The Microbiota, Autoimmune Disease, and Stool Analysis with Dr. David Brady: Rational Wellness Podcast 041
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Dr. David Brady discusses the microbiota, autoimmune diseases, and stool analysis with Dr. Ben Weitz.
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Podcast Highlights
4:53 I mentioned that I had just reread Dr. Brady’s 2013 excellent and important paper clearly laying out some of the connections between the microbiota and autoimmune diseases, Molecular Mimicry, the Hygiene Hypothesis, Stealth Infections and Other Examples of Disconnect between Medical Research and the Practice of Clinical Medicine in Autoimmune Disease. https://scirp.org/journal/PaperInformation.aspx?PaperID=27948 I consider this mandatory reading for anyone in Functional Medicine.
7:10 Functional Medicine doctors might look to the gut and order stool testing for patients with autoimmune disease but this makes no sense to conventional medicine. But Dr. Brady pointed out that medical research is in line with the Functional Medicine approach, as there are many studies linking gut dysbiosis and specific gut pathogens with specific autoimmune diseases. Here is a slide that Dr. Brady provided me on this: 
10:10 The Importance of the Microbiota and the Microbiome. Dr. Brady discusses the need to look at ourselves and our state of health in what is called the super organismal context, meaning it’s not just us and our cells, and our biochemistry, and our physiology. It’s also all of those other organisms that share our experience. The organisms that live on us, in us, through the gastrointestinal track. Research is really supporting the importance of the microbiota and the links with chronic diseases, like autoimmune conditions.
13:02 Discussion of Dysbiosis. Dr. Brady explained that dysbiosis is a term that came from EE Metchnikoff and it refers to an imbalance of the bacteria in the gut. You don’t necessarily have a parasite or pathogen. You get an overgrowth of opportunistic organisms, which when overgrown become problematic, referred to as potentially pathogens. It’s aligned more with a state of illness or lack of optimal wellness of the host.
15:58 I asked why we might have a pathogenic bacteria that comes in through our gut and it becomes a permanent resident that we have trouble erradicating, but when we consume healthy probiotics they are only temporary residents? Dr. Brady explained that this is not necessarily the case. Most pathogens fortunately pass through and don’t actually take up residence in our gut. And when you look at beneficial probiotics, like lactobacillus, bifidobacteria, they make up a small minority of the GI microbiota in its totality, which is mainly made up of anaerobic bacteria, not aerobic or facultative organisms. These beneficial organisms have an incredibly beneficial effect even though you are not really reseeding the gut, which a lot of practitioners make the mistake of thinking that they can if they just take enough billions of probiotics. They are more like pixie dust. They change cytokine expression. They are more like messengers than foot soldiers.
20:27 We discussed the link between digestive health and autoimmune diseases, including the hygiene hypothesis. Dr. Brady pointed out that he laid out some of these arguments in his paper in the Open Journal of Rheumatology and Autoimmune Disorders noted above and also in a similar paper that he wrote in the Townsend Letter http://www.townsendletter.com/June2012/autoimmune0612.html Our modern methods of sanitation and hygiene have reduced our exposure to infectious diseases in order to reduce cholera, typhoid, dysentery and and similar serious infections that result from drinking contaminated water. But we have taken it too far by the overuse of antibiotic soaps and wipes and the frequent use of antibiotics and not letting your infants play in the dirt and put things in their mouths. This reduces our exposure to microbes in our environment and prevents us from developing the tolerance that we should have and our immune system may overreact to organisms that are not much of a threat. We’re left instead with an immune system that’s stuck in an overaggressive stance, and more likely to crossover with subtle differences between what it’s trying to actually attack, which would be a microbe, and a host tissue, like a joint, or like a thyroid gland.
23:30 Dr. Brady discussed how helminth therapy (worms) can help with immune system regulation.
28:29 We discussed the best way to test the microbiota with proper stool testing, including using the GI Map test through Diagnostic Solutions that Dr. Brady is has helped to develop. Dr. Brady explained that GI Map uses a more sophisticated quantitative PCR, polymerase chain reaction, method of detecting both pathogenic and also opportunistic microbes that may have overgrown. Dr. Brady explained that this is a clinical test that can enable you to determine if a microbe that is found is clinically relevant and needs to be treated, including if it may result in autoimmune diseases. This should be distinguished from testing that uses next-gen sequencing like a uBiome test, which was not meant for making clinical decisions on patients at the point of clinical care.
Dr. David Brady can be contacted at his website https://drdavidbrady.com/ You can check out the site for The Fibrofix book that he wrote at https://www.fibrofix.com/ You can get information on the GI Map stool test from Diagnostic Solutions at https://www.diagnosticsolutionslab.com/
Dr. Ben Weitz is available for nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure as well as chiropractic work by calling the office 310-395-3111.
Podcast Transcripts
Dr. Weitz: This is Dr. Ben Weitz, with the Rational Wellness Podcast. Bringing you the cutting edge information on health and nutrition from the latest scientific research and by interviewing the top experts in the field. Please subscribe to the Rational Wellness Podcast at iTunes and YouTube and sign up for my free ebook on my website, by going to drweitz.com. Let’s get started on your road to better health. Hey, Rational Wellness podcasters, thank you so much for joining me again today, and we’ve got a very interesting topic.
We are going to talk about the microbiota, autoimmune diseases and stool testing, with a very special guest, Dr. David Brady. The microbiota is a community of commensal or good bacteria, symbiotic, neutral and pathogenic bad bacteria. This microbiome has been found in every multi-cellular organism from plants to animals that has ever been studied. The microbiota includes, bacteria, archaea, protozoans, fungi and viruses. The microbiota is crucial for the health of the host, esp. for the immune system, hormone production, metabolism and a host of other important health processes. The term, the microbiome is often used interchangeably with microbiota, even though technically microbiome refers to the genetic makeup of these microorganisms. The main place that the microbiota exists in humans is along the digestive tract. But these microorganisms also live in the vagina, along the urinary tract, the lungs, the mouth, the eye, on the skin, lining virtually every mucous membrane in the body. In fact, almost everywhere. Some would also argue that worms that have lived in the bodies of humans for thousands of years, are also important organisms that contribute to this community of microorganisms, and are important for the health of the host. Listen to episode 38 of this Rational Wellness Podcast where I interviewed Dr. William Parker about worm therapy.
Now, when it comes to autoimmune disease we’ve been seeing a huge increase in the rate of autoimmune diseases, especially in the US and other developed countries in the last 10 to 20 years. Now, autoimmune diseases are diseases in which our immune system, which is designed to kill outside pathogens starts focusing its attention inwards, and starts attacking our own tissues. This is believed to be partially related to the decline of bacterial diversity in the microbiota in the gut, and the breakdown of the gut lining, often referred to as leaky gut. There are now over 80 recognized autoimmune diseases including Hashimoto’s hypothyroidism, celiac disease, type I diabetes, inflammatory bowel disease, MS, psoriasis, lupus, rheumatoid arthritis. Properly analyzing our microbiota with accurate stool testing can potentially enable us to determine whether we have a healthy microbiota. It may enable us to intervene and potentially prevent or reverse autoimmune diseases through changes in diet, lifestyle and nutritional supplementation.
In order to help sort this out, I’m thrilled that we’re being joined today by Dr. David Brady, an internationally known speaker, Doctor of Chiropractic, Naturopathic physician. He’s also a Professor at the University of Bridgeport. He’s the Chief Medical Officer for both Designs for Health, and Diagnostic Solution Labs. Dr. Brady is a prolific writer, having published a number of scientific papers, contributed chapters to various text books, and he’s also written several books, including his latest, The Fibro Fix, published in 2016. Dr. Brady, thank you for joining me today.
Dr. Brady: Hey, thank you for having me. It’s a pleasure to be on your podcast.
Dr. Weitz: Excellent. So, before we get started with the questions, I just wanted to say, this morning while I was eating breakfast, I just reread your 2013 article from the Open Journal of Rheumatology and Autoimmune Diseases on “Molecular Mimicry, the Hygiene Hypothesis, Stealth Infections and Other Examples of Disconnect between Medical Research and the Practice of Clinical Medicine in Autoimmune Disease”. I feel like this is such an important paper. It so clearly lays out the link between the microbiota and autoimmune diseases. For me, this is one of those seminal papers in Functional Medicine, along with Dr. Fasano’s Scientific American paper on leaky gut, and some of Dr. Vojdani’s papers, that I strongly encourage every Functional Medicine practitioner and even laypersons interested in a functional approach to autoimmune diseases, to read this paper. And so, on behalf of the Functional Medicine community, Dr. Brady, I thank you for your contributions to our profession.
Dr. Brady: Well, thanks for those nice comments. I’m sorry to ruin your breakfast, but I’m very happy to be included in that prestigious list of colleagues that you threw me into. I’m not sure I deserve that, but thank you anyway. It was just me trying to get some of these concepts out there into the conventional medical literature, which we’ve always held true for my whole career in Functional Medicine, which is over 25 years. These concepts are nothing new to us in Functional Medicine, that the ecology of the gut is of prime importance to the over health of the organism. That it’s really the place where the meter, the setpoint, the balance of the immune system in general starts, is with mucosal immunity in that really quite complex and potentially full of toxins and antigenic material in the GI lumen. It was really getting some of those overarching concepts out to colleagues that may not be familiar with the way we deal with autoimmunity and we deal with chronic disease even.
Dr. Weitz: Yeah. I imagine that a lot of the conventional medical doctors, if somebody went to a Functional Medical practitioner and was concerned about autoimmune disease and ordered a stool test, they’d say, what are you doing? Are you out of your mind? What does that have to do with anything.
Dr. Brady: Yeah. It’s amazing. Medical research is right in line with Functional Medicine. What they’re looking at right now in the fields of immunology, in the fields of autoimmune disease and rheumatology, and gastroenterology, and right on down the line is really in harmony with what we’ve understood in Functional Medicine for a longtime. They’re pushing the boundaries of the granularity at which we understand it and how all the dominoes fall and how all the underlining mechanisms, and making new associations between aberrant patterns, let’s say, in the GI health area or the microbiota, and specific chronic disease including autoimmune diseases, but really we’re kind of talking the same … We’re singing the same tune, but that’s not the case when you cross over into clinical medicine.
As you said, if someone with an autoimmune disease goes to a rheumatologist, let’s say a classic rheumatology managed disorder like rheumatoid arthritis, they’re highly unlikely to have any attention paid to their GI microbiota, or their gastrointestinal environment, or the health of their GI mucosa. Getting a stool analysis, they don’t do that. That’s what the gastroenterologist does. The problem is, the gastroenterologist doesn’t do a stool analysis for those things. They don’t do any work-up in autoimmune disease. When they do, do a stool analysis, it’s a very limited stool analysis that’s really meant to look for pathogenic disorders that cause diarrhea or maybe fueling an inflammatory bowel disease in some cases. Even that is generally not done.
There’s really a disconnect right now between conventional medical research in the conventional Western paradigm, and the practice of medicine. They really don’t connect very well. I really do think that the current research and the threads of it and where it’s going really harmonizes more with the Functional Medicine approach than it does with the conventional medical approach.
Dr. Weitz: Can you explain the important of the microbiota and why it plays an important role in our overall health, as well as with the link with autoimmune diseases?
Dr. Brady: Yeah. From a 30,000 foot sort of overarching kind of concept, I will try to do that. For most of Western Medicine’s history, we’ve looked at the human condition from the standpoint of our own physiology, our own biochemistry, our own metabolites, and things like that. But, we really have just now begun to break out of that very reductionist, myopic way of looking at ourselves. We need to look at ourselves and our state of health in what is called the super organismal context, meaning it’s not just us and our cells, and our biochemistry, and our physiology. It’s also all of those other organisms that share our experience. The organisms that live on us, in us, through the gastrointestinal track. We know that they are roughly equivalent to us as far as number of organisms to number of cells in our body. We know that they house many more genes than we do, probably 100 times or more, more genetic material than we do. They genes talk to our genes. We have to deal with and process and react to their metabolites, the things that they express on their surface. It’s really a community. We think that we carry around these bugs, and maybe they’re carrying around us when you look at the numbers. When we look at our overall state of health or dis health, or illness we have to factor in all of those components, not just ourselves.
Finally, that’s beginning to happen. It’s with the microbiome project and the study of the microbiota in general. As you correctly pointed out and most practitioners don’t understand the nuance there. The microbiota are the actual organisms, their phylum, their genus, their species, that are on us, in us, around us. Where the microbiome is all of the genetic material of those organisms plus all of the metabolites that they’re producing. It’s really more, when we look at the microbiome, we’re looking at not what bugs are present, but what is their overall impact on our condition. They are slightly different, but usually they’re used interchangeably. It is true that we have a tremendous amount of organisms living on our skin, living in our lungs, any mucous membrane, but the most complex environment is the microbiota, the portion of the microbiota that has been most firmly linked to not only the association, but now the genesis of specific chronic diseases, and nothing more closely connected or the dots most conveniently connected than in autoimmune disease than the GI microbiota. All those bugs that live in the gut are of prime importance and it’s probably along with specific immune modulating antibody drugs if you will, in onco therapy, that and the microbiota and the microbiome are the hottest areas of research in the Western Medical paradigm, by far.
Dr. Weitz: You use the term dysbiosis is some of your writings. Can you explain what that means and what it’s importance is?
Dr. Brady: Yeah. It’s actually quite an old term that has had a reemergence with this sort of burgeoning microbiota research and understanding of why these bugs are so important in the gut. But, it was originally termed I believe, by E. E. Metchnikoff, who is a Russian zoologist and physiologist who is known to have coined the term, orthobiosis and dysbiosis. Orthobiosis, ortho meaning normal, biosis the microbes that live in the gut. So, orthobiosis is a healthy beneficial balance of microbes in the gut, that would be aligned with a healthy state of the organism. Where dysbiosis is where there is some sort of aberrant pattern. Things are not quite in the right balance. It’s not necessarily a state where there’s pathogenic infection that would cause acute fulminating diarrhea or some specific acute disease state, but dysbiosis is when things are just not right. There’s overgrowth of opportunistic organisms of various classes. It’s aligned more with a state of illness or lack of optimal wellness of the host.
Of course Metchnikoff is the father of probiotic therapy in the modern western paradigm, after he observed mainly populations, which we would now call a blue zone, in Bulgaria who were living high up in the mountains. They were living to very advanced ages for the time, and they were living very healthfully into those advanced ages. He wanted to know what was different about them. They lived in a very nice environment up in the mountains. They never retired. They kept working. They were very active. They had a good social network. All the things that we understand now about the blue zones. But what he really found striking is that they tended to use the milk, or the dairy from cows that were free-range feeding on the local vegetation in the mountains. They were culturing it and making what we would now call like a yogurt or a cultured dairy product from it, a kiefer, a yogurt, cheeses, things like that. They were getting a high intake of these organisms that were used to ferment the dairy. Now we know that strain is lactobacillus bulgaricus. Right? Because of Bulgaria, from that community. So he was really the father of probiotic therapy and obviously a real hero of Functional Medicine.
Dr. Weitz: Isn’t it interesting how when we consume bacteria from yogurt, or if we get some pathogenic bacteria that enters our GI tract, it ends up populating our microbiome, or microbiotic? But, when we take probiotic supplements, apparently they’re only temporary residents there. Do we know why that is? Why is it that if a bacteria, especially a pathogenic bacteria comes into our system through our gut, all of a sudden becomes a permanent resident, whereas we take these healthy probiotics and they only become temporary visitors.
Dr. Brady: Well, I’m not sure that’s always accurate.
Dr. Weitz: Oh, okay.
Dr. Brady: I think it depends on the state of the GI environment in that host. Certainly we’re exposed to pathogens transiting our GI tract all the time in food mass and things like that. They probably don’t setup more than they do. It depends on the virulence of the specific pathogen. Some of the are really nasty critters and if we get almost any exposure to them, even a robust host would be very likely to fall ill. But, we’re getting exposure to lots of organisms that we would not want to set up and colonize our GI environment all the time, and they don’t.
Conversely, the beneficial organisms, some of them colonize, some of them don’t. They can colonize from a good quality probiotics, or cultured or fermentable foods, or not. I think in both cases, I think it’s really host-dependent than it even is what the actual source of the environmental seeding of the gut is. But, you mentioned the pathogens might be more likely to take hold than a beneficial organism. Why might that be the case? Well, pathogens are pathogens for a reason. They’re very virulent. They’re aggressive. They’re very robust, so they can cause significant disease, where things that we would consider commensal or beneficial organisms don’t have that dramatic effect on us. Quite frankly, they’re extremely outnumbered.
When you look at things like beneficial probiotics, like lactobacillus, bifidobacteria, they make up a small minority of the GI microbiota in its totality, which is mainly made up of anaerobic bacteria, not aerobic or facultative organisms. But, it’s interesting, those beneficial or commensal organisms, they are very powerful. They have tremendous clinical effects as we know from the research studies, and as we know from clinically utilizing them even though they don’t represent much of the population in the gut. They have effects that are far more powerful and reaching than their numbers suggest. That is sort of a pet peeve of mine. I think even in functional medicine, in nutritional medicine, and integrative medicine, I think practitioners still make the mistake of thinking of probiotics and probiotic therapy as a numbers game. That you’re going to fundamentally reseed the gut and change the numerical arrangement of the person’s gut, and we know that that doesn’t occur, from serial assessments with molecular stool analysis.
You can change it temporarily but you don’t change it long term, numerically. But that doesn’t mean that you don’t have profound clinical effects, because Stig Bengmark, one of the world’s experts in probiotics for instance, talks about probiotics as pixie dust. Right? It’s not a matter of how much. It’s a matter that you actually introduced the organism and the peptides associated with it, and the metabolites associated with it. It’s actually talking to the GI or what we would call the enteric nervous system, but also the enteric immune system. That it’s actually changing cytokine expression. It’s changing mucosal immunology by virtue as being a messenger more than a foot soldier, if that makes sense.
Dr. Weitz: Sure. It’s about communication.
Dr. Brady: Yeah, exactly.
Dr. Weitz: You often speak about the links between digestive, or gastrointestinal health and autoimmune diseases, including what is known as the hygiene hypothesis. Dr. Parker, who I interviewed a few weeks ago, he uses an analogy of leaving your teenager home alone with nothing to do. He or she will often get into trouble. Can you explain what the hygiene hypothesis is and how this contributes to autoimmune diseases?
Dr. Brady: Yeah. There’s a couple of major thematic things that you need to understand in the modern autoimmune epidemic. I do try to go through them one at a time in that paper that you mentioned in the open, Journal of Rheumatology and Autoimmune Disorders, and also in a similar paper that I had in the Townsend Letter. The hygiene hypothesis is pretty simple. It just basically says that, in the western industrialized countries, we’ve cleaned our environment up so much, and some would argue with that because they think, what about all the toxins. We’re talking more from an exposure to microbe standpoint. The way we’ve cleaned it up is basically with modern hygienic water treatment, water supplies to large populations. We’re no longer in a village taking water out of a stream, that another village a couple miles up was going to the bathroom in.
It’s not that kind of environment anymore. We don’t live in caves. We don’t live on dirt floors. We live in houses. We use antibiotics. These days, a lot of mothers unfortunately are scrubbing their young children with antibiotic triclosan laden soap every ten minutes because they’re germaphobic. They won’t let them crawl on the ground. They won’t let them put something in their mouth that was on the ground. Really that’s part of … Infants have that oral phase where they’re putting things in their mouth all the time, purposely to get exposure to their environment, to learn to have some level of tolerance to the microbes we share our planet with and learn how to react appropriately. To have the right setpoint of surveillance, where if we’re exposed to something that could really do us harm, like a pathogen that we would mount a robust reaction, appropriately. But that if it is other organisms that really aren’t that much of a threat, that we don’t freakout and overreact to them.
Part of that learning process, when the immune system is young and learning to size up their environment, is to have exposure to a larger diversity of different types of organisms. We’ve taken away that exposure to a large degree, and we’re left instead with an immune system that’s stuck in an overaggressive stance, and more likely to crossover with subtle differences between what it’s trying to actually attack, which would be a microbe, and a host tissue, like a joint, or like a thyroid gland.
It’s interesting you brought up helminth through worm therapy. One of the things we’ve eliminated most dramatically compared to our ancestors even 100 years or more ago, is helminths, or worms. Worms have been in our intestines for the whole time we’ve been on the planet essentially. We’ve radically changed the landscape when it comes to helminths in the last 100 years, certainly in the last 50 years, in particular in the western industrialized countries, where we really don’t have nearly as many worms or helminths in, let’s say, young childrens’ intestinal tracks. Those helminths, it’s very interesting. In order to survive and be symbiotic with us, they put out different chemical messengers that actually down-regulate our immune response. The body’s response to that is to up-regulate. It’s reaction to try to kind of find this homeostatic balance. We kind of meet in the middle, if you will.
But if you very suddenly in an evolutionary context take away the helminths that are suppressing the immune system, the body’s set point then is left to hobbit in too aggressive of a stance. With that theory there were certain researchers that talked about using maybe helminths as therapy. Of course, they observed populations in what we would consider underdeveloped countries where these helminth infections, round worms and things like that, are extremely common. It was probably most observed in Laos, in Vietnam, and stuff like that, and westerners were in there in different interventions as we know. They did observe that the children there had no allergies, no atopy, they didn’t have hay fever. They didn’t have dermatitis. They had none of that kind of stuff until they started treating them for the worms. When they started giving them anti-helminthic, antiparasitic medication, all of sudden those pediatric populations started developing those disorders like we see in western children. That provided further connect the dots kind of information.
Joel Weinstock, who is a famous medical physician and researcher, did most of this work seminally at the University of Iowa, but now I believe he’s at Tuft’s in Massachusetts for quite a longtime. He did work with trichuris, or pig whipworm, in treating inflammatory bowel disease, like ulcerative colitis and Crohn’s disease, to significant success in that there’s actually helminth-based drug therapy for inflammatory bowel disease in Europe. The drug is call OvaMed, there. It’s in, I think, phase three trials here in the US, but not approved to date.
Dr. Weitz: Interesting. So, they’re actually using helminths? Is that what it is?
Dr. Brady: Yes. A lot of integrative or functional medicine practitioners use helminth therapy sort of in an off label way. They’re not a drug, per se, but it’s called h.diminuta, which some people call it, rat tapeworm. It’s not a tapeworm. It’s a helminth, or roundworm, actually. It’s really a beetle derived, or an insect derived helminth that is then consumed by rodents when they eat the insects, and then it can inhabit their GI microbiota. But, it’s a benign helminth that if you give it to the human host, it will setup there. It will exert the beneficial immune modulatory effects of a helminth, but that if you stop giving it over a time, it goes away. It will not sustain over long periods of time in the human host unless you keep reseeding it.
That’s one of the reasons why Weinstock used trichomatous, because for the same reason that roundworm can affect positive changes associated with helminths, but you have to give it continuously. So, if you do give it as therapy, you don’t then have to go eradicate it with another therapeutic agent should you want to get rid of it in that subject.
Dr. Weitz: Now, it’s my understanding that at the present time, helminths are not approved by the FDA, so how would one of your patients get a helminth?
Dr. Brady: Well, there are some practitioners who use them.
Dr. Weitz: Can they be legally administered?
Dr. Brady: I don’t know, technically. It’s not approved as a drug. They’re not being used as a drug, per se, for specific disease process, but they can be accessed, I believe online. I have patients coming in that are using them, and they are getting them, but they’re not technically approved in the US, no.
Dr. Weitz: Right. Okay. Interesting. I think the human hookworm is another one that’s being used for certain therapies. So, let’s see. What are some of the best ways to analyze the gastrointestinal system? I understand you’re involved with Diagnostics Solutions, GI-Maps is your stool test. So, a lot of us Functional Medicine practitioners have been using stool testing to try and analyze microbiota. My limited understanding of stool testing is, a number of years ago we started using the GI Effects stool test, which was a genetic based test. Genova bought it, and then at some point, I remember going to a seminar that was put on by Doctors Data, and some paper came out criticizing genetic-based stool testing, and saying that there were problems with it. As I understood it, one of the issues with it is if you’re detecting the genetic basis, of let’s say, a parasite, it could be a parasite that’s not really there. So, they were touting their culture-based stool testing.
Genova then seemed to have modified the GI Effects and started using culture again, for parasites instead of pcr genetic testing. A number of the practitioners that I know in the Functional Medicine community were not happy with that test anymore. They felt like it wasn’t picking up things that like, parasites and other pathogens that they had seen on the GI Effects and they were able to eradicate and help their patients. Now they felt like this test wasn’t finding some of those. It’s my impression that your GI-Maps test is stepping in to help out using a more sophisticated type of genetic testing to help us find what’s going on in the gut. Is that right?
Dr. Brady: Yeah. Well, that’s a long story and I’m going to probably differ from getting involved in the internal squabbles and politics between the various commercial interests in companies, but I can say that I’ve been doing stool analysis in my clinical management of patients and research for 25 years plus. Once upon a time, the only thing we had was culture-based old school microbiology-based testing, because that’s all we had. It was really before PCR was readily accessible, certainly by clinicians.
Dr. Weitz: And by the way, PCR is what?
Dr. Brady: Polymerase chain reaction. It’s what’s used to amplify DNA to be able to do a lot of the molecular or DNA-based technologies that we see today that have transitioned from research to actually clinical tests. But basically, here’s the reality. Molecular is where it’s at. A lab that does a microbial or culture-based technology claiming that molecular is not the way to go and we should do culture-based methodology, is like someone driving by on Main Street in a modern US city, in a horse and buggy, yelling that we should not use cars. This is a better mode of transportation. That’s how absurd it is. This is based on one study, with about 30 samples, funded by that lab and it was directly comparing to another lab who is a competitor of theirs who was using a test that was developed in-house with a quasi-molecular methodology, which was not a developed methodology by a major bioscience company, and had a valid third party validated. In many cases these platforms are FDA cleared for various uses. That’s not what this was. This was the first attempt in the Functional Medicine space, many years ago at a molecular stool technology, and the first attempt was at Metametrix Clinical Laboratories. They did it for all the right reasons. I applaud them for the first attempt. For whatever reasons they decided not to use one of the already developed and vetted out by very large bio companies technology, they decided to develop their own methodology, in-house. I don’t know what their exact reasons for that was. Sometimes that’s done for reasons of developing protected intellectual property rights and things like that.
We know when that test first came out, it was a big step forward. But it did suffer from some problems. One there were longer than expected turnaround times, because the methodology was a little bit long and unwieldy. It wasn’t fully molecular either. Elements of it were molecular. Elements were not. And, it actually did not suffer from not finding things. It suffered if anything from oversensitivity. And what practitioners may remember is getting a lot of what’s called, basically that the organism type was detected, but taxonomy unavailable. A lot of that was theorized to be what we call, scattered DNA. A little bit of DNA of different kind of organisms that can be located in the food mass. That doesn’t implicate all molecular technologies as suffering from those same problems. If you go to any major hospital pathology lab, at an academic medical center in the western world right now, they are running their samples using DNA molecular technology. When someone has a systemic infection, if they nick a bowel, and they have sepsis or something, and they’re coming in with some really weird infection, and they’re going into organ failure, and they need to know what it is, they need to know now and they need to know what’s going to kill it, what antibiotics will be effective, which antibiotics will it be resistant to, they do not do culture technology. They do molecular technology. That’s just how it works. You just need to apply it to stool testing in the proper way.
That’s what we set about doing with GI-Map. We developed this in the incubator at the molecular biology center at Georgia Tech University, which is the number one molecular biology center in the world. Along with one other center in Massachusets who were the first to map the human genome. Very advanced technology and talents. Basically, when we developed the GI-Map, we took a very different route. Many of us were actually involved in that first generation testing. We were sort of the ones who didn’t win out in the argument of look, we need to use a bulletproof technology that’s already been totally vetted, tested out, and in many cases cleared by FDA for certain applications. That’s what we did, but we applied it across a wide spectrum of clinically relevant organisms in a manner that a Functional Medical doctor would want to see.
In conventional Gastroenterology, when they do stool testing, even if they’re using molecular, they’re generally looking for a very short list of pathogens that may be causing diarrhea in a patient. The Functional Medicine doctor needs a much wider lens. We want to look not only across pathogens, and not only five or six pathogens, but a long list of pathogens in classes including bacterial, fungal, protozoal, helminth, viral. Right? The viral realm, but then we want to look at commensals. We want to look at beneficial organisms, and a whole range of those. We also want to look at opportunistic organisms. That’s really where the gold is, the opportunistic organisms that have the potential to overgrow if the environment is right, if the host is susceptible to it.
A lot of these opportunistic organisms when they overgrow to a certain level, can then create problems, and they are associated with the genesis … First of all they were just associated with different disorders, like various autoimmune diseases, but now we actually have the emergence of causal data and mechanisms by which we know how the higher presence of a certain bacterium, let’s say, in the gut, can actually ultimately translate to an immune attack against your joints, or against your thyroid, or against your nervous system. In the GI-Map, we’re using what’s call quantitative PCR. PCR, polymerase chain reaction, right? It’s a molecular technology. We’re hunting the DNA of these bugs, but we’re doing it with a quantitative platform. What that means is we get the actual numbers of the organisms, versus other molecular technologies, which are also good, but they’re not meant for the same application, which is caused next-gen sequencing, which many people may know of.
Examples of the two. Next-gen sequencing is a test like a uBiome test, where a lot of people get that done. It’s not a test that was ever meant for, nor was it developed for making clinical decisions on patients at the point of clinical care. It’s a research test meant for metadata collection and analysis to quantify signatures, not qualify, I should say, signatures of the microbiota. Meaning, what is a normal GI microbiota looks like on the West coast of the United States, or in Eastern Europe, or in Asia? Because it’s not going to be the same. It won’t be the same in people following different types of diet schemes. What those kind of tests do with next-gen sequencing is they look at a long, long list of organisms in the gut, many of which have no clinical significance that we’re aware of. They’re reporting them as a percentage of the total organisms. They’re never saying how many are there. They’re just saying what percentage of the total organisms does this genus of organism makeup, or they can look at it from the phylum level. They’re only looking at one little portion of the DNA.
It restricts them from getting down to the species level, and they certainly cannot get to the level of looking at the characteristics of the organism, like virulence factors for instance, which answers the question, is this form of lets say, H-pylori a problematic form, or a benign form? Because it was never meant to do that. They don’t look at pathogens. They don’t quantify anything. It’s a very valuable test for research. The reason uBiome, and companies like that are doing that test is to try to answer these questions, and find these major associations between overgrowth in one way, and a certain autoimmune disease, and what they were really doing is collecting massive amounts of data to then monetize it by selling it to pharma as a metadata set to develop drugs and things like that. That’s why you can do the test at such a small amount and actually you’re paying less than it probably costs them to run the test. Same with 23andMe. They made all their money by selling all their metadata to pharma. So, if you’re okay giving your data over, and your genetic information for that purpose, that’s fine.
The GI-Map though, uses quantitative PCR, because it’s a clinical test. We’re looking at a range of organisms in the classes of pathogens, commensals and opportunists that we know have clinical significance. If they overgrow they’re going to cause diarrhea, or they’re going to cause gastric upset, or they’re going cause disease, or they’re associated with autoimmunity. We carve out different sections for autoimmune triggers that we know have this organism has a certain expressed, let’s say peptide on its surface, which looks a lot like a host protein. Organisms like klebsiella, citrobacter, or proteus, prevotella, overgrowing in the gut beyond a certain point, puts the person at risk if they’re genetically susceptible to things like rheumatoid arthritis ankylosis spondylitis, or Yersinia overgrowth and Hashimoto’s or Grave’s disease. I can go on down the line with a whole bunch of other ones, but the test is quantifying using molecular technology across that broad range of organisms that have clinical significance so you can decide for instance, if a pathogen is coming back elevated, it’s beyond a certain cut point, which we know is clinically significant, it means you need to treat that.
You’re not going to get that from a uBiome. It’s just not intended to do that. And then parallel to that, we’re running all of the modern stool chemistry. We’re calculating for inflammation, and even bowel cancer risk. Zonulin for intestinal permeability or leaky gut. Things like elastase-1 for pancreatic excretin output. Steatitic for amount of fat in the stool. Beta glucuronidase for risk for estrogen dominance in females based on the function of their microbiota. Things like total secretory IgA and antigliadin secretory IgA, are you reacting to gluten and gliadin containing grains at the level of the gut lining, that’s mucosal immunology. It’s not a test for Celiac disease per se, but it let’s someone know, hey, maybe my immune response is not super compatible with these field grass greens.
Dr. Weitz: Let’s say you find a pathogen like Yersinia, which you’ve written about how that’s connected with autoimmune thyroid disease. Can you explain how the appearance of a pathogen in your gut can lead to an autoimmune disease that affects your thyroid?
Dr. Brady: Yeah. There’s a couple of possible mechanisms, but probably the most direct line or understood one is a process called molecular mimicry. Let’s take Yersinia as an example since you brought it up. Yersinia on its surface has some proteins or peptides that … All microbes have surface characteristics, structurally. These help communicate with other like organisms. It helps them form a locus of infection, or a colony, and provides communication and other types of things. That is where the immune system learns that organism. So, a naive T-cell let’s say, will be educated to react to that peptide on the Yersinia because other parts of the immune system have looked at it and said, this isn’t me. I don’t know this structure, therefore it must be something foreign. It’s a potential threat. It’s an antigen. Let’s develop antibodies to bind to that antigen to cover all those surface peptides so it can’t communicate and bind and form a locus of infection. But, it’s also being tagged for other cellar elements of your immune response, to take it out basically, whether its phagocytosis of other types of processes. Basically it’s using the structure of that protein or peptide on that surface of that organism.
Now, the reason why we can have an association between not just one microbe, but a long list of microbes and a certain autoimmune disease is because many of these surface proteins or peptides are conserved across various families of organisms. In rheumatoid arthritis, we have klebsiella, citrobacter, prevotella, we have proteus, we have a lot of different organisms, which we have a similar response to. It’s not a one organism, one disease type of scenario. That’s what freaks conventional medicine out, because it rocks the one cause, one disease paradigm. You have to think a little bit more complicated. But, those surface proteins on Yersinia, coming back to the question, have a structural similarity to TSH receptors on the thyroid. They’re not exactly the same, but they’re enough the same that if you also harbor a genetic propensity or an HLA pattern to overreact to that environmental antigen, that you will kind of freakout when you see that reaction. You’re going to then be susceptible to reacting to something else that looks a lot like it.
It’s a mistake in identity. It’s like the TSH receptor is a doppelganger to the protein on the Yersinia, and when you develop these antibodies to bind to that antigen to get to the gut to fight the infection, they see the TSH receptor on the thyroid and they go, close enough, and they lock into your thyroid and they tag your thyroid for destruction by the rest of your immune system and you get an erosive inflammatory response against the gland, which in the early stages creates an over secretion of the gland. So, inflamed glands generally over secrete their hormone. So with Hashimoto’s you get a hyperthyroid state, but when enough of the thyroid is destroyed and you don’t make enough thyroid hormone, you end up in the hypothyroid sort of bimodal presentation of Hashimoto’s. Most people don’t even get diagnosed until it’s in the hypo stage, where they have high antibodies, low hormones.
So, that’s an example of molecular mimicry, but there are other examples that we know, such as if you have bad oral hygiene and you have overgrowth of P. gingivalis, which is the most common organism that causes gum disease or periodontal disease. We know that that organism produces an enzyme, which actually will citrullinate host peptides, so it modifies arginine on host proteins and citrullinates them and makes them a hapten. They’re no longer your own structure. They look foreign to the immune system. The proteins that they citrullinate are things like collagen, vimentin, fibrinogen, all of the things that make up the schematics structures of joints and things like that. You’re really susceptible to develop autoimmune arthritides, basically like rheumatoid arthritis. That’s why in diagnostics when we do a rheumatoid panel, yeah, they do rheumatoid factor, but what’s the other test they do? Anti-cyclic citrullinated peptide.
What’s creating the citrullination of those peptides that has been understood for a while, we’re not finding out is the organism overgrowing in the mouth creating the enzyme, which is facilitating that protein modification. We’re going to learn a lot more about these type of phenomenon in the next 10 or 20 years, I’m sure. We’re probably just scratching the surface.
Dr. Weitz: I just want to point out that one of the really exciting things is, you can have a patient who doesn’t have hypothyroidism, doesn’t yet have an autoimmune disease, and you can find some of these pathogens like Yersinia and some of these other pathogens in the gut, and or you could do auto antibody testing.
Dr. Brady: Usually you do them in combination if you have a strong family history, you’re suspicious for some reason. If you come back with thyroid predictive auto antibodies in a serological test, then we look into the GI microbiota for sure, to find out if there is Yersinia, or is there other changes in the ecology that we need to address by either eradicating the bug that we know is associated and trying to change the landscape to the level of our ability to do so. But, also addressing things like hyperpermeability or leaky gut. We’ll have our eye on the zonulin and the calprotectin marker. We’ll look at anti-gliadin secretory IgA in the case of autoimmune thyroiditis, because we know agglutinate and antibody complexes have an affinity for the thyroid. That’s why people with let’s say, frank’s Celiac disease, where they have significant reaction to gluten and gliadin, they have about 20 times the rate of autoimmune thyroid conditions as non-Celiac’s.
Dr. Weitz: Through this analysis and through a Functional Medicine approach you can truly prevent some of these autoimmune diseases before they’ve even developed. I just think that, that’s so amazing.
Dr. Brady: Hypothetically, we don’t have the long term, longitudinal studies to prove that, but certainly there’s no harm in doing so, and there’s potential big upside. I can tell you that clinically we have seen patients who we did all of these things, taking what we call the straws off the camel’s back. We can’t change their genetic propensity for a certain autoimmune disease. We can’t change our HLA patterns and things like that. Right? At least now. At least yet, but what we can do is change their exposures within our ability to do so, within the ones that we understand. Right? Which is if I have someone that’s coming back with HLA B27, and they’ve got a family history of rheumatic arthritides and things like that, well, I’m for sure going to be doing a stool analysis on them looking for klebsiella, citrobacter, patellare, all of those.
If I find those things, I’m using things to eradicate that to the best of my ability and I’m usually using standardized botanicals, volatile oils, things that have a little bit more of a functional nudging affect and are going to take down those opportunists without bombing everything out. Without getting rid of all the normal organisms, I’m going to backfill with probiotics and the right pre-biotics. I’m going to use the right kind of blocking agents to block antigen antibody interaction and immune proliferation. Things like N-acetylglucosamine. Things like mycologist botanicals. We use these in gut therapy all the time, whether its okra, cat’s claw, aloe, there’s slippery elm. There’s all these kind of botanicals that have historical use in gut function that we used to think just coated the gut and allowed it to heal. Actually they work in a much more complex fashion with glycobiology on blocking immune proliferation and docking of the antigen or the antigen with the antigen presenting cell to the T-cell. And we’re going to be doing things like glutamine, and other things to help the gut lining. Making sure the vitamin D levels are good, because that affects junction expression proteins that can treat leaky gut. We’re going to get them on a good whole fresh food diet. We’re going to get them off of dietary antigens.
Sometimes we’ll run a cellular response test looking for up regulation of innate immunity or inflammation due to certain foods, like an ALCAT test or something like that which is not a food allergy test. It’s innate immune response to food test. We’ll utilize those types of strategies and basically bring everything we can to the fort to change their lifestyle, change the landscape to where … Fasano talks about the triative autoimmune disease. Genetic susceptibility, an environmental antigen and leaky gut. We can’t change the genetic susceptibility, but we can change the exposure in many cases. We can certainly change the leaky gut. That’s where we go after, on those two legs of the stool, if you will.
Dr. Weitz: So, leaky gut or hyperpermeability, you’ve mentioned that several times. That is where the mucosal membrane of the gut breaks down, creating spaces where toxins say, given off by bacteria like endotoxins and other toxins can enter our system and create problems.
Dr. Brady: Right. Correct. Not only LPS, and things from the microbiota, but actual toxins themselves in the food mass, and toxins that are metabolites of the microbiota, but also foods themselves. If we’re allowing translation of complex peptides that are not broken down enough in the digestive process, of food that maybe perfectly benign if you had an intact gastrointestinal lining and adequate stomach acid and digestive enzymes, becomes antigenic and fuels the fire of the immune system if you’re not producing enough hydrochloric acid, or you’re taking a PPI, or histamine receptor, antacid type of medication, and or you’re not putting out enough digestive enzymes, and you have leaky gut. Sometimes it takes a bunch of things to gang up on you, but these things are not all that uncommon.
What the GI-Map tries to help the clinician do is answer a lot of those questions. Are there pathogens there? Are there overgrowth of opportunistic organisms? Are there not enough commensal organisms? But also, is the pancreas putting out enough enzymes? Do you have enough secretory IgA to have proper immune surveillance along the GI mucosa? Are you reacting to gliadin in a way that would be more excessive than what would be considered normal? Is there signs of inflammation, which causes damage to the GI mucosa like calprotectin being elevated? And, are you producing the glycoprotein that can actually directly cause leaky gut, which is zonulin? Trying to put all of those things together, all the clinically relevant markers that make sense for the clinician to need to know.
Dr. Weitz: Do we know how accurate the zonulin measured in the stool is compared to serum zonulin versus zonulin antibodies?
Dr. Brady: I don’t have a nearly as much familiarity with serum zonulin and zonulin antibodies. I know some laboratories do that. I know that there’s been some controversy over serum zonulin as a valid marker of intestinal permeability. But the best data and information out there is on fecal zonulin because that is where the rubber meets the road. It’s the enterocytes producing the zonulin, which is creating the hyperpermeability. I don’t think serum is the logical place to look for zonulin. I think the stool is the logical place to look for it.
Dr. Weitz: Great. This has been an amazing podcast, Dr. Brady. Thank you so much for bringing our listeners some really interesting and clinically useful information.
Dr. Brady: Sure.
Dr. Weitz: Where can listers learn more about you, and your GI-Map testing?
Dr. Brady: Sure. Well, if they just want to access some information about me and a lot of my articles, including the autoimmune articles we talked about and so forth, they can just hit my website at, drdavidbrady.com. Just D-R davidbrady.com. There’s a media tab with articles and things like that. A lot of full text stuff you can pull down. There’s a lot of interviews on different topics, in the media tab as well. If they want more information on global pain and fatigue syndromes like fibromyalgia in my new book, The Fibro Fix, they can just go to fibrofix.com. F-I-B-R-O-F-I-X.com. And then finally, if they want information on the GI-Map test, from Diagnostic Solutions Labs, just go to diagnosticsolutionslab, so diagnosticsolutionslab.com. There’s a whole whitepaper, all supportive literature, lots of webinars, tutorials on interpreting the test, and there’s full clinical support when you order your first couple of tests and you need some assistance with that, as well. There’s instructions there on how to get test kits and so forth.
Dr. Weitz: That’s basically for practitioners. For laypersons who’d like to get your stool tested see a functional medicine practitioner, like yourself Dr. Brady, like myself, Dr Weitz. If you want a listing for a functional medicine practitioners, you can go to the Institute of Functional Medicine website, and they have a listing of functional medicine practitioners. I think a good idea to see somebody like that who can really go through and interpret the data and help you to set up a program to improve your overall health.
Dr. Brady: If there are practitioners out there who are not ordering clinicians with diagnostic ordering privileges, the GI-Map is also available for those practitioners through Evexia Diagnostics. So, E-V-E-X-I-A Diagnostics.com, formerly known as Doctor’s Choice. They have you work with physicians to get the test ordered.
Dr. Weitz: Cool. That’s great. Thank you so much, Dr. Brady.
Dr. Brady: You’re welcome. Thank you.
