How the Gut Microbiome Influences Everything from Cancer Treatment to Inflammation

Coming up on this week's episode of the Doctor's Pharmacy.

Brand new studies in the last year or so have shown that depressed individuals have a depressive microbiome. Hey everyone, it's Dr. Mark.

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That's D-R-H-Y-M-A-N. And now, let's get back to this week's episode of the Doctor's Pharmacy. Hi, this is Lauren Fein, one of the producers of the Doctor's Pharmacy podcast. There has been an explosion of research and understanding about the importance of our gut microbiome. Yet despite regulating so many bodily functions and being critical to our overall and long-term health, conventional medicine has not integrated this knowledge into its teaching or practice. In today's episode, we feature four conversations from the Doctor's Pharmacy about the importance of the gut microbiome and why finding a practitioner who understands significance is vital to your health. Dr. Hyman speaks with Dr. Steven Gundry about why the microbiome is necessary to consider in treating every illness, with Dr. Mark Pimentel about how IBS can begin with food poisoning, with Dr. Uma Naidoo about the connection between gut health and mood, and with Dr. Zach Bush about the important elements of the microbiome and how to care for it.

Let's dive in. The average practitioner or even the exceptional practitioner out there, if they're trained in traditional medicine, is not paying attention to this at all. I mean, my daughter now is in medical school in Utah. I said, Rachel, what are you learning about the microbiome? She's like, nothing. Like, wow. I think, you know, my daughter in medical school has not learned anything about this. And it's unfortunate because it's key to being able to help so many people with everything from heart disease to cancer to diabetes. to Alzheimer's, to autoimmune disease, to allergies, to digestive problems, to depression, to anxiety, to ADD, to... I mean, the list goes on and on, right? So can you talk about how you came to understand this and also how our gut microbiome is directly linked to our health and longevity? Like what's going on?

Holy cow, where do we start? Yeah, no, but let me continue on what you just said. I have the privilege of seeing third-year family practice residents rotate through my clinic for a month at a time. And they're, you know, about to go into practice. This is their final year. And just probably won't surprise you, but it might surprise our listeners that not one of these individuals have ever heard of ordering a fasting insulin level.

Oh, my God. I know that's how. Don't get me started on that.

That.

No, none of them have ever of, you know, HOMA-IR, which is a way of looking at insulin resistance.

Yeah.

And they go, well, what does that have to do with anything? I go, well, so you're right. I mean, one would have hoped, you know, you and I, we didn't know about this. You know, we thought that the GI tract was a hollow tube and crud went in and some digestive enzymes happened and whatever was left, we pooped out. And that was the end of the story. But the human microbiome project, which we really just completed in 2017, opened our eyes to this incredible tropical rainforest of 100 trillion different bacteria that we just didn't even know were there. And so what that's been able to do is, okay, now we know they're there.

There's like 100,000 petabytes of data in our microbiome, like that's doing stuff all the time.

And, you know, I argued in one of my previous books that what I think we've done since they have so many more genes than we do, and that genetic information is constantly being modified by viral genomes being inserted and cross filtering of genes between bacteria that I proposed that we've actually done most of our computing. We've loaded it into our cloud computer or our brown computer. And the more we see the influence that these guys have on everything that's going to happen to us, the more you realize what an amazing, elegant design and what a brilliant idea to outsource most of our computing power to this tropical rainforest within us.

Yeah.

And this is not that new of idea, you know.

Dennis Burkitt, which you learned about Burkitt's lymphoma in medical school, he was a British scientist and he went to Africa on a missionary trip and he noticed, you know, all the villagers and the traditional tribal populations had no chronic disease. They were really healthy. And as soon as their cousins essentially moved into the city, they would get all the Western diseases. and for some reason, I don't know how he got this idea, but he decided to study their poop. And he basically found that the urban dwellers had stool weight of four ounces, and the hunter-gatherers and travel people had stool weights of two pounds. And I just came back from Africa, you know, and saw the elephant poop. It's like, it's like, it looks like a basketball, you know, like one little piece of it. And then they have huge amounts of fiber. And I saw, you know, the Hadza population. which is the one of the last 100 gather populations on the planet. Now, they have 20, up to 20 of their diet as honey, which is all you think, oh, that's bad, you know, sugar. But the other thing they do is, is their Hunter and gatherer. So they gather a lot of tubers, these roots. And these root vegetables are, I don't know if you can call them, what you can call them, more like, more like chewing on wood. But they basically, they basically dug one up and they dug up this wild yam, and they eat about 150 grams of fiber a day. and that it mitigates any of the harm from the, the honey that they're getting. And they, and they actually are, are, don't have these chronic Western diseases. So I think in our society, we've just done such a disservice. We saw the same thing in this study years ago about burkina, a south, like these kids who are eating Western diets versus, you know, these traditional diets in burkina, a south. And they, they had profoundly different microbiomes, profoundly different health outcomes, no allergies, no autoimmune disease, none of the stuff we see here. So it's so intimately tied to our microbiome and yet it's shocking to me that in traditional medicine, we, even though we sort of now acknowledge it, there's no roadmap to do anything about it. And that's why gut check is such a great roadmap, because it provides people an understanding of what's going on, why it's a problem, and actually what to do about it. There's some really fascinating research around some of these polyphenols called Elijah tannins that are in foods called pomegranates that we can eat or walnuts, berries, and, and what, you know, you, you have this great term called gut buddies. Like, literally these gut buddies is that a good guys living in there. The problem is we don't have that many friends anymore. We don't have any good buddies left or maybe very few good buddies left in our gut microbiome. So when you don't have these, it can have serious health consequences. And you talk about this particular symbiotic relation between some of the foods we eat, our microbiome and compounds they produce, something we call postbiotics. I just did a podcast with Uma and I do, and she was talking about psychobiotics. Yeah. Not crazy bacteria, but bacteria that act like psychiatric drugs to modulate mood, which I thought was great. But this whole concept of prebiotics and probiotics, people understand fibers, prebiotics and probiotics are like taking lactobacillus. But then there's these postbiotics, which are things that made by your bacteria from eating certain foods that are molecules that then you absorb and regulate your biology in ways that have profound impacts on your health. So one of those metabolites is called Urolithin A, and I've talked a little bit about the, on the podcast, but this is such a great story because it illustrates it well and it's so much research around it. So it's one of the most researched factors around this whole post-biotic phenomena. So can you explain, you know, the, the data around this, this, this phenomena of ureidin A on super centenarians and their microbiome versus people who don't have this, this microbiome that actually can metabolize these phytochemicals. And so basically you can eat pomegranate all day long, but you're not going to make ureidin A, right?

Right.

Like 20% of the general population is, is able to do this. That means 80% of us aren't. But in the super centenarians, a lot more have this microbiome that actually makes your L-thyrosine. So, can you explain this whole interaction between our L-thyrosine content in our diet and the bacteria that are regulating it and this metabolite that it creates for your L-thyrosine and what that does and how it relates to our health in general, our mitochondria and mitochondrial uncoupling that you talked about?

Yeah, I wanna. Maybe it's a. It's a bad.

I mean, that was a lot, but I just. It's, like, really important. And I think. I think it's such a beautiful story because it illustrates this phenomena so clearly for people and why it's important to take care of your gut buddies and invite more good gut buddies in there. Yeah.

You know, I hate to use the expression, but it takes a village. And what we're learning and what I want people to understand from gut check. is we used to think, okay, you need prebiotic fiber and your gut buddies will take prebiotic fiber and they'll make postbiotics. And by the way, gas transmitters are postbiotics. And that's a good thing. But what we now know is you may have to have four or five guys each doing one job, almost like an assembly line. and if the first guy doesn't make the next product, the second guy can't make what he needs. And it may need four or five different bacteria to get the end product. So let's take, for example, urolithin A. We know that the precursor is in pomegranates, in walnuts, in raspberries, but that you're right, only about 14 to 20% of individuals, you could give them all of these precursors. They will never make urolithin A. And so you then look at super old people, and at least 50% of them make urolithin A. It could be as high as 70%. So we now understand that there are multiple guys that are involved in making this compound. and if you don't have those multiple guys, you could eat all the pomegranates in the world, but you'll never come up with this compound. So what's so cool about this compound is, and this is work out of Switzerland. I've, I've had the folks from Amazonian.

Yeah.

On my podcast several times because I'm so impressed with what they've done. So this stuff is actually makes mitophagy, makes mitogenesis. It actually, and I off camera with them. I'm pretty convinced it's because of mitochondrial uncoupling. And they have a recent paper that shows it has some really cool anti-cancer properties as well. And I'll argue it's because of mitochondrial uncoupling. But it's fascinating that these super old people have this set of gut bacteria that are able to accomplish this job. Another, I think, really beautiful study that came out of Stanford with the husband and wife team, the Sonnenbergs, about the importance of understanding that it's more than just, say, prebiotics as a part of this. They gave individuals prebiotic fiber and they looked at their gut microbiome diversity and they looked at their markers of inflammation, which was hs-CRP, C-reactive protein. They took a second group and gave them the same Prebiotic fiber, but they also gave them fermented foods. It was primarily yogurts and vinegars. And lo and behold, the group that only got the Prebiotic fiber had no change in gut diversity and no change in inflammatory markers. It was the group that got the fermented foods plus the fiber. that had a change in the gut microbiome diversity and lowered their inflammation. And again, it's this conversation. It's this communication that makes the difference.

Was it because of the fermented foods that had bacteria in them and the probiotics in them? Was that the reason? Or was it because of the polyphenols in, in those?

It's even better than that. I've got a whole chapter in gut check. that dead men tell no tales, but dead bacteria do. And it turns out that there's folks don't eat your yogurt to have active yogurt cultures. Most of those probiotics will be killed by your stomach acid. But it's the dead bacteria cell wall, and it's the post biotics that are made during fermentation that is what you're actually looking for. And we now know that these compounds carry messages that are read by other bacteria. And that one of the things that was interesting in Akkermansia research is that dead Akkermansia have much the same effect as live.

Yeah. Really? Yeah.

And it's like, what? Well, I have three male dogs, and they're.

I'm not gonna ask why, but.

Well, they're rescues, but that's okay.

They.

They're out sniffing at everything, and they're putting urine on anything they can. And you go, what? My dog on. What are they smelling? I don't smell anything. Well, they're getting messages.

They're.

That the other dogs have left for them. And we now know that bacteria leave messages that other bacteria read. And it's those messages that are necessary to tell the other bacteria what to do with that prebiotic.

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And they found that it increases without exercise, this is crazy, without exercise increases muscle endurance, muscle strength, increases your fitness level measured by VO2 max, which is like what you usually have to do wind sprints to fix. It increases ATP production, it reduces C-reactive protein, improves your overall metabolic profile, meaning your insulin resistance. It reduces muscle loss. It stimulates mitophagy or cleaning up the old mitochondria, improves mitochondrial gene expression. It inhibits something called mTOR, which we've talked a lot about on the podcast, which is important for longevity. It basically crosses autophagy or cleaning of your cells. It upregulates SIRT1, which we'll talk about in a minute, which is a really important set of transcription factors that is involved in longevity and insulin resistance and DNA repair. So basically helps all the things with aging. It even improves your immunity by improving stem cell regeneration for T cells. T cells. And it has anti-tumor activity. So I'm like, whoa, wait a minute. you were talking about eating a pomegranate, having some bug in your gut, and having all these downstream effects. And just to be clear, everybody, we're talking about one food and one compound. We're talking about not all of the other things that are going on in your gut with trillions and trillions, probably 40 trillion bacteria in your gut, and 2 to 3 million bacterial genes doing all kinds of stuff. But that's, that's a hundred times as much genetic material as we have. And what, what genes do is produce protein. So that means they're producing all these molecules. And I was sort of on a panel with Stan Hazen at Cleveland Clinic, and, and he was like, yeah, I said, Stan, how much of the, of the metabolome comes from our microbiome? Meaning how much of the things that we can measure in our blood, not we get on a regular lab test, but when you do these scientific studies, comes from the microbiome. Probably a third to a half. And I'm like, what? A third to a half. So we literally are kind of in this constant dance with our gut. And this is why your book is so critical, this gut check book, because it helps us to really understand on a granular level the science of why. So we go like, oh yeah, okay, I get take probiotics, whatever, you know, take prebiotics, whatever. But you actually give us the science of why. So that's the urolithin story. Let's talk about resveratrol and SIRT1, which is this really important transcription factors that are in the mitochondria that are actually were first discovered by Lenny Guertin at MIT and David Sinclair and the whole resveratrol story. But people don't realize you had to drink about 750 bottles of wine to get the amount of resveratrol they did in this time. Yeah. You're talking about- Work, work, work, work. I don't know, I could drink that much wine and you'd die.

You'd die.

But basically it has been shown to help with cardiovascular disease, but also maybe impacting the brain and metabolism maybe even more than the heart. So how can this resveratrol compound that comes from grapes, and by the way, I don't think we can get it from red wine. I think that's going to cause problems. And you talk about it in your book. I'm like, don't drink so much. So, we can get into a long gall story there, but I think the key is the phytochemical. So talk about how resveratrol can be used to help or treat and prevent neurogenerative and metabolic diseases and how it relates to the gut microbiome?

Well, again, I think resveratrol is a very poorly absorbed compound. And again, we've known that for years. And so, and David Sinclair is a friend, and we've through the years talked about his love of resveratrol and mine, and he loves pharmacologic doses of it. but what's really cool about resveratrol is it is a, it's a signaling molecule, and it literally activates Serd1, and it's a really good way to come full circle of uncoupling mitochondria as well. But it, it literally tell, it tells, it repairs DNA breaks. It actually Fosters the production of short chain fatty acids like butyrate. And the more we look at the downstream effects of resveratrol activated by the microbiome, we're beginning to see, okay, well, why is it that, you know, the French paradox works? And, you know, it's just, it's, we've, the middle guy that allows resveratrol to work is the microbiome making it an absorbable compound. And that's what we, none of us knew until really, the microbiome project got finished.

Amazing. It's, it's quite amazing. I mean, I think the, the other thing that, you know, I want to dive into, because, I mean, we could talk for hours, and I don't, unfortunately, we both have work to do. That's right. Other, we have other jobs. patients and all that. But, but I think, you know, the other issue is sort of the microbiome in the brain and mood. And, and you, you talk about a, you know, major depression is a big issue, and depression is the biggest cause of disability in this country. And, and how the microbiome of people who are depressed is different. And in, in 2022, there was a study of microbombs of over a thousand people with depression, and they found changes in about 13 bacteria. And, and these bacteria are known to produce various neurotransmitters. So can you kind of unpack that for us and just give us a little taste of the, the mood, brain, gut, microbiome connection.

Yeah, I guess, you know, I, I suppose we should have known this, but again, now that we're being able to look at individual bacteria and the compounds that they produce, you're right. Brand new studies in the last year or so have shown that depressed individuals have a depressive microbiome and you can constitute these particular abnormal species. What's really interesting is let me step back one. We've known that glyphosate, which is a lovely weed killer, was actually patented as an antibiotic. And one of the recent findings about glyphosate is that glyphate Glyphosate targets the tryptophan pathway bacteria in our gut. Now, why should that be interesting is because tryptophan makes 5 HDP, makes serotonin, which and GABA for that matter. And so glyphosate is really good at knocking out all the feel good bacterias specifically in our gut. and isn't it interesting that this epidemic of depression and anxiety correlates pretty doggone good with the advent of glyphosate? And yeah, and now we know, we can say, oh, well, glyphosate is bad for you, but wait a minute, glyphosate is after the bacteria that are essential for our mood. I think that's so case even.

Yeah.

It's like, what have we done? Yeah.

Yeah, it's true.

It's the unintentional side effects that happen from things we think we're trying to do good. Oh, weed killer, great herbicide, we need it, blah, blah, blah. But, but these, this, this, you know, people say, oh, glyphosate, cancer, this and that, maybe. Okay. There's been some, you know, lawsuits that have been successful around non-Hodgkin's and Plomin. I guess if you douse yourself in it. But what's really striking me about glyphosate in really small amounts, it wipes out your microbiome. It doesn't take a lot. It's not like you have to drink Roundup in order to actually mess yourself up. It literally is in small amounts. And, that has led to maybe an increasing epidemic of low microbial diversity that we're seeing and an increase of all these chronic diseases including psychiatric disorders which could be really from this sort of altered microbiome in part from glyphosate. I mean, there's a million other reasons. Obviously, xenobiotics and other toxins and other things that are really, really important. you know, the, the, the thing I want to sort of dive into a little bit more is, is cancer, because people don't think about cancer and your microbiome. But there was a, Charles Ang, who's a, was the head of the genomics research center at Cleveland Clinic. When I got there, she was so happy to see me. She said, what took you so long to get here? And I'm like, well, I don't know. I didn't, I didn't want, I didn't really want to go to Cleveland Clinic, but they dragged me over there. and, and she has told me about all her research on the microbiome and breast cancer. It's like fascinating. And they were really, then this is like, you know, some Russian lab, you know, trying to do some research. This is like Cleveland Clinic. And they're, they're digging into this. Stan Hazen, you know, is digging into the microbiome and heart disease. And, and so can you talk about how the microbiome determines not only a risk of cancer, but also how we respond to certain immunotherapy drugs that are now basically some of the best drugs we have against cancer. But if your microbiome is not right, the drugs don't work.

Right.

Yeah.

You know, a number of years ago now, there was a, there's a paper, and I'm sure you're aware of, that looked at the tongue scrapings of people with pancreatic cancer and the oral microbiome, and there was a very strong correlation between the oral microbiome and predicting pancreatic cancer. And people go, wow, this is great. Now we'll have a diagnostic test, and we'll just scrape people's tongues, and we'll know who's at risk for pancreatic cancer. And then people went, wait a minute. What does that have to do with cancer? Well, now, of course. And now, of course, we go, wow. There is, like I talk about in the book, there is a colon cancer microbiome, there's an ovarian cancer microbiome, there's a breast cancer microbiome, there's a pancreatic cancer microbiome, there's a lung cancer microbiome that is distinct to those cancers. And the question is, did they cause the cancer? Are they facilitating the cancer? And that answer is not there yet. But like you mentioned, we know that certain patients are going to respond better to chemotherapy if we actually do targeted antibiotics to change the microbiome. And other people aren't gonna, and it's this whole personalized medicine, but we're now going holy cow, why didn't we realize that there is this microbial component to cancer? And again, I'm not saying cause and effect, but they're there and we certainly owe it to ourselves to figure out, well, okay, what part are they playing in this?

Yeah, this story is definitely being unpacked. We're not quite there yet, but our friend Will Lee talked about his mother who had stage four uterine cancer. did her microbiome test and found low Akkermansia or no Akkermansia. And he then did some research and showed that, geez, people did not respond to these checkpoint inhibitors in immunotherapy, which are great advancing cancer, if they didn't have Akkermansia. It's like, wait a minute, how come this powerful drug doesn't work if you don't have this one little lowly bacteria? But literally we are, we are just uncovering how powerful these microbes are in regulating so many aspects of our health or response to therapies. And I think he was able to give her these polyphenols that we talked about and boost her acromania. And, she got the immunotherapy again and was cured of stage 4 cancer.

It worked.

Yeah. So, think about that. A probiotic or polyphenols curing stage 4 cancer in conjunction with a drug that wasn't working before. That's kind of radical.

Yeah, and you brought one other thing which is actually a good segue. You brought up xenobiotics. And so, xenobiotics are all these environmental toxins, these endocrine disruptors, plastics, petrochemical products.

BPA, PCBs, PFAS, everything. All the- Phthalates. Phthalates, all the crap.

All this awful stuff.

Yeah.

When you write about this in the book, when you look at these super old people's microbiomes, you know, 95 and above and they're thriving. They have a microbiome that eats xenobiotics.

Oh, wow.

Yeah. And you go, well, son of a gun. And they go, and people go, well, wait a minute. Xenobiotics. Look, you can engineer bacteria that eat oil spills, for goodness sakes. They just want it.

That's right.

They're just looking for carbon atoms. That's right.

That's right. So, yeah.

And one of the Hallmarks of these guys, besides the fact that they make urolithin A, is that their microbiome eats xenobiotics. And it's like, well, of course.

Now, do we know which microbes do that? And where can I, where can I buy some? Yeah. Or what do I need to eat to grow them? Do we know?

Well, you see, that's what's really kind of fun about all this.

Because I never heard this before. And I think I just, the reason I say it's important is because we're, we, we, they're doing their best. We still can't eliminate our exposure to these compounds. everywhere and they're in us. And so, so if we have, if we can take some kind of probiotic to offset the harm from the xenobiotics, I want that.

We now believe that food poisoning starts the whole process. So you and eating is part of it. You know, back in the day, meaning like 40, 50 years ago, when we were in kindergarten, we would sit in a sandbox and eat the sand. Now we eat salad out of a bag until we go to club med. And for the first time in our life, we see salmonella. or we go somewhere and we get traveler's diarrhea, or we get food poisoning or whatever, we start to explore the world of food. But food poisoning triggers this. And we now have identified the toxin in food poisoning, the CDTB toxin, that trips off some antibodies in the human body that then cause your nerves of the gut to fail or to be impaired. And so when the flow of the gut is slowed by this impairment, bacteria build up. And there's two bacteria that just flourish when it's a little more swampy. So, I used to watch Survivor shows on TV and Discovery Channel, you probably watch those. And they always say, They're like from loss.

I used to watch loss, which is kind of like Survivor.

It's a little bit different. There's a little more raunchiness. With Survivor, you're just kind of trying to make it to a road somewhere. But the point was that he always, this guy on the Survivor Show, would always say, if the water's not moving, don't drink it. If the water's flowing fast, drink it because it's cleaner. And the same thing with the small bowel. If the small bowel stagnates, it becomes swampy and bacteria grow in it. And the same thing is happening in the human small intestine. And so it's a sequence. So food poisoning, the antibodies, and then you develop the bacterial buildup.

So, you're almost saying it's like an autoimmune disease of the nerves of the gut that develops that kind of sluggish. So, this is a kind of a radical idea that irritable bowel is an autoimmune disease, isn't it? I mean, this is kind of not what most doctors typically think of when they think of IBS. They think of IBD or inflammatory bowel.

Disease, but they don't think of, you know, irritable bowel being autoimmune. But, the interesting thing about contrasting IBD, to IBS. So the antibody that we discovered is an autoantibody that is directly related to the pathology. So the higher that antibody is, the sicker you are. The antibodies in IBD are markers of IBD. They're not directly implicated in the pathophysiology. The antibody to vinculin that we discovered is directly related to the pathophysiology. We can make rats have IBS just by giving them this toxin. and so that that's very cool because it allows us to study new drugs and new therapies coming in.

Not so cool for the rats though. So this is fascinating. So you were saying there are different kinds of bacteria. Can you explain, you know, what are the kinds of bacteria? And then, and then what type of food poisoning is it any, like if you get Giardia or if you get Salmonella, Shigella, Campylobacter or and amoeba or like, you know, what are the kinds that typically cause the problem?

Well, the four horsemen of the apocalypse of IBS are Campylobacter, Salmonella, Shigella, and some E. Coli, food poisoning type of E. Coli, pathogenic E. Coli. Giardia can do it too. It turns out it has vinculin in its structure and so maybe that's how you get the antibodies from Giardia. The viruses are less likely to precipitate IBS. So, the four horsemen, Campylobacter jejuni, Shigella, and E. Coli. It starts to occur about three months after you get sick. Patients will remember. Some don't remember, and they'll say, they have a couple of days of diarrhea and they don't pay much attention to it, but they remember going on a trip to Hawaii and they end up in the hospital with bloody diarrhea. And then ever since then, nothing's been the same.

I have heard that story so many times. I went to Thailand or India or, you know, Jamaica and, like, sort of trip the whole thing going.

Yeah. Or the taco truck in Venice.

Yeah.

So a lot of possibilities.

Wow. So. So this explains, like, sort of 60, you say, but, you know, not all of it.

Right.

What are the other things that may be driving irritable bowel syndrome? And are they also related to SIBO or is it, is it all. Something else?

Well, so based on culturing the bowel, we've been able to isolate that 60% of IBS is SIBO. The other 40% is a mixed bag. So, for example, and you probably talk about this now, Ehlers-Danlos syndrome, POTS syndrome, we're starting to recognize those illnesses as characteristically GI-centric, at least in their early presentations as well. so some of the leftover 40% have Ehlers-Danlos syndrome or POTS or some of them are celiac that we've missed. Some of them are food sensitivities, some of them are histamine sensitivity, some of them, so it's a mixed bag of a number of other disorders. And some of them are fungal overgrowth. So we see that in about 6 to 10% of that 100 pie. So there's still more to unpack. We're not ignoring the other 40. We're trying to figure the rest out. but it's a little bit harder to unravel.

So, let's pause there for a minute because you just said something that I think might slip by, which is this whole idea of fungal overgrowth or what often is referred to as C-FO, small intestinal fungal overgrowth. And, in my coming of age as a functional medicine doctor, basically people would laugh when we talked about yeast overgrowth or anything like that and candidiasis, and it was just like a quacky alternative concept, but it seems to be now understood as potentially playing a role in some of these cases. Can you talk about the current understanding of this and actually some of the treatment? And then, I'll sort of loop back to the how do we start to treat and think about IBS differently?

Yeah, I mean, Satish Rao, Dr. Satish Rao in Georgia has done a lot of the seminal work in this, but more recently we've done shotgun sequencing of the small intestine and we've been seeing this fungal overgrowth.

That doesn't mean you shoot somebody in the got with a shotgun.

Shotgun sequencing means we sequence every single piece of DNA we can find and then characterize it and see what organisms it represents.

Yeah.

And it represents fungus about 10% of the time. And that when the fungus is higher, the patients are experiencing more abdominal pain and more diarrhea. So there is a subclass of these patients that it is fungal, but it's smaller than some would like to believe. but larger than those who are naysayers, as you've probably heard. And so it is there, it's real, but it's a little more challenging to identify. There's no breath test for it, you got to go in and chase it, and that's the challenge.

Chase it by doing stool cultures or...

Well, chase it, it could be by stool, but if you want to find small intestinal fungal overgrowth, you got to get into the small intestine and that's really...

Sample it.

You have to have endoscopy and all that. That's how Dr. Rao identifies it.

Yeah. And any particular species of fungus or is it sort of a broad array?

So, what we found in this, quote, shotgun sequencing is Candida albicans is a big part and a little bit of Candida glabrata. And, there's a few other Malassezia and all these other organisms that are very minor, but they generally aren't at a high number that we think are as consequential as the first two I mentioned.

Yeah, no, I definitely have seen that on cultures. And, you know, in my experience, maybe it's not Universal, but it tends to lead to more constipation. And so people tend to have more constipation. And also, I can tell because they might have other fungal symptoms. They might, you know, eat tons of sugar and starch. They might actually have fungal rashes on their skin or dandruff or other kind of Clues that they have kind of a yeasty kind of situation going on. But I, I think it's important that it's been identified and going back to kind of the treatment of that, how, how would that normally be treated?

Well, yeah, generally in allopathic medicine, we try an antifungal. There are natural antifungals as well, and I, you're probably better versed in those than I am, but we, we do use fluconazole. We do use nystatin. Occasionally we use more radical, more advanced antifungals, but, but those are the typical first two choices.

Yeah. Sometimes you can take what we used to call amphoterrable, which is a horrible first generation antifungal, but it's not absorbed. So if you take it orally, to absorb and that can totally be effective. Yeah. Oh, yeah. You know, and then, and in terms of the bacterial stuff, you know, you talked about these three different bacteria, right? You've got methane producing, hydrogen producing, sulfide producing, and they all are a little bit different. And, you know, said the methane producers are not really bacteria. They're archaea, but, you know, for, you know, simplicity's sake, let's call them bacteria. And, and I don't, I don't think most people know what our case is. It's Arcane, right? So, yeah. So, what is your approach to starting to kind of differentiate these and then how do you determine what the right treatment is for a patient and can kind of guide us through what to do both in terms of, you know, lifestyle, diet, and any kind of supplements that might be helpful and medication?

Yeah.

So, first of all, we helped develop the first three gas breath tests, so just full disclosure. But it's changed my practice because there are patients who fell through the cracks without knowing hydrogen sulfide. So unpacking each, the hydrogen positive breath test patients are generally, we actually just published this paper, it came out literally yesterday, there are two bugs, that's it, that caused the hydrogen overgrowth. It's Escherichia coli, the non-pathogenic one, and Klebsiella pneumoniae. Those two characters, when they come into town, everybody leaves because they're so opportunistic and bullies. And we think they produce even toxins to the other bacteria around them to try and get rid of the inhabitants. So it's like you've got a gang that comes into the small town and everybody leaves. So it's a disruptor of the microbiome and then they rise very high in number. so that's the hydrogen one. The second category is the methane or methanogens and those characters live both in the colon and the small bowel and we have a paper coming out showing exactly where they're living and it's pretty universal in a lot of these patients. So hence we call it intestinal methanogen overgrowth and not SIBO methane because it's not just the small bowel, it's colon also. And when they produce methane, It gives you a lot of constipation, a lot of gas, and you can't pass the gas, and these people are quite miserable. And then the third is the hydrogen sulfide, which is the new kid on the block, which has changed my practice because some of those patients, we didn't know. Breath test is normal, everything looks fine, and then the hydrogen sulfide is positive. We get rid of it, and all of a sudden they feel better than they have in their life. And for some reason, when you get rid of hydrogen sulfide, it doesn't come back so quickly, which is beautiful. I have patients who've gone a year, just one treatment, and they're done. And so, I'm really excited about that. So, I mean, I could talk about.

The treatments if you like now or-- yeah, yeah, yeah. Go through the treatments because they're real different. And, this is important to understand for people because just because you have a real bowel, it's not like a one-size-fits-all approach. You've got to differentiate what type it is. And, these tests that Dr. Pimentel developed, the tests for anti-CdTB and anti Viculin antibodies are really important. And then, the breath test that allows you to look at hydrazine, methane, and sulfur. So, can you talk about what are the different treatments for each of these?

Yeah.

So, I mean, if I have an IBS patient with diarrhea or a patient with diarrhea and bloating, my practice now I do the antibodies because I want to be able to say was it food poisoning or not? And, if the antibodies are really high, it makes it harder to treat. But, also, you travel. you better take prophylaxis because you could get into further trouble with these antibodies going higher. So, I universally do that.

Dr. Like prophylaxis like what?

Like Zifagen? I give Zifagen prophylaxis. That's what I do in my practice and a lot of the GIs now do that because if the antibody goes higher, the damage to the nerves of the gut is more intense or the effect on the gut is more intense and at least that's what we're seeing in our clinic. So, we're very careful with those patients who have the antibodies positive. When it comes to then we do the three gas breath test in all of our patients. And if it's hydrogen, and we all know Rifaximin got FDA approved for IBS with diarrhea, on the basis that IBS was in part a microbiome disease and now we understand that microbiome condition is SIBO. So I give Rifaximin for that. If it's methane, we have one double-blind study that we can lean on and it's rifaximin plus either neomycin, which is what the double-blind study covered, or rifaximin and metronidazole. And then the third category is hydrogen sulfide. And we give rifaximin, but we give it with bismuth, because bismuth is an anti, it blocks some of the synthetic functions of hydrogen sulfide in the sulfate reducing bacteria. Point is the hydrogen sulfide goes down, the bacteria are reduced and therefore the patient's normal bacteria take over and things get better more permanently in that group at least looks like.

And that's basically Pepto-Bismol and yeah, yeah. Interesting. So in terms of diet, is there a different approach to each of these in terms of what you would recommend from a food perspective?

We haven't sorted out and or had time to sort out the different diet approaches, but I envision smarter people in the diet will come up with a way. What we do now is what we call low fermentation eating. We don't use low FODMAP in our practice because you can't do it indefinitely. But low FODMAP will reduce the amount of calories you're providing to bacteria and therefore they'll ferment less and that might help. But long-term low FODMAP hurts your microbiome and can cause nutritional deficiencies. so you can't stay on the full FODMAP indefinitely.

And FODMAP is like fermentable oligo, saccharides.

That- yeah, fermentable oligosaccharides, monosaccharides, et cetera. And basically it's too restrictive. But you probably, most people have probably read about FODMAP diet. It's very popular in the last few years. But we use what's called low fermentation eating, not as restrictive. and the philosophy of that was with a low fermentation diet, you can go to any restaurant in the country and you'd find a meal. So it's, you know, you don't want to be the person at the table just because you have IBS that spends 10 minutes with the, with the, you know, 10 minutes trying to explain your dietary restrictions on a low fodmap diet. So, you know, that, that's part of the reason we want our IBS patients to feel as normal. and as socially non-isolated as possible. And, and that's part of it.

What is a low fermentation diet?

So it's basically restricting non-digestible carbohydrates. So low fiber, no dairy, and then none of the artificial sweeteners because, of course, they're easily fermentable, and then spacing your meals. So you don't eat for five hours between meals because the damage of the nerves, we talked about that earlier, the damage to the nerves causes a reduction in cleaning waves of the gut. So the cleaning waves only occur when you're not eating. So your gut is sort of like got two computer programs, eating mode, cleaning mode. If all you do all day is spend time in the break room taking a bite of a bagel that's in the break room, you never go into cleaning mode. So so in addition to the construct of what to eat, we tell you when to eat and to try and space your meals up.

So anyway, it's interesting. You know, the typical dietary recommendation when I was in medical school for IBS was more fiber, like Metamucil, basically. What you're saying is that you want to restrict soluble fibers that are digestible. And that, and low, low fiber diets seem to be kind, you know, it seems like a contrary notion when you want to create a healthy microbiome because good bugs also live on fiber. So how do you, how can you navigate that?

Well, you know, I may be punished for saying something like this, but everything has fiber in it now. Even Cheerios, they put fiber in it because it prevents colon cancer and it's colon health and all this stuff for 20 years. How many, how much have we heard about colon health? And what have we, what have we got now? We've got colon cancer happening in the 40s and we're doing screening colonoscopy at 45 now. I'm not saying it's fiber causing that, but all the fiber we've been pounding and the cardboard we've been eating hasn't really done as much as we thought it might. So I'm a little unclear about fiber. But from the point of view of bacteria, you put more fiber, you're gonna have more of the bacteria. If you had bad bacteria to begin with, there's gonna be more of them. For a healthy person whose microbiome is healthy, no problem. But not for these patients with these microbial conditions.

Now, if you've gotten these antibiotic treatments, you've gotten diagnosed, you've gone through the testing, you've gotten the personalized treatment, you do the course of antibiotics. What prevents the bacteria from coming back? And in my experience, it often does. So how do we manage the sort of recurrence that occurs? Because you don't want to keep giving people antibiotics because intuitively people go, Wait a minute, antibiotics are bad for the gut.

So why are we giving antibiotics to someone who's got a gut problem? Seems counterintuitive. Well, I can answer that in two or three ways, but I'll try to touch on a little bit of each. we looked at rifaximin before and after treatment, the small bowel. And when you get rid of the bullies in the town, all the inhabitants of the town come back. So it goes opposite of what people think. We're not, you know, being cataclysmic. It's getting rid of the E. Coli and the Klebsiella in SIBO that allows the regular bacteria to re-flourish, repopulate and take over again for a period of time. But remember, the problem is those cleaning waves are working. So it is possibly going to come back. It depends how badly damaged. And that's where that antibody comes in, because if the anti-vinculin, which is that auto antibody for the autoimmune disease of IBS, is very high, the neuropathy is more high or more intense, and you're going to relapse or reoccur more frequently. So that's where we were able to have some further strategy. But first of all, take the antibiotics. They actually repopulate the town counter to what you think. We've never seen antibiotic resistance to rifaximin so far. Knock on wood. It's a very unique chemical drug. And then we get them on the low fermentation eating diet. That's what we do. And for those where the antibodies high or those who relapse, we do put them on a prokinetic. So they space their meals, everything's going right, but we want to stimulate those cleaning waves at nighttime because that's the longest time you're not eating. and make you clean up as much as possible at night so that the bacteria don't have a chance to come back. So we don't do all three things for everybody. It depends on, you know, if somebody relapses in two years, we don't need to put them on a drug every day to prevent. But if they relapse every three months, then we can stretch it out to a year by adding the prokinetic or doing more aggressive diet strategies.

So this is something that's a chronic condition that has to be kind of re continually retreated in some ways? Is that what you're saying?

That's right. It's sort of that way for now, but that's the point of the antibody. If the antibody is causative, get rid of the antibody, get rid of the disease. So the focus of our lab right now is get rid of that antibody.

More and more, as I've studied the microbiome and the gut-brain connection, I've moved from more general, when I first started my clinic, for more generalized suggestions based on, you know, someone's individually telling me what their diet is and essentially what they're doing to a very highly personalized plan. And some of that is based on some fascinating research that has come up around things like yo-yo dieting that he's shown that in some animal studies that, and the science was very nicely done, that there's almost a, there's almost, for one of a better word, like a memory in mice that were overweight that was recorded in the microbiome. So it has taught me that each person is so different and that I have to think about them more in terms of what they're eating, what their symptoms are, what their makeup might be. And so I, you know, first obtain a proper history, ask them what they think they should be eating and what they are eating. eating. And often in that history taking, I'll uncover something that is a startling, most often something startling that they didn't realize. And I've talked about some of those examples in the book where they may be eating something that they perceive to be somewhat healthy, part of a diet, part of a cultural diet, whatever it is, and they actually either packing in sugar that they didn't know about, something that is obviously driving the gut in the wrong direction or driving sporiasis.

And then what's an example of that?

Sure. So for example, I had, and I speak about her in the book, I had a patient who was pregnant and had a healthy pregnancy and was eating a lot of her favorite spice, which is a Korean spice called gochujang. But when you get the store-bought version, there's a very high, some of those preservatives, but there's a high sugar level in that. And she was just adding this to her healthy foods, her vegetables and her lean proteins and stuff, but she was consuming a larger amount of it because she sort of was craving it during the pregnancy. And so some of what we had to do is really peel back on that and figure out other ways we could do that. Either we created a sauce that, you know, worked on a little recipe that would give her the flavors for that. but take away the unhealthy ingredients. So, you know, it's sometimes it's little things like that.

All right, so talk about how specifically the studies recently have shown that diet can have a profound impact on our mental health, things like ADD, depression, anxiety, sleep issues, dementia, OCD. I mean, we don't think of, for example, OCD is being diet related or ADD is being diet related, but how are these linkages being discovered in the science? because I've been witnessing them for decades as a clinician and waiting for the science to catch up and it's kind of catching up. So what have you found? You're at the Harvard Medical School. This is not some fringe idea. This is now mainstream. So talk about what these studies show and how we can learn about how these things are all connected.

Sure. So, you know, the basis of how I describe a lot of it is around the gut microbiome. and how, and I'm sure your audience is very familiar with just how information gets formed and things like that. The way that it works with examples of things like anxiety, and I will speak about that because it's one thing my clients are coming in most commonly with right now, the uncertainty, the fear, loss of jobs, quarantine, you know, restrictions changing, going back the next day is really creating an immense amount of anxiety. And what the studies have shown is that there's certain things that, so the way that I look at it is the things that you, in terms of food that you need to embrace and the things that you need to avoid. And the things that seem to worsen anxiety include things, foods with gluten in them. And it's not necessarily people who have celiac disease or celiac glucose sensitivity, but there seems to be a correlation in the studies around the level of anxiety and eating and consuming gluten.

So.

Things that are positive are the use of things like turmeric with black pepper.

What makes the gluten become a problem? What is the mechanism? Has anybody figured that out?

I think that from what the studies have shown, that it's that there's some sort of disruption that occurs in the microbiome that leads to dysbiosis in individuals who have anxiety. So I've had patients who can tolerate gluten, but if I were to give a general recommendation to someone based on what we've learned, we try to have them avoid it. With the turmeric and black pepper, we know that curcumin and turmeric is activated by the piperine in black pepper and it actually increases the absorption by a significant percent. And a study also showed that where Omega-3s are involved that can enhance the absorption. So this combination and the work that's been done on Omega-3s in both anxiety and depression, for example, there was a study of medical students done that looked at treatment of anxiety using Omega-3s. And we've heard about Omega-3s and people know about using it for mood, but it targets anxiety as well. And the combination of turmeric black pepper as well as Omega-3s, and I'm talking mostly about food sources of Omega-3s, some people do take supplements and it's perfectly fine, actually is quite powerful for lowering anxiety levels. So those right there are things that people should move to ward.

There's also some so maybe like sardine curry with a little black pepper.

Exactly, exactly, you know, or, you know, some sort of like really fancy glaze that you put on on seven, you know, and it could be oven roasted, it could be baked and, you know, using all the healthy oils and to make a life, you know, as well as some other things. So, so that that's, you know, that those would be a good, a good way to go. With the status of depression, there have been trials that were done using folate and methylfolate decades ago by some of my mentors at Mass General. But adding them in as leafy greens are thought to be helpful. And so there's a real logical way in which adding simple recommendations that we make about fruits and vegetables, adding that fiber back into your diet it actually drives down any type of inflammation in the gut and therefore with the gut-brain connection lowers any type of potential neuroinflammation. The thing that many people, and I think I'm more aware of these types of things now, is that serotonin, the happy hormone, 90% or more of the serotonin receptors are in the gut. So it really does make a difference what you eat because if you're eating poorly, those serotonin receptors are going to be affected. And the passage of serotonin in a healthy way back and forth, it all depends on what's being transported via the vagus nerve to the brain. And by eating the poor foods and creating dysbiosis in your gut, you're driving the mechanism in the wrong direction for you.

Dr.

So one of the things you said, which I want to back up on, which is so important, you kind of glossed over it, which is this whole idea of neuroinflammation. Now, when your joint hurts, you get arthritis, it's inflammation in the joint. It hurts. If you have a sore throat, is inflammation in your throat? It hurts. If your brain's inflamed, it doesn't hurt, but it shows up as depression, anxiety, ADD, dementia, OCD, whatever, right? Autism. These are all inflammatory diseases of the brain. and what you're saying is that a lot of the source of the inflammation comes from imbalances in the microbiome, in the bacteria in the gut, which you call dysbiosis, which is the difference between symbiosis, which is a nice balance with your gut flora, which is dysbiosis, which is really bad bugs that are growing that drive inflammation. And when you're eating different foods, you're feeding different bugs. And that may be how the mechanism of works with mental health. Is that what you're saying?

Exactly. So a few different things and thank you for backing up on the neuro information because it is such an important point. I'll give you an example of a patient. A gastroenterologist referred me a patient who was having severe panic for the first time at a stage in life that you wouldn't expect someone to develop anxiety and panic disorders going by the DSM-5 TR criteria. And as I took a history and spent time with him, It turns out that his actual, even though he was presenting with the panic to me, what was distressing him was his irritable bowel. He was very uncomfortable. He had developed these symptoms over time. And as we took, you know, found out more information, he had moved to a new job, highly stressed, eating very few meals at home, eating either in the afternoon from the vending machine, eating lunch out, getting takeout, and getting fast food on the way home. From being a relatively healthy weight and from being someone who was eating, I would say probably three, from what I remember, three to five meals at home in the evenings, his diet had changed over the period of 18 months. He developed discomfort in his bowel. He had lots of diarrhea and constipation, but he presented to me with panic. and rather than do that, as we tried to figure out the details and placed him on the proper diet, these symptoms took time, but these symptoms abated over time. So much so that he didn't need clonazepam or Xanax or a certain really for his symptoms of panic.

So you're saying you fixed his gut and that fixed his anxiety and his panic attacks.

Exactly.

But you and I went to medical school school. We're old enough that we went to medical school, and we were taught that there's something called functional bowel disease or irritable bowel syndrome, which we had a pejorative way of talking about as a supratentorial phenomena, which in English means it's all in your head. But maybe it's actually something else. Maybe it's an infrared diaphragmatic phenomena, meaning it's below your diaphragm or in your stomach.

And.

And yet, as psychiatrist, how much did you learn about. the gut, zero, right? Exactly.

As well as nutrition, you know, these are not things that where we've made the connections yet. There are treatments for depression like vagal nerve stimulation. You know, there are things that actively target the vagus nerve that will help to treat depression. So we sort of know some of the science around it, but we haven't put this in, and some of it goes back to something you said at the beginning, Mark. You know, going back to my story of the Dunkin' Donuts coffee from there just began to have more of an open mind around these questions. And I don't, I didn't know when I tried to help him evolve and change his diet that it would work. Part of it was trying to see if it, if it would.

Yeah.

And this was also someone who had developed these symptoms also in the context of that poor diet. He had not early on in his life, you know, for want of a better name for the syndromes, that that was what his gastroenterologist called it. But as that evolved and he ate healthier and it did take time, it seemed like he can cause a better bacteria to grow and some of that really kicked in. So I do feel that that root cause part of it may take time, but we just have to figure out where it is.

Well, this whole gut connection is so fascinating because what you're saying is the type of food we eat changes the the type of bacteria. How does it do that? And why is it important that we focus on that?

Sure. So, you know, if you take a typical, you know, the standard American diet, that unfortunately is the diet used as the point of comparison in a lot of nutrition studies. You know, it's generally, here are some fun facts. A lot of fast food french fries have sugar in them. And gluten. And gluten.

I don't even know the story, but I had this patient who was like, I went to get some french fries at a fast food place. And it's like, I want to make sure the french fries don't have any wheat in them. And they're like, oh, no, no, they don't have any wheat.

We just dip them in gluten and.

Then we fry them.

There you go.

So, since it's absolutely true, they have a lot of stuff that we don't realize is in them because you're just thinking it's a potato. But no, it's It's very far from that, and it's made through a whole process of extrusion to make it a truly processed food. But the point being that it's a simple thing, and you think, oh, I'll just get some dinner on the way home, as that particular patient was doing. But there's so many added, just bad ingredients in foods that you don't realize. So you're familiar with sort of the added sugars and savory foods, salad dressings, ketchup, fruited yogurts and stuff. just one element of it. Then there's the added gluten in people who are gluten sensitive. Then, you know, it's the, the, the unhealthy fats that you don't realize are there. You know, the last time I checked, there was 61 other names for sugar.

I think there's 250.

I'm sure there are. By now, I'm sure there are. And, and so, so I, I will, you know, teach people to just think about four grams of sugars, one teaspoon. Look at the food labels. see what's in it. Because any of those poor foods that are, you know, the foods to avoid are the things that are going to disrupt those gut bacteria. So basically the imbalance is going to be the bad bacteria having a party and the good guys are, you know, not doing well because they're being overrun. And that imbalance is what leads to the leaky gut or the intestinal permeability. And, you know, that's when it really starts to back up and also then causing your inflammation.

Well, you know, this is music to my ears because 20 years ago, I remember having conversations with physicians talking about intestinal permeability and dysbiosis and leaky gut and they just and gluten and they just looked at me like I was from Mars, like I was some kind of quack. They didn't know what he was talking about. I'm like, all I know is what I'm seeing and I see when patients change their diet, when we fix their gut, they get better from all sorts of things. and your work is so important because, you know, we, we've had on the podcast a psychiatrist who's talked about metabolic psychiatry, which is a role of sugar and insulin. But you, you, you're taking all this down into the gut. And there's an incredible bunch of studies that were looked at by psychiatrist Stephanie Chung and her colleagues that looked at gut health and depression, and they found that people with major depressive disorder had about 50 different types of species in their gut microbiome that were different from the control groups. that didn't have depression. And a lot of recent research shows that these bacterial species are associated with high quality of life, often depleted in people who are depressed. And bacteria that cause inflammation are found in a lot higher numbers in people who have depression. So can you talk about what these studies showed and the connection between this inflammation and depression? Because, I mean, I, I saw a study recently that just made me crazy, which was using TNF alpha blockers for depression. which are these powerful drugs that cost $50,000 a year they use for autoimmune disease to shut off inflammation. Why not deal with the source, which is the gut? So talk about what these studies show and how this connection exists between inflammation and depression.

So the more that we learn about the gut, the more that we realize there might actually be certain specific bacteria that are involved with the positive drive of depression versus the negative drive. I wanted actually I just mentioned a study, and the reason I'm talking about it is that it's linked to this in the sense of how people don't realize the impact of certain gut bacteria and a food mechanism that can help you. A study that looked at yo-yo dieting, and this becomes significant because my patients who come in who've gained the weight from, say, a medication don't know how to get off it and they might start to lose weight and then they gain it back in the sort yo-yo piece of dieting has also happened with, say, reality TV shows, and people don't realize that they could actually be a mechanism in the gut. The study that was done and published in Cell sometime this year showed that in particular lean mice and mice that had gained weight, they identified that certain gut bacteria were driving and it was almost for want of a more elegant word, like a fat memory coded in the bacteria in the gut. Then they found that if they fed back proper and certain antioxidants that those, the inflammation caused by this gut memory improved. And I think that what is so cool about this is it's one of those studies that directly showed a mechanism where antioxidants worked in a positive way. And I think that for me, it goes back to the Stephanie Chung study and those that have shown the multiple bacterial species, a quality of life factor, a lowering of depression. And, you know, I think I appreciate what you've been saying all throughout this conversation, Mark, because Going into this, you know, I think that I didn't, when I said at the beginning, you know, the illness that I had didn't lead to the book. It was because I wasn't sure that there was a book. I had been doing the work. But it was some of the work that got more publicity that led to my writing the book because I knew the science was there and what this did for me is it pushed me to look at, like you were saying, you know, 700 references condensed to over 550 because there was science behind it. And sometimes, you know, we get pushed to the side as complementary alternative or soft science, but there's real data behind it. And I think that the more we can explain that to people and have them try things that, you know, it's not going to harm someone unless you have an allergy to try a different and to use these mechanisms to feel better. And we can be highly specific in some of these situations.

Yeah, exactly. And what you're saying is so, when you said it was so important because, you know, if you're looking at trying a drug that's very expensive or that has potential risky side effects, the bar is a lot higher than saying, why don't you stop eating sugar and gluten and eat some vegetables and fiber and fix your gut? And the evidence is there. We may not have large randomized trials. but we have a lot of evidence, like you said, and the kinds of studies that are done now are just so compelling and so beautifully done. I remember one of the studies I looked at was the SMILES trial, which looked at just swapping out people's normal processed food diet with more whole foods, and it was as good as any antidepressant, right?

Exactly. It was as good as an antidepressant, and they added in counseling and so you had, you know, you followed this diet and then they also had someone check in with you and ask you some questions and see how you were doing. So, you know, a lot of, say, weight loss programs have built in coaching now because there's this almost contact part and accountability part that is very helpful to people. There was a great trial done by my colleagues in Australia and I think that, you know, one of the things that we're trying to do more of is really larger human trials. the difficulty is that how to capture some of the actual food that people eat becomes a little bit of a challenge. And so, you know, I think that we're... Because we're not lab rats, you can't just lock us away and feed.

Us the same diet. Feed us the same diet.

Exactly.

Free living humans are hard to study. It's hard to study.

It's different if you're prescribing, you know, if you're doing a pharmaceutical trial. And, you know, there's also a lot of a lot more funding that goes to pharmaceutical trials and very little incentive that goes to nutritional science and nutrition epidemiology studies. There's definitely a difference. And so, you know, I do think that with the studies we've looked at, even if the numbers are smaller, we've looked at the science and tried to pull out for people facts that will be digestible to them that they can actually take home and say, well, I can try to do that. And at the end of the day, you know, I think we can always find a study that's pro one thing on the same day, a study that's against the same thing. It's how we interpret it for people and show them the balance of what has worked. And that's where clinical, like you said, with so many patients that you've treated, that's where the clinical piece also becomes so important.

Tell me about the moment you sort of began to connect the nutrition piece and then the microbiome, because you really have gone deep into these areas. in far more than most physicians.

Yeah, that's actually tied into my cancer research quite a bit. So my research was focused on mitochondria, which are elements within the microbiome. These are archaea. Archaea are the precursor to modern bacteria. So somewhere around four billion years ago, three and a half billion years ago on planet Earth, we see the emergence of the archaea. And then within half a billion years afterwards, we start to see more modern versions of the bacteria that thrive and create most of the biodiversity. But one of those archaea bacteria were absorbed into a more complex methane producing bacteria some billions of years ago. It seems in the fossil record to create the first mitochondria. And at the moment that we had a functional mitochondria, it changed the way that energy was produced in the cell. And so my research in chemotherapy was around maximizing the signaling system out of mitochondria. So how do these ancient bacteria that live and thrive within our human cells, create all of the energy for ourselves, and create a network of communication within ourselves. How do they communicate back to something as complex as our genome or our pathways of enzymatic function? So that was my area of research, and I didn't think of them as microbiome. I thought of them very much, and I think I was really trained to believe that they were part of the human cell. And they were just like this little organelle inside the human cell.

Nobody told me they were microbiome. Nobody told me they- well, they look like bacteria. If you look at them under a microscope, they look like little bacteria. And they're actually- yeah.

They have different DNA actually than your human genome. I think they have their own genome, which isn't taught to us either. We're not taught, maybe I hope that med school students today are, but certainly in my generation of physicians, we were not taught at all the fact that mitochondria have their own genome and that they are archaea makes them very unique. The new stuff around genomics is fascinating around us. I don't want to go down that rabbit hole, I guess. But this was the entry point to when I started a nutrition center and started seeing people not responding to health food regimens that had been proven out for 40 years from the likes of Colin Campbell and Esselstyn at the Cleveland Clinic. And I was applying masters level information that these guys had produced over the years to my patients and seeing them fail. I was seeing them actually get worse, not better, on things like kale and so I was trying to figure out why kale could cause an inflammatory reaction. And it took me a while to believe that the patient was actually eating the kale. Like, I thought, well, maybe they ran out and ate a Twinkie at the same time. Like, I really blamed the patient for a long time before I developed enough relationship to find out that I really trusted them and actually came to realize they were eating healthier than I was. And so in that journey, we had to start asking really tough questions about what does kale look like today to to find out that it's devoid of alkaloids, the medicine within the food, to find out that it's actually got an abnormal ratio of soluble to insoluble fibers compared to kale 20 years ago, to find out that it's laced with a chemical called glyphosate or Roundup was a big aha moment for me. And so that was the journey into realizing that we were going to have to look deeper than just a nutrition.

Protocol and start asking tough questions about the food, which immediately took us into soil. And so, yeah, wait a minute.

That's powerful.

I just got unpacked that. So you're basically saying that you realize that your patients were eating what you thought was good food. They weren't responding at it. And so you traced back to what the quality of the food was and what it was missing compared to decades ago when we had better soil. And then it had lower levels of fiber and lower levels of nutrients. It had lower levels of other compounds. It even had higher levels of compounds like glyphosate, which I really are going to get into with you about it. So, so you, you just sort of connected the dots. And that is, that is a moment when you, I guess you realize that you can't just go to the grocery store, you have to go to the farm. That's right.

That's right.

Yeah.

And at that moment, this was like 2012, we were studying those soil, we were starting to study soil, and we found a family of molecules that are vast and variety. Each species of bacteria and fungi are capable of making 10 to 15 variants of these carbon molecules. And they happen to look a lot like the chemotherapy I used to develop that was disrupting and changing mitochondrial metabolism. And so I suddenly realized that the soil could potentially hold highly intelligent medicinal qualities to it, which that ultimately really proved that not only do we have issues with our farming industry in regards to its productive quality, we had perhaps a deficiency at the soil level of medicines that had never been discovered before. And I'd always had this vision. And I was dealing with plant medicine. I was doing vitamin A extractions and all of that. And then fast forward in my clinic and I'm trying to use herbal extracts and I was investigating homeopathy, I was investigating herbal medicine and all this stuff. So I was starting to really welcome in all this, only to find out that 4,000 years of looking at the plants for medicine might have missed a deeper story that the microbiome of the soils were capable of producing even a higher level of intelligence within the cellular systems of communication, nutrient delivery, and the like. that was the closing point of where I really pivoted to that point. And I started a biotech lab at that moment to start studying soil and the possibility of a whole medicinal capacity to soil. And so that's what we do now. We produce out of Virginia soil compounds that carry these carbon molecules.

Okay, this is really a radical idea. I just want to pause and emphasize this because we know about the rainforest and we hear about the medicinal plants and all the medicines that come out of the rainforest. And nobody thinks of dirt or soil being a reservoir of compounds that have utility in human health. And yet we know there are a lot of things in soil that have produced medicines. A lot of medicines do come from the soil. And what we're finding is that we're driving the extinction of our soil. So we don't think about, oh, the destruction of the rainforest, the destruction of the soil. We're not really talking about that. There are a few people like us, but it's really not out there in people's consciousness that soil is actually so critical for human life on the planet, not just to produce food, but as a reservoir of all these compounds. So take us down that road and tell us what kinds of things specifically you find in the soil that people don't know about that are so beneficial and helpful that we've discovered?

Yeah, you know, we could spend hours on that in a lot of different directions, but to focus it in on these carbon molecules for a moment, because I think it's profound new concept of medicine in general. Not only is it a novel source, you know, coming from soil, but it totally changed my whole perspective on what we should be doing as physicians or a pharmaceutical industry, which is instead of trying to micromanage a single pathway. So something like Nrf2 is commonly talked talked about. So, NRF2 is a pathway that regulates a bunch of our oxidant, antioxidant relationship to the world around us, and inflammation cascades can be really disrupted when NRF2 is affected and things like this. So, we align with that as a pharmaceutical industry and say, okay, we want to find things that upregulate or downregulate NRF2, and we try to find man-made chemicals that we can patent and change that pathway. From the nutraceutical world and dietary supplement world, we say, okay, we want to find a bunch of plant things or natural compounds that can affect NRF2. NF2. And in this way, I think that, you know, while we're moving in the right direction, obviously, with functional medicine and integrative medicine, we have a tendency to kick the allopathic medicine mindset off the stool and then sit right back up on the same stool and simply offer a different, you know, toolbox to do the same reductive kind of effort towards changing biology or micromanaging the NF2 pathway with this, this beet extract instead of with that pharmaceutical drug. But in the end, we're failing to realize that the NF2 pathways perturbed for a reason upstream. And so we tend to be very reductionist in our mindsets and we tend to focus on symptoms as the problem rather than an upstream phenomenon. And so these carbon molecules, when I saw them, were very unique because I had studied extensively redox chemistry and mitochondria, which are oxygen-based compounds that allowed for the release and exchange of hydrogen and therefore electrons. And so redox chemistry intracellularly is mainly produced by the mitochondria and they allow for trafficking of information. So it literally works as a liquid circuit board inside your cell system to coordinate cellular behavior at complex levels. And that redox chemistry is in that is a wireless communication network between the systems, between cells even. They have to go through gap junctions because they can't go into the extracellular space because the extracellular space is too variable in its Osmolarity, it's pH, it's all of these different things that can destroy that domino effect of oxygen-based redox chemistry.

What I found is- hold on, before you go to the next thing, I just want to unpack that for people because it was a mouthful. So, what you're basically saying is there is inside your cells a balance between antioxidants and things that are free radicals or oxidants. And, that balance is critical to health. when it's out of balance, it changes all the chemical signaling in your body that can lead towards disease. Did I get that right?

Spot on.

Yeah.

So redox is a reduction of words of reduction and oxidation. So oxidation is the pulling away of an electron from the environment and reduction is an addition of electron. And so by moving electrons between reductants and oxidants, you can get a stream of electricity. And so to create a wireless network of communication at the cellular level, you want to pass electrons. And the oxygen molecules that are produced by the mitochondria, when they produce a single molecule of ATP, which is kind of the fuel that we're purportedly running on, the ATP production in its byproducts is producing a bunch of 15 different variants of these oxygen compounds. They're things like ozone, hydrogen peroxide, O2H, which is kind of the opposite of H2O. all of this. It's a very unique oxygen containing molecules. The issue or the limitations of intracellular mitochondrial based redox chemistry is that every one of those oxygen based molecules only lasts for about a millionth of a second. And so they are down in the quantum physics realm of communication. If you try to take that quantum environment outside of the cell into like a soil system or into your gut lining, you lose the capacity of that domino effect or electron potential because you can't maintain a consistent current. What we found in soil was these large carbon molecules with the right side of the molecule looking a lot like the redox chemistry that I used for my chemotherapy. The idea that this big carbon backbone would be produced by bacteria and fungi to stabilize redox chemistry in extracellular environments was super exciting. It was just massive goosebump moment. When my colleague and I were going through this white paper on dirt, I didn't know anybody knew anything about dirt, let alone a 90-page white paper on soil science. I was blown away paging through this thing, this molecule goosebump moment of not only is there medicine in the soil, it could be so much more stable and deliverable as a medicinal kind of effect than our oxygen compounds and those that would affect it. The exciting thing about redox ox chemistry again is it resets our concept of a medicinal. Instead of trying to affect a single pathway, in fact, instead of trying to do anything to a human body, for example, all you're trying to do is reconnect the communication system so that the cells can communicate. And when cells have uninterrupted information, they become healing machines. They know how to mobilize stem cells if they're too damaged to repair. They know how to repair themselves at a faster rate. They know which proteins are missing. And so that was the excitement. And as we started putting this into cancer cells and and neurons and proximal renal tubules in our lab, we were immediately seeing things we had never seen before. This was a cumulative experience of over 120 years between scientists that were involved in everything else of basic science, looking under microscopes, John Gilday, PhD, UVA, master of microscopy and cell biology. He was seeing things that had never happened before under the microscope. It was because for the very first time, we were not treating human cells and health and disease as if it was an isolated event. We were bringing in a biologic compound of communication network made by bacteria and fungi and introducing it to a petri dish. For the first time we were watching biology happen in the context of an ecosystem. And the last 10 years, you know, journey has just been mind-blowing to find out how powerful we are as healing machines when endowed with with the communication network that's up and running.

So how are you using the soil science that you learned and these microbes in the soil that actually regulate these pathways? How is that linked up to human health directly? Yeah, make it a little practical. How do we actually see this in real life?

Yeah, so the first thing that we did was study gut lining because we had come, John Gildea had done a lot of work around deep reading and understanding of glyphosate, which is the roundup active compound herbicide, most ubiquitous chemical that we spray in the world, over four billion pounds a year now into our soil systems, water system around the world. And so this molecule was ever present in his mind. And one of the main things that this molecule was becoming recognized to be capable of was destroying barriers. And so it could break down the gut barrier, break down the blood-brain barrier, kidney tubules, and this would lead to a leaky sieve event and the chronic inflammation in the population. And so, of course, the debut in 1976 and then the spraying directly of wheat in 1992 and then the GMO crop of Roundup Ready genetic modification in 1996, you can see that the uptick in chronic disease, autoimmune disease, inflammatory conditions of neurologic, degenerative conditions, all of these upticking with every introduction. And the ground zero seemed to be in this protein destruction of the tight junctions.

These are the Velcro-like proteins.

As soon as we put this one- that's what people call leaky gut, right? leaky gut, leaky brain, leaky kidneys, and the symptoms tend to be bloating, poor digestion, poor energy level, fatigue after meals, cravings, poor sex drive, poor sleep quality, brain fog, short-term memory loss, and then inflammatory conditions of vascular disease, diabetes, metabolic crash, all of that is set up by the breakdown of the single protein, which is so interesting that ground zero is boiled down this simply. The Velcro that holds all of those cells together is called tight junctions. And as soon as we put this communication network back in, we saw something extraordinary happening, which was cells knew how to lace themselves back together. So we could destroy a gut membrane, small intestine or colon immediately. Within six minutes of Roundup, you've got massive leak going on. But if you gave it back a wireless communication network made by the microbiome, those cells would lace themselves right back up into a cohesive, coherent, highly protective barrier. We've subsequently shown this on the blood-brain barrier. We've shown that the relationship between the gut and the brain injury is very interlaced. If you give Roundup and gluten, for example, to the brain barrier directly, it doesn't do much. But if you first give gluten and round up to the gut lining, then the blood-brain barrier blows apart. And so it's so interesting to see how this cascade of putting this chemical Roundup into our food system set us up for this breakdown in these different barrier systems. And it's so beautiful that here is the chemical that we're destroying planet Earth soils with, and yet she planted as an antidote to this chemical, these compounds within her soils 60 million years ago. And that's how we extract these carbon molecules. So we go to a fossil layer of soil in the southwest United States, and we then bring that to our labs. We crush that into nanoparticles, and we go through a multi-stage process to liberate small carbon molecules and get hydrogen to bond to the oxygens again and get a redox effect. And when that system of communication from fossil soils goes back in to a modern human experience, it's unbelievable, you know, what can happen. And again, it's not because the compound's doing anything, it's because the human cell is capable of that when it's grounded in the intelligence of soil, when it's grounded in the intelligence of nature. And so that's been the journey towards this, you know, extraordinary realization that if we don't fix the agricultural industry, we're going to fail. So now our biotech company with all of its supplements are channeling all of our profits back into root cause solutions and one of those being our non-profit, which is an awareness and education effort, to allow chemical farmers to realize that they're actually the most potent members of change for the transformation of human health. And this is poignant because they are facing the highest levels of chronic disease in the world. The last 90 miles of the Mississippi River that collects some 80% of the roundup in our environment is cancer alleys. We see farmers with third time, fifth time cancers of different organ systems. Their children are affected by ADHD and autism and brain defects. And I've seen just the most horrific stories of tragic human health on these farms as we've been filming over the years in these environments. And so you can only imagine how devastating it is to, I give these talks out with PowerPoint presentations literally in farm fields. And so it'll go dark while I'm showing a part. And these farm families are just riveted sitting around on bales of hay listening to this story, realizing that their children's diseases that they're treating and their own cancer is coming from the very chemicals.

They have to handle every day. Thanks for listening today. If you love this podcast, please share it with your friends and family. Leave a comment on your own best practices on how you upgrade your health and subscribe wherever you get your podcasts and follow me on all social media channels at Dr. Mark Hyman. And we'll see you next time on the Doctor's Pharmacy. Hey, everybody, it's Dr. Hyman. Thanks for tuning into the Doctor's Pharmacy. I hope you're loving this podcast. It's one of my favorite things to do and introducing you all the experts that I know and I love and that I've learned so much from. And I want to tell you about something else I'm doing, which is called Mark's Picks. It's my weekly newsletter and in it I share my favorite stuff from foods to supplements to gadgets to tools to enhance your health. It's all the cool stuff that I use and that my team uses to optimize and enhance our health. And I'd love you to sign up for the weekly newsletter. I'll only send it to you once a week on Fridays. Nothing else, I promise. And all you have to do is go to drhyman.com/picks to sign up. That's drhyman.com/picks P-I-C-K-S and sign up for the newsletter and I'll share with you my favorite stuff that I use to enhance my health and get healthier and better and live younger longer. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic and Function Health, where I'm the chief medical officer. This podcast represents my opinions and my guest opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only. It's not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you're looking for help in your journey, seek out a qualified medical practitioner now. If you're looking for a functional medicine practitioner, you can visit ifm.org and search their find a practitioner database. It's important that you have someone in your corner who is trained, who's a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health. Keeping this podcast free is part of my mission to bring practical ways of improving health to the general public. And in keeping with that theme, I'd like to express gratitude to those sponsors that made today's podcast possible. Don't forget, there's a way to listen completely ad free. With Hyman Plus on Apple Podcasts, you can enjoy every episode without any breaks. Just open Apple Podcasts and tap Try Free to start your seven-day free trial.