Michael Roesslein:

Everybody is trickling in now. We will give a second for that. I like your blur. I can’t see all the mega spores anymore, but [crosstalk 00:01:18] here today.

Kiran Krishnan:

I figured I give people less distractions.

Michael Roesslein:

That’s fine. Let’s just do a little intro. I forget sometimes that not everybody knows all of us. So I’m Michael, I’ll be the host. I am one of the co-founders at Rebel Health Tribe. Kiran is the chief science officer at Microbiome Labs. We’ve done about 119 webinars over the last seven years and they’re always tons of fun, always lots of Q&A, lots of cool questions, lots of interaction. I’m usually blown away by the end of it and learn a whole bunch of things I didn’t already know. Even though we did chat yesterday, I’m sure there’s going to be new stuff for me.

Michael Roesslein:

There’s a chat feature right now. I think that sometimes the default setting is set to hosts and panelists only. You have to switch that to everyone if you want everyone to see your chat comments. If you have questions that are specifically questions that you want to make sure that we try to answer at the end, put those in the Q&A. There’s a Q&A button on the bottom. The chat can get kind of nuts. So in the chat right now, though, before we get started, make sure you let us know where are you checking in from and if you can see and hear us, that the audio and the video is working fine before we start doing any sort of webinaring. Just drop something in the chat, let us know that you can see and hear us.

Michael Roesslein:

Good. All right. So I see a couple there. Where’s our overseas people at? We’re usually seeing some crazy hours of the night. Brisbane that’s tomorrow, Wisconsin, DC, Florida, Charlotte. Cool. I hope everybody that’s in the path of that storm is okay. I have some friends that are in Louisiana right now doing relief work and it looks pretty chaotic from what I’ve seen. And we’ve got fires-

Kiran Krishnan:

We’ve got Alburn, also.

Michael Roesslein:

Alburn, Brisbane. Yeah. We’ve got a whole bunch of Australians that are always on our webinars, so that’s great. I need to visit once that’s available to do. Cool. So everybody can see and hear. Use the chat if you have questions that are specific that you… I mean the Q&A, if you want questions that you have that are specific. The chat can move kind of quick sometimes. I do my best to operate it, but it can get lost in there. They’ll for sure not get lost in the Q&A. We’ll do the best we can to get to some of those at the end and now we’re going to get started.

Michael Roesslein:

So, we are talking gut brain today. I think this is one topic we haven’t done before. I tried to look to see if we had done one on gut-brain before. If we did, it was probably [crosstalk 00:04:07]-

Kiran Krishnan:

It was a long time ago.

Michael Roesslein:

Yeah, five or six years ago. So I’m guessing some things have changed and you’ve got a presentation for us?

Kiran Krishnan:

I do. So in fact, this has been a topic that has been one of the most requested in a lot of the conferences that I’ve been speaking. The presentation I have is actually 51 slides. It tends to get very technical, but I’ve been able to cut it down by another 10 slides or so and I want to just warn people, if you’re not a technical, if you’re not a doctor that’s on here, a scientists, some of this may get technical, but I’m going to try to be very careful about giving you the important big picture.

Kiran Krishnan:

On some of these slides as you’ll see this, there’s graphs and data and all that. I tried to minimize those kinds of slides quite a bit because it’s not so time distracting, but there’ll be some really key points that I want you to extract from it and really understand so you understand this amazing connection and you also understand how the gut affects the brain and in a very significant way. Then the issue of psychobiotics and what really is a psychobiotic? What should it be doing in your system? That’s a very, very exciting area in this whole field.

Kiran Krishnan:

So, one of the things I also want to note as a general thing is, that in the last about seven, eight months since we really started educating around psychobiotics and the gut brain access, I’ve actually come across and met a lot of amazing psychiatrists in particular from Harvard and all of these really well known institutes who are really taking a deep look at this whole area of gut-brain connection and psychobiotics. The reason for that is, when you look at psychiatric care, it has not changed really in the last 60 years, almost. The same class of drugs are being used in slightly different versions of it, anti-anxiety meds and then of course, SSRIs, which are the selective serotonin re-uptake inhibitors. Those are the ones they use primarily for depression, but the same exact class of drugs have been used for decades now with minimal success. So, psychiatrists and people in that field have their hands tied to a certain degree because they don’t have a whole lot of tools.

Kiran Krishnan:

As it turns out, the natural world has all these different ways of managing the issue and really getting to the root cause of it and the root cause of it is not necessarily stemming from the brain. That’s why this is so powerful because what you’ll start to see is in the biggest psychiatric psychology meetings globally, gut brain is going to take center stage. It already is in many ways, and psychobiotics are a big part of that.

Kiran Krishnan:

I know Michael’s doing some awesome stuff in this whole area of mood and managing emotions and things like that too. So there’s lots of cool stuff in this area, and it’s such a needed area. It’s so relevant right now. We’ve all been through a very crazy rough time in the last 18 months and so many aspects of the last 18 months has driven a more dysfunctional gut brain connection.

Michael Roesslein:

A little bit of stress.

Kiran Krishnan:

Yes, a little bit of stress.

Michael Roesslein:

A little bit of stress. I remember we talked about how stressed out everybody was before there was a chaotic global pandemic that goes on for infinity. So this webinar actually came about because I had a call scheduled last week with you. That was on, I don’t remember what day, but whatever day it was, I came home at the time of the call and there was a little box on my porch. I get excited when I get little boxes from Microbiome Labs, because if I get products for myself, they come from Rebel Health Tribe. They come from where our distribution is. So if I see a box that has your company’s tag on it, that means there’s something new for me to try.

Michael Roesslein:

And I’m very poor at paying attention to the internal communications. So I usually am caught off guard by these, and I opened up a little box and it was very interesting. I said, “I want to talk to Kiran about this. Good thing I have a call with him in about 30 seconds.” Then we kind of looked at the schedule and our schedule is booked out pretty far right now. We had this, where you’re like, “We could do it real quick, next week, right away.”

Michael Roesslein:

So, we did, and we just threw it on the schedule and it’s probably the shortest lead time I’ve ever gotten to book you on for a webinar.

Kiran Krishnan:

[crosstalk 00:08:29].

Michael Roesslein:

And it was a miracle that it had happened. So here we are and like you said, this has been the mental, emotional, mind, mood, all of that has been a big focus of mine for a couple of years. I’m kind of in the loop in that world right now, even within natural supplements and things and probiotics. I had not heard the term psychobiotic and probiotics aren’t mentioned a lot. There’s a lot of different kinds of herbs and different kinds of amino acids that people take that can modify some neurotransmitter production and things like that. But I’m excited to learn about this so I can bring it to my friends over there.

Kiran Krishnan:

Yeah, and there’s very few probiotic strains that actually have good research on its impact as a psychobiotic. So I’m excited to talk about that as well, towards the end of the lecture. So if it makes sense, should I just jump in?

Michael Roesslein:

Yeah, go for it.

Kiran Krishnan:

Okay. Awesome. So I will, as usual, if those of you know, I like to turn off my camera when I’m doing the presentation part of it, and let’s see. Let me get it going on full screen mode. Okay. Does that look like full screen?

Michael Roesslein:

Yes, it looks good.

Kiran Krishnan:

Okay. Awesome. Thank you. So, jumping into this. So there’ll be a couple of parts to the lecture. The first part, just to give you an overview of the connection between the gut and the brain. Once you have a little bit of understanding on that, then we’ll move on to really two of the biggest toxic sources of dysfunction to the brain.

Kiran Krishnan:

So, we’ll boil it down to two different mechanisms that have a huge impact, that not only of course will compromise cognitive function, but of course is also associated with anxiety, depression, and all of those mood disorders as well. Of course, anytime you’re messing up the brain in any way, you’re going to mess up sleep as well. The problem is, when you mess up sleep, you continue to you create this dysbiosis that further messes up the brain. So it becomes this vicious cycle. So we’ll talk through all of that.

Kiran Krishnan:

Again, some of these slides may look crowded, may have lots of graphs and data and all that. It’s more important to pay attention to what I’m saying, instead of trying to kind of read all the different portions of the slides, because it can start to get a little bit heavy, especially if you don’t have a trained scientific background.

Kiran Krishnan:

So, the very first part that’s really important to note, and this is just kind of an interesting nuance, so the gut and the brain really stem from the same part of the embryo. So when you look at a fertilized embryo, it all looks the same. But then as the fetus is developing, the embryo goes through this cellular differentiation that means different parts of the embryo, which all start off as the same type of stem cell, will differentiate into different types of cell that make up the rest of the body.

Kiran Krishnan:

When you look at it in the embryonic stage, the brain tissue actually is the same portion of the embryo that also differentiates into the gut lining tissue. So the tissues are very, very similar. You’ve all heard of leaky gut equals leaky brain and so on. Those connections are really quite true physiologically as well.

Kiran Krishnan:

Then the gut and the brain are also connected through a number of different mechanisms. One of the first things is through the vagus nerve. The vagus nerve directly connects the enteric nervous system to the brain. The enteric system is this neurological system that wraps around the entire digestive track. Of course, the microbes in your gut have full access to the enteric nervous system.

Kiran Krishnan:

And through the enteric nervous system and through circulation, the microbes in the gut have number of ways of effecting the brain. One of the first ways is through something called the entero-endocrine system. That is cells within the epithelium, the gut lining can be triggered by microbes to produce compounds like 5-HT and other precursors to hormones and neurotransmitters that will then make its way to the brain and have an effect on the brain.

Kiran Krishnan:

We also know that there’s an immunological connection, a very deep immunological connection. We know that the brain has its own lymphatic system. We know that that lymphatic system is now connected to the main part of the immune system through the gut. We also know that activation of inflammatory pathways in the gut can impact the activation of microglial cells in the brain and create inflammation in the brain directly, all of it going through the immune system.

Kiran Krishnan:

Then there are of course bacterial molecules, which we call postbiotics. These are molecules that are made by bacteria in the gut, so not things that are derived out of diet or not things that your own body makes, but these are specifically compounds that are made by bacteria. Things like GABA and certain types of short chain fatty acids, and hormone precursors and of course the stimulation of serotonin production that occurs in the gut. So there’s all of these postbiotics that can impact the brain directly as well.

Kiran Krishnan:

Of course, all of this also is anchored through this bi-directional communication with the vagus nerve itself. I call it bi-directional because signals from the brain also go down into the gut and then signals from the gut go up into the brain. So we’re very, very well connected between the gut and the brain. They’re not two separate systems. They’re really one and the same.

Kiran Krishnan:

The enteric nervous system I mentioned is a highly, highly dense network of neurons. It’s only second to the brain in terms of nerve endings. It has over 100 million neurons there, more so than your spinal cord itself. So this is a very, very complex and dense neurological system that surrounds your entire digestive tract. And again, your gut bacteria have full access to it. So, your gut bacteria have complete access to your neurological system, which feeds into your central nervous system up to your brain and so on.

Kiran Krishnan:

And almost every known neuro-transmitter that’s found in the body is also found in the enteric nervous system and typically made through the microbiome in some way or the other and released into the enteric nervous system. So, these are all the main neurotransmitters that are known that have been found. We’ve always thought of these neurotransmitters as things that were either derived from food in some degree, or created by our body, our endocrine system, but as it turns out, the gut microbiota makes all of these same things as well. So, in fact, there’s some evidence that our endocrine system learned how to make these neuro-transmitters from microbes itself. So microbes have taught ourselves how to make these types of neurotransmitters.

Kiran Krishnan:

Now, as much as the gut can affect the brain, we have a way of also affecting our gut because of lifestyle choices. So when you look at things like, of course, diet, exercise, your health state, and then in particular stress and mood, those things can impact the microbiome directly because these different things will control release of certain types of neurotransmitters, especially stress related hormones and neurotransmitters. So things like norepinephrine, epinephrin, dopamine, cortisol and so on.

Kiran Krishnan:

When these things are released because of external stressors or mood dysfunctions, or health state that you put yourself into by choices, it can actually cause a release of these, which will then affect things like biofilm formation, increased resistance to host immune control of some of the pathogens, increase the virulence factor of certain pathogens, or can even decrease the virulence factor of some pathogens. So we do have an impact on the microbes in our behavior and how we perceive stress and what situations we put ourselves into and all that will have an impact on the microbes. This becomes important when we talk about this continuous perpetuating cycle of inflammation and stress, which affects the brain, affects mood disorders and so on, which I’ll get into a little bit later, but just keep in mind, we have an impact on the microbiome as well at the end.

Kiran Krishnan:

When you look at neurological disorders that are been clearly linked and associated with gut dysbiosis in animal models studies, they’ve elucidated all of these types of disorders to be directly associated with gut dysbiosis. Then in human studies, they’ve looked at some of these. So these are the ones that we have a good handle on in human studies. Then all of these are ones that are very well-documented in animal studies.

Kiran Krishnan:

Now, of course not everything from animal studies translates perfectly to human studies so there’s a lot of work still to be done, but when you look at these neurological disorders starting with schizophrenia, Alzheimer’s, autism, Parkinson’s, MS, depression, Huntington’s disease, all of these things have a connection with gut dysbiosis. They were demonstrated in animal models first, shown to be similar in human systems. And then there’s a whole bunch of other factors within the animal system that still needs to be proved out in humans.

Kiran Krishnan:

But they’ve also looked in these animal models of interventions, things like the use of probiotics, prebiotics, antibiotics, and so on, and how they affect these conditions, how the risk of these conditions move up and down. So there’s a lot of work going on in this area, but there’s also a lot that we already now know of the impact of gut dysbiosis on neurological conditions.

Kiran Krishnan:

We also know that we affect one another quite a bit. We all live with this microbiome cloud, if you will. So this is a very interesting study that illustrated this problem. So this study followed individuals that were diagnosed with some condition and infection of some sort, and then were given a prescription of antibiotics.

Kiran Krishnan:

What the researchers did was, found these individuals, did a bunch of stool sampling prior to the start of the antibiotic and then followed them and did a bunch of stool sampling during antibiotics and then for upwards of six months after they were done with the course of antibiotics. Now, it comes with no surprise at all that the individuals that were taking the antibiotics saw a significant shift in the microbiome during the course of the antibiotics. That negative shift was also seen upwards of six months after stopping the antibiotic. That’s not surprising because there’ve been other studies that have demonstrated similar things.

Kiran Krishnan:

What was surprising is the fact that household contacts of that individual who are not on antibiotics, so the household like roommates and siblings and even romantic partners who are not taking the antibiotics, also saw the same type of dysbiosis as the individual that was taking the antibiotic. So that influence of the individual in the household taking an antibiotic, experiencing severe dysbiosis, that influence had a impact on those that were living with that individual. So we share this cloud of microbiome microbiota and we share dysfunction with one another.

Kiran Krishnan:

So, if you’ve got a dysbiosis or dysfunction or somebody in your household does, that is associated or leading to cognitive dysfunctions, leading to things like anxiety, depression, and so on, that can very well become a community structure of that household. So that’s something really important to keep in mind.

Kiran Krishnan:

Now, looking and boiling down to the two biggest offenders, because there’s a lot of things we can talk about when it comes to gut dysbiosis and its impact on the gut brain access. But there’s really two that drive a lot of the root cause issues that we see when it comes to gut brain access and the dysfunction associated with that.

Kiran Krishnan:

The first one is LPS endotoxemia. Now, those of you who’ve heard me speak before, heard me speak a lot about LPS endotoxemia or leaky gut, if you will, and the inflammation that’s driven by LPS.

Kiran Krishnan:

The second one is something called stress induced basal inflammation. So this is what happens from an inflammatory standpoint in the body when you experience external stressors, whether you’re driving through traffic and somebody cuts you off and it pisses you off or a coworker or sibling or loved one at home conflicts, external conflicts, conflicts on social media, all of these things. All these different sources of stress, what happens inside the body from an inflammatory standpoint when you have exposure to that external stressor?

Kiran Krishnan:

So, those two things, the leaky gut from the inside, the endotoxemia, endo indicating that the toxicity is created in the inside and then the external source of stressors. These are two of the hardest things to get away from because it becomes really hard and impractical to think that you’re going to remove yourself from all sources of external stress. It just won’t happen. We live in a world, we live in a complex world. We live in a crowded world. We all have complexities in our lives and families and friends and all of these things. We’re always going to be surrounded by external stressors, but what that external stressor does in the body will change based on the health of your microbiome. That’s what we’ll talk about later on.

Kiran Krishnan:

Then also the leakiness in the gut. That’s something you can’t just remove yourself from. The endotoxin exposure has to be arrested in the gut itself or at the gut lining. So let’s talk a little bit about this LPS endotoxin.

Kiran Krishnan:

It’s got this lipid A tail. This lipid portion is the part that really makes it toxic and then it’s got this kind of a carbohydrate polysaccharide. So one of the things that it does really well is, it lodges itself into cells, including our own cells. It’s actually part of bacterial cell membrane structures in the gut.

Kiran Krishnan:

When it’s sitting in the bacteria cell, when the bacteria is functioning normally there’s no danger to us at all. But when the bacteria dies and releases this LPS as an individual component, and if this LPS is allowed to leak into our circulation, that’s when it starts creating a significant amount of problem. Your immune system identifies it as a toxigenic compound from pathogenic organisms.

Kiran Krishnan:

So, when your immune system sees LPS, it triggers a really robust inflammatory response that creates this chronic low grade inflammation. Depending on where the LPS has lodged itself, whether it’s in your joints, in your heart tissue, in your lungs, in your vascular system, in your brain, it’ll trigger inflammatory processes in those tissues.

Kiran Krishnan:

Let me show you some examples of how this all comes about. When you have a healthy microbiome, you tend to have high diversity within the microbiome and protective strains. These are all these species that protect the microbiome, protect the lining of the gut, maintains this really healthy mucin layer, this mucin 2 layer on the inside that’s nice and thick and acts as a protective barrier and it keeps producing that layer to maintain this barrier. This high production of short chain fatty acids maintains healthy inflammation, communication between the microbiome and the immune cells in your epithelium, all types of metabolic benefits and so on and then all of that leads to well-formed tight junctions so your gut lining is not leaky at all.

Kiran Krishnan:

Now, if you undergo a course of antibiotics or some other form of dysbiosis, whether it’s poor eating choices, lots of stress, and I’ll talk about how stress drives dysbiosis later, exposure to things like herbicides, pesticides, or really just kind of living in the modern world where there’s plenty of things that drive dysbiosis, what tends to happen is, you get an imbalance of microbes that are beneficial, who maintain this structure compared to microbes who tend to want to eat away in the structure. So, as you become more and more dysbiotic, as you get exposed to more and more things that disrupt the microbiota, what you tend to get is this overgrowth of organisms that can come in, flood and overgrow and start eating away at this mucin layer.

Kiran Krishnan:

When they eat away at the mucin layer, then you get a huge influx of all of the microbes in the system, moving into this area right next to the intestinal epithelium. When you get microbes really close to the intestinal epithelium, that causes inflammation in the lining of the gut. It damages those cells and opens up the spaces in between those cells, then things like LPS, the endotoxin, will leak through.

Kiran Krishnan:

Once it leaks through, it’s now in circulation. Once it’s in circulation, it can make its way throughout the body and it especially can make its way into the brain. Once it enters the brain, it’s going to create all kinds of inflammatory responses in the brain. When it creates inflammatory responses in the brain, it’s going to lead to damage to the brain tissue. So that’s the leakiness in the gut driving brain inflammation and damage to your cognitive tissue.

Kiran Krishnan:

So, what happens when you have some of that happening? So when you look here at basal and LPS-stimulated inflammation, so inflammation that’s stimulated by LPS. And when you look at markers of an individual symptom of depression, here in this paper, and what’s important to point out here, and again, this may look like Greek to some people, but if you’re familiar with the science, you can read this and really appreciate the paper.

Kiran Krishnan:

But what they’re trying to show here is that… what they hypothesized was that inflammation is predictive of the severity and the course of a subset of major depressive disorders symptoms. So within the whole category of major depressive disorders, there’s a set of symptoms they call sickness behaviors. Now sickness behaviors, if you have those, or if an individual has those, those are the things that really disrupt quality of life. If you take a symptom like anhedonia, anhedonia is the inability to have pleasure. So think about the quality of life when you suffer…

PART 1 OF 4 ENDS [00:27:04]

Kiran Krishnan:

… pleasure, right? So think about the quality of life when you suffer from this condition that causes you to have an inability to experience pleasure. That means nothing that used to excite you and make you feel happy and all that. Whether it’s your family or experiences or foods or whatever it maybe, it no longer can trigger that happiness elation feeling, right? So nothing helps your mood. Even things like anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, malaise. These are all sickness behaviors. Now having major depressive disorders with sickness behaviors is a much more severe condition. And what they found was that basal and LPS-stimulated inflammatory markers were more strongly associated with sickness behavior symptoms, and up to nine years of followup compared to non-sickness behavior symptoms of depression. So there are some people with depression that don’t have many of these sickness behaviors. And those people tend to not have really elevated LPS-stimulated inflammation, but those that do have elevated LPS-stimulated inflammation will have a lot more of these sickness behaviors.

Kiran Krishnan:

And this type of study has been shown over and over again. In this case, it’s in an animal model study. Previously, it’s in human studies. They also show that cytokine production in the case of depression and anxiety, they show that LPS-stimulated inflammation was associated with increased odds of depressive and anxiety disorders. So they were looking at people who had risk factors of anxiety and depressive disorders. And what they found is if you have elevated levels of LPS in circulation and the resulting inflammation that LPS in circulation causes, you have a much higher increased risk of depression and anxiety disorders. So it’s a confounding factor in the issue of developing these cognitive dysfunctions. And they showed here, LPS-stimulated inflammation is associated with more severe depression.

Kiran Krishnan:

So the severity of the problem is driven by how much LPS is in your system and how much inflammation is triggering symptoms. And this is compared to the symptoms of basal inflammation. And it says again, unlike basal inflammation, so unlike standard inflammation, LPS-stimulated inflammation was still associated with anxiety, symptoms severity, after adjustment for lifestyle, and other health disorder. So when you take other lifestyle factors out, independently LPS-associated inflammation was a major driver of the severity of the condition. So if you’re finding that the condition is getting worse and worse and worse, it’s likely that the leakiness of the gut, the inflammation, the presence of LPS is increasing over time. So the severity of the condition gets worse and worse and worse, right? It gets to a point where it becomes absolutely hard to manage, the sickness behaviors kick in that has a huge disruptive effect to quality of life, and even just basal functionality in the world.

Kiran Krishnan:

And that in itself can drive people into further depression and anxiety and so on. Now we’ve been talking about anxiety and depression and those sickness behaviors, but looking at age-related disorders to the brain, things like Alzheimer’s disease, studies have found that microbiome-derived LPS, which is coming from the gut has been shown to be present and enriched in the perinuclear regions of people with an Alzheimer’s disease, right? So Alzheimer’s disease is an inflammatory condition that leads to neurodegeneration in the brain. Eventually you get something called beta plaquing. Alzheimer’s disease is started and driven by inflammation that’s triggered in the brain from LPS that’s coming from the gut, right? So same type of inflammation that drives anxiety and depression and mood disorders also drives neurodegeneration and LPS. And you see the same thing in Parkinson’s disease. The other really scary neurodegenerative condition of aging, right?

Kiran Krishnan:

So Alzheimer’s is a pretty scary neurodegenerative condition. And in fact, Alzheimer’s-like symptoms can start in your late forties, early fifties. There are studies showing people with early onset of dementia in their late forties and early fifties, where it starts with slower cognition, slower neuromotor reflexes, and so on. That is early signs of the inflammation that’s going on in the brain, the neurodegeneration. Again, all of that being driven by this leakiness in the gut and LPS. Same thing in Parkinson’s disease, which is so interesting when you look at the inflammatory response associated with Parkinson’s disease, they’ve shown in this particular study, and this is a review article. So this is an article based on reviewing a bunch of studies on this topic, right? So this is a consensus report, if you will.

Kiran Krishnan:

They show that increases in gut permeability and exposure to endotoxins, LPS from bacterial products will induce something called alpha-synuclein aggregation. So alpha-synuclein is this protein-like compound that is found to build up an aggregate in the central nervous system of people that end up experiencing Parkinson’s disease. What’s interesting about it is that the buildup starts in the vagus nerve before it gets to the brain, right? So it was noted that this alpha-synuclein level was elevated in the brain of people with Parkinson’s disease, but it doesn’t start in the brain. It starts in the vagus nerve that’s in the gut. And it builds up in the gut for a period of time. Sorry. And then it moves up to the brain eventually. On its way to moving up to the brain, it actually disrupts your olfactory nerve, for example. And you start to lose smell and taste as you get older.

Kiran Krishnan:

There’s actually a functional test or smell test, a scratch-and-sniff kind of smell test that Dr. Tom O’Bryan promotes quite a bit. And that inability to smell and distinguish smells of particular things as you age is an indication of neuroinflammation and the accumulation of these alpha-synuclein. And in fact, when the alpha-synuclein actually accumulates in the vagus nerve in the beginning, the effect of that is constipation. And the very first symptomology of Parkinson’s disease is constipation. So chronic constipation is this accumulation and inflammation. There’s other drivers of chronic inflammation, of course, but that’s one of the effects of developing this. And then it moves up, it affects the olfactory nerve. And then eventually it goes up into the brain. Once it starts affecting the brain, then you really start to see symptomology associated with it, right?

Kiran Krishnan:

And all of this is driven by leakiness in the gut and the accumulation and exposure to LPS. LPS can also get into other parts of the brain like the hypothalamus, where it can induce something called central insulin resistance. When LPS is accumulates in this part of the brain, it creates enough inflammation and damage in the brain where your brain now no longer can read your blood sugar levels, right? So you don’t have to be obese. Your pancreas doesn’t have to be damaged. Your insulin cells that make insulin can be perfectly well functioning, but your brain can’t read your blood sugar levels to make those adjustments of producing insulin versus glucagon and so on, right? So this is part of the reason why we’re starting to see younger and younger people of normal body weight presenting with type 2 diabetes, right? And then other brain disorders like Alzheimer’s and dementia and so on are thought of as type 3 diabetes because it’s the progression of the same dysfunction, right?

Kiran Krishnan:

So all of this stems from the gut and leakiness in the gut. And then when you look at review papers, they show that the gut-brain is in major depression when you look at intestinal mucosal dysfunction with an increased translocation of LPS, which again comes from bacteria within your gut, and they call it leaky gut, which is awesome, I’m glad they put that in the title of the paper, plays a role in the inflammatory pathology of depression. So depression is driven by inflammatory pathology that starts in the gut, right? And that is so clear now because there are so many studies that have shown this. Depression is not something that starts and occurs in the brain. The brain is an affected organ of something that’s happening in the gut. And the gut-brain connection is the most important thing to consider here when we’re thinking about these types of conditions that we associate with the brain, but really they’re coming from the gut.

Kiran Krishnan:

So then the big question is we now know LPS is highly toxic to the brain, right? It causes all kinds of issues that we talked about. It disrupts blood sugar reading. It creates inflammation and plaquing and all kinds of awful things on the way to even disrupts the vagus nerve, the olfactory nerve, and so on. So how do you stop… How do you support the healthy gut barrier, so you don’t have LPS leaking through all the time? That was our big main goal initially as a company. And of course, we do that with the spore-based probiotics. Some of you may be familiar, but as I understand that maybe a lot of new people here that aren’t familiar at all. So we launched the MegaSpore product back in 2013. And we published our first study on the role of spore-based probiotics in stopping this endotoxemia and migration of LPS in 2017.

Kiran Krishnan:

And since then, we’ve done additional work on this particular topic. And what we showed was just taking the probiotic for 30 days, a spore-based probiotic for 30 days, we saw over a 60% reduction in the amount of LPS and the incidents of LPS migrating into circulation from the gut, right? So it was a huge decrease of that endotoxemia reducing the amount of LPS circulating around. And then of course, because you reduce the amount of LPS, all of the inflammatory markers associated with elevated LPS in circulation also come down. This is something called a heat map. So this is the placebo group. This is comparing the placebo group on all of these inflammatory markers from their baseline to 30 days after taking the placebo. And in fact, all of them for the most part increased in inflammation, right? So in this case, in the heat map, the more light the color becomes, the more green yellowish the color becomes, shows an improvement in the marker. The more red it becomes, it means an increase and an issue with the marker.

Kiran Krishnan:

So in the placebo group, as you can see, those individuals actually became more inflamed over that 30 day period. And we saw that with actually increasing endotoxemia. Whereas in the treatment group, all of these markers improved significantly in that 30 day period, including a very important gut-brain marker, which is the response to ghrelin, which is the hunger hormone. This was super interesting. And I’ll explain what this table means in a second. But note that ghrelin is your hunger hormone, right? So your brain stimulates a release of ghrelin when you’re hungry and it gets the hunger signals from your gut. So the growling occurs in your gut when you’re hungry, right? You hear that growling. That’s a communication that’s occurring between the gut and the brain where the brain realizes that there’s no food in the gut. And it’s releasing this ghrelin, this hunger hormone to motivate you to go out and find food.

Kiran Krishnan:

Now, once you get food and you’ve consumed it and you are satiated, or you have enough in your GI tract, there has to be a signal that goes from your gut back to your brain to say, hey, we’ve got enough food in here. Stop producing the hunger hormone. Because if you don’t stop producing the hunger hormone, then the individual will continue to eat and end up overeating, right? Which is really a big fundamental issue with obesity. A big fundamental issue with obesity is ghrelin resistance. The inability to stop eating when you are satiated or not even understanding satiety until it becomes so uncomfortable where you’re now full beyond comfort levels, right? So when you look at young kids, for example, I’ve observed this in my kids where they have good gut-brain connection. Even if it’s a food they absolutely love like a cupcake or pizza, the moment they’re satiated, they stop eating it and they have no interest in it at all, right? They stop.

Kiran Krishnan:

And it could be one and a half slices of pizza, and they won’t even finish that half slice even though they love the taste of it because they’re satiated and they’re ready to move on to the next thing. But in adults, it becomes very hard because we don’t eat to satiety. We eat to some sort of emotional satiation. And we also eat to the point where we finally stop when we’re very uncomfortably full, right? So this is a signal of ghrelin resistance. So what this showed here in the probiotic group, this is in the probiotic group. The red bars indicate what happened after 30 days of probiotics. The blue bars, what happened at baseline, right? So they came in fasted. At time, zero here. So ghrelin levels were relatively high, as you would imagine, because they’re fasted. So they’re making hunger hormone. Now at this time zero, after we took this measurement, we give them a 2000 plus calorie meal. So they’ve got plenty of calories, plenty of food in the system.

Kiran Krishnan:

And as you can see, ghrelin levels barely drop. And then not only do they barely drop, they start to increase again right after the three hour mark, right? Which is not how the ghrelin response is supposed to occur. Then they were given probiotics for 30 days. The leaky gut was resolved, the LPS endotoxemia, the inflammation, all of this. So now we’re re-establishing the gut-brain communication. And this is now how the ghrelin response in these same individuals after 30 days where even the ghrelin levels were actually lower at baseline, which means better hunger communication within the gut and the brain. But then as soon as you give them food, the ghrelin levels drop very dramatically as they’re supposed to. So your brain now knows there’s plenty of food in the gut. We should stop eating right now, right?

Kiran Krishnan:

So instead of ghrelin, then you get things like adiponectin that increases, which works against ghrelin and it starts to stimulate your body to burn fat, instead of craving more food. So this really highlighted a real establishment of the gut-brain connection. So that’s LPS endotoxemia, leaky gut, and the spore-based probiotics. That becomes a very important basal foundational part of helping support the brain because all the other things you might do, including the next part that I’m going to talk about, if you don’t arrest the migration of LPS, you’re going to continue inducing inflammation that then compromises the central nervous system and the brain and so on.

Kiran Krishnan:

So addressing that LPS endotoxemia becomes a really important part of just basic brain support brain health and cognitive function, right? So that’s the first thing. And that’s one of the most toxic things to the brain is endotoxemia. Here’s the second part of it that’s really important to address. And that’s stress and other drivers of what we call basal inflammation that occurs in the brain itself. And a lot of this is really due to external stressors that impact your inflammatory responses, your microbiome, and so on. And I’ll talk through that in a second. So when we look at stress and the activation of inflammation, stress can have a direct impact on your corticotrophin-releasing hormone, right? That occurs in your HPA axis, the hypothalamus-pituitary-adrenal axis. So you’ve got this HPA axis that would start to the hypothalamus and the pituitary gland. And then of course, that also speaks in part through the nervous system and through the immunological system to the adrenal glands, which then affects the release of things like cortisol.

Kiran Krishnan:

So what tends to happen when you get an external stressor or some sort of adversity, interpersonal conflict, so on, social isolation, that immediately triggers a response in the hypothalamus and the pituitary. When you get a triggering of the hypothalamus and the pituitary, you get a release of signals from the pituitary glands that then turn on the adrenal glands. When the adrenal glands are turned on, the adrenal glands are going to release cortisol. When the adrenal glands release cortisol, one of the things that cortisol does is it starts to increase inflammation in the body. And in particular, it can start activating macrophages, or in the brain they’re called microglial cells, right? So now you’ve got this increased inflammatory immunological response in the brain in order to prepare the host for removing him or herself from the stressor, because part of what this inflammatory cascade does from the external stressor is not only does it increase inflammatory cytokines and chemokines, but it also creates acute phase reactants.

Kiran Krishnan:

Acute phase reactants will have an impact on things like the sympathetic nervous system on vasodilation increasing heart rate, all of these physiological changes that you need in order to do your flight or fight response, right? And all of that, of course, feeds back into the hypothalamic pituitary axis and trigger something called activation of NF-kappaB. This is another inflammatory pathway that then brings down things like monoamines and lowers trophic factors to the brain that help with brain function increases the excitotoxicity in the brain. And again, I’ll explain all of these in a second. I’ll give you some examples of that. But just note that what is happening here as an external stressor comes in, it activates the HPA axis. The activation of the HPA axis actually activates an immunological response, not only systemically, but also in the brain. And then eventually that immunological response translates to this continuous activation of inflammation in the brain itself.

Kiran Krishnan:

Now, what’s interesting about this is this whole axis runs through the gut in order for it to impact the brain. So an external stressor comes in, the hypothalamus and pituitary gland increases ACTH that activates the adrenal gland, which releases cortisol, and in some cases can release other types of stress hormone. So things like norepinephrine, epinephrine, and so on. These signals actually go through the gut. And then in the gut, these signals get translated back up to the sympathetic nervous system through circulation, up the vagus nerve, and then back into the brain to perpetuate inflammation in the brain itself. So the impact of external stressors on the brain and the resulting stress and anxiety and depression and sleep disruption and all that is felt is actually translated first through the gut, right? So that is something that’s really important to note.

Kiran Krishnan:

So how does it affect the system through the gut? So when you look at this, so look at this pathway, right? You’ve got nutrients coming in from diet. One of the key nutrients is tryptophan. We all know tryptophan is a really important amino acid. In this case, when things are functioning properly, tryptophan will be metabolized and formed and converted into serotonin. Serotonin can then be converted into melatonin. And melatonin and serotonin, as you know, serotonin is a happy hormone, melatonin helps you sleep. So now, tryptophan is being differentiated in a healthy state, so this left-hand side here is a healthy state, into really beneficial hormones and neurotransmitters, which will impact a positive sleep, improves circadian rhythm, gives you a positive outlook, provides resilience to stress, improves memory, and so on. All of these neuroprotective pathways get triggered from the metabolization of tryptophan to serotonin and melatonin, right?

Kiran Krishnan:

Now if you’ve got inflammation that’s coming from HPA activation, and then that inflammation as it moves through the gut is actually amplified by dysfunctional microbiota, then that inflammation in itself can trigger a deviation on the metabolism of tryptophan, where tryptophan instead of becoming serotonin and melatonin will actually become kynurenine. And from kynurenine, it can become quinolinic acid. And from there, it goes into neurotoxic pathways that can actually create depressed mood, increase irritability, reduce resistance to stress, create poor sleep, and reduce concentration, right? So the same starting nutrient and compound, tryptophan, when you’ve got inflammation and dysfunction in the gut that is translating external stressors, it’ll actually change the biochemistry of how your body responds to certain foods and nutrients. That change in biochemistry will take a good compound like tryptophan. And rather than making a neuroprotective, it will actually make a neurotoxic, right?

Kiran Krishnan:

So this is how the translation of external stressors through the gut amplifies all of the physiological changes that you see when people are have anxiety, stress, sleep disorders, and so on, right? And so the gut is really the deciding factor or the linchpin, if you will, of how external stressors impact the host. Because if you had a very healthy gut, the external stress stimuli through the HPA axis and through cortisol release will actually get arrested at the gut when you have a healthy microbiome. The inflammation that it triggers will actually be stopped by the microbiota and control by the microbiota, so you don’t get the differentiation of tryptophan into this neurotoxic pathway. In fact, it’ll allow it to move through the neuroprotective pathway, right? So a healthy microbiota can either arrest the inflammatory cycling, or a dysfunctional microbiota will perpetuate the inflammatory cycling, because now as you get more inflamed and you end up with more neurotoxicity by this dysfunctional microbiota, it actually makes you more susceptible to the impact of external stressors.

Kiran Krishnan:

So you become less resistant to stressors. That means more stressors will more easily affect you. And as those stressors affect you, it’s going to trigger more HPA axis activation, more release of cortisol. That’s going to actually drive significantly more dysbiosis in the gut. That dysbiosis is going to create more inflammation that makes it even harder for you to deal with the next stress. So it’s a continuous cycle that makes you less and less tolerant to stress over time, right? Things, smaller and smaller things start to bother the individual. And again, when it bothers you during the waking hours, right? What’s happening is these lots of inflammation being triggered, that inflammation has all kinds of damaging effects in the body. But then as you get towards the end of the day, it’s also disrupting sleep cycling, which of course has further damaging effects on the body as well.

Kiran Krishnan:

So then the question is, how do you address basal stress and the induced inflammation? Because again, we can’t get away from stress, external stress at all. How do we arrest that cycle, right? What can be done to stop the cycle of that inflammatory pathology that makes it even harder to deal with stress, and then that stress makes you even more dysbiotic, creates more inflammation, and so on? And as it turns out, there’s this magical compound called peptidoglycan that from the in-utero stage becomes a really important part of brain development and how your brain deals with stress and function in general, right? So peptidoglycan is a particular type of compound that is a amino acid. So the “peptido” part of it, the peptide part of it and glycan is a sugar component to it, right?

Kiran Krishnan:

So what studies have shown is that peptidoglycans from mom’s gut, in mom’s gut bacteria in particular are actually transported through circulation through the placenta and into the baby during development. And studies show that the neuro-development process is actually improved when the baby gets stimulated and exposed to more bacterial peptidoglycan, right? It proliferates neurological connections. It helps differentiation of the different parts of the brain and specialization of different parts of the brain. It creates something called synaptogenesis, that’s formation of more and more synaptic regions within the brain. And the more complexity and more synaptic regions you have, the better cognitive function you have. It helps in myelination, which is the insulation required on nerve cells. So nerve signals don’t get thrown off. It’s no different than the insulation around your electrical wiring so that the current stays in the wire and doesn’t shoot off everywhere.

Kiran Krishnan:

Myelination is, of course, really important for nerve conduction and conduction of signals in nerve cells. And then, the blood-brain barrier formation. All of these things are really critically determined by the amount of peptidoglycan that the baby gets exposed to from mom’s gut bacteria, right? Neuro-development and behavioral disorders are all controlled in large part by the amount of exposure to peptidoglycan. And when you see that babies aren’t exposed to adequate levels of peptidoglycan because mom’s gut is dysfunctional, you start to see an increased risk for neurodevelopmental and psychiatric disorders. So peptidoglycan from the time you were being formed in-utero becomes such an important, critical part to your brain. And again, this is a bacterial component that is now in the fetus. In the fetus is…

PART 2 OF 4 ENDS [00:54:04]

Kiran Krishnan:

… That is now in the fetus, in the fetus’s brain, helping the fetus’s brain develop. So think about that symbiosis there, right? We have outsourced signaling and developmental cues. One of the arguably, one of the most important parts of our body, our brain to bacterial components from a gut. So this peptidoglycan, no surprise turns out to be extremely important for the rest of your life as well, right? Not just in utero and in development. What they show is that peptidoglycan from keystone species, like B longum, bifidobacterium longum can actually have huge impacts on things like IBS, chronic fatigue, depression, sleep, and so on.

Kiran Krishnan:

All of these inflammatory pathology often mediated by something called interferon alpha can be actually blocked and arrested by adequate levels of peptidoglycan in the gut, right? And peptidoglycan is something that’s found on certain species of bifido longum. That’s part of why bifido longum is considered a keystone organism because it’s so important to so many pathways that start in the gut that impact the rest of the body. And it also supports other organisms within the microbiome itself.

Kiran Krishnan:

So here’s what’s unique about it, not all bifidobacteria and certainly not all bifido longum in particular have this peptidoglycan layer. So this is a bifidobacteria, bifido longum specifically that does not have this Xcel polysaccharide. The peptidoglycan layer is called an Xcel polysaccharide. This is what it would look like in a micrograph. The ones that do have the peptidoglycan layer have this thick layer with all of these tentacles and spikes and all that sticking out, right?

Kiran Krishnan:

So it’s this peptidoglycan layer that actually makes it more resistant and more resilient. It helps it actually survive through the gastric system and actually helps it survive through bio. So it’s got this coating on it. And then when it gets in the large intestine, this peptidoglycan Xcel polysaccharide is what mediates all of the inflammatory responses.

Kiran Krishnan:

So let me go through some of the clinicals studies around this particular organism. And this strain is called a bifido longum 1714 strain. This is a human isolate. It was isolated at a research, probably the world’s most preeminent gut brain research institute called the APC, which is based in Cork, Ireland. What they were doing is looking at stool samples and looking at isolates of organisms from people who had depression and anxiety versus people who did not ever have depression anxiety. And what they find is that the people that really did not ever have any mood disorders seem to have a higher level of this type of organism. And in particular, this B longum 1714 strain, which has a high amount of peptidoglycan Xcel polysaccharide.

Kiran Krishnan:

So some of the initial studies that were done were an animal studies. And what they concluded in four different published animal studies was the 1714 strain and do something called interleukin 10, which is an anti-inflammatory cytokine, right? And this starts in the spleen itself. So now you’ve got this really important anti-inflammatory cytokine that’s being expressed by the presence of this species in the gut. And it also reduces pro-inflammatory transcription factor, that NF-kappa B. If you remember NF-kappa B, that’s one of those inflammatory factors that activates in the brain to drive neuroinflammation from external stress. Because it can arrest this NF-kappa B activation. The idea is that maybe it can reduce and stuff stop that cycling, that continuous cycling of inflammatory processes that leads to inflammation in the brain and more release of cortisol and so on, right?

Kiran Krishnan:

And they also show that it reduces all kinds of other pro-inflammatory cytokines, interleukin-1 beta, TNF-alpha, and so on. And it reduces other pro-inflammatory cytokines in the spleen and mice that were fed a high fat diet and then who we had induced obesity in, right? Because again, obesity is also associated with an increased level of these inflammatory cytokines, of course, increase incidents rate of anxiety, depression, and so on. So not only does it do it in mice that are none obese, it does it in obese mice as well and reduces all of these inflammatory cytokines.

Kiran Krishnan:

So the conclusion from all of these animal studies is that 1714 is an anti-inflammatory strain with the potential to help with inflammation mediated stress, right, which is what we’re talking about here. And then I skipped a lot of the other studies in the interest of time. I’m going to jump to give you some overview and background in some of the human clinicals. And I’m not showing all the human clinicals in the interest of time. It would take a long time. This was why this was a 51 slide deck and I was able to reduce it by about 10, by cutting out some of the human clinicals.

Kiran Krishnan:

But in general, what has been studied, I’ll give you an overview, is how the 1714, how does bifido longum 1714 translate as a psychobiotic to modulation of stress response and then brainwave function, and then eventually sleep as well, right? Can this strain in the face of induced stress, can it modulate things like cortisol levels and epinephrin levels, and then perceived stress response and other biometric measurements like heart rate and so on? In general, what we saw in the first couple of clinical trials on stress response is that 1714 reduce perceived stress and cortisol output.

Kiran Krishnan:

So there was a significant reduction in the amount of cortisol that was released when stress was induced. And this was in healthy male volunteers. It was associated with the reduction of the pro-inflammatory tone in all of these patients looking at the pathways by which cortisol release was induced. So it is arresting that inflammatory cycling. And because it’s arresting that inflammatory cycling, eventually the HPA access triggering slows down and then shuts off, and you get less and less cortisol and other stress hormone being produced as well.

Kiran Krishnan:

Then we also looked at a number of studies where we were looking at human activity studies, where we were looking at, how does stress like social isolation and all that impact brainwave function, right? And we know that having elevated delta and beta wave is associated within heightened state and a stress state within individuals. So measuring the brainwave function, what was seen is that there was a significant decrease in beta wave function and a significant increase in theta wave. Theta wave is that flow state that people want to be in, right?

Kiran Krishnan:

So when we’ve talked about being really calm and having really good cognitive function, being able to concentrate really well, not being distracted, that’s called the flow state that a lot of artists and all that talk about. That flow state is actually measured as an increase in theta wave function in the brain. And what we were able to show here is that taking this probiotic, because it arrests this inflammatory signaling in the gut, which impacts the brain, eventually, it can actually alter brainwave function. And it was demonstrated in this particular published study.

Kiran Krishnan:

So what it showed that it was also able to enhance something called, a measure called vitality and reduce of course, mental fatigue, because your brain is not as inflamed. You’re in a better state of mind. You’re in that theta wave function. And then modulates your own response during social stress. So when we induce social stress in individuals, it improves the coping mechanism of stress, and it regulates the negative emotions that come from stress induced behaviors, right? So it’s really changing how your body now deals with and perceive stress in a very significant manner. And of course, because of all of that, it reduces inflammatory pathways, it activates centers of the brain that is associated with vitality and a significant control of negative emotions. It improves many different indices of sleep, right?

Kiran Krishnan:

In two separate studies that were done, which I’m not showing you here, what we were able to show is a reduction in the time to sleep. So how long it takes you to get to sleep, to fall asleep. And then it also improves the quality of sleep. So more REM type of sleep, more efficient sleep occurs when you reduce this inflammatory cycling as well. And it improves a number of quality of life parameters, such as improved social function, vitality, and so on. So this becomes so applicable to this day and age and this constant external stress based inflammatory cycling that’s going on, that’s of course, mediated through the gut. So this is something that becomes really important.

Kiran Krishnan:

So in conclusion, we could say that the brain is certainly profoundly affected by inflammation, which is likely the primary driver of most cognitive dysfunctions and major cause of inflammation is a dysbiotic microbiota, right? And we know that this presents a unique brain support opportunity, because if we can curb what’s happening in the gut, both from the LPS side and the cycling of this inflammatory pathway that starts with external stressors, we can dramatically improve how a person responds to the world around them, especially from a cognitive perspective.

Kiran Krishnan:

So if we can address both this LPS and this stress induced basal inflammation, we can dramatically improve people’s quality of life and really give them the ability to deal with life in general, in a much better way. And this has all kinds of long-term implications as well. So when we looked at this, we said, “We’ve got to create a product set with the 1714 strain that addresses that external stress induced inflammatory pathways.” And then of course, we’ve got MegaSpore that deals with the LPS side of it. So we created two products here, one called Zen floor cope, and one called Zen floor sleep, right? Because this product does also impact sleep indices.

Kiran Krishnan:

And so if you’re somebody that deals with daily stress and mood issues, and you also have a hard time sleeping, which most people deal with daily stress, then the idea is you would take one of these Zen floor cope and one Zen floor sleep in the evening. So one during the day, one in the evening, and it deals with both conditions. If you are just dealing with mood issues during the day and not sleep issues at night, then you would just take two Zen floor cope in a day. Or if you’re just dealing with sleep issues and not the mood and stress dysfunction, then you would just take one Zen floor sleep at night. And we can give those particular instructions as we do Q and A and all that.

Kiran Krishnan:

So we call this total cognitive the support, right? Because we’re dealing with a two big pathologies that really drive dysfunction in the brain that’s stemmed from the gut. Between these two, it’s going to make such a significant difference in people and people’s lives. And we’re super excited. We’ve had the product out now for about three days, but a lot of our employees have had them now for 30, 40 days. And I can tell you just from empirical evidence on our employees and friends and family and all that using it, wow, it’s made such an impact in people in a relatively short amount of time.

Kiran Krishnan:

And I think Michael, you had an example of that as well, right? I think either you or Mira taking it. So I’ll stop sharing there. And then let’s, oops. Stop sharing that further sharing. And turn this back on. Hopefully that make sense. Understandable. It wasn’t too heavy and hopefully it would give people some perspective on what’s really going on between the gut and the brain.

Michael Roesslein:

I’m going to watch that about five times personally. There was a lot in there and it was great. I’ve heard some of that before, and I’d not seen it put together all in one place. Everybody will be getting the recording. Don’t worry. I put links to the products in the chat. I’ll put them again. But there’s a Zen biome sleeps and by biome cope. And we actually built a bundle. So there’s a Zen biome bundle, that’s both products. And we put some coupons there for one or the other, or both, if you want to try them. And yes, I actually put together those supplement things that, I guess are for drugs, but I use them for supplements with the four per day, Monday, Tuesday. I made all those and then I left them on my kitchen table when I went to Chicago for six days.

Michael Roesslein:

So I haven’t tried them because I got them the day before. But Mira messaged me halfway through my chair and said, “It was either the Zen biome or you being gone. But I feel great this week.” [crosstalk 01:07:12] And she’s been struggling a bit with not great mood for the last while. And it’s definitely made an impact with her. She’s taking the cope one. I don’t think she’s taking the sleep at this point. I hope it’s the Zen biome and it wasn’t that I was out of town. The recording will go out probably on Thursday. So in two days. You’ll get to watch it again. I’m going to watch it multiple times. We’ve got a ton of questions.

Michael Roesslein:

She’s seen a big difference because you put a saffron in that, right? Saffron has actually been clinically tested up against some of the more popular antidepressant drugs and beat them. And so I like the synergistic ingredients you put in with the bifido longum as well. And the sleep one has the theanine and is it lemon balm, right?

Kiran Krishnan:

It does. Yeah. And the whole idea there is we want to be able to give people some more quick response dealing with some of the more pressing symptomology while the bacteria is in there fixing the root cause problem, which is this inflammatory cycling. So it’s worked so beautifully in just the short time that we’ve had people on it. We’re so excited about this product. I would say this is probably, MegaGuard was one of my favorite ones that came on after MegaSpore. But this is, to me, one of the most exciting things we’ve done in a very long time.

Michael Roesslein:

It’s really cool. And it’s got crossover too. I mean, this is a functional medicine. People would be interested in this. And then I have a whole bunch of friends now and colleagues in the mental health space who would be interested in something like this. So I just put them back in the chat again, the Zen ten one product either. And then I put the coupon in there. We do have a ton of questions.

Kiran Krishnan:

One more mention, think about for kids as well. Right? So if you look at kids with behavioral disorders and all that, behavioral disorders are a symptom of anxiety in kids. When young kids are having temper tantrums and so on, they’re really panicked and anxious, right? That’s the way they respond. In adults, we quiet down or we hyperventilate and we’d go sit in the corner. We’re feeling anxious and depressed. In kids, they overreact. And so this is really a great time to address that inflammatory cycling in kids as well to help with some of those mood and behavior issues that you might see.

Michael Roesslein:

Perfect. And I did put a warning in the chat that I’m going to go to the questions that are relevant to this presentation first. And then if we have time, we’ll get to other questions, but I’m going to get to the ones first that are relevant to gut brain directly. So let’s start. Products, these are safe for children. You just mentioned that. Is it contraindicated to take these products with any sort of medication?

Kiran Krishnan:

Not that we know of right now because they don’t interfere with the metabolization of function of any medication. Because they’re working purely on the inflammatory pathways. So far, no. We haven’t seen any of that in the numerous clinical trials and all that, that have been done.

Michael Roesslein:

Okay. The difference between the two new products is one cope is more for stress mitigation and sleep is for sleep improvement, would be the short answer there, right?

Kiran Krishnan:

That’s right. And if you happen to be like the majority of people that have both issues, so when you’re looking at daily mood disorders, stress management, coping issues, but then you also have a hard time sleeping and having good quality sleep, then you would get both products, but you would take one cope per day and then one sleep per day. So the cope bottle will actually last you 60 days because there’s 60 caps in the cope bottle. If you’re only looking at the coat, then you would take two cope per day and that’ll last you 30 days. Or if you’re only looking at sleep, you’re just take one sleep per day and that’ll last you 30.

Michael Roesslein:

Got you. So it’s 30 days of each if taken alone and then if the cope is taken with the sleep, it’s 60 day of the cope.

Kiran Krishnan:

Yeah, that’s right.

Michael Roesslein:

Okay. Go you. So you wouldn’t take cope in the morning and at night and the sleep at night, the sleep one takes the place of the cope.

Kiran Krishnan:

Of the second cope. That’s right.

Michael Roesslein:

So the 1714 strain is the main ingredient.

Kiran Krishnan:

It is. Yeah. That’s bifido longum 1714.

Michael Roesslein:

They are called Zen biome. I thought the products are called Zen biome. They are called Zen biome. There’s Zen biome sleep and Zen biome cope. We’ll take notes on… Penny. He explained in, she said, “I thought bifido didn’t survive the digestive tract. How is this different on the slide where it showed the…” I don’t know what that stuff was on the outside.

Kiran Krishnan:

Xcel polysaccharide, it’s called.

Michael Roesslein:

That’s how this one survives, correct?

Kiran Krishnan:

Yeah. So similar to how the bacillus spores survive because of a coating, that they have a natural coating, this bifidobacterium actually survives through gastric system, bile salts and all that because of its coating as well. Which is really interesting because, one of the factors, remember I mentioned throughout the presentation that we share microbiome cloud, right? And maybe one of the reasons of this type of organism has that Xcel polysaccharide is it becomes an easier organism for people to share with each other when you live in close proximity. So that should perpetuate a healthy mindset of the community itself when everyone is sharing this organism together.

Kiran Krishnan:

And most bifidobacterium, the moment it comes out of the body, it’s going to be dead in exposure to oxygen. But this one, when it comes out, because of the Xcel polysaccharide, can survive outside and be reinvested. So it’s a very unique strain of bifidobacteria. In fact, as a side, we had done experiments where we took the bifidobacteria and knocked out the Xcel polysaccharide gene. So it couldn’t make the Xcel polysaccharide, but everything else was the same. And when you do that, it doesn’t have the same effect. So that Xcel polysaccharide is critical to its effect.

Michael Roesslein:

Interesting. Okay. Yes. The new product can be taken with MegaSpore. I bet they would work really well together.

Kiran Krishnan:

[inaudible 01:13:58].

Michael Roesslein:

The MegaSpore knocks down a lot of the leaky gut and the inflammation from one side, and this would help mitigate it from another.

Kiran Krishnan:

Yeah. There’s really two major pathologies that lead to brain inflammation and all kinds of issues. One is through endotoxemia and LPS. That’s what’s being addressed by MegaSpore. And the others from external stress induced inflammatory cycling, and that external stress induced is dealt by the 1714. So if you’re already in MegaSpore, you’re like 50% there. And then you add in the 1714, and it deals with the other component to inflammation and activation in the brain.

Michael Roesslein:

You still have a practitioner database on your microbiome labs website, don’t you?

Kiran Krishnan:

Mm-hmm (affirmative).

Michael Roesslein:

Sorry. I’m multitasking right now. Okay. Man, I hosted a webinar solo a couple of weeks ago, and I’m used to having somebody else here. I’m used to doing the chat and the questions and you talking. It was quite the challenge when it was only me, because if I stopped talking to do the chat, then nobody was talking. So someone taking psychiatric medication, “Is it okay to explore probiotics? Are there any contraindications? Currently, my son is being stabilized with medications, so he needs to continue for a while, but I’d also like to add gut brain support. He definitely has gut issues.” No contraindication there, right?

Kiran Krishnan:

No Contraindication. Keep in mind that psychiatric medication, most of them work directly on the brain. And things like if he’s taking SSRI, for example, that’s interfering with the serotonin re-uptake pumps in the brain. And so all of that’s happening right in the brain. This working through the gut modulates inflammatory responses. So it doesn’t interfere with how those medications work.

Michael Roesslein:

Okay. Well, can they get these products in the UK microbiome labs? I don’t know your distributor there, but can they get them?

Kiran Krishnan:

They should be within about a month or so. Yeah. There’ll be carrying it there in the UK.

Michael Roesslein:

Okay. Right. “What are the mechanisms to how cortisol has a negative impact on microbiota?” You covered that in the slide. Could you summarize that just a little?

Kiran Krishnan:

Yeah. So this is part of that continuous feedback loop, right? So what happens is when cortisol increases or even epinephrine and norepinephrine increases, there are a lot of opportunistic organisms within your system that remain latent and dormant because they’re not really strong pathogens. They are opportunistic for a reason because they look for the right opportunity to turn on their virulence factors. Many of these organisms have evolved to look for stress, hormone signaling as the right opportunity to turn on the virulence factors. Because they’ve learned that the host immune system is suppressed when the host is under stress, right?

Kiran Krishnan:

So when you have cortisol levels elevating, when you have epinephrine or norepinephrine elevating, what you tend to get is latent pathogens that are opportunistic seeing that, and then them turning on their virulence factors and starting to multiply. So studies have shown that even short bounds of external stressors can modulate the microbiome in a very significant way, where over time, over days, weeks, and months, you’ll start getting severe dysbiosis, just the short bouts of external stressors. And of course that dysbiosis will make you more susceptible to external stress, more susceptible to inflammation, more susceptible to cortisol release, which then will create further dysbiosis, right? So it’s a continuous cycle.

Michael Roesslein:

Got you. “Why do those LPS toxins cause different conditions in different people, even though the toxins are the same? Why do they cause anxiety and some dementia Parkinson, chronic fatigue, syndrome and others? I would guess it’s the spot where they land and start doing damage.”

Kiran Krishnan:

Yes, totally. So it’s a number of factors. Number one is certain people have certain genetic susceptibilities to immune responses in parts of the body, right? So take somebody that has SNPs, if you’re not familiar with what that is, it’s called single nucleotide polymorphism. So when you have changes in your DNA or mutations in your DNA that modulate your immune response, that makes you more susceptible for auto immune conditions. If you’re continuously exposed to LPS and the inflammatory responses associated with that, that may lead to an auto-immune condition in you in the case of what happens to your response to LPS.

Kiran Krishnan:

Somebody else, when the LPS gets in, it starts aggregating in the joints and then triggers rheumatoid arthritis in the joints. Some people will move up the vagal nerve and interfere with serotonin and dopamine binding creating mood disorders. And so it depends also on other lifestyle factors, right? What are you eating? What are you influenced by? Who is around you? All of those things. It’s a really prolific and it’s a very pervasive endotoxin that can trigger inflammation and disruption in numerous pathways in the body. So it really depends on what you’re unlucky with, right? Whether it’s genetic susceptibility, lifestyle choices, who you’re around and all that. It’ll affect you in different ways.

Michael Roesslein:

Interesting. Okay. Let’s see. “A new product’s been tested via brain map to show how the neuro-transmitter and brainwaves respond to the probiotics. How are those, tests were done using…” I always get them mixed up, where you showed the brain and the brainwaves, is that [inaudible 01:20:18]. One of them is the heart and one of them is the brain.

Kiran Krishnan:

Yeah. This one is actually a much more complex piece of machinery. Let me bring up that slide again. Let’s see. Where’s the share slide thing? Do you see this machinery right here? This crazy… Yes. It’s not a simple stick electrodes on your head EEG type of monitoring. It’s a much more sophisticated piece of equipment. And to be honest, I’m not an engineer who looks at these things, so I’m not even sure how to describe…

PART 3 OF 4 ENDS [01:21:04]

Kiran Krishnan:

The engineer looks at these things. So I’m not even sure how to describe this thing.

Michael Roesslein:

That’s a big thing.

Kiran Krishnan:

It’s a big device. This person is sitting in that device for hours on end. We’re inducing all kinds of social stressors in a number of different ways. And this was all done at this university hospital, which is one of the most prolific university hospitals for psychiatric disorder research. And here’s what’s really interesting. This professor actually is one of the most resistant to the idea of the gut-brain connection, and probably one of the most resistant to the idea that probiotics or nutritional products can have any impact on the brain at all.

Kiran Krishnan:

And that’s part of the reason why we ended up working with him because we said, if we can prove if someone that’s highly skeptical can design a very well-designed study and demonstrate this and become a believer and end up talking about it in lectures, then it’s really something that’s well put together. So this is Study All Design by Professor Paul [Anke 01:22:11], who is probably one of the most prolific skeptics in this space. But of course now, he lectures on it.

Michael Roesslein:

Wow. Good idea, picking the skeptic though. That makes the study more valuable.

Kiran Krishnan:

More robust, yeah. And to his peers, right? People know that he’s quite skeptical about these things. And if he’s done the study, then the idea is that, okay, he’s really designed the study to be as objective as possible and not subjective in any way. And so yeah.

Michael Roesslein:

That was in Germany?

Kiran Krishnan:

That was in Germany. Yeah.

Michael Roesslein:

Okay. A question that’s coming up a lot in the chat, are these colonizing organisms, this bifido longum? Like, will they overtime it will build up and you might be able to go to like a maintenance situation or take breaks and you’ll just have more of it doing its thing?

Kiran Krishnan:

Yep. And you can kind of modulate that around. We say, three, four months after you’re taking two caps a day, for example, you’re taking the cope, you can go down to one and see how you do. And a lot of people will be perfectly fine with one for long periods of time and won’t have to go back to two or sometimes you can even go to one every couple of days over a period of time.

Michael Roesslein:

People don’t often realize. And it’s like, usually my answer to questions like that. Because I take a bunch of supplements and I… Some of them, I probably could go less on and it’s, I choose not to. And it’s like, what are we exposed to on a daily basis? What amount of stress? What amount of toxic, whatever? What amount of food ingredients that are in food? What amount of here, air toxicity? Because we have fires now. And what amount of all these things that it’s like, we need all the help we can get in some of these regards. Unless someone’s going to be living in like a pristine wilderness situation that is free of all stress with a super diverse diet and a perfect sleep and all of those things, it’s like, we need all the-

Kiran Krishnan:

[crosstalk 01:24:04]…

Michael Roesslein:

… support we can get. Has there been any studies done on this stuff with autism, kids with autism or adult autistic populations?

Kiran Krishnan:

Not yet. In fact, that’s some of the areas that we’re going into. We’re going into deeper, more major depressive disorders, other psychiatric disorders, including spectrum disorders as well. That’s really the next area. We know that spectrum disorders are a gut-related disorder, at least the gut plays a role in it. We know that inflammation from the gut to the brain plays a role in it. We also know that certain types of pathogens play a role in it. So we feel pretty confident that it would be helpful, but we haven’t done the studies yet, but we are. We’ve got a lot of studies still to come on this particular probiotic, even though we’ve already done and published maybe eight or nine studies on it.

Michael Roesslein:

Okay. I would like to know, is it possible that activating the vagus nerve could potentially make severe mental conditions worse if the person has severe dysbiosis? Below are two resources I found a year ago. And that’s why I asked. Also, I’ve heard the body slows down the vagus nerve function as the gut gets worse. So I thought maybe it was the body’s way to protect the brain or slow destruction.

Michael Roesslein:

I think the thought here, I’m not fully following. I have the studies linked, but it’s that increasing vagal tone or things that increase vagal tone could cause more bad stuff to go up into the brain?

Kiran Krishnan:

Well, so it depends on what the tone is, right, what the signaling is. So it’s called sympatho-vagal tone because it really depends on whether is it sympathetic or parasympathetic activation. And the vagus nerve is really a transducer or transduction of signaling. But what is the signal is the thing that makes a difference.

Kiran Krishnan:

So it’s not about just shutting off the vagus nerve or slowing it down or activating it. It’s about the type of tone that’s created. And that’s really the significant thing. So in this case, in that kind of external stressor, cortisol, HPA axis, continuous activation, you are activating the vagus nerve, but you’re activating the sympathetic part of the vagus nerve, not the parasympathetic, right? So the parasympathetic will do different things into your system than sympathetic activation.

Kiran Krishnan:

So it’s not quite as cut and dry as like toning down the vagus nerve or activating the vagus nerve. It depends on what signal’s actually going through it.

Michael Roesslein:

Okay. That makes sense. I’m kind of just see if we have any… which neurotransmitter precursor… That was answered. All right. [inaudible 01:26:58], that one. Answer live. Done. Answer live. Done.

Michael Roesslein:

Now, if you have questions that are not related to gut brain, and I’m not answering them right now or getting to them, you can email me at michael@rebelhealthtribe.com. And I will try to get you some responses. We’re trying to stick to on topic for the questions for this.

Michael Roesslein:

Are these products, dairy, soy, and grain free?

Kiran Krishnan:

Mm-hmm (affirmative). Yes. Absolutely.

Michael Roesslein:

Okay. Yes. You can take it even if you’re on an antidepressant. I would recommend talking to your psychiatrist, but there is no known contraindication. Weird. They’re saying the bundles link isn’t the right link. Hold on. They’re both on there.

Michael Roesslein:

Somebody said that the Zenbiome collection bundle only has Zenbiome Sleep, but I’m on that link right now and I see both products. So I will put the link again in the chat and you can try that one.