Dr. Shoemaker is a pioneer in understanding how low-dose biotoxin exposure, including toxic mold and algae, impacts our health and contributes to disease. Find out what chronic inflammatory response syndrome is, how people get exposed, and who is susceptible.
A few years back, we were living in a home that I later learned had mold, and I was exposed to mold and started to develop some symptoms after my long journey back to health. I started to feel some symptoms again that I hadn’t felt in quite some time and knew that it was something different than what I had been dealing with before. And so over the last year or few years, I’ve been investigating that further, exploring a few different avenues, and after quite a bit of research, I came across SurvivingMold.com, which is Dr. Shoemaker’s fantastic website. So I have a personal interest in this topic for my own health, and then it’s something that we’re also seeing a lot of in the clinic, so I think you’re really going to enjoy this interview.
In this episode, we cover:
4:38 What is chronic inflammatory response syndrome?
12:56 How people get exposed to biotoxins
29:18 Who is susceptible to exposure?
Links we discuss
Chris Kresser: I’m Chris Kresser and this is Revolution Health Radio.
Hey, everyone, it’s Chris Kresser. Welcome to Revolution Health Radio. If you listened to the last episode, you’ll know it was our last with Steve Wright as the host of the show. After several years of doing it together, Steve is moving on to other projects that he has in the works, so from here on out, at least for the foreseeable future, I’m going to be hosting the show myself. I’m going to have more frequent interviews with guest experts, and we’re going to have guest hosts, like Dr. Amy Nett from our clinic, California Center for Functional Medicine, as well as other guest hosts.
So in that spirit, today I’m going to interview someone that I’ve been wanting to have on the show for quite some time. We had a couple of scheduling snafus, but we finally worked it out.
Dr. Ritchie Shoemaker is a pioneer in understanding how low-dose biotoxin exposure, including toxic mold and algae, impacts our health and contributes to disease. He’s the author of eight books and multiple published academic papers. His latest book, Surviving Mold: Life in the Era of Dangerous Buildings, is a guide through diagnosis, treatment, remediation, and return to health. Dr. Shoemaker is currently retired but continues to lecture throughout the US on chronic inflammatory illnesses that are caused by exposure to moldy buildings and other biotoxins.
Before we jump into the interview, I want to put this in a little bit of context for you. A few years back, we were living in a home that I later learned had mold, and I was exposed to mold and started to develop some symptoms after my long journey back to health. I started to feel some symptoms again that I hadn’t felt in quite some time and knew that it was something different than what I had been dealing with before. And so over the last year or few years, I’ve been kind of investigating that further, exploring a few different avenues, and after quite a bit of research, I came across SurvivingMold.com, which is Dr. Shoemaker’s fantastic website, and just spent several hours devouring the content there and then purchased some of his training materials and just took a really deep dive into the world of chronic inflammatory response syndrome, which we’re going to talk more about in the interview.
Then I joined the physician email list, Dr. Shoemaker’s community, and since then have been pursuing this also with patients at the California Center for Functional Medicine for the past six months or so. We’ve been testing patients for this syndrome and beginning to treat them, and it’s been quite an eye-opening experience. It’s turned out to be extremely common in our patient population, and as you’ll hear when I speak with Dr. Shoemaker, it’s something that potentially could be affecting a pretty significant percentage of the population.
So I have a personal interest in it for my own health, and then it’s something that we’re also seeing a lot of in the clinic, so I think you’re really going to enjoy this interview. It’s a little bit longer than our typical episode, and interviews may be like that in the future, but we barely even scratched the surface. It’s a pretty complex and fascinating syndrome, and I’m definitely going to have Dr. Shoemaker back to talk more, and I will also be talking about this syndrome and writing about it more as we go forward. So without further ado, I’d like to introduce you to Dr. Shoemaker and start the interview.
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OK, now back to the show.
Dr. Shoemaker, thanks so much for joining us. It’s a pleasure to have you on the show.
Ritchie Shoemaker, MD: Well, I am delighted to be talking to you today, and thank you so much for asking me to join you.
Chris Kresser: My pleasure. Since this is my audience’s first introduction to biotoxins and biotoxin illness, I thought maybe you could just give us a brief overview of chronic inflammatory response syndrome, and then we can get into some details after that.
What is chronic inflammatory response syndrome?
Ritchie Shoemaker, MD: It’s hard to use the word ‘brief’ when I look at the last 18 years of my life, but if you look at what happened to me, I was a very happy rural family practice physician on the eastern shore of Maryland. We’re between the Chesapeake Bay and the Atlantic Ocean, and there’s not a lot of people here but a lot of really pretty things, and I had a nice idyllic life. Rural family practice is what I wanted. My wife was teaching pre-K, daughter was growing up, didn’t lock our doors, and then an unknown organism called Pfiesteria started making people sick in the local rivers, especially the Pocomoke River nearby. The illness was one that no one had ever seen before, although there were rumors that the organism had made people sick in addition to killing fish in North Carolina, and the state of Maryland saw that, yeah, we had some dead fish here, but I kept on saying we’ve got sick people!
Chris Kresser: Yeah.
Ritchie Shoemaker, MD: And the illness was unusual. It wasn’t one that had abnormal blood tests. There were no markers that we could find, and yet these people were definitely ill. They had fatigue and muscle aching and cramping and abdominal pain and respiratory symptoms and impressive cognitive issues, and what in the world was causing this? One lady had terrible diarrhea, and at a loss and being an interventionist like I am, I said, “Well, I can stop your diarrhea. Here’s a nonabsorbable anion-binding resin that is constipating.”
Chris Kresser: Right.
Ritchie Shoemaker, MD: “It’s called cholestyramine.”
Chris Kresser: Right.
Ritchie Shoemaker, MD: “It’ll stop your secretory diarrhea.” And she says, “Thank you very much,” and two days later was very happy when she called and said, “My diarrhea has gone away.” And I said, “Yeah, old fashioned drug. Us rural docs know all about cholestyramine.” And then she said, “You know, but my cough stopped and my muscles stopped aching. My headache went away, and my memory’s back to normal.” And I said, “It is?!”
Chris Kresser: Wow. Just two days of cholestyramine did that.
Ritchie Shoemaker, MD: Yeah. So all these months of agony, what’s going on, and arguing with politicians if there is a thing, and being accused of all kinds of creative things. I was a quack and a whacko and a kook and all that, but I guess that was not unusual for the time. If you don’t understand something, throw rocks. But nonetheless, I started giving cholestyramine to all my patients who had exposure to the waterways, and they got better.
We had, Chris, no biomarkers. I’ve been working with you, and I keep on saying, “You need biomarkers. You need to measure the labs. You need to do this.” I had none. Talk about being on the seat of your pants. I started seeing people with syndromes similar with other dinoflagellates in Florida. Blue-green algae problems came along. Mold problems mimicked all these things. And by golly, give them cholestyramine, and you know full well their multi-system, multi-symptom illness is going to get better. And that was fine until 1999, three years later, when I started giving people who had Lyme disease, still sick after antibiotics, cholestyramine, and I expected, “Well, this will be no big deal.” And uh-oh, I was wrong.
Chris Kresser: Right.
Ritchie Shoemaker, MD: Boy, did I slam those guys. What in the world could make everybody so much worse? At that time, all we thought the illness was — and I was working with good researchers at the time. After we got a couple papers published, folks stopped calling me a kook quite so much — but nonetheless, with Lyme, this was more than just a toxin, and we know that there had been a patent issued for a Lyme neurotoxin, so I wasn’t on total soft ground, but yet this illness had something more — inflammation from chemicals called cytokines. It was all the fad back then to talk about tumor necrosis factor-alpha, and it was all new, and now when you look at Phil Mickelson on TV, he’s pushing his TNF blockers. And rheumatoid arthritis.
Chris Kresser: Right.
Ritchie Shoemaker, MD: What a difference 15 years has made. Holy cow. But nonetheless, why did only some people get sick and other people didn’t? Here came the immune response genes, or HLA. That was in 2000. My goodness. All the sick people had a particular molecular makeup of immunity, and more cytokines came along, and it wasn’t too long before people in Australia were publishing about a germ that didn’t cause too many symptoms in the nose but lived there but created chronic pain and made chronic fatigue appear, and if it was already there, made it worse. So we started adding coagulase-negative staphs that are biofilm formers to the whole protocol.
Then, you know, people were getting better and that was great, but some, darn it, they just didn’t get better. What were we missing? And it didn’t take too long before complement with C3a and C4a came along. Every year. VEGF would be one thing, and gliadin antibodies another. It wasn’t too long before we had this cast of characters that took about 30 tubes of blood to diagnose. Fascinating development, and this was not funded by NIH. This was not funded by my good friends at the CDC. They didn’t like what the acronym actually stood for, which is the Centers for Discussion Crushin’. But nonetheless, you know, it was a fantastic idea.
So our name was early on a chronic neurotoxin-mediated illness. Then we find out some neurotoxins didn’t cause this, so we had to turn it over to a chronic biotoxin-associated illness because NOAA, the National Oceanographic and Atmospheric Administration, had a lab where they looked at biotoxins down outside Charleston, South Carolina, and Ciguatera and Pfiesteria were organisms they studied, the dinoflagellates. But you know, it wasn’t until 2008, after three years of begging, finally a lab started agreeing that they would run, for $65 a pop, transforming growth factor beta1, or TGF-beta1, and suddenly what we now knew is this was way more than just a toxin illness. This compound could be present and it would deplete the protective effects of special T lymphocytes, these white blood cells that you’ve heard about with HIV populations, CD4 and CD8 population cells, but these were different ones. These were T regulatory cells, and now we had high TGF-beta1 and low Tregs, and folks acted like they were biotoxin patients, but they weren’t. They were much different but still in the same category.
Chris Kresser: Mm-hmm.
Ritchie Shoemaker, MD: And what illness has complement involved and proinflammatory cytokines and antiinflammatory cytokines and genetic susceptibility and TGF-beta1 and then complement? What has all of those at the same time? Well, our good friend sepsis. It’s an acute inflammatory response syndrome, and I said what a minute. That is called SIRS, or systemic inflammatory response syndrome. In 2010, a group of people working in the mold field published the consensus report of expert treating physicians for mold, and we call this illness a chronic inflammatory response syndrome. It didn’t go away on its own, but it was caused by exposure to water-damaged buildings.
So the long answer — sorry for the long answer — is, CIRS is in the jargon, it’s in the books, if you type it in on PubMed you’ll get a lot of hits and a lot of things to read about, but that, in a nutshell, is short of where we were, and I know we’re going to talk about where we’re going.
Chris Kresser: Absolutely. Thanks for that. It’s really important to get some of the historical perspective because I think that helps to shed some light on the context and where we are now with it.
How people get exposed to biotoxins
Let me break down just my understanding of this, and then maybe we can talk a little bit more about biotoxins and how people get exposed. This can be complex for people who are new to it, so I just want to give a brief summary, and of course, you can correct me if I’m wrong, but it basically starts when someone is exposed to a biotoxin, and in most people, this isn’t necessarily a problem. They might feel sick while they’re exposed, but then the biotoxin is tagged and identified by the immune system and broken down and removed, and this is a normal physiological process. But in some people who have certain HLA genetic haplotype, they are unable to recognize those toxins as toxins, and those toxins get recirculated and they trigger this ongoing chronic inflammatory response, and those people remain sick even after they’ve been removed from exposure for years or even decades in some cases. Is that an accurate summary?
Ritchie Shoemaker, MD: It sure is. It might help a little bit to think about the immune system as having a left hand and a right hand just for the sake of a visual analogy. The left hand is where we think about traditional immune responses, and you’re talking about antibody production, which is defective in this illness but not in classical asthma or hayfever or that kind of thing, what we think about antibodies as being overproduced in so many autoimmune illnesses as well.
Here is the other hand of the immune response where inflammation is created by structures called receptors that are designed to recognize foreign antigens, foreign invaders coming from the environment. We breathe them in, sometimes we eat them, sometimes they get inoculated beneath our skin, but the issue is that these structures are not us. Because they’re foreign, there is this innate immune response, just like we talked about in sepsis, reacting to a toxin made by usually gram-negative bacteria, setting off so many cascades of inflammation.
So when we start thinking about complexity, this illness has way more than what people will think about when they get a cold or when they have a bowel problem, what have you. This is looking at every inflammation response system, essentially, that there is in the body.
Chris Kresser: Yeah. You mentioned earlier on a couple of examples of biotoxins — Pfiesteria, Ciguatera — but it’s not just limited to those and to mold toxins, is it? There are quite a few toxins that have been identified so far that can contribute to CIRS.
Ritchie Shoemaker, MD: The list grows every day. A few years ago, I was at a conference on biowarfare, and one fellow from Togo got up and says, “Is Buruli ulcer, a disease of the tropics, a biotoxin illness?” And I had never heard of Buruli ulcer, and it was not published back then that an unusual mycobacterium called Mycobacterium ulcerans — not Mycobacterium tuberculosis; most people have heard about that one — but this organism makes a biotoxin called a mycolactone, and as such, it creates this spreading superficial ulcer that won’t heal and knocks out white blood cell response. And guess what? Good old topical cholestyramine will fix it.
You might have some recluse spiders out there in California or some that act like that. I know lionfish can be popular aquarium items, and they make their own biotoxins. Lyme sure does. We know that Babesia makes a toxin that’s called GPI — glycosylphosphatidylinositol, for all the crossword puzzle lovers — but the real issue is that we’re not looking at an unusual finding at all. New biotoxin formers are being identified, it seems, just about every day. We know that with the growth of red tide. We know with the change of sea lion populations on the West Coast that some of the diatoms are making unusual biotoxins as well. These compounds are made by biological creatures, hence their name, but they’re small. They can move from cell to cell.
Tetanus is a living bacterium. It makes a toxin. We all know about tetanus, and we know about gangrene and botulism. Those compounds aren’t called biotoxins even though they’re made by living creatures because they’re so big and they don’t move from cell to cell. But moreover, these organisms make compounds that not only move from cell to cell, but they set off inflammatory responses. They are recognized as being foreign invaders. So there’s a whole series of things that go together with what biotoxins are, but you can’t have a biotoxin without inflammation. You can’t have inflammation without a biotoxin.
Chris Kresser: So if we could break these down, these biotoxins, into categories based on where they’re encountered, I’ve heard you say there are three subtypes. There might be CIRS that you acquire from biotoxins that you would encounter in a water-damaged building. These could be mold mycotoxins. Then you have CIRS that you can encounter from Lyme and other tick-borne diseases, like Babesia, which you just mentioned. And then you have biotoxins that you might encounter from dinoflagellate and algae sources.
Ritchie Shoemaker, MD: Klamath Lake used to be one of the resources used nationally and internationally as a source of spirulina, blue-green algae. Wayne Carmichael, who retired and lives now in Oregon, kept on warning people, “Look out. Spirulina can be contaminated with microcystins,” and sure enough, it now is. I think the growing force of cyanobacteria or blue-green algae illnesses, especially in areas that have cycles of drought and flood like California seems to be going through right now, are going to explode. We see the same thing in Florida, we see the same thing in North Carolina, but interestingly, the worst of the cyanobacteria can either be in some of the Great Lakes — and Lake Erie was in the news last year about that — but then we look in Nebraska and Kansas and Montana, areas that are outside, way far away from buildings where you would have indoor toxins. And you’re right; mycotoxins have a role, but inside buildings we have bacteria making toxins, we have actinomycetes making toxins, and then we have a whole host of compounds that by weight and by mass are far, far more important than, say, mycotoxins. And these will be things like beta-glucans and mannans, so don’t be surprised when you hear more and more about biotoxins, especially as we have kind of dried-up lakes coming back to life in California.
Chris Kresser: Right. Well, let’s talk a little bit more about water-damaged buildings because I think a lot of people are initially surprised, at least my patients when I tell them how common water-damaged buildings really are, and you’ve done some great research on this and talked about it a lot, so what do you say to the person who says, “I live in Phoenix or Las Vegas, and mold can’t possibly be a problem to me because it’s so dry here.”
Ritchie Shoemaker, MD: Well, it’s an important point, in that I just simply say, “Do you live indoors?”
Chris Kresser: Right.
Ritchie Shoemaker, MD: “Do you have plumbing? Do you have a roof? Do you have a swamp cooler?” — a funny air conditioning mechanism that’s guaranteed to make people ill. And the guy says, “Well, yeah. They never hurt anybody.” And I say, “Well, as a matter of fact, they do.” Once you create environments of additional moisture, unwanted moisture intruding into what we call the building envelope — that’s the roof and the walls and the floor and the windows and all the accoutrements that go with homes — once you have that water intrusion, you create microhabitats. And then actually to think about it, whether you’re in Phoenix, where it might be 120 — but a dry 120 — outside, it might be 65 to 75 inside, and that’s not going to be so dry if your roof leaks or if you have the wrong size HVAC equipment so you never dry out the air. So even areas that you would never dream to be a problem are at just as high a risk to be moldy as if you lived in Hurricane Alley down in the South.
Chris Kresser: Did you see that in your practice when you were treating patients, that the distribution of CIRS didn’t follow a particular geographic pattern? Or did you find that it was more concentrated in particular areas?
Ritchie Shoemaker, MD: People would not travel from the Southwest much to Pocomoke — it’s hard to get to; you have to fly to Philadelphia or Charlotte and then to Salisbury — unless there was a really good reason, so I had fewer patients from the Far West, but interestingly, they were sicker. And the key issue to me was that they had, I think, underestimated the possibility of acquisition or exposure because of this idea that the outdoors is the only criterion. And there are a few people that truly are sickened by the outdoors — and in our conference, which we’re going to have in Phoenix, you’ll hear from Erik Johnson, who has done some wonderful observation work — but the vast majority of people are not sickened by outdoors. They’re sickened by indoors.
Chris Kresser: Mm-hmm. So what are the statistics? What proportion, on average, of buildings are water damaged? Are we talking about 5%? Are we talking about 50%? I think I recall something around 30% or 40% from one of your talks.
Ritchie Shoemaker, MD: If we are going to believe the researchers from NIOSH, the National Institute for Occupational Safety and Health, in 2011, they tried to answer that question and came up with 50%. The answer for people who have been sickened, who have particularly adverse and increasingly susceptible HLA types, is that when they’re told they have to move out of their home or workplace or school — which is a devastating directive to give as a physician; it’s very expensive to give up your home, very expensive to give up your job — but when they finally buy into this idea of I have to leave, then you start seeing, “Well, I went to the apartment complex. It had a flat roof, and I was looking at a flat that was below grade, so I was in the basement. And there was no evidence of any water, just a musty smell all the time, and I got sick within two days.” Someone else would say, “Well, I left my job and I worked on Figueroa Street with all those big tall high-rise buildings in downtown LA, and I had no idea the women’s bathroom on the sixth floor flooded all the time, and I was on the twelfth floor, and I was getting sick from the air in there. There was nothing wrong with my building at all.” And then the fellow from Chicago says, “I couldn’t be sick from my building. It’s a brand-new structure. It was build lickety split, just the finest in workmanship.” I said, “Oh, really? And built lickety fast?” “Well, yeah.” I said, “Well, how many plumbing leaks are there? How much wallpaper is put up that won’t let air breathe through a wall?” And how much and how much and how much? You start to find out that easily 50% of the buildings in the US, whether they’re homes or workplaces or especially schools, are ones that will make previously affected people ill.
Now, newly exposed people, the numbers are not quite so much. There has to be an intervening illness that almost primes or sets off the susceptibility of the HLA, and in those people, we’re back down to our 24% incidence of people with new kinds of illnesses. And every time we screen large numbers of people, whether teachers and students in a school or workers in a building, 24% shows up, and that parallels with greater than 95% certainty the HLA types. So if you say, “I don’t have a mold-susceptible HLA. What are my chances of getting sick?” Less than 5% is the right answer there. But if you do have an HLA that’s susceptible — and there’s six different kinds that are really rough on you — you have a 95% chance of developing it.
So if we look at 24% of the population found in 50% of the buildings, golly, we’re down to about 40 million people that are theoretically at risk. They’re walking around saying, “I’m a little tired because I’m stressed or maybe I’m having some trouble at work or maybe I’m having trouble at home. My daughter or daughter-in-law, found out she’s doing heroin now, and boy, I’m just having trouble.” And the guy says that to the doctor who doesn’t take a history of the multi-system, multi-symptom illness, on the antidepressants they go and away goes another patient misdiagnosed.
Chris Kresser: Yeah, and it’s only going to get worse from there. This is certainly a huge problem. As you know, we’ve been addressing this in our practice for the past six months or so, and I think I’ve yet to see an HLA test with someone who didn’t have a mold-susceptible gene. And of course, I’m treating people who are very sick, so it’s not a representative sample of the general population, but I was somewhat shocked even to see just how common this genetic susceptibility is in my patient population. And of course, as you also know, this is something I’m dealing with myself and have a great personal interest in, but it’s just really remarkable to me to see the percentage of sick people that are susceptible to CIRS.
Ritchie Shoemaker, MD: I deal with a lot of physicians in similar stories. Oftentimes it’ll be a loved one or a personal illness or a family member that kind of gets them clued into looking into what may be true, but let’s be fair here, Chris. You have picked up on this illness rapidly and aggressively, and quite frankly, compared to just about everybody else that has gotten into this field, you’re running with it with more authority and, quite frankly, courage, so if I can give a little tip of the hat and a shoutout to you, let me do that because I mean every word of it.
Chris Kresser: Well, thank you. I appreciate it.
Who is susceptible to exposure?
So let me just take a step back because I know for some people some of this might be going over their head. As you just said, there are kind of two components to determining who is susceptible to this. One is having a certain genetic haplotype, and as you said, that’s present in about 24% of the population. But that’s not enough alone. You also said there has to be a sensitizing event or illness, so what kinds of things are we talking about there?
Ritchie Shoemaker, MD: To put this in perspective, we’re born with our given HLAs. We can’t change our HLAs. But given the HLA and, say, exposure to elementary school, high school, what have you, many people will not be sickened until they have one kind of illness that’s dominated by a lot of inflammation.
In Mold Warriors, I put out the story of Libby Kyer, a famous artist living on the Front Range in Colorado. She was fine, almost had a spring running through her basement with mold everywhere, but it never bothered her until she had a terrible CMV pneumonia and was in the hospital. They were going to put her on a respirator, and she comes home to recover only now to be slammed by what’s been in her basement for years.
The post-Lyme syndrome is a real bugaboo for folks who live in Lyme-endemic areas because they struggle to get better, struggle to get better, not knowing the inflammation from Lyme has set off their HLA susceptibility, and now if they’re exposed to a water-damaged building, they’ll get sick, but they wouldn’t have before Lyme disease.
Chris Kresser: Right.
Ritchie Shoemaker, MD: There are some other things that are a little unusual. You think about mono and I mentioned CMV, but Epstein-Barr virus is one that gets a lot of play in the chronic fatigue world. HHV-6A and HHV-6B get a lot of play in the chronic fatigue world, bornavirus as well, but these are all inflammatory illnesses, and once you recover, people develop the post-bornavirus syndrome and the post-EBV syndrome, and some people think that these viruses are very important, and yet what do they do? They set off defective antigen presentation.
It could be an enterovirus, coxsackie and echoviruses. My good old friend, the unusual illness name, my favorite name, Kawasaki’s disease. And when I say that, people make jokes about motorcycles, but it’s no joke if you are getting an aneurysm from Kawasaki’s disease.
It could be even, of all things, multiple yellowjacket stings. We’re seeing some folks who take an antibiotic, Cipro, are developing these kinds of inflammation. The Gardasil vaccine for those that are 11-3-52B, fortunately only about 1% of the population, but this can be devastating to young women who take Gardasil if they have that particular HLA makeup.
So there’s not a limit to inflammation-causing illnesses to result in activation of HLA, and whether that occurs at 5, 15, or 55 is only predicted by what is going on with the immune responses.
Chris Kresser: Mm-hmm. OK, so we have this genetic predisposition; we have an inflammatory illness that triggers it. Now I want to talk a little bit about the signs and symptoms here, but as a framework, I want to go through the biotoxin pathway because I think understanding, at least in broad terms, how CIRS affects the body physiologically can help people understand how it’s possible that it could cause such a wide range of symptoms because it’s really vast.
We’ve talked about Stage 1, which is biotoxin effects, you know, get exposed to a biotoxin and then people with this genetic haplotype can’t get rid of it.
Stage 2 is the cytokine effects, where you have this whole cascade of things that happens from elevated cytokines. So tell us a little bit about the symptoms that we might see in this stage with the cytokine effects.
Ritchie Shoemaker, MD: The classic story is people who develop flu-like symptoms. You have an influenza virus or one like that, and you know you’re getting sick. You don’t feel good. Your coworkers say, “Are you feeling all right? Your eyes don’t look right.” You get a headache, and you get a problem with being tired. “Gosh, I can’t get my head off of my desk.” And your muscles are aching. “I need to go home. I need to lie down. Give me some chicken soup,” or whatever you’re going to do. But this is the type of response that goes with proinflammatory cytokines. There is going to be a nearly immediate, maybe 4 to 8 hours’ lag time before there is a compensatory anti-inflammatory cytokine response. And here is the time where you have IL-4 and IL-8 and IL-10 and IL-13 come pouring out to knock out those bad proinflammatory cytokines, and here’s where people start noticing the chills and fever and these shaking issues. This is the cytokine warfare, this storm going on throughout you, and if you heal that storm, the chills and fever go away, a day or so goes by and most people will say, “Boy, that was rough. I lost a weekend. I slept for 12 hours.” That is a situation where our protective anti-inflammatory mechanisms worked.
But what if there is a complication from a cytokine event early on in the course of the illness? This cytokine activity can actually bind in the brain to a receptor for the most important calming neuroregulatory peptide called melanocyte-stimulating hormone, MSH. MSH will correct innate immune excess beautifully if it’s present in normal levels and normal amounts. But cytokines bind to the receptor that is needed to make MSH, and if those cytokines log on and stay attached to the receptor in the hypothalamus, you now will go to the second phase where you have your IL-10. Your anti-inflammatory cytokines now don’t have anything to regulate them. They will initiate additional cascades, C3a, C4a coming out within 4 to 24 hours, TGF-beta1 coming out within 16 to 24 hours. So in terms of symptoms, it doesn’t take too long before a headache and muscle ache and feeling bad and red eyes turns into exhaustion to the point that you can’t get your head off the pillow, and someone looks at you and says, “Well, you look fine to me.”
Chris Kresser: Right. And a lot of the typical labs that might be tested aren’t necessarily out of range either because, of course, most physicians aren’t testing for MSH, they’re not testing for MMP-9 or TGF-beta1 or C4a. I often see patients who have CIRS, who have been to 15 or 20 different doctors and they’ve had the basic workup, and they’re told that they’re normal. This is a common story I’m sure you encountered plenty of times, too.
Ritchie Shoemaker, MD: One of the fascinating issues is this attitude — and I sometimes will pick on physicians that believe what they say. They make an assumption, and they assume that the assumption is correct. I call it ass-squared medicine. Assumptions of assumptions are a problem. But there’s also an attitude that says the physician is the keeper of all knowledge, and if he doesn’t know what the illness is, therefore the illness is psychiatric.
Chris Kresser: Right.
Ritchie Shoemaker, MD: That’s one of the most poisonous attitudes of all. Fortunately, and I know as you’re getting into NeuroQuant, you’re starting to see that there is an answer to the psychiatric diagnosis. I mean, show me the blood test for depression, will you?
Chris Kresser: Right.
Ritchie Shoemaker, MD: How about manic depressive illness? Or how about somatoform illness or malingering? Show me that on a blood test. Well, we now can show CIRS in the brain sorted by the kind of illness that engendered the difficulty with executive cognitive function and anxiety and depression and all that. It’s absolutely fascinating then to initiate treatments for the proper illness of inflammation because you can do the tests. These tests are all covered by most insurance companies, and you can check with Medicare. They’re getting a little pennypincher. But the real issue is that once you show that there’s inflammation, you can image the brain and show that these cognitive issues previously blamed on psychiatric causes are actually just due to plain old inflammation.
Chris Kresser: Or aging, right? Just getting older.
Ritchie Shoemaker, MD: Yeah! I get to hear that all the time now. You youngsters.
Chris Kresser: Yeah. OK, so we have Stage 2, the cytokine effects, and essentially you feel like you’re sick all the time. You feel like you’re getting a flu. And when I explain it that way to patients, there’s a light that goes on and they say, “That’s exactly how I feel all the time!”
Then we move into Stage 3, which is reduced VEGF, and this is vascular endothelial growth factor. So tell us what happens when VEGF levels go down.
Ritchie Shoemaker, MD: When I made up the biotoxin pathway initially, it was without information about TGF-beta1. TGF-beta1 is one of the fast reactors, as if VEGF, and if there is a problem with a reduced delivery of oxygen in the capillary beds, so-called capillary hypoperfusion, VEGF will be released. It has the job to increase oxygen delivery, and if it’s around long enough, it’ll increase formation of new blood vessels. That’s why VEGF is a big deal in cancer and anti-VEGF drugs are wonderful cancer chemotherapy agents, but low VEGF is so common in this illness because initially capillary hypoperfusion from cytokines comes pouring out. VEGF rise triggers TGF-beta1 to come out secondarily. It suppresses VEGF. So now this milieu of low oxygen delivery inside the matrices of delivery factors for cells, now it’s complicated by worsening of oxygen delivery.
You hear a lot of people saying, “Well, I have a mitochondrial illness. I have this wrong with mitochondria.” If you’re not giving oxygen to the poor mitochondrion, it’s not going to do what you want. It’ll only make 5% of the energy, or ATP, from each glucose that you have. So if you start needing to move around and you have a low VEGF and you have all this inflammation, you’ll burn up your glucose like crazy.
Chris Kresser: Right.
Ritchie Shoemaker, MD: If you’re like most people with this illness, as MSH starts to fall, leptin can try to drive MSH, and leptin can rise, making people get heavy. And it does so by protecting fat stores so that the poor body — remember, someone is not feeling good. They got out of bed and tried to make a cup of coffee and had to sit down without even making a piece of toast or an egg or anything, and they try to do something more. They are now burning sugar until it’s gone. When they burn sugar up, they tell their body protein to break down into amino acids. Two of them, alanine and glutamine, are pretty quickly converted over to sugar. So the guy can get through a day, but he’s burned his sugar reserves and now he’s burning protein as well. He’s losing lean body mass, but he’s gaining fat mass. So this illness is now in a stage with reduced VEGF. Now we have metabolic processes. As MSH declines, so too does the level of beta-endorphin made when MSH is made, so we have chronic pain, chronic fatigue, and unexplained weight gain that will never go away.
Chris Kresser: That’s fascinating, and this is something I haven’t asked you about, but it just occurred to me, and it makes perfect sense. If you have a hypoxic situation where energy production isn’t able to occur or it’s limited and there’s a shift to anaerobic energy metabolism, do you see a corresponding rise in lactate and other markers that you would expect to find in some mitochondrial conditions?
Ritchie Shoemaker, MD: I told you you’re perceptive. I really meant that. We measured lactate in the brain using MR spectroscopy before we had NeuroQuant, and that was one of the most sensitive indicators of capillary hypoperfusion. We saw as a consequence of lactate elevation we had a reduction of glutamate, the excitatory neurotransmitter, to glutamine, which is an inhibitory transmitter, and that was one of the elements that compounded this brain fog and confusion that people had. And even before we could show damage to gray matter nuclear atrophy — and we can show that — we were able to show the high lactate had direct measurable correlates in the central nervous system.
Chris Kresser: Yeah, that is really fascinating.
OK, so Stage 3 was reduced VEGF, and Stage 4, we go into immune system effects, inappropriate immune responses, which could include antibody production to gliadin, AKA gluten sensitivity, autoimmune conditions like antibodies to actin or ANCA, like ulcerative colitis, cardiolipins. And what’s really interesting to me is there have been a number of triggers identified already for autoimmune disease, but here we’re talking about CIRS being a trigger for very common autoimmune diseases, and it’s rarely investigated as a potential underlying cause — and even more than that, a treatable cause.
Ritchie Shoemaker, MD: Well, that’s, once again, very perceptive. Now that we know that TGF-beta1 levels as they rise are acting as one of the controlling mechanisms in this illness, it will send — remember we talked about the good guy, T regulatory cells — it will send Tregs into tissue to suppress inflammation and suppress autoimmunity, and that’s exactly what it does unless in CIRS there’s reduction of a tissue-based component, another acronym, retinoic acid orphan receptor, or ROR. If your ROR is low and the Tregs come in, those cells are plasticized. Here’s the tissue basis of CIRS, and these cells, as they’re plasticized, are turned into T effector cells that worsen inflammation, worsen autoimmunity, and stimulate increased production of TGF-beta1, which — guess what? — in return, will send more Tregs into tissue. Remember I told you about the Treg imbalance with TGF-beta1. Hugely important in this cascade of illnesses because if you’re trying to fix, say, a Lyme patient with post-Lyme syndrome and you don’t fix their Tregs, they will never get better.
Chris Kresser: Have you actually had situations, then, in your practice where you’ve seen gluten intolerance and other autoimmune conditions resolve after taking a patient through the various steps of the protocol?
Ritchie Shoemaker, MD: Oh, absolutely. It’s one of the things that’s kind of hard to tell other people. If you think that you have the non-celiac gluten intolerance syndrome — and Alessio Fasano, who is kind of the father, in my mind, of the immune thought about celiac disease, is really looking at this more carefully. MSH is hugely invested throughout the GI tract, and in MSH-deficient states, Tregs are allowed to reside just underneath the tight junctions primarily of cells in the jejunum and ileum, and they loosen those tight junctions to the point that gliadin — remember that’s about an 18-amino-acid piece, a fairly large molecule, as far as the body goes — can actually get beyond the tight junctions. They’re loosened from zonulin and all this, but they get into the Tregs. The Tregs say, “Here’s a foreign invader,” and they set off this autoimmune response to gliadin. It all comes from eating gluten, but when you break down the mechanism, the mechanism is MSH deficiency, which comes from early on in the stages of reduction of MSH due to cytokine excess.
Chris Kresser: Yes, Dr. Fasano is an incredibly sharp guy. We had him on the podcast a while back, but at that time, I didn’t know anything about CIRS or MSH, so I didn’t get a chance to talk to him about that. I didn’t know he was investigating that as well. That’s really interesting.
So this takes us through Stage 5, actually, because this was low MSH, and as you said, I mean this was one of the big aha moments for me when I learned about this, is how low MSH can actually be a major contributing factors for leaky gut. Because what I was noticing was that patients that we had in the practice, we would do all the things that we normally do to address gut health that are usually helpful in most cases, but in this subpopulation of patients that we had, they just weren’t getting better, and their gut was not responding to any gut treatment. And I think this has been one of the missing pieces, that we weren’t at that time looking at CIRS or MSH as a contributing factor. So no matter what these patients ate, no matter what we did about other gut problems they had, like SIBO, they would continue to have symptoms, and I’m really excited now to be investigating this further because I do think that MSH is a big player here.
Ritchie Shoemaker, MD: We’ve talked about MSH more than once on this discussion, and there certainly is a lot we could add in, but somewhere we have to recognize that MSH is a compound that’s being intensively investigated. There’s a pharmaceutical company that went public with their IPO and generated $170 million to research MSH. It’s a very small protein compound. They never came up with anything in six years, despite raising all that money. They sold the rights in 2007, I believe it was, to an outfit in Korea for $500 million, and still we’re waiting for a medication to do what MSH does. It suppresses inflammatory responses. It suppresses cytokine changes. It corrects so many problems with surface and immune function and mucosal immunity. It stabilizes so many hormones that are way out of whack in this situation. Whether it’s ADH and osmolality or ACTH and cortisol or androgens, MSH is kind of the master player along this way.
But there’s another master player that does similar kinds of things actually and more, called vasoactive intestinal polypeptide, or VIP, so that while we can’t get MSH legally in the US and the FDA is pretty fussy about what it’s going to let us do, we can get VIP. So every time I’ve mentioned MSH, if you have a transcript of this discussion, just substitute VIP in for what I said for MSH and recognize that all in due time, at the proper time in this protocol, we can step in with VIP and correct these abnormalities. And more importantly than fixing the autoimmunity of gliadins and fixing ulcerative colitis and all that, we also know we can fix the underlying changes in the human genome created by inflammation.
Chris Kresser: Which is just so fascinating and exciting. My audience knows that one of the principles of functional medicine is getting to the root of the problem instead of just dealing with symptoms or downstream effects, and you can’t go really any more fundamental than that, than what VIP is doing with the genome.
Ritchie Shoemaker, MD: I don’t want to jump in and disrupt kind of how you planned this discussion, but now that we know — and preliminary results of a paper we’ll be publishing in about two months — now that we know that not only can we correct regulation of gene transcription — that’s an important element — but we also can correct regulation of regulation of gene transcription. This is a whole other layer of control where we are seeing disruption of normal activity of regulation of regulatory elements. Chris, I’m sure you read through the genomics paper I published in April of this year.
Chris Kresser: I did.
Ritchie Shoemaker, MD: It’s a whole new world of gobbledygook, and if you start thinking that, “I’ll just read through 25,000 protein-coding genes and memorize those acronyms,” I’ve got news for you — it’s not going to happen. So as we go forward, we have to be letting your audience know that, yeah, the blood tests we measure in the blood, or proteomics, are incredibly important, but the genomics go hand in hand, and if you’re looking for the ultimate cause, this lack of regulation of regulation of gene transcription is where we are. That’s where epigenetics is living. That’s where a final return to a healthful state needs to be. It’s in our radar sights right now.
Chris Kresser: Well, I’ll definitely have you back on the show to talk more about genomics and PAXgene analysis and NeuroQuant and VIP and some of the treatment part of this. There’s so much, of course, that we could talk about.
We’re nearly through with the biotoxin pathway. Stage 6 is MARCoNS, and this is a good segue because we’ve been talking about low MSH and the downstream effects of low MSH, so tell us a little bit about MARCoNS — you mentioned it earlier in the show — and what happens when someone has a colonization of antibiotic-resistant coagulase-negative staph in their sinuses.
Ritchie Shoemaker, MD: Remember the first time you were a medical student and you drew somebody’s blood. They had a heart valve condition and they were doing poorly, and you were asked to do the work, and back from the laboratory came a report of a skin organism, a coagulase-negative staph. Maybe it never happened to you, but it happened to me, and the attending would say, “What’s the matter? Didn’t you clean the skin properly, stud?” And come to find out now if you have an artificial hip or some prosthetic joint put in or if you have a heart valve that’s been installed, the third most common cause of those hips and heart valves needing to be pulled out are these coagulase-negative staphs that form biofilm, and they laugh at the idea that they’re benign. So does the guy who had to have his chest cracked a second time.
The group at Newcastle University in Australia between Sydney and Brisbane were the first that I know of to publish in the world’s literature showing these organisms make a compound called a delta toxin that breaks down MSH by itself. They also will cause a change in these organisms and start making antibiotic resistance factors, and curiously enough, as they make compounds they send out from their biofilm — you know, biofilm is like a polysaccharide or a sugar igloo that lets these little organisms that should be swimming around like planktonic forms, being very nice and happy by themselves, in a group they will have differentiation of function. It’s fascinating. Why these organisms can live as a group together is curious, number one, because everybody was independent to start, but they start living like a multicellular creature by some organisms having genes turned on and other ones turned off, and they go around and round and round, making these extracellular products that are genomically active, that knock out MSH, that foment inflammation, all the while sitting in the back of your nose, not announcing to anyone in the world that they’re there. The Australian group found them.
We do nasal cultures with a special lab technique that stops the overgrowth of these slow-growing organisms. Normally if you try to put those onto a culturette, what’s normally in the nose will just grow so fast, the biofilm former hadn’t even woken up to get out of its biofilm to, say, make a new cell, so your culture comes back negative. But we now know that specific of these coagulase-negative staphs not only must be eradicated to return to health, but can be reacquired with re-exposure to water-damaged buildings or to loved ones who have these organisms or to, of all the things, the family dog.
Chris Kresser: Right. All right, so finally we have pituitary hormone effects, which, of course, can cause a just shockingly diverse range of symptoms because the pituitary governs all hormone production in the body and hormones regulate just about everything. What are the main players here, and what are some of the characteristic symptoms? One that comes to mind is the electric shocks from static electricity, a red flag symptom there for CIRS.
Ritchie Shoemaker, MD: I can remember when I used to collect data on ACTH And cortisol. I would see some people with an ACTH of 100 and cortisol of 25. You’d go, “My god! He has an ACTH-secreting tumor!” And I said, “Well, I’ll fix the CIRS first and then see what happens,” and guess what? ACTH would return to normal. Cortisol would return to normal.
Or someone who was told they had adrenal fatigue or some idea like that with very low ACTH and low cortisol, and lo and behold, as you fix the inflammation, that returns to normal as well without poisoning the person with extra cortisol.
We saw the same thing with testosterone. Levels were low and because the enzyme called aromatase is upregulated like crazy, we saw high levels of estradiol, all due to little MSH. And without adequate MSH effects on gonadotropin, you never had normal testosterone pathways, so it was disaster if people took, you know, a little bit of testosterone to try to improve that.
But over 75% of patients will have a problem with antidiuretic hormone. You’ll see these folks, and they say their headaches are migraines that last a week. Well, that’s not a migraine. You’ll see them in the cardiologist’s office with a positive tilt table because they’re volume depleted with low ADH because they’re not holding onto free water. They walk around with high levels of osmolality. Their headaches are there from the salty blood. They’re tired because when they stand up they start feeling weak, woozy, and wobbly, and they’re told they have POTS syndrome if they have pulmonary hypertension and low VIP along with it.
But you’re right. The best symptom of all — one day I had two people tell me that they turned on a lightswitch with their elbow, and I said, “What in the world would you do that for?” It was not in any book, and I had read the book and it wasn’t there. And they said, “No. It hurts a lot less when I get the static shock on my elbow compared to my fingers.” I’m going, “What. You have a bad light switch or something, grounding?” “Oh, no, no. It’s doorknobs, on a car, outdoors, and people and drinking fountains.” I’m going, “Wait a minute. How in the world does this person have an electromotive force on their skin being discharged to ground,” and so I took a wild-ass guess and said, “Let’s measure their electrolytes in their sweat,” because we do that with cystic fibrosis. The highest chloride levels you find there are in cystic fibrosis. But the levels of chloride in these folks with static shocks was even higher! They were batteries on their skin. It was all because without ADH they lost free water, the blood got saltier, the sweat gland poured out extra salt onto the skin in an effort to bring the osmolality back to normal, and that all worked fine until the person tried to open a door.
Chris Kresser: Yeah! And that’s a memorable symptom. It’s not one you’re likely to overlook once you tune into the fact that it can be a red flag for CIRS.
Ritchie Shoemaker, MD: You know, if your listeners are paying attention, and I’m sure they are, they’ll probably say, “You know, I have that as well.” And yet when you as a physician ask a patient, “Do you notice that you get an increased frequency of static electrical shocks?” They’ll look at you with this, “How did you know?!”
Chris Kresser: Yeah, it’s amazing.
I want to wrap up because we’re nearing the end of our time here. I’m definitely going to have to have you back at least once, if not more, because there’s just so much to talk about here, and I think this is so significant. Like I said before, we’re seeing it so commonly in our practice, and I just want to finish up by saying a couple of things.
First is that Surviving Mold, which is Dr. Shoemaker’s website, is just an incredible wealth of free information. When I first discovered that website, I think I spent about three hours on it, reading everything I possibly could. You can get a ton of information there, and I highly recommend that you visit if you’re interested in this and you think you might be dealing with this syndrome.
The second thing is Dr. Shoemaker has several books, and those you can also learn more about in the store. The most recent, I believe, is Surviving Mold: Life in the Era of Dangerous Buildings, which I’ve read and is a great introduction to this subject if you’re new to it. Is there anything else that you would like to tell folks that are new to this and who are just kind of dipping their toe in the water in terms of initial resources to check out?
Ritchie Shoemaker, MD: Your listeners may know more about surfing than people who live around me. A big wave here is 4 feet.
Chris Kresser: Yeah!
Ritchie Shoemaker, MD: We’re like the rider who is on the crest of the wave as it starts to curl. There is a huge cascade of inflammation — and if that’s water in this analogy, so be it — but this inflammation is going to explode. It’s not just the genomics. It’s going to be use of medications to correct genomic abnormalities. So sure, learn the basics, get past the jargon problems. There must be 50 YouTubes if people want to use that for some learning. If you want to buy a book, Surviving Mold: Life in the Era of Dangerous Buildings. I call it Mold and Peace because it’s too long, but at the same time, there is so much new, and the key issue for me is there also is a lot of material that you might hear from the internet or out in the world that’s just plain wrong, so stick with material that is based on science, that’s been peer-reviewed and published. We’re not guessing. We’re not playing games with people’s lives here. We’re looking at what is real and what can we do to restore lives of our patients.
Chris Kresser: That’s exactly what this is all about. Dr. Shoemaker, thank you so much for being here, and thank you so much for the incredible contribution that you’ve made in this field. It’s just astounding to me the way that you’ve put all of these pieces together over the years, and as a clinician treating patients — I know that you know this — it’s such an empowering thing to have a new framework or understanding that can offer hope to people who have basically been hopeless and have lost all hope that they could ever get well, and that’s really what I live for, is being able to help patients like that to recover their health, so thank you for playing such a big role in that discovery process for me.
Ritchie Shoemaker, MD: Well, your words are very kind and they’re much appreciated. I was getting goosebumps when you were talking because to me it’s clinicians like you coming along, replacing the old guys like me. It’ll be you that takes this to the next layer. It’ll be you that takes the next step. It’ll be the Kressers of the world that truly are giving far more than what I have learned.
Chris Kresser: Well, thank you again, and I look forward to having you back so we can geek out even further on NeuroQuant and VIP and PAXgene analysis.
Ritchie Shoemaker, MD: Sounds good to me. Thank you so much for your time. Bye now.
Chris Kresser: Take care. Bye-bye.
Update: See my next interview with Dr. Shoemaker: RHR: Genomic Testing for Chronic Illness—with Dr. Ritchie Shoemaker
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