, the rest of it is due to other factors, which we'll talk about, then the fire trucks don't have any idea of where to go, where the actual fire is.

So chronic inflammation in the body, especially elevations of things like interleukin-1 beta, that potent signal I talk about, or interleukin-6, those chronic inflammatory alarms that are going on in the body actually completely drown out the signals that the microbiome is trying to translate to the immune system to alert them to the presence of an infection.

That is a really important fundamental thought because when you think about what are the conditions that create the most risk for adverse events with this particular type of virus, for example, the SARS-CoV-2, it is conditions that are associated with chronic low-grade inflammation, diabetes, cardiovascular disease, obesity, chronic obstructive pulmonary disease, age is a big factor, all of those things are related to chronic elevation of interleukin-1 beta, interleukin-6 and inflammatory alarms going on throughout the body all the time.

And so, when the virus enters and in that local area, the microbiome is trying to signal the immune system, because that same inflammation is going on all over the body, the immune system doesn't see those signals. So they don't make it there fast enough. That gives the virus a certain amount of time to replicate quickly, infect many, many cells before the immune system ever even notices they're there. And that's part of that latency period in the virus because your immune system hasn't yet responded to it, so you don't really feel too much. And so the virus is just replicating, and you've got that five, six, seven, upwards of 14 days before symptoms set in.

During that time, the virus is infecting many, many, many cells and producing many, many copies of itself in your body. And then finally, the immune system realizes that there's something going on. But at this point, the viral load is so high that the immune response becomes really robust. Now you've got a lot of blowtorching going on. And that's when you really start to feel the symptoms.

So remember, the symptoms in any infection are not necessarily because of the contagion themselves, not what they're doing, it's the immune response to the contagion and how big the immune response has to be. And this virus does something really special, which makes it even harder for the immune system. So I can jump into that, unless there's a question to that?

Jason Prall: Yeah, I just want to kind of finish some of that up. Some interesting thoughts that came to mind. When we say, just on a normal basis, I'm getting sick. It's interesting because really, what we're saying is, I'm actually getting well, typically.

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Kiran Krishnan: Yeah, totally.

Jason Prall: Most of the time, that thing that we feel that we don't like, the headaches and the fatigue and the inflammation and the whatever it might be, that's actually us getting better.

Kiran Krishnan: That's your immune response, yeah.

Jason Prall: And I was kind of thinking about as you're talking about this, this initial innate reaction, innate immune system response, kind of explains at least partially why children and younger people aren't being impacted so severely. Because their innate immune system is boom, generally, ready to go. It's primed in a young person. And so, that's built in, they have that already. And there's generally lower inflammation in young people, especially infants and kids. So there's a high contrast for the immune system to be able to recognize something quickly.

And as opposed to the elderly people, almost all of us as we get older, especially in our 80s and 90s, it's like, we're just going to have inflammation, that's just getting older. That's the reality that we're dealt with. And so it's a little more problematic.

Kiran Krishnan: Yeah. And the energy that the immune system needs to respond is also compromised because one of the key energetic molecules that actually fuel that innate immune response are things like short-chain fatty acids. So butyrate, that's produced in the gut, which is really important for overall gut health to begin with. But it's also the fuel for that fast, energetic response of the innate immune system. Because all of these things that the immune system does requires a lot of energy.

Imagine, you are a basophil or a mast cell or a neutrophil or a dendritic cell, you have to circulate throughout the body. That in itself requires a lot of energy because you're constantly producing energy to circulate around. You have to show up to an area of infection. They produce all kinds of compounds like reactive oxygen species, the complement system, which is this huge series of chemical byproducts that kill off bacteria, viruses and infected cells.

They have to engulf, in the case of macrophages and dendritic cells, they have to engulf entire bacteria or viruses or infected cells and digest it on the inside and then present antigens from those bacteria and viruses and those invading contagion on their surface area. They have to then migrate with that presentation to get to T cells in the lymph nodes in order to present that, "Hey, immune system, we've got something new here and this is what it looks like."

All of those jobs that your innate immune system does is really energy-driven. And as you get older and your gut microbiome is producing less and less butyrate and short-chain fatty acids, you've got lower diversity, which is a

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factor, a major factor in aging. You've got more inflammation. All of those things drive a dysfunctional response, especially to this particular virus.

Now, here's a unique thing that this virus does that really accentuates the dysfunction that some people have. Most of our cells, especially our epithelial cells, which are the ones that tend to get infected when new viruses come in. Those are the cells that line tissues, like they line the lungs, the inside of the vessels, your arteries and veins, the intestinal epithelium, the lining of your gut, your intestines. They have protective mechanisms to signal to the immune system as well with the help of the microbiome when they are infected.

If I'm an epithelial cell and I'm just sitting there doing my job as a cell, and then here comes a virus and attaches on and then starts squirting its RNA or DNA into me to try to get my cellular machinery to replicate the virus, the first thing our cells do is they have a default response where they instead start triggering the production and release of interferons. Interferons are very, very powerful antiviral compounds that every one of those types of cells can produce.

So if a cell gets infected by a virus, it automatically turns on its interferon production, so that it can try to kill the virus that has infected it. That also completely slows down the cell's metabolism. So it tries to shut itself down. And then your immune system can read those interferon signals and go, "Holy cow, that cell is distressed, and it is producing antiviral compounds. We got to go and eat that cell up and get rid of it." So that's one of the protective mechanisms.

The second part of the cellular response when a virus enters is it does release those inflammatory cytokines. The interleukin-1 beta that I mentioned, the interleukin-6, and that again, is like a flare or an alarm to the immune system that, "Hey, I'm infected, come and help me." So both of those things occur the moment a virus comes and infects.

Now, viruses are also smart through the course of evolution and they have ways of working around those things. Most viruses, including influenza, one of the things that they do is they code within their DNA or RNA little blocks for the interferon production or little blocks for that inflammatory response production. So that the moment the virus invades, it'll quickly try to take over some of your cellular machinery to get you to produce the blocks to interferon and blocks of the inflammatory response. That way, the virus has some time to replicate in the cell before the cell starts producing antivirus or starts signaling to the immune system that there's an infection going on. So influenza does that beautifully.

Now, one of the ways that our body fights against influenza is the microbiota in the lungs and upper respiratory tract recognize that the cell is under distress and it triggers something called the inflammasome. The inflammasome then acts as the surrogate signal to your immune system that this cell is infected. So your microbiome is working with your own cells to help monitor, detect

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damage, especially because the influenza itself has a way of shutting down those signals from the cell.

Now, what's unique about SARS-CoV-2 is it comes into the cell. It does the shutting down of the interferon, which is normal like a lot of other viruses do. But here's what it does to the inflammatory response. Not only does it not shut it down, it seems to amplify the inflammatory response, which is a unique strategy, which is not really seen in other coronaviruses either. So it seems to amplify that inflammatory response by the cell, thereby increasing ACE2 receptors in nearby cells. Remember, the ACE2 receptor is a receptor on our cells that the virus itself targets.

Now, one of the things that occurs when you have inflammation going on in all of the tissues around you is the tissue starts getting damaged from that inflammation. And because of the damage, your cells start expressing these ACE2 receptors. So what the virus is doing is it's going in, it's using your cell to get replicated. It's also amplifying those inflammatory signals from the cell so that the neighboring cells start releasing more inflammatory markers, but also start expressing more ACE2 receptors. So that when new viruses come out of this cell, they have more targets to bind.

So that's one of the things that really drives this systemic inflammatory response from this virus. Because this particular virus really amplifies the inflammatory response in the body on its own. It's doing that on purpose. So now, imagine, that your microbiome is unhealthy. Your microbiome is not really detecting this big disruption that's going on. The inflammatory signals are getting really big, so your innate immune system is a little bit confused because not only is there this big inflammatory signal here, but you've got diabetes or heart disease, and so you've got inflammation all over your body. So the immune system doesn't know where to respond just yet.

And throughout that process and that confusion, this virus is allowed to replicate in really large amounts and then you end up with a huge viral load. When you have this huge viral load and your innate immune system finally realizes that there's this new contagion, then the innate immune system further amplifies the inflammatory response to try to recruit more cells to that area, thereby setting you on the course to that cytokine storm.

And that cytokine storm just basically takes over, damages tissue. The tissue damage leads to more ACE receptors, leads to more inflammatory response and you start kind of spiraling out of control. And then that's when people go into real severe distress. And if it's happening in the lungs, that's what can drive the respiratory distress and respiratory failure. If it's happening in the vascular system, it starts driving clot formation because all of that damage to the tissue causes big clots to form. And those clots then can end up in the brain causing strokes in 30-year-olds. The inflammatory response in the upper respiratory tract can cause a loss of smell and taste. All of those really interesting complex

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things that we're seeing with this virus is really driven by this kind of cascade of inflammatory response.

Now, if the virus is trying to do that in a body that has low basal inflammatory response, that virus triggering of the inflammatory response in itself will be detected very quickly by the immune system, will be signaled by the microbiota to the immune system, and then you'll get a good robust quick response to shut it down. You will never even really feel that escalation of the inflammatory response. Does that make sense?

Jason Prall: Yeah, it makes a lot of sense. And the way I think about it is sort of like the body always has this hierarchy of needs, so to speak. Almost like Maslow, I guess. We have a limited amount of energy and capacity to do work. Of course, if we get great sleep and we eat a good diet and perhaps we're doing some fasting or intermittent fasting and we're cleaning things up and we do all these amazing things for ourselves, then the body has more energy and capacity to do its job. But if we're overloading ourselves with exercise, if we're getting poor sleep, if we are stressed mentally and emotionally, and then I'm also just recovering from knee surgery.

And you got all these things going on that's adding to the sort of allostatic load of inflammatory signaling, combined with low energy capacity, then the body's just going to have to go, "Okay, well, I have limited resources here to work with. I'm going to have to address what I think is most important based on what's happening."

And I'm just sort of imagining the initial infection or onset of the infection may be pretty low priority given a body that has so many things going on and so much inflammation, but then at some point it tips over. And if you've got lots of inflammation, lots of things going on with limited energy capacity, then we may tip over at a late stage, in which case it's very difficult to overcome or to recover from it. Is my thinking on the right track?

Kiran Krishnan: Yeah, exactly. And I like how you put it because it's that prioritizing for the immune system. So if you are someone that tends to have systemic inflammation, whether it's from diabetes or obesity or high blood pressure, hypertension which is another big risk factor, all of those conditions create constant inflammatory response and epithelial damage in your vascular system. So you've got hundreds and hundreds of miles of vascular tissue in your body. So much of it is always inflamed and damaged by the high blood sugar, the hypertension and so on. So your body's always tending to that damage in the vascular system, trying to repair it.

The immune system's coming along, trying to control any potential issues in that area. All of that work is just constantly going on. And then here's this little inflammatory blip that's starting to occur in your lungs, but your body is so busy working on other things until it gets to a point where the surfactant and the characteristics of the alveoli start to really change.

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And now you are becoming short of being able to breathe appropriately. Your saturation of oxygen is dropping. Then your body all of a sudden goes, "Holy crap, that is now priority number one." And then everything gets thrown into that area and that area becomes saturated with inflammatory activity and then that quickly puts you into respiratory distress.

And so absolutely, what you're saying is totally true in that in a body that has a lot to handle all the time, it's trying to handle and prioritize things and it will allow this new infection to go on because it's prioritizing other repairs that it's doing all the time, until it becomes a real serious thing. Until the lungs start signaling that we can't expand anymore, that there's too much fluid now building up in the lungs. The characteristics of the alveoli are changing and that is signaling the innate immune response. Then all of a sudden, it becomes priority number one. So, absolutely.

So one of the important messages, I think, from all of this, hopefully, that people are getting, is your immune system and taking care of your immune system goes well beyond taking vitamin C. It goes well beyond taking your vitamin D, taking your zinc, those are all important. I take all of those things quite religiously every day so that I know I have adequate amounts should I need it of those micronutrients, which play a role in many aspects of the immune response. But your microbiome, your environment, the level of chronic low-grade inflammation you tend to have, lifestyle, like Jason said, if you're not sleeping enough, you're going through more damage throughout the day, you're not having enough repair period overnight where your body can rest and repair.

And then when you wake up, your body's at a much lower basal work rate so that it has more energetics and ability to respond to things you might come across. Stress, of course, drives leaky gut, more chronic inflammation. All of these things play a really important role in allowing your immune system to respond adequately when something new comes in.

Jason Prall: For those of our audience that are listening that have maybe diabetes. They might just be overweight, or they've got some cardiovascular issues, whatever the case might be. What would you recommend they do to put themselves in the best position to not only take care of themselves where they're at, but also sort of prevent or put themselves in a great position going forward with any sort of novel infection or yearly flu virus or whatever it may be that might be impacting them?

Kiran Krishnan: Yeah, that's a really important question. Because unfortunately, in the US, 6 out of 10 adults fall in that category, 60% of adults. And that's one of the things that kind of scared me a little bit about this particular pandemic. When the research started to come out of who actually is vulnerable, what are the mechanisms that are going on in the body that the virus tends to take advantage of, that scared me a little bit because then you start to think that, "Wow, we've got such a big population that falls under that category" so it could be really quite

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devastating for us if things didn't work out in such a way where we could control the spread of the infection. So that question is really important.

I think, A, people need to really focus on improving their microbiota, so improving the diversity in their microbiome. There's lots of evidence now on ways in which you can improve the diversity of the microbiome because remember, that's the neighborhood watch for your immune system.

If you don't have an adequate neighborhood watch to alert your immune system to the presence of a new contagion, no matter where in your body it enters, then your immune system is going to be completely handicapped in its ability to survey your system and find invading pathogens, so you need your microbiota.

The simple things there is having some good degree of diversity in your diet. Incorporating in some intermittent fasting. Intermittent fasting increases diversity. Using and working with the spore-based probiotics. We've shown with studies that the spores themselves can actually increase the diversity in the microbiome. Getting in some oligosaccharides or prebiotics, those things can dramatically increase the diversity in your microbiome and also produce high levels of the short-chain fatty acids, butyrate, propionate and acetate, all of which are really important for your immune response. That's one whole category of things people should be doing.

The second thing, if you're already in a high-risk group, is you should be working on reducing your chronic low-grade inflammation. There are lots of amazing compounds that have been shown clinically to bring down chronic inflammation. Things like even garlic extracts, omega fatty acids, herbals. A number of adaptogens that can bring down inflammatory response.

One of the things that I use on a regular basis is curcumin. So I tend to use high levels of curcumin because of its ability to bring down low-grade systemic inflammation. And kind of bring down all of those alarms and signals that go on throughout your body so that when a contagion enters in, and that's causing an alarm, it's much more noticeable for the immune system. So that'll be a really important aspect of improving your resilience and your body's ability to realize contagions.

And then the last part of it is managing leaky gut, managing stress that leads to leaky gut because that drives inflammation. Leaky gut is arguably the most prevalent cause or factor in driving chronic low-grade inflammation. There are a number of studies that have addressed this. For example, a 2015 publication in the Frontiers of Immunology, they went through a meta-analysis and reviewed dozens of other studies. And what they concluded was that intestinal permeability and the translocation of bacterial toxins in intestinal permeability is the biggest driver of mortality and morbidity worldwide in terms of driving the onset of chronic illness because it sets up the most prolific low-grade chronic inflammation in the body.

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And if you have heart disease, if you have diabetes, if you have obesity, a lot of times that chronic low-grade inflammation from intestinal permeability was there to begin with and is part of the reason why you might have diabetes, part of the reason why you might have obesity or cardiovascular disease. One example of that is the CORDIOPREV study.

CORDIOPREV study was published about two years ago, 460 patients over 60 months, a large-scale study on diabetes. What they were looking for is, what are the markers in pre-diabetics that are the best predictors of whether or not you'll develop diabetes? And what they found was that there was only one marker of all of the things that they looked at and monitored over a 16-month period that was the only one that basically 100% predicted the onset of diabetes. And that is LPS or endotoxins in circulation. That means a leaky gut and those endotoxins are leaking in from the microbiome, from your gut into your circulatory system.

That one marker was the only thing of all of the markers they followed that was predictive of the development of type 2 diabetes, because it sets up this chronic low-grade inflammation that damages your pancreatic cells, your islet cells, damages the part of the hypothalamus that reads the blood sugar levels. So those other things that are functioning in your body right now, you've got to bring down that chronic low-grade inflammation.

And the beauty of it is not only will that make you more resilient in terms of immune response to contagions, it also will improve the condition that you're actually dealing with, the primary condition. Because it's such a root cause driver of the chronic illness you're dealing with.

Jason Prall: I love it. And this is always what's so interesting to me when we talk about any disease or condition, which is that some people are not affected at all. Some people are affected a little bit and some people are affected in a big way. And that spectrum to me is very important because it suggests that it's not a this causes that. There's something about the conditions of the body and the state of the mind, even perhaps, that is leading to the development of these symptoms and the spectrum that we're experiencing.

So to me, that's such an empowering recognition. Because it means that I'm not subject to some predestined fate. I actually have a role to play here. And it doesn't matter what condition we're talking about, there always seems to be this component of the gut that comes into play. And oftentimes, it's one of, if not the most important thing that we need to look at. I mean, it is the fundamental interaction with much of the outside world. And so it makes sense. And it stands to reason that it's so important.

So, I think it's interesting when we look at fecal microbiota transplant studies, and we see people that are overweight or obese and we see a transplant from somebody that's thinner or in shape and the person that's overweight or obese actually loses weight dramatically, right?

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Kiran Krishnan: Right. Yeah.

Jason Prall: So it's like the population of the bacteria is actually dictating the metabolic state of the person. So it's not a because you're obese, you have bad microbiota. It actually can be the bad microbiota can lead to poor metabolic health and obesity. So it's amazing, right?

Kiran Krishnan: Yeah. It can change how your body responds to food and that's inherent in our terrain. And I've been hearing a lot of people talk about terrain. And I think it's so relevant right now because of that spectrum you said. We've got millions of people that are susceptible. Everybody has the capability of catching a virus like this. None of us have an immune bubble around us where the virus can't enter our system so all of us can catch it. But the spectrum of response to something like this is so wide.

And fortunately, the vast majority of people actually respond pretty well and don't really ever know that they have it. So that's a good thing about what we're dealing with here right now. But then there are the very scary cases for people of different ages, predominantly the older population, but there are younger people that respond really severely. And that's all about what your terrain, what your system looks like on the inside and so much of that, if not most of it, is under your control.

And that's why I love participating in programs like this because this is the kind of stuff that gives people information and empowerment to know and figure out how to improve their outcomes should they ever come in contact with something like this. And believe me, this is not going to be the last contagion that circulates the Earth.

Jason Prall: Exactly.

Kiran Krishnan: It wasn't the first and it's certainly not going to be the last. And there's so many more that we are encountering all the time that we have no idea we're encountering. And so you maintain resilience in your system, and you have that control to be able to do that. Your immune system is there to function for you. It's looking for your health to be able to do its job.

Jason Prall: Well I think that's the thing. We can either walk through life being afraid of the next thing and interestingly enough, fear itself lowers our immune response. So the much better way I think, a much more efficient way is to really understand what we can control and do our best with what we've got so that we don't have to constantly fear the next thing and/or look to things outside of ourselves like vaccines in order to save us, right?

Kiran Krishnan: Mm-hmm (affirmative).

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Jason Prall: We have the power to sort of save ourselves or to improve our chances at least as we walk through life. And that really is such an easier way to walk through life. And hopefully, with things like this, the information you share is so vast and really helpful just at a baseline level to understand how this stuff works. And I find that the more information that we have, even if it's about things and how they work, even if we're not going to deal with it, it's like a biology lesson.

There's just something about learning about it that helps calm the fears a little bit. It makes it seem not so foreign. It's like, why are people afraid of snakes? Because they don't really understand them. Or tarantula, right? Like these things we don't understand. We're kind of afraid of. We don't know how it's going to move, how it's going to respond. And yet, as we learn about these things, there's just something about it that makes us feel a little bit more safe. And especially if we're giving these things to do.

So reducing systemic inflammation, depending on whatever we're dealing with. And the starting point is reducing systemic inflammation, getting better sleep, improving the gut microbiota through probiotics, prebiotics, through intermittent fasting, a diverse diet, super critical. Am I missing anything in there that's obvious?

Kiran Krishnan: Yeah, and one of the things you tend to talk about a lot is just reducing the toxic load on your system. Because I mean, environmental pollutants, chemical pollutants, electronic pollutants, all of these things increase that stress. And again, like Jason said earlier, basically distracts your system because there's so many things they have to deal with.

And then your immune system and your body or your repair mechanisms of the body have to prioritize its jobs because there is limited capacity. And so the less of those things that you are exposed to, the better your immune system can function and more alert and ready it is to deal with a contagion that it may encounter.

So, yeah, take that, reduce that toxic load on the body as much as you can. That plays a huge role.

Jason Prall: Amazing. Kiran, thank you so much for your amazing wisdom, your insights. You always seem to be on the ball when things like this come up in the development of new science and new developments in the microbiota world. So I always look to you to keep me abreast on what's happening. So, thank you so much. You never disappoint.

Kiran Krishnan: Thank you, my friend. I appreciate the opportunity and I love getting that message to people that they are in control and their systems are prepared to deal with things like this. Just support it. Help your system. And using programs like this, this is where you learn how to deal with it. So, It's my pleasure. Thank you so much for having me.

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Jason Prall: And before we sign off, just let people know where they can find your stuff.

Kiran Krishnan: Yeah. So if you want to learn more about what we do and the research we do and the products we work with, come to microbiomelabs.com. That's labs with an S at the end of it. Also, you could throw my name, Kiran Krishnan, in Google or YouTube. You'll find lots of interviews and videos like this. But we always invite people to come in and spend a little time on our website and learn and study. We put a lot of content out there because we're very focused on this type of education. So come check us out.

Jason Prall: And they got lots of good webinars from their site. They've got actually the live events too. So if you want to meet Kiran and check out some of the stuff that he does live, that really cool keynote presentations to visit. So definitely, go check them out. And Kiran, thanks so much. We'll see you on the next one.

Kiran Krishnan: Thank you, Jason.