Gut Connection In Chronic Illness

Kiran Krishnan

Well, first thank you so much for having me. I really appreciate the opportunity to be here and be able to chat about this topic, which is really important and so relevant for people as they’re struggling through endless chronic issues. Looking at US adult population alone, 50, 60% of people have one or more chronic illnesses. So for me, the journey always started off as being just a very curious kid. So I was always that kid that wouldn’t take anything for granted in terms of how things worked and how things functioned. I always wanted to just hand the world around me a little bit better. And so I was always curious, asking questions and all that. And so both my parents were scientists of a sort. 

My mother’s a medical doctor and then my dad was a engineer as a microelectronics engineer. And so they each had this kind of different parts of the brain. My mom’s the biological sciences and all that. And then my dad is more the hard physics, math kind of science and he had a much more inventive side to him. He had over 200 US patents in his name in microelectronics. And so I got, I think, I feel like I got best in both worlds maybe. I got the love of the biological science and then, but thinking about biological science from a systems perspective, which is where my dad came from. And so for me, it was all about systems biology and all about how everything is connected and how everything influences one another. But there’s a significant missing piece as you go through your training in science and all that, especially when we did. 

And that’s because we’re missing this whole component of functionality and that’s the microbes. And then we started to realize in the early 2000s that maybe there’s something much more here to in terms of what’s influencing us and driving our functionality beyond our own genes. Because that was the human genome project. In fact, the university where I was working at the time, one of the biochemistry labs was a key lab in the whole human genome project. And one of the things that kept coming up that was really puzzling was we don’t have enough genes to function. We don’t have enough genetics. We seem to be very sophisticated organisms. 

We’re at the top of the food chain, at the top of the evolutionary ladder, we’ve got amazing cognition capabilities and so on. we have 22,000 or so genes. And then compare that to an earthworm or rice plant that has about the same amount of gene as we do. And so then you go, how are we so sophisticated? And prior to the completion of the human genome project, it was estimated that the human chromosome would have somewhere around 130, 150,000 genes. We have a fraction of that. And so then the big question is how do we do all the amazing things we do? And hence through that was the birth of the human microbiome project. And I was already in with studying microbiology because the invisible world fascinated me so much. It was either A, I was gonna become a quantum mechanics researcher, or I was gonna do microbiology, it was one of the two. I’m glad I went microbiology. And so what was really interesting to me is that as you’re training in microbiology and you start looking at careers that are associated with it, a lot of the medical microbiology side are very focused on pathogens. And pathogens make up less than 1% of all the microbes that we know. So my big question always was what about the 99.9% of other microbes. 

We’re heavily focused on pathogens all the time in terms of career and research and all of that, then the micro human microbiome project kicked off and I was like, ah, that’s where the answers are gonna lie. Because now we’re finally looking at everything else. And so for me, that became an automatic focus for the next foreseeable future in my career was getting involved in the microbiome space. So that’s kind of how I jumped in and I was always a proponent of functional and natural medicine. I grew up in India where we used a lot of Ayurvedic medicine. There’s lots of herbs and things that are being used, my grandmother and all had lots of home remedies and things like that. So I knew that there was a power to a lot of these things, not a lot of science had been brought to it where they should be. And so to me, that became an immediate focus, was like, okay, I wanna work in the functional medicine space, but I wanna bring in the power of the microbes to work as a tool in that space.

Eric D. Gordon, M.D.

And what what’s exciting, the regular viewers will know that I always throw in something about Robert Naviaux and his cell danger response story, but what is exciting is that Dr. Naviaux’s real push these days is something he calls salutogenics or salutogenesis which is how to heal. And one of his things that he’s very frustrated with is just as you said, is the NIH, the National Institute of Health, like almost all of their budget is on pathology, what makes us sick? And we don’t focus on what gets us back to health. Because the reality is when you have chronic illness, it’s very rare that just removing the cause, the pathology is gonna get you back to health. 

The reason you have chronic illness is that system that normally brings us back to health has gotten stalled, doesn’t have the right information. And it’s the natural system of healing. And the microbiome is obviously a big source of that, something that, again, the natural past have been trying to, and the… A lot of people have been trying to tell us for the last 100 years or longer that it all starts in the gut. But so you, and you have… You are one of the people who help not just study, but you are helping us really get real information, real data. So how, at this point in your career, what do you think is a healthy microbiome and how does that help us?

Kiran Krishnan

That’s one of the most important questions because we know clearly what is not a health microbiome. we know that there are certain signatures of the microbiome associated with certain conditions, obesity, there’s a certain signature to the microbiome, autism spectrum disorders, depression, all of these things, IBS have specific signatures that are associated with the microbiome. But when you look at what is healthy, so what the goal that we should all strive for? One thing that just keeps popping up is diversity in the gut microbiome, and that may be different for other biomes. 

So other like your skin microbiome, your vaginal microbiome, the oral microbiome may have slightly different rules, but when it comes to the gut microbiome, which is the vast majority of the organisms live there, it’s diversity and having high levels of Keystone species. There are some organisms that are designated as Keystone species because there’s so important in maintaining the rest of the population. They’re also inversely correlated with disease to the host. And as we lose Keystone species and lose their numbers, we start to see the system dismantle. And so having high diversity, having high levels of Keystone species is key to a healthy microbiome. And there are a nice variety of studies around this as well. 

So there’s a lot of population based studies that look at a broad swirl of the population, on diversity and how that impacts pathologies and how that impacts risks and so on. But also it’s important that they’ve looked at things like even longevity. How long you live is gonna be determined largely by how diverse that microbiome is. And to me, the number one health goal that I have is not to be in some sort of perfect health or not to have perfect lifestyle, perfect choices, it’s about being resilient. I want my body to be, and my system in general to have some degree of resiliency so that when I do abuse it a little bit, which we all are gonna do, that it has the capability to handle that. 

So when I do travel or you do have a good Friday night out with your friends as a celebration or something, or if you make an perfect choice in your eating, your body can handle it and can adapt. so you can follow the 80/20 rule, 80% pretty good decisions and 20% you’re gonna do some fun stuff on the side. And so building some degree of resiliency is key. And having that diverse microbiome is a huge key to resilience, and that’s a big difference.

Eric D. Gordon, M.D.

And when you say Keystone species, how many have you… Again, this is an ongoing study, but at this point where do you feel, what has your data shown you as for numbers of Keystone species, the ones that are really, I’ll let you talk more about that and also how they support the rest of the microbiome.

Kiran Krishnan

There’s really about 8 or 10 well known Keystone species that can be shown to be inversely correlated with disease. Single organisms that have a huge impact on your disease, risk and outcome. These are organisms like faecium, bacterium, protozoea F protozoea has been shown to be inversely coordinated with everything associated with inflammatory conditions in the bowel. So IBD, Crohn’s colitis, colorectal cancer and so on. Those are all inversely correlated. And then akkermansia muciniphila is another example, metabolic syndrome, and all of the 40, 50 diseases that fall under that whole umbrella metabolic syndrome are all inversely correlated with this single organism and, obesity, diabetes, heart disease, dementia, polycystic ovarian syndrome, all of these things that are that fall into the umbrella are protected, you’re protected against if you have high levels of akkermansia, then there’s Bifidobacterium longum for example, and we work with the longum, very unique longum that contains an exopolysaccharide layer on the outside, which seems to be a really powerful psychobiotic, which means it’s a microbe that has an impact on brain function, on mood, on sleep and so on through the gut brain access. 

So there’s about eight or nine, somewhere between 8 or 10 organisms that have been identified to be somewhat Keystone, meaning that they have this really important global impact on the host. And what’s interesting about how the microbiome is structured. So when you get down to the species level, most people are different from one another. In fact, you could have identical twins who have 100% the same genetics, lived in the same household and still have huge differences at the species level of their microbiome. 

Now, one of the reasons why we can all exist and have very different distribution of microbes at the species level, and yet function in very similar ways is that there’s a lot of functional redundancies within the microbiome. You might have one type of organism that produces a lot of your butyrine, I might have another that does the same thing for me, but they’re different species. So those functional redundancies are important, however, when it comes to Keystone species, they seem to be unique in what they do. And so having those Keystone species across the board and everybody becomes really important.

Eric D. Gordon, M.D.

It’s much like genetics is that there are some genes that if they’re off you die before you are born or within the first 10 years of life, and then the rest were just so different. You find this across populations as well ’cause one of the things that’s frustrating is that, well, America, we do have but so much is aimed at least in genetics world, it seems like at the white Anglo-Saxon world. But what about in the microbiome, do we have a little more diversity of samples there?

Kiran Krishnan

So yes, across the board, we do. we have great sampling from many different ethnic backgrounds and so on, but what we come to find out is it’s not so much the determinations of your microbiome are not so much ethnic or culture, race based, it’s really geography. Geography really tells a story when it comes to microbiome. You take people of African descent if they live here, their microbiome is gonna be completely different than their family that lives in Africa itself because they’re just, they’re different environment. And the microbes are of course heavily influenced by the environment, the type types of food sources and all that. 

But speaking of diversity, one of the things we’ve seen very clearly, and we’ll be coming out with more and more of this kind of data as we work through mining all of the thousands upon thousands of sequences that we’ve done of people. And in fact, fortunately for us of, everyone that we’re sequencing as some sort of ailment, a lot of the database information that’s out there that the NIH and all had put out were on healthy normal individuals. So you can get a sense of what that quote unquote healthy normal-

Eric D. Gordon, M.D.

Quote unquote, healthy because when I’ve worked in projects, I’ve been amazed in at how not well the controls often are, but still are.

Kiran Krishnan

Exactly.

Eric D. Gordon, M.D.

If they’re walking and talking, they’re not complaining too much.

Kiran Krishnan

Exactly. They actively managed for

Eric D. Gordon, M.D.

Disease.

Kiran Krishnan

For disease conditions. But all of our data set are people with actual serious conditions, or ones that are at least causing them to go see a doctor or practitioner are quite actively. And so we’re getting a much more what I would call a representative data set of most of the people that are probably listening to programs like this are going in to see their doctor for help. Because now we’re starting to understand what the actual microbiomes are looking like for people that have ailments. And one of, and to me, the scariest thing that I’m seeing in the microbiome analysis is how low our diversity is. When you look at the average North American microbiome that we’re measuring, we’re finding somewhere around 120, 150 different species if they got microbiome. And that’s scary because when you look at like the Hadza tribe of Tanzania or the Papua New Guinea tribes, and so on, they have upwards of over 300 different species.

Eric D. Gordon, M.D.

We’re 50% down before we start.

Kiran Krishnan

Exactly. We’ve lost half of the microbiome that our ancestors really went through a lot to preserve and harbor and pass down to us. And we have squandered it away over the last generation or two by our practices. And what’s scary about that is what’s it gonna look like 30 years, 40, 50 years from now? What are we passing down to our kids? And the scary part about that, and I call it a mass extinction because it’s really an important thing that we need to use, a dramatic term for because more and 50% of our capabilities come from our microbiome. And if we’re losing microbes and large families of microbes, we’re losing capability of being human. And we’ve already lost half. 

And what is that half that we’ve lost? What has that cause for us? We don’t have that data yet, but I would argue the prevalence rate of all of our chronic illnesses and birth defects and all of that stuff are likely driven by missing many of those microbes. And so it’s equally alarming to me and I give people this analogy to help them wrap their head around it, because it’s so hard for people to see the importance of this, it’s somewhat esoteric for most people. But what if I were to tell you that the next generation of kids are gonna be born without a spleen because of our choices today and then they would have to go through their entire life trying to adapt and do therapies and surgery and all that to try to live without a spleen. And then the generation after that are gonna be born without a spleen, and maybe just one kidney. It’s like losing entire organ systems when we lose huge groups of our microbes. And so that we’re seeing in the data. And the diversity of the microbiome in North American population is pretty scary, it’s pretty-

Eric D. Gordon, M.D.

Are you seeing it decrease by age?

Kiran Krishnan

Yes. So with age, it goes down automatically. And a lot of that has to do with a number of different factors. I think one, as you get older, there’s more chance you’ve taken more and more medications, you’ve been exposed to more things that harm the microbiome over time. You’re drinking eventually more glyphosate than you did when you were 15 because you’ve just been consuming for so much longer. So I think all those things will take a toll when the microbiome will start to shrink. The other things that I think affected are as you down, and you’re not getting out much, you’re not going on hikes the way you used to, maybe not even interacting with people as much as you used to.

So all of those things that give you exposure to microbes, those behaviors get reduced, and then the consumption and all stays about the same. And so the net reduction in microbes occurs. Now, how diverse your microbiome is as you get older is also gonna predict how long you live. So it becomes really important for people as they’re getting older, as they’re getting into their 50s, 60s, 70s, and beyond to really be paying attention to what the diversity of the microbiome looks like at the moment. And so it becomes really important to do a test and understand where it is, and then start to really think about solutions that you can either A, use to maintain your current diversity or even increase the diversity.

Eric D. Gordon, M.D.

One of the things and aside, and I’m putting in a plug for your company, we usually don’t do this as part of this, but can you just talk a little bit about, ‘ cause your microbiome, micro, we wanna call, the test that your company has has put out BiomeFX is something I’ve been using for the last year and a half. I said, it’s been educational for me because of how clearly you lay out the different microbes that as a practitioner, I have to admit I always found, I knew the pathogens really well ’cause I’ve been doing stool testing for literally almost, like 36,37 , a long time since that was one of the first things I did in the ’80s with stool testing. And so we were those days, we were really following, finding the pathogens, the klebsiella and things of that sort that we knew shouldn’t be too much of. 

But, and then in the last 10 years, we’ve started ever since we, the PCR technology started to come in, we started to be able to get long lists of bugs. Like to be honest, I didn’t know what to do with most of that. Most of that looked to me like I was gobbledygook and it was so much information anyway. So I like your test still has a lot of information, but it’s a learning curve that’s seems be worth it now because I’m learning something from it. So, but tell me what makes your test a little bit different than the others that are out there as far as how you are identifying these species?

Kiran Krishnan

So that’s a really important question. And the only reason why we came up and developed this test was because we were frustrated with what was being offered out there to health practitioners with the microbiome testing because it was missing the both in many, many respects. So the first thing in is most of the tests out there still use a 16S Technology. 16S is a type of sequencing technology, these days it’s very cheap to do. You could probably run a 16S sequencing for 15, 20 bucks. And so, but the problem with 16S is it doesn’t give you much accuracy at the species level. So it, the genus level, you can be pretty accurate that you’re picking up the right genus, but at the species level, it’s maybe 50, 60%.

Eric D. Gordon, M.D.

Can just loop people a little idea, the difference between the genus and the species just maybe sort of just make it.

Kiran Krishnan

Yeah, absolutely. So when you look at every organism on earth, we all have this hierarchy of where we belong on the phylogenetic chart. And every bacteria, when it comes down to it and everything starts the kingdom, of course, but then when it comes down to it, you have a genus and then you have a species. So you have genus, like for example, lactobacilli is the genus. So there’s many different types of lactobacilli and you distinguish them based on the species. And those species could be lactobacilli reuteri or lactobacilli acidophilus. So the genus is that grouping that they all fall under but then to understand which type of lactobacilli they are, you have to get down to the species level. 

Because at the end of the day, the genus will give you some information because many of the microbes that fall under that genus will have certain properties, but really the key functionality is gonna be, what species are they? And that’s gonna determine whether or not they’re pathogenic, for example, because there are many microbes that could be within a genus, some of those microbes are pathogenic, Some of ’em aren’t, some are beneficial and so on, like take Clostridia, for example. You have lots of Clostridia in your body. Many of the Clostridia that fall under that gene are perfectly fine and fact really beneficial, but then there are some that are pretty egregious, that are gonna cause you issues like C. diff like Clostridia difficile. So understanding the species level becomes extremely important. And when you’re doing 16S like most of those tests are doing, you’re not getting clear resolution on the genus level, on the species, you’re only seeing it on the genus. So you can’t really map out what the microbiome looks like. 

The second part of it is the PCR that you mentioned. When you’re using PCR to detect for pathogens in the gut, number one, when you’re using PCR, you have to know what you’re looking for because you have to put the probes. PCR works by these probes. You have to add those probes into the task. So you have to already know what you’re looking for. And if there’s something else there that you didn’t have a probe in for you won’t pick it up. So they’ve just got a set of standard pathogens, knowing that they could be other ones that are present causing problems that you’re not picking up. 

So that in itself is, makes it often. The second part of it is most of those other tests are very pathogen centric. And when you use PCR, you artificially amplify the genome of those organisms, so doesn’t give you the accurate information on the proportion of the organisms in the population. And that’s the key aspect of pathogens because it’s perfectly normal for us to have pathogens in our system. They’re part of our flora. When they’re above a certain threshold in terms of relative abundance, that’s when they become a problem, not CFU count. So anytime these tests show you a CFU count, it’s meaningless because a pathogen is only problematic if the rest of the microbes around it are inadequate. So one of the things I always tell people about microbiome, understanding the ecosystem, the microbiome is it’s not just important who’s there, which is what a lot of tests are looking for like, is this bug there, is that bug there, is this bug there, it’s who else is there because it’s a system And so that context around the rest of the population is really important. 

And to give people a little better understanding on that, on why context is important, one of the analogies I use is like, if you were a city planner, and you’re planning out this new city, and you’re trying to figure out all the different departments of the city and so on, and if somebody came up to you and said, “Hey, there are five police officers in that city.” Is that enough? Are those enough police officers? The first question you’re gonna ask is what’s the population? If it’s 1,000 people in the city, five police officers are probably perfectly fine, or 5,000 people, or even 500 people, you’ve got five police officers, active duty patrolling, probably okay. 

If it’s a million people in the city or 500,000 it’s wholly inadequate. So then number of officers is not as important as understanding the population dynamics. And so when you’re doing a PCR based test and you’re doing the 16S based test, you’re really only getting that kind of information like, oh my God, you have five police officers. Well, that could be fine depending on the rest of the context. So we were very big on making sure we understood the got context and we’re mapping out the entire microbiome so we can look at everything from a system perspective. And the only way to do that is by using whole genome sequencing, which is the advanced next stage sequencing and it’s a shotgun whole genome sequencing, which means that you actually go in and you blast the genome and you break up all the genes that are in there and you’re finding trillions of trillions of genes. 

And then it all gets reassembled and reassembled in and looking at and you assemble a microbes gene from beginning to end. So you identify a micro by finding its entire genome sequence, and then you get the most accurate and most relevant data out of it. So what we’re doing is we’re really changing how you can look into the microbiome. One more quick change, one more quick addition to that is we also started really focusing on functional groups of microbes because we talked about earlier how you and I can have different microbes at the species level, but still have the same functionality because there are a lot of functional redundancies within the microbiome. So instead of looking at one organism in the sulfate, reducing bacteria group, for example, we look at the relative abundance of all the organisms that fall within that group. And then we give you an understanding of how many sulfate reducing bacteria you might have in your gut versus the population, the general population and so on. And so you have a better understanding of what your functionality is in the microbiome.

Eric D. Gordon, M.D.

Yeah. It is so important ’cause in medicine, especially, a lot of the people who are listening to these programs are they’ve had to self educate. They’ve done a lot of reading. And one of the problem when you do that is that you lose the context. So people will see the name of a bug that’s considered a pathogen and get panicked more or less, Oh my God, I’ve got this. And first I’m understanding, first of all, most of the things that that will kill you easily are when these pathogens are maybe in a different organ. If you find this bug in your lungs, yeah, it’s a really bad infection, but it’s in your gut and it’s in a small amount, It’s just fine, it’s part of a system. And one of the thing and the CFUs that we have a colony forming something. So again, this is just a way to measure population of bugs. 

Don’t get confused by that. But again, once again, it’s balance and understanding balance is not easy. One of the examples I give all the time is that our brains are engineers by nature. We like to think that A causes B and we get confused when A, B, C, D, E, F, all can cause something that looks a little bit like B. And that’s hard for us. Our brains are, are really do well with one cause one effect, and that’s how medicine works and thinks. And that’s why people with chronic illness have such a hard time because that’s not what’s happening for most of us.

Kiran Krishnan

That’s exactly right. And at the end of the day, when you look at the microbes world, it becomes even more complicated than our own system which, and of course they are part of our system. And so starting to be able to map out your microbiome like this and starting to understand the tendencies of your microbiome and what it tends to do well, and what it tends to not do well based on the microbes that are present and their relative abundance, that becomes really important insight information for people to start to figure out how they can improve their outcomes.

Eric D. Gordon, M.D.

And tends and tends, remember that word, tends to affect you. Don’t freak when you see the wrong bug.

Kiran Krishnan

Exactly. Yeah, absolutely. And it’s so much like our own epigenetics. Just because you have a gene, if you did a 23 on me and you found a gene for some crazy rare disease, it doesn’t mean it’s gonna show up in-

Eric D. Gordon, M.D.

Yeah, oh, please, you do that all the time or what I call or the rabbit hole of the MTHFR world.

Kiran Krishnan

Exactly.

Eric D. Gordon, M.D.

There is a subset of people that that really is crucial, but there’s a lot of that that’s just part of their genetics and they have so many compensations for that, not a problem. Anyway, and so now we’re bringing this around, we’re gonna come back to the global stuff because it fascinates me. I always say this is about educating Eric as well as our people, but where do you see how mycotoxins influence the microbiome? ‘Cause you mentioned glyphosate as one of the pesticides so we’ll come back to those ’cause we’ve talked a lot about glyphosate recently, but just in general, the mycotoxins that most of our viewers are familiar with.

Kiran Krishnan

Yeah, absolutely. So in fact, there’s good research out there showing that mycotoxins exposure, especially through food and drink and all that, because I think somewhere around 25% of agricultural products are contaminated with mycotoxins. So we’re getting exposure to it. And we know that certain types of mycotoxins can create dysbiosis in the microbiome. These are compounds like the aflatoxin, octoxin, DEOA, ZEA, all of these compounds that we get exposure to will actually create shifts in the microbiome over time. Some of the most egregious shifts are when it really favors gram negative bacteria versus gram positive bacteria. And for the viewers that are listening that aren’t familiar with that, every bacteria in the world can be categorized into one or two categories, gram negative or gram positive. 

Gram positive means that when you put a particular stain on the bacteria, it picks up the stain because it has as a cell wall and it’s a cell wall that’s picking up the stain. Gram negative bacteria don’t pick up the stain so they’re called negative when you look at it on the slide. The problem with gram negative bacteria is they have this component called LPS, lipopolysaccharide that is in their cell membrane. That LPS is a really toxinogenic endotoxin. And so what tends to happen is over time exposure to certain types of mold toxins will start to shift the microbes in your GI tract to being more gram negative, which means that now you have more exposure to this endotoxin that’s being produced by the gram negative bacteria which drives inflammation and leakiness in the gut in your intestines. And that leakiness in the gut and inflammation will actually drive more damage from the mycotoxin than it would in somebody with a really healthy gut and no leakiness. 

So it reduces your resilience to the mycotoxins So that part is really important because you could take two people, they can be exposed to the same level of mycotoxins and one person will feel just fine and the other one will get really, really sick. And a key difference from the perspective of the microbiome is that one person that feels okay, probably had microbes in there that helped clear the mycotoxins because there’s lots of microbes in your gut, the healthy microbes, like bacillus that we work with that can actually metabolize mycotoxins when they’re in the gut and get rid of it, or they have a dysbiotic gut and in fact that helps the mycotoxin be more toxinogenic So, yeah, and that’s all fundamental differences in what their microbiome looks like.

Eric D. Gordon, M.D.

Are there families that tend to help suppress, maybe help your body detoxify in a way or deal with the mycotoxins? You mentioned, was it lactobacillus you were talking about?

Kiran Krishnan

No, bacillus.

Eric D. Gordon, M.D.

Bacillus species. Yeah.

Kiran Krishnan

Yeah, Bacillus, like subtilis for example. And we know this because there’s been a lot of research in the agricultural space with farmed animals. So farmed animals, if they get high explosion to mycotoxins, they will die. And then farmers will lose huge swats of their herd and it costs a lot of money. In fact, I think mycotoxins really were discovered in the 1960s because of contamination in farmed animals.

Eric D. Gordon, M.D.

Yeah, I explain this to patients is that most of the data on mycotoxins is on the agricultural world, because if your cow dies, it costs you thousands of dollars.

Kiran Krishnan

Exactly.

Eric D. Gordon, M.D.

And when people die, it causes great suffering and pain for the individual, but we don’t, we just wrap that up and it doesn’t get into the research funding for somebody.

Kiran Krishnan

It doesn’t which is crazy. I know you have these trillion dollar industries like agriculture, every penny that they lose on each animal and each crop has a huge rippling effect in terms of the money loss and so they they’re funding research like crazy. So the mycotoxins, there was this crazy little epidemic among turkeys called Turkey X Syndrome or something that went through and they found that it was a mycotoxin contaminant that created all of this illness in birds. And so what they started doing was looking at probiotics to deal with mycotoxins in birds in poultry and all that. And so there’s a number research studies that have come out where they show certain geniuses like bacillus. And there are about four genuses, the other ones people wouldn’t have heard of ’cause they’re not probiotic bacteria that are available to anyone. 

But bacillus became one of the most prevalently used probiotic bacteria to reduce the impact of mycotoxins on the health and lifespan of these birds. So there’s a good amount of research out there on it. And what that also tells us is how important the microbiome is for resilience. Because depending on having the right types of species, the right type of diversity, no leaky gut in your system, you could be exposed to a mycotoxin and deal with it fine. But if you’re like the vast majority of the population, the people we’re seeing all those biome effects tests on with the low diversity, low levels of Keystone species and all, those people get exposed to mycotoxins, they’re gonna few very sick. And so that’s a big, fundamental difference, that resilience factor.

Eric D. Gordon, M.D.

Right, right, right. ‘Cause that’s it. ‘Cause we do see that. So many of the the bacteria that we consider pathogenic, are the lipopolysaccharide producing and that’s it, you get gut a little leaky and then your liver starts having to work harder. And you just saying when your liver works harder, your brain isn’t gonna feel as good, It’s just-

Kiran Krishnan

Yeah, well, and then that of course compromises all your detox pathways. So when your gut is unhealthy, when you have low diversity, you have low Keystone species, you have shifted to more gram negative bacteria, the cascading of effects work like this. You basically start to get more permeability. So you’ve got, your intestines are already permeable. And this is all before you get exposed to a mycotoxin. Your intestines more permeable. You tend to recruit a lot more innate immune cells to the lining of the gut. So the lining of the gut, there’s a constant battle all going on and it’s constantly damaging the lining of the gut, the mucosa, the intestinal epithelium. So you’ve got this leakiness going on all the time, that leakiness compromises your immune system as well. And then your liver takes a big brunt of the hit because all of those migrating endotoxins, that’s the LPS that’s formed by the bacteria are going first to the liver. 

And so the liver keeps taking hits. And part of the problem with the liver taking hits is that your bile acid pool reduces ’cause your liver can’t make enough bile ’cause it’s starting to become fatty, it’s starting to get, take all the hits from the toxin exposure, the endotoxin exposure. So in then in that condition, when you get a mycotoxins exposure on top of it, now your system’s aren’t ready to deal with something like that because the gut is already leaky, that means an endotoxin that comes in is gonna be more permeable and moves through and end up in circulation, your immune system’s not functioning properly. So your immune system can’t help you as much as it should. 

You don’t have the right bugs in your gut or microbes in your gut to metabolize it and reduce the amount translocating through. And your liver is under a lot of stress to begin with so it can’t really help you the way it should to detoxify you. And the endotoxin is gonna make your gut even leakier because we know that endo, sorry, mycotoxins, we know that mycotoxin exposure increases intestinal permeability. So now you’re just, you’re going down this cascade where your body is not resilient and ready to be able to deal with it. So then the big question comes, okay, well, what if I’m already in that state? What if my gut was already messed up, it was already leaky, it’s all this damage, and now I’ve also been exposed to mycotoxins, what do I do now? Well, just like before, if your gut was healthier and you had more diversity, you had more Keystone species and all that, you would deal with the mycotoxin better. So it still becomes re really important as you’re going through your health journey of trying to improve life after mycotoxin exposure, you still have to fix that component of your gut.

Eric D. Gordon, M.D.

Right.

Kiran Krishnan

‘Cause then your gut’s gonna play that important role in starting to rid your body of the impact of the mycotoxin.

Eric D. Gordon, M.D.

Yeah. Removing yourself from mycotoxin exposure is number one, but if you don’t heal the rest of the system, ’cause as we always tell people, everybody’s exposed to mycotoxins and most people do fine. And so it’s, there’s a problem. but so is there a… Gonna touch supplements in a minute. Other than eating dirt, what’s your other suggestions for really making sure that you can increase the diversity and maintain it?

Kiran Krishnan

There’s a number of things that have been shown to be able to increase diversity of the microbiome. Number one, then this is counterintuitive, it’s fasting. As it turns out doing some degree of intermittent fasting, or at least providing your system with somewhere around 12 to 14 hours of no active food intake can actually dramatically improve your diversity because there’s lots of microbes that actually are much more active and proliferate during periods of fasting. And what’s so interesting about how you look at your microbiome is there’s a cascading effect of nutritional utilization. So when you first eat food, lots of the fiber and things, the roughed general that move into the large bowel because they’re not broken down and digested and absorbed into the human system, into our system, so it goes down into your large intestine where there’s a whole series of bacteria that are really good as primary digesters to break down the big molecules, the big carbohydrates, the big fibers and all that. 

But then as they’re break those down, they create smaller molecules and metabolites and then there’s a whole other layer of microbes that only use those smaller molecules and metabolites. And then they produce even smaller molecules and more metabolites and there’s another layer of microbes that utilize that. So when you want all of those microbes to get to feed and get to do what they do and multiply and thrive, you need a period of time where the primary digesters aren’t functioning. So you have primary digesters and then they produce all the byproducts and then they take it easy and go to rest and then the next secondary tertiary start to ramp up, and that occurs over a period of 12, 14, 15 hours. 

And so having some degree of fasting in your system whether it’s four or five times a week, once a week, whatever it may be, could be beneficial, getting outside is really important. Studies show that if you spend more time outdoors in places like the woods going for hikes kind of untouched land. So sit walking up and down, the sidewalk is not quite the same, it’s about being in more of a natural environment and being prescriptive about it. I tried to prescribe myself three times a week, 30 minutes at a time being outside in a natural environment. So we all know that that’s intuitively we know that that’s good for you, but we have to be a little bit more prescriptive about it so we ensure we get enough adequate time that way. Another one is getting a dog. 

Studies show that households that have dogs tend to have people with more diverse microbiomes, kids with less allergies and so on. And then walking the dog out, number one, it forces you to go outside and then number two, the dogs will bring up all kinds of wonderful microbes into your system, into your home. So in fact, in the beginning of 2020, it was kind of like the year of the pets because so many people were stuck at home so they were like wanting to adopt pets when they’re lonely, which is great. But in beginning of 2020, they published a study showing that bringing a dog into your household, increase your longevity by measurable amount. So through the microbiome is likely one of the ways it does that. So you could do the intermit fasting, you can bring in the dog, you could also reduce the amount of sterilization in your home. Most surfaces in your home don’t need to be sterilized. You work last year.

Eric D. Gordon, M.D.

This is you were one of my, what I wanna say, unfortunately, when people become chronically ill, the basic desire of self protection increases. And so obsessive compulsive behavior which we all have some of, everybody’s got their thing, but in inflammation seems to trigger that. And then the need for cleanliness goes up and then on top of this, this was there, and then we had COVID and the absolute, what I consider public health disaster, forget about COVID of people wiping their hands and washing with alcohol based and other and cleaning every surface, it makes me insane because no, these bugs are not, that’s not how you’re going to get the things that kill you.

Kiran Krishnan

Right.

Eric D. Gordon, M.D.

I’m sorry. just makes me nuts ’cause it was a great book from many years ago, The Epidemic of Absence, and just the lack of expo… we’ve got a lot more pesticides and a lot more EMFs and a lot less other healthy bugs in our existence and it it’s rather frightening. But one other thing I wanna throw in before I go back to what you had to say is just Dr. Pimentel who talks a lot about irritable bowel, his very example, if you do not have at least a significant number of hours, 8, 12, 14 hours without putting something in your mouth, you don’t get your cleansing waves just don’t have. And without that You are not probably feeding those bugs in your large intestine what they really need on some level.

Kiran Krishnan

Exactly. You’re not. And in fact, the microbiome is a diurnal system. So it works off of a 24 hour clock, 12 hour phases. And and part of the key is kind of getting your own circadian rhythm match with your microbes. And that’s one of the difficulties of overseas travel is that your bugs cycle and your cycle kind of go off outta whack a little bit. And so one of the key aspects of that is within the microbiome, how there is housed a number of microbes that turn on housekeeping gene. And these housekeeping genes are really important for repair and clearing things, and for example, the process of mitophagy or autophagy this is the removal of damage mitochondria or damaged cells and DNA and protein and all that. So cleaning things up, things that if left untouched would clutter the system and would cause risks for more scary things like tumor formation and all that. So we have to clean all that up.

There’s a lot of damage and destruction that occurs living day to day just from your immune system protecting you, the metabolic processes, all of those leave debris. So you need to clean all that debris out. That process is triggered in large part by the microbiome. And it does so when you’re not feeding the microbiome. When you’re feeding the microbiome, which means you’re feeding yourself, most of the work and energy goes towards breaking down and dealing with food. We know that, we know then the sympathetic nervous system kicks in. We know that all the blood flows going to the gut, we know that from a big meal, how tired you get, there’s a lot of focus on it. So you can’t do all of the housekeeping work and all the cleanliness working, cleaning things up when there’s constant food coming in. So yeah, that to put a finer point on it.

Eric D. Gordon, M.D.

Are there particular genuses that are involved in this circadian rhythm?

Kiran Krishnan

There are. So well, most of the microbes will play some role in it. They do the quorum sensing, they read and speak to each other to a certain degree, but for example, akkermansia. Akkermansia does a great job of proliferating and all that in a fasted state, it becomes active. and Akkermansia is one of those Keystone species. So it becomes one of those kind of the key element of really generating a lot of that, that housekeeping gene activation. So one of the genes that it turns on, for example, that is really important when akkermansia is allowed to proliferate is a MUTYH gene. 

The MUTYH gene is the genome that triggers our own goblet cells to start producing more mucus, to start getting rid of the old mucus that’s captured all the toxins and viruses and all the stuff that we don’t want to make it inside our body and starts flushing that out and then reproducing more mucus from the inside. So clearing that sticky layer that helps protect us and protects every square inch of the inside of our body. So there are certain microbes that are really important during that time of repair that’s really good. Another functionality of akkermansia and I keep bringing that up because it’s such a fascinating organism to me because we only have one species of akkermansia in our whole microbiome, Muciniphila. There isn’t any other akkermansia in there. 

So it’s one of the few organisms where there’s only one member of that genus. The other thing it does is it is it takes polyphenols that have come in through your diet and converts it into urolithins. And urolithins are hugely important set of compounds that trigger things like mitochondrial repair, cellular repair, and so on. So those urolithins are only produced when akkermansia is active and akkermansia increases when you’re fasting. And so it becomes so important to understand that that when you think about eating, we’re not just eating for ourselves, we’re eating for this massive set of microbes that are in the system. So we adjust our pattern of thought on not just what’s pleasurable or good for us as we’re eating, it’s has to be equally good for your microbiome too. And that’s why certain diets like, for example, if you decided I’m gonna start bodybuilding tomorrow. So, and I read online somewhere that I need to have 150 grams of protein a day. 

And so then I’m starting to just eat nothing but chicken breasts all day long and eggs. But that’s not very good for your microbiome. So even though that might help you put on mass to a certain degree as you’re lifting, and that’s important to you, it’s not good for your microbiome. It’s gonna cause a loss of diversity. It’s gonna cause too much ammonia production, which can actually harm many, many of the organisms within your microbiome. So I think we have to as a population, start shifting our perspective a little bit to go, we’re not just feeding ourselves. We’re feeding these very important guests, if you will, that are living in the system and really running the system.

Eric D. Gordon, M.D.

Yeah. It’s just so important for people to have this concept that, the fed state is there to build tissue but the unfed state is when you repair tissue. ‘Cause remember we were designed to live in times of scarcity. And we have no idea, probably the most destructive element of society is the supermarket. If we close the supermarket, like, maybe like two days a week, they just, we might, it might help but the unobstructed or unlimited exposure, we have to food, to calories, not necessarily healthy food, but just calories is probably the biggest source of chronic illness that we have like of degenerative illness, not the infections type probably, but the degenerative illnesses, ’cause we don’t have time to repair. But going back, are there particular foods that you think are that you mentioned like just too much, obviously too much of one type of food is not going to be good. But are there foods and-

Kiran Krishnan

Yeah, without not surprisingly, what seems to be really good for the microbiome and overall health is having to of diversity in the diet as well. There are anthropological studies that show that our ancestors ate upwards of 600 different types of foods on an annual basis and of course they ate seasonally because there were only certain things available in certain seasons. So there, but we have access to everything all the time and our systems are not necessarily designed to eat things out of season very well. 

We’re supposed to get a certain ebb and flow within our microbiome which actually helps us adapt to different seasons, but we don’t get that ebb and flow anymore. And when you look at the average American, they probably eat maybe 12 different types of foods compared to the upwards of 600 different types. ‘Cause our ancestors, they were hunter, gatherers, foragers, they ate everything and they dug for lots of roots and tubers, they plucked stuff, they ate insects, they ate all kinds of things. And so we really have to help ourselves increase the diversity of our food intake. Now, then we also have the problem with that is that so many people are so sensitive to so many things. So then the response to add sensitivity is to go on elimination diets and slowly start removing huge categories of foods which is crazy when-

Eric D. Gordon, M.D.

So far, there are sometimes when we need, but in general, I have seen that. That is the, not the road to destruction so often at the time, again, self protection begets more self protection, unfortunately.

Kiran Krishnan

Yeah, exactly. And you put yourself in more and more and more of a bubble. And I talk to endless people all the time and they say things to me like, oh, I feel fine as long as I don’t eat this, this, this, this, and they list like 40 things that they can’t eat anymore. And to me, that’s not healing. Avoidance is not healing. Just like if you are starting to develop anxiety, one of the worst things you can do is give into the anxiety and avoid behaviors that you feel are gonna trigger your anxiety. 

So that kind of avoidance is really not good for the microbiome. So it’s about refining the system and refurbishing it to a point where you can tolerate a more diverse set of food. So being able to eat a diverse set becomes key. Now, groups of foods that are hugely important, I would say things like resistance starches, roots and tubers, they’re so critically important because again we should really be focusing on feeding the large bowel bacteria and then probably the unsung heroes in the food world that probably do more for us than we ever recognize our polyphenols. Polyphenols are so critically important to our functionality. And they haven’t really to me gotten their heyday as being super help food.

Eric D. Gordon, M.D.

I thought, like berries or just colored food.

Kiran Krishnan

Exactly, yeah. Berries, anything like with the pigment to it that are high in carotenoids and all that stuff. And because I also see a lot of people they’re like, oh my God, I have Cevo, I can’t touch any of those fruits. So, and again, they’re scared of the sugar that’s in the fruits or then go to the vegetables that are colored, that give you some of those polyphenols, but they don’t quite get the same heyday as like say fiber does. Fiber, I think most people start to recognize that, yes, we need fiber in our diet, but polyphenols are so critically important. They act as prebiotics in your microbiome. They are the precursors to a number of neurotransmitters and nutrients and all that microbiome produces for you, including that one critical one I mentioned earlier, urolithin A. Urolithin A is a critical compound that basically controls your cell repair and cell turnover and we can’t get it from our diet. It has to be metabolizing and created in the microbiome from the digestion of polyphenols. So cannot overstate the importance of that.

Eric D. Gordon, M.D.

Ah, yeah. And so when are there, you said there are these Keystone species that you think are important if we, how are there, I know that your company makes some spore based probiotics by and other probiotics, are they mostly there? Or how do you if you need to supplement them, how do you recommend doing that?

Kiran Krishnan

Huh. The difficulty is most of the Keystone species you can’t supplement because most of them are strict anaerobes. So they can’t exist on outside the body very well. Many of ’em the moment they come out of the body through defecation, for example, they die within 30 seconds or a minute because oxygen is toxic to ’em. And so really our best shot is increasing what is naturally already there. And I know that you can do tests as sensitive as ours, BiomeFX and you may find that there’s no detectable level of let’s say akkermansia or faecium bacteria. It doesn’t actually necessarily mean that it’s not there at all. The reason for that, so if you it’s part of it is a probability game. 

So what’s coming out in the stool is not homogenous. It’s like every single stool you have is a perfect representation of the proportion of everything in the microbiome. There’s some variations in there as to what was coming out of that time. So if a certain microbe is at a really small, low level in your gut, the likelihood of finding it in a non homogenous sample becomes lower and lower and lower. And so you might get your stool sample, you send it in and then the test doesn’t pick up any. It doesn’t mean it’s not there. It means it’s such low levels that your probability of finding it is very small. And so I don’t want people to be discouraged and go, oh my God, I have no akkermansia ’cause we see this on test all the time, but then you do all the right things and the next test you actually pick up akkermansia. And it’s not that we’ve put it in, it’s just that now we’re giving the akkermansia the condition it requires to proliferate in the GI tract. 

And then the more the number is the more, the higher likelihood is that you’ll pick it up in the test. In a healthy gut microbiome, you can have upwards a 5% of your total microbiome as just akkermansia. 5%, that’s a huge amount when you look at. 120, 130 different species making up the whole population, giving 5% prevalence of one organism. And then on top of that, the other Keystone species, I talked about a lot Faecium bacterium protozoea can make up 5% as well. So just almost 10% of your entire microbiome, just these two species, that’s how important they are to maintain health wellness and all that. And we routinely see undetectable levels of these organisms in people’s tests. 

Now, if you start doing the steps that you need to do to start growing those organisms, so fasting, getting in the polyphenols, and particular really likes resistance starches and fiber, taking those in, getting better exposure outside, taking the spores. We saw that the bacillus spores, we published this study actually increases the Keystone species even without a dietary change. One of the things I really love about bacilli that is so unique to them, I haven’t seen this with any other genus of microbes is that they are regulators of the gut microbiome. So they can go into the gut microbiome and then they can actually figure out what’s growing at too high a level, what’s not there enough and then they’ll bring down overgrown problematic organisms, they’ll increase the growth of beneficial organisms. 

We actually have shown and published that when you add bacillus to your gut microbiome, it actually increases the diversity of the gut microbiome, independent of feeding. So it’s just that organism, that’s what it does. We’ve outsourced that job to bacillus because we can’t do it ourselves. Nature did not intend us or foresee that at some point we’d be putting concrete walls up between us and these bacilli that are outside in the natural environment. And so through the course of symbiosis and directed co-evolution, we developed this mechanism by which we’ve given them the job to maintain and regulate the microbiome while we give them a happy place to live, which is in the gut. So that’s why we’ve honed in on the bacillus so much in the probiotic space, because we find that the things that they do in the gut provides all kinds of universal benefit. 

So we’ve published studies on reducing triglycerides dramatically, reducing acne lesions dramatically, leaky gut, of course, inflammatory pathology. We have a study finishing on rheumatoid arthritis, all of those seemingly unrelated conditions, acne, triglycerides, rheumatoid arthritis, all on the same formulation. And the reason for that, it’s not that it’s some sort of magic pill and it does everything, it’s just that when you start to support the fundamentals of the gut microbiome, you start to see all of these benefits across the board.

Eric D. Gordon, M.D.

That’s amazing. And that’s the kind of information we all need because we’re struggling. No matter how hard we try, we do live in a concrete world except the few of us who are lucky to have gone back to nature, the rest of us live a pretty sterile environment compared to where we should be in. And it’s a amazing turn of events now. And I just hope that we all learn that it’s the interconnectedness, that’s important in everything. So I have to kind of wrap up, but I’m just, this has been an amazing in conversation and hope that we’ll come back again and go into more detail about what we can do and how we can supplement and support our internal environment. So thank you so much. It’s a pleasure. And just reminding people that it’s microbiome labs and BiomeFX I said is a test worth doing and working with your practitioner on that. You can just begin, it just one other window into what’s going on, remember that, don’t get hung up if it doesn’t look so good, it’s organic. It can grow and change.

Kiran Krishnan

It can, yeah. It’s an ecosystem so it’s all about the inputs. What you put it in, what you put in the system will affect the system dramatically. So this, the BiomeFX effects gives you an opportunity to understand what inputs are best for your microbiome. But yeah. Thank you so much. I appreciate the opportunity. It’s always great to be able to talk microbiome science and hopefully, somebody learn something from it and they’ll make a change and that change will improve their lives. So I appreciate that.

Eric D. Gordon, M.D.

No, it it’s working towards health and balance, as you say, resilience, ’cause that’s really what health is all about. So thank you again.

Kiran Krishnan

Thank you.

Eric D. Gordon, M.D.

Be well.