Leaving the era of reaction and entering the new era of prediction. I’m Dr. David Brady, with the Division of Health Sciences of the University of Bridgeport. Just some disclosures upfront. I am the chief medical officer of Designs for Health and Diagnostic Solutions Laboratories, and a consultant for Cell Science Systems Labs.
My talk today will be summarizes in two papers that I published, one in the Townsend Letter and another in the Open Journal of Rheumatology and Autoimmune Disease. These papers are available at my website, at Drdavidbrady.com, or the websites of these publications.
There’s no doubt that there’s an epidemic going on, an epidemic of autoimmune disease. There’s an increased incidence of autoimmune diseases across a large spectrum of disorders. In fact, any autoimmune disease you can think of is growing at epidemic proportions. When you look at this slide here, you can see, from about 1950 until about now, the rise in autoimmune diseases, whether they are classically TH1-dominant disorders or TH2-dominant disorders, in the old classic sense of how we looked at autoimmune diseases. They’re growing just way out of proportion with other disorders.
Genes don’t change that fast. The environment has certainly changed a lot. We’re gonna look at how our genes are dancing with our modern environment and what may really be behind fueling this disease epidemic. When you look at this epidemiology data put out in a graph, it looks very similar to only one other phenomena in epidemiology, and that is an infectious outbreak. We’ll even look at microbes and pathogens and opportunistic organisms and what role they may play in the genesis of this epidemic.
But in order to really look at autoimmune disease in the modern sense, the way we’re beginning to understand it, we have to look at it differently, particularly those of us who are not researchers, but those of us who are clinicians. This is the way we learn the immune system and immune diseases and autoimmunity in medical school. We look and dissect the immune system, all the white blood cells, the lymphocytes, all the different sub-types, the cytokine networks, everything, in really minute terms.
This is very, very useful to understand the patho-physiology of these disorders. It’s very useful for researchers and to guide the development of future therapies, but it really doesn’t do us all that good in the office with Mrs. Jones tomorrow. Sometimes we need to look for those simpler, more global or foundational leverage points that we’re able to use with patients immediately, that can really impact their health and their course to either develop autoimmune disease or for autoimmune disease to further establish itself.
So let’s look back at some of those foundational elements. Let’s go all the way back, in fact, to the beginning of the 20th century, and E.E. Metchnikoff, the famous Russian pathologist, the sixth-ever Nobel laureate in 1908, and the father of the orthobiosis theory, and also the person who brought probiotics to modern medicine.
Orthobiosis is simply a good balance, a healthy balance in the environment of the gastrointestinal tract or, as today we know it, the microbiota. What Metchnikoff said was that if the gut is not healthy, the organism is soon to follow. Basically you cannot be fundamentally healthy with an unhealthy gut.
This is not Metchnikoff’s original idea. In fact, if you look into very old traditional forms of healing and medicine, such as traditional Chinese medicine, Ayurvedic medicine, South American Shamanic medicine, old European eclectic medicine, they all came to this same conclusion, hundreds and, in some cases, thousands of years ago, that if the organism or, in this case, the person or the patient in front of you has a bad intestinal situation, they’re just flat-out not going to be very healthy.
Now we move forward to modern medicine and modern science. With things like the human micro-biome project, we’re able to really study the microbiota of the GI tract, very, very specifically, and correlate that with different diseases and chronic disorders. Now, of course, it’s the hottest area of medical research, with abhorring patterns of the micriobiota in the gastrointestinal system being associated with diseases from cancer to cardiac disease to obesity and so forth, but there’s nowhere where there’s more defined associations and now even causal data to show that abhorrations in the GI microbiota can directly link to the genesis of autoimmune diseases.
After all, it makes sense. The gastrointestinal tract is this hollow tube running through the middle of us, that’s not us. It’s technically outside the body, but it runs through the middle of the body. It’s an environment that’s full with millions, trillions, actually, of bacteria. They outnumber our cells at least 100-to-one, and they have orders of magnitude more genetic material than we do. They’re inside of us, basically, or running through the middle of us, I should say, but they’re producing metabolites. They’re expressing proteins and LPSs and many other things that our immune system has to learn to deal with or to combat and to control.
So if you look at the complicated GI lumen running through the middle of us, the only thing that separates that environment full of bacteria and viruses, parasites, yeast, also toxic substances and food proteins that would be antigenic, the only thing that separates that from our immune system proper or our blood stream and our lymphatic stream is a one-cell lining thick, or one-cell thick lining or layer, called the GI mucosa. If the GI mucosa is not healthy and doing exactly what it should do at bringing through things that we need, such as nutrients, in a very efficient way, but keeping out the things that would be deleterious to us, toxins, antigenic proteins from foods, and also metabolites and other things expressed by bacteria, and/or microbes themselves. If the lining of the gut breaks down, we can get basically a deluge of antigenic material, which can overrun the immune system and actually trigger a massive immune response.
There are also situations where, if the GI environment is not exactly healthy, there can be pressures put on the immune system, that we’re going to look further, can make it, essentially, go out of balance and go off the rails, if you will, and actually trigger the body to start actually attacking itself.
Let me illustrate to you simply how just the change on one organism, a bacteria in this case, can cause massive changes and actually even cause autoimmune disease. This is a mouse model study. It was published in The Scientist. There was a very similar study at about the same time in nature, where they took wild-type mice, and they basically had healthy mice. They introduced one bacteria, called helicobacter hepaticus, or H. hepaticus, into these experimental mice. What happened is they caused, essentially, inflammatory bowel disease, which is a classic autoimmune disorder.
It turns out that the helicobacter hepaticus activated TH-17 cells, which released cytokines strongly associated with inflammation, like IL-17. What they then did is they introduced one more bacteria to this very complicated GI micro-environment, and that was B. fragilis. B. fragilis, on the other hand, expresses a polysaccharide A or a PSA. When it’s added to the gut, the dendritic cells of the immune system take it up, present this PSA molecule on their surface, and in turn, activate CD-4 T-cells and inflammatory T-regulatory cells. The T-reg cells release IL-10, which suppresses the inflammatory action of the originally induced IL-17, in effect, shutting off the inflammatory bowel disease.
So long story short, they took healthy animals with a normal GI microbiota for that species. They put in one additional bacteria and caused such massive inflammation and such a massive immune response, that they created inflammatory bowel disease. Of course, inflammatory bowel diseases, like ulcerative colitis, like Crohn’s Disease and others, are running rampant in human populations right now, particularly in western countries. All they did was introduce one other bacteria, and it basically reversed it all, and it returned the animals to health.
We understand what happened with the interleukins and the cytokines and the T-cells and everything else. But to the clinician, the take-home message is it doesn’t take much to go wrong in the GI micro-environment to actually create sort of a foundational stew, if you will, for the production of autoimmune disease. If you look into the scientific and medical literature right now, you will see a whole host of different disorders. In fact, the list gets longer every day, of disorders that are associated, I should say, with either GI dysbiosis or the imbalance of microbes in the gut and/or intestinal hyper-permeability, or leaky-gut syndrome.
Generally, these go hand-in-hand. If you have dysbiosis, you generally have leaky-gut syndrome. It’s really the intersection of those two things in a genetically susceptible individual, with the right environmental antigen that they’re exposed to, that lays the foundation for autoimmune disease.
If you look down this list of disorders, you’ll see a lot of the chronic disorders of our time and a lot of things that end in “itis,” which in medical parlance, of course, means inflammation. But what you will see a lot on here are all types of autoimmune disease, from atopic disorders such as eczema, urticaria, and so forth, to other types of even more complicated disorders with inflammatory arthropathies and inflammatory thyroid disorders and even degenerative neurological conditions that are autoimmune in nature.
So we have to really look to the laboratory, in multiple ways, to try to find out what’s going on in the GI micro-environment, to limit the antigenic exposure of the individual, particularly the genetically susceptible individual, and maybe take some of these triggers off the table, so that they either never develop the autoimmune disease to begin with, or that we can sort of slow down this autoimmune process that they may be suffering from. One of the places we have to turn to to look at the GI micro-environment is, of course, GI testing of the microbiota, using stool analysis.
Now, really through most of my career even, the gold standard in GI stool analysis was using microbiological technologies, plating out bacteria and trying to grow them and seeing what made them grow further, so comparative sugars tests, things like that. It was very, very limited because you really only could deal with anaerobic bacteria or, I’m sorry, aerobic bacteria in some facultative organisms. But the vast majority of the GI microbiota is anaerobic, and you really can’t work with that in the lab, in the traditional sense of microbiological plating.
So we really were only able to look at maybe 5%, 10% at most, of the organisms that we were really concerned with in the GI microbiota, using that type of technology. But with the advent of PCR and then molecular technology, first in research and now available in clinical testing, it really took the blinders off the GI microbiota. We could now look at the GI microbiota in a very detailed fashion, very quickly, very cost-effectively, patient-by-patient, and really determine what is the state of their GI health, at least from a microbial standpoint, and what triggers may be there that we need to modify.
One such test is the GI map, by Diagnostic Solutions, which I helped develop, which really goes through and looks at various classes of organisms, including pathogens, not only bacterial pathogens, but parasitic pathogens, even viral pathogens. The so-called virome is looked at. These organisms are looked at quite commonly in conventional gastroenterology, because they often cause overt symptoms, like diarrhea and different GI distress. However, people can have elevated DNA recovery of these different organisms, particularly the parasites, and even the viruses chronically, which can cause lower-level symptoms, which never create enough of sort of a medical emergency for them to see a gastroenterologist or for this type of testing to be done.
But what we’re doing is we’re leveraging this molecular technology in more of an integrative or functional medicine paradigm, by looking with a wide lens at the GI microbiota. So we’re also using this technological platform to look at beneficial organisms, the so-called probiotics. We’re also looking at a large range of opportunistic microbes, which can usually be found at some level in human GI tracts, in most cases, not always. But if the environment is right, if the stage is set, they can overgrow or over-express. That’s why they’re called opportunistic organisms. They can cause a lot of havoc, including making the immune system sort of do things it should not do and eventually even attack itself.
There’s a lot of specific organisms that are even pulled out on this test in an area which is labeled “potential autoimmune triggers.” These are some of the organisms we will talk about specifically, like citrobacter and klebsiella and proteus, in the genesis of autoimmune inflammatory arthritities, like rheumatoid arthritis and ankylosing spondylitis, for instance, your sienna enterocolitica and autoimmune thyroiditis, and we’ll look at some other associations as well.
But also looked at on here are opportunistic fungal organisms and parasitic organisms, and then you have a normal array of chemistries to look at local mucosal immune response, to look at signs of inflammation, other surrogate markers of infection, the production of pancreatic exocrine enzymes, for proper digestion, and just standard stool analysis markers, such as looking for blood secretory IgAand the like. But this type of testing can be really just invaluable in working with patients either with established autoimmune disease or those that come from family histories of autoimmune disease, and we can really be proactive or preventive in strategies to take some of these triggers off the table.
What the molecular test opens up also is the ability to look at antibiotic resistance genes. So when it comes to treating these different opportunistic or pathogenic infections, if we’re resorting to prescriptive antibiotics, we can try to pick the ones that are most likely to work, that the organisms do not have resistance to, and that the whole GI microbiota . . . that you’re not fostering further resistance by using the inappropriate therapeutic agent.
So why do we really need to look at testing like this? Why do we need to look at the GI microbiota? Well, specifically, I’m going to give you a few examples here, and there are many more than I have time to go into today. But if we look at a simple matrix between overgrowth of gut microbes in a sort of dysfunctional GI microbiota in a patient, and the prevalence of systemic pathologies, you will see on here, for instance, that patients that have autoimmune inflammatory arthritis conditions, namely rheumatoid arthritis and ankylosing spondylitis, almost universally, have an over-expression or an overgrowth or an elevated DNA recovery of organisms like klebsiella, like citrobacter, and even proteus. We’ll talk more about proteus overgrowth in the urinary tract as well, and how that might specifically trigger an autoimmune phenomena.
We’ll look at sienna enterocolitica overgrowing in the gut of many people who have Hashimoto’s or Grave’s or any other autoimmune thyroid condition. Also, campylobacter jejuni and guillain barre syndrome, overgrowth of E. coli, proteus, in general, in autoimmune disorders.
Now what’s going on in these situations where someone may have an overgrowth of this bacteria, let’s say, in the gut? How would that make the body attack its own joints or attack its own thyroid or whatever the tissue may be? It’s really quite simple. If a patient has a genetic uniqueness to their immune response and system, namely they have a certain HLA profile or human leukocyte antigen present, that on their immune cells will recognize an antigenic protein. It could be a protein expressed on a bacteria or by a bacteria, such as a bacterial metabolite. It could be a virus. It could be a protein that’s associated with a certain food that they ate.
All these proteins or these peptides, if you will, have a certain structure. They have an amino acid motif. They’re like trains put together with train cars. If you have a long enough sequence of the same or a similar amino acid sort of train, if you will, that represents this antigenic protein that you, as a unique individual, have an HLA antigen to recognize, to grab onto, and to hold out and wave to the rest of the immune system and rest of the immune cells, “Hey. Look at this protein. This is not me. This is potential danger. We need to get into gear here and act against it. We need to mount and attack.”
Well, that may be exactly what you need. If you have an overgrowth of a certain bacteria, let’s say in the gut, you don’t want it to become a problematic fulminant infection. So the immune system goes to work to sort of knock that bacteria down. It does so by recognizing a protein, by forming an antigen antibody complex, by tagging the organism and calling in the other troops to destroy it.
What happens if the protein expressed on that organism or even a wide range of organisms has a structural similarity to a protein that’s on your host tissue? In the case of klebsiella and citrobacter, they express peptides on their surface that look a lot like peptides that are on the synovial joint linings of your joints. So in an inflamed individual, a person that doesn’t have great immune balance to begin with, maybe they’re eating a very inflammatory diet that doesn’t agree with their immune system, maybe their GI environment is a mess, maybe they’re taking lots of antibiotics. Who knows what the situation might be? But that’s not uncommon these days.
When they’re exposed to this environmental peptide in the form of this bacterial overgrowth or a food peptide, if they have this HLA antigen, they hold it out. They start waving it around. They call in the immune troops, but the structure is similar to a protein on their host tissue. So when these antigen antibody complexes start rolling around the blood, and they see that tissue, they see that protein that looks like the original protein that was environmental in nature, and they stop being able to discriminate between the two. Essentially, they can no longer tell the foreign invading antigen from their own proteins. So they can no longer tell self from an invader or from harm.
This is a phenomena known as molecular mimicry, because one protein mimics the other enough, structurally, where a relatively confused immune system can get very, very confused and start attacking itself. We see the literature very clear here, when we look at data that shows associations between these various types of overgrowths of different microbes and diseases like ankylosing spondylitis, ulcerative colitis, Crohn’s Disease, and many more. In the case of rheumatoid arthritis, this study talks specifically about organisms like klebsiella and proteus.
This is a really interesting study. This was done overseas. This comes to us from the Ukraine. What these researchers did was they mapped or looked at the microbiota in the gut of healthy individuals versus those with rheumatoid arthritis. They very quickly found that the healthy individuals . . . Their mucus membranes of their GI tract were colonized by what you would expect bifidobacteria, lactobacillus, bacteroides, benign E. coli, and other types of things.
When they did the same testing on RA subjects who were actually expressing the disease, it was very, very different. Lots of citrobacter, lots of klebsiella, lots of enterobacter species that are not exactly very, very healthy, but it was clearly different than healthy people. So that shows an association between this abhorrent pattern and rheumatoid arthritis, but it certainly doesn’t really directly suggest that it’s related to the disease or certainly that it causes the disease.
But what they did, and other groups have replicated this since, is they looked at rheumatoid arthritis patients when they were symptomatic versus when they went into a relative stage of being asymptomatic. This happens all the time in autoimmune disease. They basically flare up and become very symptomatic, and then they abate, and then they’re quiet for a while. You see this, for instance, in MS patients. They’re really bad. They can’t even walk. No balance. They’re in really bad shape. Then for no known reason, they get a whole lot better, and they’re better for several months, and then they exacerbate again.
Ulcerative colitis, same thing. You look patients that’ll be in an ulcerative colitis exacerbation. They’re having 30, 40 bloody diarrhea incidents a day. They can’t leave the house. They can’t go to work. They can’t go to school. Then all of a sudden, it gets better. Then they relapse again. Well, what’s changing? Something has to be changing.
What they found here is the GI microbiota is radically shifting. Basically when these RA patients were symptomatic, they had the abhorrent pattern. When they were asymptomatic, they had the pattern of the GI tract of normal people. So that brings up a very interesting question, basically the chicken or the egg phenomena. Right? What happened first? Did the disease flare, and it changed the GI microbiota? Or did the GI microbiota shift, which exacerbated the disease?
Well, we didn’t know in the beginning, but it turns out, from subsequent studies, that it’s pretty apparent that the GI micro-environment shifts, which flares the disease. That also lends more toward actual causality, not just association. We’ll go further with that in a minute.
But if you look at one of these molecular GI map tests, for instance, this is actually on a patient who came in with inflammatory joint disease, having been diagnosed prior at a rheumatology center of excellence near my practice. You can see elevated DNA recovery for citrobacter, for klebsiella, and for proteus. So this is sort of a triple threat here to the immune system, on causing a molecular mimicry over to the joint structures themselves. In fact, that was going on.
So what do we do about this? Well, you can’t undo damage done. If they’ve already had a . . . Let’s say rheumatoid arthritis, ankylosing spondylitis. They have joint anatomical derangement. They have loss of functionality. You’re not going to restore that, but you can slow down the process and maybe even hopefully halt the process, so that they don’t have further damage and further loss of function, because that certainly will occur if you do nothing. Of course, many of these patients are on immuno-suppressants and biologics and prednisone and other anti-inflammatories to control the symptoms, to alleviate some of their pain, to reduce the inflammation, and in many cases, just sort of squash the immune response, but it’s not . . . Those may be valuable, but it’s not really getting at the heart of the matter. It’s not getting at what’s making the dominoes start to fall.
Where if we can take these triggers off the table, we actually may be able to pull the feet out from under the disorder itself. Certainly klebsiella, citrobacter, proteus are not the only characters here though. Provatella or prevatella, I should say, has been strongly associated with rheumatoid arthritis. Other organisms, such as P. gingivalis, for instance, this is an organism very strongly associated, the most common organism, I believe, to cause periodontal disease or gum infection.
So people with poor dentition, bad dental health, do not get proper dental hygiene, don’t take care of their teeth, have bad gums, are much more susceptible to certain autoimmune processes, including rheumatoid arthritis. We talked about the gut being very important in autoimmune disease. We can’t forget that the gut starts in the mouth. So taking care of the oral cavity is very, very important. In fact, P. gingivalis is interesting. This is the first organism where it went from association to causality.
It turns out that P. gingivalis, which is a bacterial strain which drives periodontal disease, produces an enzyme, known as peptidyl arginine deiaminase 4 or PAD-4. This basically mediates the citrullination of proteins, like vimentin, like collagen, like fibrinogen. So it basically takes your own host proteins, those that are very common in the joint structures, for instance, and it actually enzymatically converts them. It citrulinates them, which it puts a citrulline on them. So no longer are they the same structure. So the immune system no longer looks at it as you. It looks at it as a foreign protein. It basically makes your own proteins haptens. Of course, haptens are foreign proteins.
So the P. gingivalis is actually fueling this by the production of a specific enzyme. Herein lies a mechanism of causality. We can take this one step further before we leave rheumatoid arthritis. This is the work of Alan Emriger in the UK, at Kings College. Alan Emriger. I should say Sir Alan Emriger.
He’s been knighted by the queen. So he has the sir designation. So we’ll use it.
Emriger spent basically his career looking at rheumatoid arthritis and what causes it. He took a very different tact than most other researchers, which were looking at agents to suppress the immune system and so forth. He was trying to get to the bottom of what actually may be triggering rheumatoid arthritis. His papers are very well-known, and his work has been replicated around the world. So what I’m about to tell you about Emriger’s work is not unique to the United Kingdom, to their population, or to their environment. It’s been replicated basically in every quadrant of the planet. I can show . . . I show you on this slide all of the different research teams that have worked on this and the years in which they did it.
But what Emriger has basically established is that many, not all, and I stress that, not all, many people with rheumatoid arthritis have an overgrowth of proteus mirabilis. This bacteria can overgrow in a stealth manner. So it’s a stealth infection. By that, I mean they do not have overt signs or symptoms of an infection. They never know that they have it. In fact, proteus can overgrow in the gut, like we talked about previously, but it can overgrow in the urinary tract. It does not cause the classic urinary tract infection symptoms and sequella that we learn in medical school. It doesn’t progress to pain on urination and urgency and to kidney or flank pain and then to actually kidney infection, which is classic in E. coli and other types of acute UTI.
This proteus can lie stealth. It can sit there. It can cause a little bit of inflammation, but it can cause an immune response, a prolonged chronic immune response, that can actually have its sort of bad manifestations somewhere else in the body. It turns out, like this proteus overgrowing in the urinary tract, makes the immune system go off the rails in the following way. The bacteria produces metabolites, like any organism would, including a bacterially derived hemolysin and a bacterial urease enzyme.
The immune system reacts to this hemolysin and urease by producing antibodies against them. These can become auto-antibodies against host tissues, which have a similar structure. In fact, the urease structure is similar to hyaline cartilage and the hemolysin to the HLADR-4 antigen, common in RA patients. So once again, there’s genetic uniqueness here. This can drive damage to the synovial tissues, ultimately expressing in a disease that would be diagnosed as rheumatoid arthritis.
What Emriger did, though . . . It went beyond hypothesis. He actually looked at the structures, and he found the amino acid motifs and the structural similarity between the hemolysin and the urease produced by proteus, and the structures that are actually attacked in an autoimmune phenomena in rheumatoid arthritis. This really explains some of the things that we learned about rheumatoid arthritis in our training, all the trivia that helps us diagnose it and hallmark rheumatoid arthritis, but they never really told us why. Now we know why.
But for instance, we always learn rheumatoid arthritis has a strong female predominance, of at least three-to-one. Well, guess what. So do urinary tract infections. Right? Anatomically, females and males are different. Females are much more susceptible to urinary tract infections, just because of sheer anatomy. The disease onset between 30 and 50 years in RA, this happens to be the time when chronic UTIs become much more prevalent in women. Exacerbation after pregnancy of rheumatoid arthritis. Increased UTIs are a common phenomena after pregnancy, particularly after vaginal delivery, because once again, anatomical structures are further altered, which can create more susceptibility to infection.
The presence of rheumatoid factor in the blood is often a B-cell stimulation against the proteus antigen antibody complexes, created because of the stealth infection. Then finally, sort of the a-ha lock-down moment here is this molecular mimicry structural amino acid sequence similarity between the proteus hemolysin and the HLADR molecules in the rheumatoid arthritis patients’ immune characteristics, but also the proteus urease and the similarity to collagen, but not just any collagen, type-11 collagen.
Why do I say that so specifically? Because type-11 collagen is only found in the joints affected in rheumatoid arthritis, small joints of the hands, for instance, wrists, but it spares large joints, hips and knees, for instance, for the most part. It’s because of the relative level of type-11 collagen in different joint structures. We all learn which joints RA spares and which joints it attacks. But when they taught us that, they didn’t tell us why. Emriger answered why.
So Emriger’s treatment is not right to biologics and strong anti-inflammatories and prednisone and things like that. His treatment really looks more like nuts and bolts, naturopathic medicine. First of all, clean up the diet. Use dietary agents that are diuretics, for instance. High dose of vitamin C, for instance, can be used to diurese the patient, to flush out the organism, but foods that are high in specific sugars, like D. mannose, that are blocking agents, that glob up the protein receptors on organisms that tend to cause urinary tract infections and promote autoimmunity, so that they can’t bind to the host and form a locus of infection, so things like cranberry juice, for instance, aloe, blocking agents.
Women have used cranberry juice as a natural remedy for UTIs for a long time. We know how it works. It’s D. manos in the cranberry. Unfortunately, they usually use Ocean Spray, which is full of sugar and feeds the infection more than it blocks it. But if they used real, true, organic, tart cranberry, it works very, very well. Better yet, today, we have nutraceuticals. We have just straight D. manos powder or other types of nutraceuticals that can get the job done here. But those can be used, along with urinary acidification, once again, high dose vitamin C, lots of water, and diuresis.
Emriger does not turn to even NSAIDS, let alone biologics, unless all of this fails. But one of his main interventions is antibiotic therapy, to kill the proteus. Now the drug he tends to use, that he shows in his research, is ciprofloxacin. Of course, Cipro is a fluoroquinolone which is very toxic antibiotic. So we really try to avoid that if at all possible. It can be very problematic in some patients of mitochondrial function. Some people get sipro-toxicity, which is not fun. So if you really have to use it, you use it, but it’s really a second, third-tier antibiotic, only when other things don’t work.
What we tend to do is be more functional. I put up here, without the name on it, just a commercially available formulation that I’ve used a lot successfully in this kind of scenario, which has the sugar I talked about, this blocking agent known as D. manos, but also things like a very well-researched and standardized hibiscus extract, also urtica dioica or nettles aloe because aloe has a lot of these mucopolysaccharides that also can block bacteria from binding to the ureter, to the bladder wall, to the intestines, and also horse tail and some other botanicals that can be very, very useful.
Sometimes we also use silver as well. Silver compounds, particularly water cluster silver, can be very useful in knocking down many of these organisms, including E. coli, that also causes urinary tract infections, but also even very hard to kill organisms, like MERSA and others. In fact, pharma, with all of the antibiotic resistance, is now turning back to old standard medicine and actually using some silver and impregnating it into antibiotics to improve their kill rate dramatically.
How about other things besides inflammatory joint disease? Well, let’s look for a minute at infections, autoimmunity in the thyroid. We know, for instance, that molecular mimicry has long been theorized in autoimmune disease, including in thyroid autoimmunity. We know that viruses, for instance, can trigger autoimmune phenomena across the spectrum of tissues, most notably in MS, but certainly in thyroid disorder as well. Stealth viruses, like HSV, EBV, cytomegalo virus, HTLV-1, HIV, SV-40, many others, in a stealth presence, can stimulate an autoimmune response against the thyroid, but so can bacteria overgrowing in the gut.
We mentioned yersinia previously, but yersinia has, on its surface, peptides or proteins that look very, very much like the TSH receptor of the thyroid.
Therefore, if yersinia is overgrowing, your immune system learns that peptide, builds antibodies against it, tags the yersinia for destruction. But when those antibodies are cruising by the thyroid, they see the TSH receptor. They say, “Hey, close enough.” They lock into that, and they basically direct the troops of your immune system to attack your thyroid gland.
This phenomena is evident in studies out of Japan, showing the prevalence, for instance, of yersinia antibodies being much higher in those with thyroid conditions than subjects without thyroid conditions. That’s why we look for yersinia as one of the things we hunt for on a molecular stool analysis, in patients who have thyroid disorder, particularly if they have Hashimoto’s or Grave’s, or if they even have a family history of a lot of people on thyroid hormone replacement or certainly if they have a history of actual Hashimoto’s.
Oftentimes here, we’ll intervene with natural agents where possible because they’re more functional. They don’t kill everything in the GI microbiota. Yeah, we can throw big-time antibiotics at it. We can give them xifaxan, rifaximin something like that, even locally acting GI antibiotics, but they pretty much wipe everything out, and then you’re starting from scratch, and it’s really hard to institute good microbiotal balance from there. You run the risk of C.DIFF. So we try first, at least, with botanicals and volatile oil combinations, which we know tend to really wack down pathogens even, but certainly opportunistic organisms and are relatively sparing, not totally, but relatively sparing of the normal flora that you want to keep.
So here’s another sample formula, for instance, that has things that many people know, anybody who does any herbal or functional medicine, know has good GI antimicrobial. So berberine-containing herbs, like berberine aquifolis as a source of berberine sulfate, barbary or berberis vulgaris, also bearberry or arctostaphylos uva-ursi, but things like artemisia, standardized to the artemisan content, and things like tribulus. Now tribulus terrestris is not known in western herbology and medicine much as an antimicrobial, but in fact, it’s probably its best use. It’s used mostly in the west for libido issues and increasing androgynous testosterone production. Frankly it’s not very good at doing that. It’s much better as an antimicrobial. It’s not used much. There’s not much resistance. Therefore, it’s a really good choice.
But also, volatile oils, things like grapefruit and citrus seed extract, magnesium caprylate for caprylic acid, black walnut or juglans nigra. These are all really, really good things to try to knock down organisms in the gut, whether they’re bacterial, fungal, or parasitic, even.
Autoimmune thyroid disease, though, is not just about triggering from bacteria. Now we get to another area which is equally as important or more, which is foods. Right? How does your immune system dance with the foods that you eat, from a unique individualistic perspective? We know, for instance, if we go to the dramatic and go to celiac disease, for instance, someone who has such frank intolerance of gluten and gleten, that they develop an inflammatory bowel disorder, autoimmune in nature, known as celiac. We know that they have 10 times at least the rate of Grave’s and Hashimoto’s for autoimmune thyroid condition.
So is there a link between gluten and gleten and autoimmunity of the thyroid? There is. Antibody antigen complexes developed to gluten and gleten fragments have an affinity for thyroid tissue and the central nervous system. So today, earlier in the process, it may be Grave’s or Hashimoto’s. Later on, it may be early onset dementia, ALS, or some other devastating neurological condition.
Now, the data is really firm in frank celiac disease, but I think it’s reasonable to assume that lower levels of gluten/gleten intolerance, so-called non-celiac gluten sensitivity, also opens someone up to a much higher probability of autoimmunity in general, but most specifically, autoimmunity to the thyroid and the central nervous system.
So in addition, in patients who either have autoimmune thyroiditis, or they’re on hormone-replacement therapy for thyroid, or they’re . . . Let’s say it’s a young woman in my office, in her 20s. She has no known thyroid condition so far, but her mother’s on Syntheroid. Her aunt’s on Syntheroid. Her older sister is on Syntheroid. We don’t wait until they have it. We start looking around for triggers that may promote an autoimmune response to destroy her thyroid, to eventually send her down the same path as all of her relatives. We don’t want that to happen. We want to actually practice preventive medicine, not reaction-after-the-fact medicine.
So we look for these type of triggers. For instance, this is just one of those cases. Yersinia was identified. But if you look further down in additional tests, you’ll see immune tests showing elevated secretory IGA and, more specifically, elevated anti-gleten secretory IGA. So there is levels of intolerance at the mucosal immune system level, in the GI tract, which may be far short of celiac disease. But yet, it shows that there’s trouble brewing, and maybe we should clean up the GI environment, get the gluten out of the diet, get proper microbial balance, and do some other things just for general health, to make sure she has the best chance and not developing autoimmune thyroiditis.
We have to start with diet and food. There’s no doubt that we have an autoimmune epidemic, and there’s also no doubt that our food intake has changed dramatically. Now this is something comparing paleolithic man or primitive man to modern man. You can see massive difference. No other species on the planet probably has undergone such a dietary change and survived it.
Back in paleolithic times, 99% of the diet was vegetables, fruits, roots, legumes, nuts, tubers, things like that, very little, if any, whole grain, cereal, or field grass grains. Today, refined grains make up to 60% of the modern western diet. Our immune system, in many of us, just does not tolerate that very well. We become inflammatory. Some of us even become autoimmune. It opens up to a lot of chronic disease. Now you add to that all the extra refined sugars, all of the saturated fats from animals fed the wrong kind of feed, so that they have very pro-inflammatory fat in their flesh, less whole fresh fruits and vegetables. Of the whole fresh fruits and vegetables or the fruits and vegetables, I should say, most of them are covered with pesticides or genetically modified. It’s just not real food anymore. Is it any wonder why our immune system has gone off the rails, and we’re in an epidemic of autoimmune disease?
Let me give you two examples that too few people know about. Juvenile-onset diabetes, which most people don’t even call it that anymore, but I call it that for a reason, because it illustrates that insulin-dependent diabetes mellitus generally is a disease that hits younger people in their juvenile years. They go from being remarkably healthy young people to, overnight, having diabetes. How did that happen? They were perfectly fine yesterday, and then they pass out. No one knows what’s wrong with them. They end up in the emergency room. They do some blood work, and their blood glucose is 300. Well, what happened?
Something happened dramatic between them being healthy and them being in the emergency room. Well, many of them had a triggering event. They’ve been exposed to an environmental antigen or protein that their immune system was genetically susceptible, as a unique individual, to overreacting to. There is molecular mimicry or structural similarity between the offending environmental peptide and a host protein on a cell that subsequently was destroyed.
One pathway that we know for sure is that if genetically susceptible children are given cow’s milk or dairy, there are peptides or proteins in dairy that look a lot like the islet cells peptides expressed in the pancreas. Now if you give a young kid dairy, like every mother is told to by the media campaigns, a lot of kids are okay, but the genetically susceptible kids that have an intolerance to it will, over time, have an immune response that’s sort of building and building in its an aggressiveness. At some point, usually in the juvenile years, it will cross a threshold where it can no longer discriminate between the dairy peptide and the similar protein on the eyelet cells which produce insulin in the pancreas, and it directs an immune response which is very rapid, destroys those cells. The person doesn’t make enough insulin anymore, and here you have it, juvenile-onset diabetes.
Now, I’m not saying that cow’s milk sensitivities or allergies cause every single incidence of early-onset diabetes. That’s not the case. There are multiple environmental triggers that can run you down the same path. We know that viruses can do this, for instance. We even have some reports in the literature that insect venom or insect bites from wasps or bee stings might be the triggering event and produce the peptide which causes the molecular mimicry.
We have instances. This is research from right up the road from me, at Yale, in New Haven, in Connecticut, by researchers there, showing that the modern processed-food diet is much higher in salt, as we know. It’s not just an issue with blood pressure, potentially. It’s actually an issue with autoimmunity. Higher sodium induces more TH-17 cells, which produce inflammatory cytokines, like IL-2. So increased dietary salt intake is another environmental risk factor for the development of systemic inflammation and autoimmune diseases, through pathogenic TH-17 cell activity.
That’s why it’s very important, and it’s a must. It’s a foundational element of dealing with anybody with autoimmune disease or suspicion of autoimmune disease or someone who wants to be proactively healthy, is to essentially get a referendum on how they uniquely tolerate the foods that are in their diet stream. How does their immune system get along with their food proteins? There’s no better test to do that than the cellular response test from Cell Science Systems, known as the Alcat Test. I’ve used this test in my practice for over 20 years, actually. I’ve seen amazing results by applying elimination diet strategies and reintroduction strategies, being guided by the Alcat Cellular Test.
It’s just invaluable because you can’t connect these dots between all these foods and symptoms, because sometimes the symptoms aren’t even overt. Many times, the symptoms are multiple. People are eating all the time. These are delayed or persistent reactions, and activation of the inflammasome is not something that people just immediately recognize. So they never connect the dots. It’s not like an IGE immediate allergy to peanuts or strawberries or shrimp or something like that, where you can’t breathe, and your lips swell up. That’s not how this stuff happens. So by using a test like the Alcat, you can really use that as your guide to elimination and reintroduction diet strategies, to try to connect the dots between the foods and the symptoms and the food intake and the disease progression.
So the Alcat Test is really, really important to do that, as the physician, but it’s really important for the patient to be able to see this. They love seeing these results. They love having something that’s actionable for them to work into their own life, to help in their health outcomes.
I put this slide in here just for dramatic effect, but this is what you learn in medical school about parasites, unfortunately. If someone comes in your office, and all this stuff is coming out of their backside, and they were just in Africa or somewhere in the Amazon jungle, then you better break out the big anti-parasitic medications. While that may be true, basically after that, they don’t really teach you much about parasites.
On this picture, you see round worms there on the left. You see liver flukes in the middle, and you see about a 30-foot tapeworm on the right. These are the dramatic things about parasites that you learn. Short of that, they don’t really teach you much. Well, parasites are back. Turns out, they’re much more important than we ever thought. They’re much more of a problem than we were led to believe in our training, but they’re also a problem in that too many of them may have been eradicated.
When you look at the global prevalence of autoimmune disease, it mirrors that of inflammatory bowel disease, which is what you have on your screen right here. Inflammatory bowel disease is a classic autoimmune disorder. If you look on this map of the world, where you see red is where there’s extremely high incidents of autoimmunity and autoimmune disease. Yellow is medium, and blue is low.
What emerges very quickly is this is a phenomena of the western industrialized countries. In the underdeveloped world, the third world, if you will, however you want to classify it, that is not as industrialized, doesn’t have as much processed foods, they live more of an indigenous lifestyle and eat a more traditional diet, they do not have these same kind of issues. If you look at Australia and South Africa, for instance, they’re sort of out there, way away from the western industrialized world, but they kind of act like us, eat like us, to some degree. So they’re kind of halfway toward us in the epidemiology. Japan is in that same boat, and South Korea as well. It’s amazing when you look at epidemiology like this.
But if you look at the turn of the 20th century, barely more than 100 years ago, the incidents of inflammatory bowel disease was about one in 10,000 people. Right now in the United States, it’s about one in 250 people. That’s an amazing difference. You can’t explain that by genes because genes don’t change that quick. Environments do. So it’s the way the genes may be dancing with the environment.
What’s different about our environment than the underdeveloped world? Well, one thing that emerges very quickly is that they live in relative filth, compared to us. They still sample their environment, particularly when they’re young. They don’t live in sterile little . . . semi-sterile little boxes called houses with carpets and draperies, off gassing chemicals. They don’t get scrubbed my mothers multiple times a day with antibacterial triclosan laden soap. They don’t have mothers that are afraid to let them play in the dirt. They don’t wash every scrap of food they eat because it’s full of chemicals. They dig it out of the ground and eat it with the bacteria that were in the soils when they eat it. That’s the way we all used to live, and that’s the way our immune system developed.
We’re too clean. This is the hygiene hypothesis, basically, that our modern western existence is too clean. Yes, there are benefits to that. We don’t have the bacterial outbreaks and the plagues and things like that. There’s no doubt about it, but there’s also a price to pay because there’s usually a yin and yang of everything. Basically the price we’re paying is, yeah, we don’t have as much infectious disease, because we’re not pulling our water out of the stream that the village upstream went to the bathroom in, but our immune systems are all out of tune.
Look at our kids. They’re full of asthma. They’re full of hay fever and seasonal allergies. They’re full of overt, dramatic food allergies. You can’t walk through an elementary school right now without signs all over the place, “Child in this room allergic to peanuts. Child in this room allergic to fish. Child in . . . ” That didn’t happen when I was in school. It wasn’t like no one just understood it or recognized it, because those kids legitimately . . . If they have those foods, they might die. It wasn’t happening to us. There’s a big change.
In the literature, it’s interesting. They look at even modern children, and they can map differences in their immune system and immune response, whether they live in the city, whether they live in the suburbs, or whether they live on a farm. They have very different immune systems and very different instances of atopic disorders like asthma, hay fever, things like that. The kids that grow up on farms, that are exposed to animals and livestock very early, when their immune system is developing, particularly if they drink raw milk, eat raw cheeses, cultured dairy products made on the farm, they have good immune systems. They don’t get these atopic disorders like the kids in the suburbs and, particularly, the kids in the city do.
There’s one exception to that, and we’ll talk about that in a minute, but something as easy as bringing an animal into a child’s life, letting them play out in the dirt a little bit. Yeah, wash them up at night and clean them off. No doubt. But don’t be afraid to let them sample their environment because sooner or later, they’re gonna confront it. Either they learned how to deal with it, or they didn’t. If they didn’t, they’re gonna overreact to it. They’re not only gonna attack that. They’re gonna attack their thyroid, and they’re gonna attack their joints, and they’re gonna attack their brain. That’s just a fact, Jack. So we can’t deny it. So we’re too clean. So go out and get dirty. That’s your assignment for today.
Now, let’s take this to an even more dramatic conclusion. Parasites. It turns out that in our cleanliness, in our treatment of water the way we do and the use of antibiotics and other types of drug agents and the difference in our food supply, we’ve eradicated worm-like organisms or helminths for the most part. They lived with us for hundreds of thousands, if not millions, of years. They’re very sophisticated organisms. They secrete lots of cellular messengers that down-regulate our mucosal immune response. In reaction to that, our system is up-regulated its immune aggressiveness and stance because it is depending that the parasite is going to be there, pushing a downward influence on the immune response. So over many, many generations, we found sort of a equilibrium or homeostatic balance.
It’s only been a very, very short time, from an evolutionary standpoint, that we’ve used modern public hygiene and water systems and things like that and basically pulled all these parasites off the table. Perhaps our immune system is not readjusted yet, and we’re now left in a more aggressive stance without the down-regulating force.
Now researchers have put that theory to the test. Researchers like Joel Weinstock did a lot of this work at the University of Iowa. He’s now at Tufts in Boston. But he took inflammatory bowel disease patients, ulcerative colitis, Crohn’s disease, and he induced a helminth which is porcine or pig whip-worm. Why did he use pig whip-worm? Because it’s a helminth, has the effects of a helminth or a worm, but in humans it will only stay in the GI tract about three days, and then it’s gone. So you don’t infest someone with something that you then have to eradicate. You just have to stop giving it. Three days, it’s gone.
Plus, this was going toward drug development, and no one wants to develop a drug that you only have to take once, after all. They want a drug that you have to buy repeatedly. Right? So it’s great if they base it around something that you have to keep taking. But if you introduce helminths, you see dramatic changes in the immune system. You alternate immunity favorably away from inflammation. The cytokine patterns, the interleukins change. You induce regulatory T-cell changes that are anti-inflammatory. You change the intestinal flora and actually promote the growth of beneficial organisms, and you block effective T-cell proliferation, which fuels the autoimmune response. These are all good things.
In fact, drug development has proceeded to the point where, in Europe, there is a drug based on this organism, called Ovamed. It’s been approved. It’s used for inflammatory bowel disease in Europe. It’s not yet approved in the United States. There are various agents in drug development and various stages. I think we will see these emerge.
However, in the integrative functional medicine market, without resorting to pharmaceutical preparations based on this model, because they’re not available to us in the United States, there are things that are available in non-drug channels, including H. diminuta, which is a helminth. It’s given in a larval stage. It’s cultivated in beetles, but it is benign to humans. It can grow in the human GI tract. It doesn’t stay there after a while, just like the other organism. You have to keep giving it therapeutically, but there’s been some really impressive trials showing that this organism could induce these same changes of helminths. Actually there’s some trials that showed that it was just as effective as steroid therapy, at least in animal models of colitis.
There, by the way, has been some trials with helminths that have failed though, in inflammatory bowel disease. A noted one by a startup in the San Diego area was a combination of a German and a US pharmaceutical interest. They halted the trial because of lack of efficacy. However, this was in Crohn’s disease, and Crohn’s disease seems to be a different animal than ulcerative colitis. There are many different types of disorders that we all call Crohn’s disease. One of them seems to be fueled by micro-bacteria deep in the GI lumen. In fact, micro-bacteria in subspecies avian, and this is very related to micro-bacteria that cause tuberculosis, for instance, but also cause Saint John’s disease in cattle.
So when I said there’s one exception in people who live on farms with autoimmune disease prevalence, it’s Crohn’s disease. It may be that when they drink the raw milk or eat the raw dairy products from a cow that might be infected with a micro-bacteria related to Saint John’s disease, that they may actually induce a micro-bacteria-derived Crohn’s disease variant. This was theorized for a long time, but antibiotics don’t seem to work very long in Crohn’s disease. Wouldn’t they work if it was bacterial? The answer is probably not. Remember, TB is very, very hard to kill with antibiotics because this is a granulating disorder that walls itself off in tissues. It’s very hard to get the antibiotic to penetrate down to where the organism is. Usually you have to use very aggressive combinations of antibiotic therapy. In fact, they seem to work in this variant of Crohn’s disease.
But we have to also look at the health of the GI mucosa, the villi, the structures that are involved, and make sure that it’s not eroded, it’s not inflammatory, and it’s not hyper-permeability, which leads to so-called leaky-gut syndrome. So we could also look for these type of things in the lab, looking at markers of inflammation and infection, like lactoferrin, calprotectin, and others.
People like Alessio Fasano, a respected colleague who’s now at Mass General and Harvard, did a lot of his work at the University of Maryland, mainly in celiac disease models, was really the first to bring this whole idea of hyper-permeability and leaky-gut back to the conventional medical establishment and research and clinical establishment, more research establishment right now. It’s starting to emerge in clinicians as well, but to immunologists, rheumatologists, those studying autoimmune diseases.
However, this has been something we’ve been dealing with in functional medicine for several decades. We’ve been treating it. We’ve been testing for it, but it turns out that it’s even more important than even we thought, not only in celiac disease, but in all forms of autoimmunity.
Fasano points out that, for instance, during the past 35 years, the prevalence of Crohn’s disease, I’m sorry, celiac disease in the US has doubled every 15 years. This is another epidemic-proportion rise, almost like an infectious outbreak. Fasano put forth the model that you need to have a triad of things in play for autoimmune disease to be manifested and to continue. One is an environmental antigen. We’ve been talking about those the whole program so far, bacteria, viruses, food proteins.
So you need the environmental foreign protein or peptide exposed to you. You need to have a genetic uniqueness to your immune system, where you recognize it and, in a sense, overreact to it. In the case of celiac, for instance, it’s HLADQ-2, HLADQ-8. There are other markers of celiac, genetically, which makes you susceptible. So you need to have the environmental offending peptide, number one. You need the genetic uniqueness, number two. But number three is you need hyper-permeability of the gut lining. You need leaky gut, and you need all three.
So if you need all three legs for that stool to stand on that supports the disease, the question immediately is, “Which is the easiest leg to pull out from under the stool so the disease can’t stand anymore?” So it falls. Probably, I agree with Fasano on this. It’s the leaky gut because . . . Yeah, in celiac disease, we know it’s gluten and gleten, and we can try to get them out the best we can, but it’s hard to get gluten and gleten out of your diet 100%. A lot of these other bacteria, viruses, stealth viruses . . . We’re just starting to understand what all these triggers are. We don’t know what they all are. Many times, it’s multiple triggers. Many times, it’s a perfect storm or a concoction of triggers that does it. They’re hard to fully get off the table. We will try, but we’re never gonna be 100% at that.
We can’t change the genes, not right now. Right? We can’t change someone’s genetic characteristics of their immune response. We can’t change their HLA pattern, but we can treat the leaky gut. Fasano has been doing this in a drug-delivery or drug-development model, based on the action of a peptide produced by the enterocytes, known as Zonulin. Zonulin receptors open up channels between joined mucosal barrier cells and cause temporary leaky gut. So that certain immune challenges that we can’t deal with locally at the mucosal level can actually penetrate and come through and confront a much more robust immune response. So the body can use this mechanism of opening up the flood gates strategically when it wants to.
However, it appears that those with autoimmune diseases across the spectrum have an overproduction of Zonulin. Therefore, they have a persistent or a chronic hyper-permeability of leaky gut. So working on all the mechanisms of action, of how Zonulin docks in its receptor, how it opens the flood gates, a drug analog is being produced, which is a Zonulin receptor agonist, essentially. It’s in drug approval process right now. I think it’s in phase two or going into phase three trials.
I have a prediction. When this does hit the market, if it’s approved, you will learn about leaky gut like you never have before. It used to be this thing that only functional, integrative, crazy docs talked about. The minute there’s a drug for it, it will be on every commercial, in every sitcom, in every reality show that you can watch on television, just like low-T syndrome wasn’t real until it became real. Right? So watch out for it. Leaky gut. It’s
coming to a TV near you.
Fasano has shown interesting things though. For instance, celiacs produce about 30 times as much Zonulin as non-celiacs, even though the non-celiacs weren’t even eating gluten for many, many years, at least two years in his study. So it suggests that there’s something else besides gluten. Something else is dancing here with the genes. Maybe it’s Zonulin. Maybe it’s different micro . . . Maybe it’s different bacteria, I should say, in the microbiota. Fasano’s group is studying that right now as well.
Now we treat the leaky gut all the time. We don’t have the drug yet, but we have things that treat leaky gut and treat it very, very well. This is a functional GI-soothing repair powder, if you will, that I’ve used for a very, very long time. It has things that feed, fuel, and repair the cells of the gut lining or the enterocytes, things like therapeutic levels of L. glutamine, mucilaginous botanicals that coat and heal the GI lining, things that were classically old-school anti-ulceratives, for instance, slimy things, chamomile, okra, cat’s claw, slippery elm, aloe vera, the stuff you put on sunburns for the same reason. It’s slippery. It’s slimy. It helps heal things up that are inflamed.
But these also have the mucopolysaccharides that block bacteria from dancing with antibodies. So it blocks antigen antibody formation. It’s perfect for autoimmune disease in the gut. Something like inositol glucosamine, which we’re gonna talk about now a little bit more specifically, is naturally occurring molecule. It can attach to T-cell receptors and form branches or latices that basically block the antigen from docking into and activating the T-cell. It forms these little . . . It globs up the lock-and-key kind of orientation between the offending antigen and the genetic uniqueness of the person’s immune system. You basically block the signal. You put a lot of static on the line, and you stop the autoimmune reaction and proliferation.
So antecedal glucosamine, it’s cheap. It’s natural. There’s no side effects. It actually helps your joints and other things. It’s incredible therapy in autoimmune disease, and there’s great trials on it, specifically in multiple sclerosis, for instance, with an entirely different mechanism of action than the drugs.
The last thing I want to talk about with therapy is vitamin D and the gut. We think of vitamin D as a vitamin. We all know now it’s really more of a hormone. It’s the sexy hormone. Right? It’s the test everyone is doing. We still don’t really understand a lot about it. We do know that vitamin D . . . Low vitamin D is a surrogate marker for autoimmunity. Therefore, vitamin D is generally low in most people you test with autoimmune disease. We don’t know that that’s related to causality of the disorder or a result of or an artifact of the disorder, but we know that vitamin D is an immune regulator for sure. It’s involved in a healthy good immune response.
But what most people don’t know is vitamin D dances with 300 or so genes. It’s not monolithic in its mechanism of action. In fact, experiments demonstrate that the VDR, the vitamin D receptor, mediates the activity of 125-hydroxy-D, that induces junction protein expression. Basically it produces peptides at the genetic level. It induces you to make peptides, which tighten up the junctions in the GI mucosa. It directly has a mechanism of action to treat leaky gut syndrome, but it’s also an antimicrobial. The more vitamin D you make, the more endogenous antimicrobial peptides you make, things like cathelicidin or CAMP. These are little antibiotics that you make internally. It’s your own antibiotics. You make them inside yourself when you need them, and vitamin D is one of the things that triggers you to make them.
So more vitamin D, more androgynous antibiotics being made by yourself. Maybe this is part, at least partly responsible for the beneficial symptomatic effects we see in vitamin D therapy in autoimmune disease. Maybe it’s also treating the pathogens that are driving the disease through molecular mimicry. Some of the strongest data on vitamin D is in multiple sclerosis.
We also have models of multiple sclerosis being induced by chlamydophila, for instance, a pathogen, basically. Right? A microbe. This is Charles Stratton’s work at Vanderbilt, but you also have a lot of information in the literature on various viruses triggering multiple sclerosis. Can vitamin D be acting on those pathogens as well? We simply just don’t know yet.
There’s also conflicting information on vitamin D, particularly as it pertains to sarcoidosis and maybe activation of macrophages due to the inflammation and infection and over-conversion to 125-hydroxy-D. So there’s a lot of controversies out there on vitamin D yet to be resolved, but the vast amount of data suggests that in most autoimmune conditions, it’s worthwhile trying to establish better vitamin D levels with vitamin D repletion.
The final thing I wanted to talk about is where we’re going with early intervention and prediction of autoimmunity. We really need to get out of the model of medicine where we wait for the disease, diagnose it, give it an ICD-9 code, and then try to figure out what the heck we can do about it. There’s a lot of lip service given to preventive medicine, but preventive medicine is not just vaccine programs. Preventive medicine really needs to be real preventive medicine. That means stopping the horse from leaving the corral before it leaves the corral, not closing the gate after it does.
We have a window to do that in autoimmune disease. We can do these using these molecules called auto-antibodies. Look at this from . . . I think it was New England journal of medicine. They use lupus here as the model. You don’t just develop lupus overnight, where you go into a doctor, and there’s enough clinical signs, and they say, “Hey. You have lupus.” It took you years to get there. You went from normal immunity to what they call benign autoimmunity. There’s trouble brewing, but there’s no overt signs of it yet, to pathogenic autoimmunity, where the immune system literally goes off the rails, starts attacking your own tissue, and then there’s even more years until you manifest the clinical signs and symptoms of the disease where a physician can diagnose it.
They’re not treating it until it gets to that last stage. Then what are they reduced to? Anti-inflammatories, immune suppressants, biologics. Many of these drugs are not easy to take. Lots of side effects. I have young people on them with terrible osteoporosis, gastritis. If you look at the side effects of the biologics, little pesky things like leukemia and lymphoma, these are not benign side effects. I don’t mean to say that the majority of the people, by any stretch, would develop that. I’m not saying they shouldn’t be used. I’m just saying I wish we had more. We do have more, but we have to act early.
We can put these auto-antibodies into play. Here in lupus, we see that the auto-antibodies classic in lupus, such as anti-nuclear antibody, is present in the blood years, six, seven, 10 years before you’d ever diagnose it clinically. If we can pick it up, change the person’s environment, change their immune function, get them less inflammatory, test them for the foods that they’re not compatible with, using Alcat Testing, check their GI microbiota, using the GI map, clean that up, maybe they never develop it to begin with.
We don’t have great outcome studies looking forward on the effectiveness of this, but it makes sense, at least from medical hypothesis. It does no harm. We actually see people with already manifested autoimmune diseases having reductions in their symptoms, clinically.
Now, there’s a lot of these auto-antibodies out there that can be tested. They can be tested through standard commercial laboratories or specialty labs built into arrays that you can do more as a screening test, if you will. So I look forward to the day when we use arrays of these auto-antibodies to check young people, particularly if they have a family history of autoimmune disease in older relatives, just like you do a blood-chem and a CBC and check your cholesterol, at least at intervals maybe not as often as those tests. We check for auto-antibody emergence.
Look it here, Hashimoto’s Disease, anti-thyroid peroxidase antibodies. The PPV or positive predictive value is 92%. If you have that auto-antibody present, you have a 92% chance of developing Hashimoto’s disease in your lifetime, not only in your lifetime, but in seven to 10 years. They had this all actuarily worked out. This is hard science. Doctors aren’t doing it because there’s two separate things. There’s medical science and research, and there’s medical practice. They’re influenced by different entities, and they seem to go along totally different paths. I don’t know why, but it is. We know that the literature takes probably 10 to 15 years to get into the clinicians’ office. This literature is out there. The actuarial data is clear.
For instance, Crohn’s disease, anti saccharomyces cerevisiae antibodies 100% positive predictive value within three years. You have Crohn’s disease. Celiac, anti-tissue transglutaminase anti-endomysial antibodies, and there’s many more sophisticated ones than even these, but these are really interesting to put into play. There’s rheumatoid arthritis, rheumatoid factor, anti-cyclic citrullinated peptide. Remember, we use this as a marker in the laboratory. If you remember right, I talked about P. gingivalis overgrowing in the mouth, producing an enzyme, PAD-4, which citrullinates your host proteins, and they become citrullinated peptides.
We use a lab test, anti-cyclic citrullinated peptide. So the physicians are using a lab test based on a mechanism of causality which they don’t really even quite understand. They do the lab test because they were trained to, but they don’t understand that the bacteria overgrowing in the mouth is what’s making the enzyme that’s causing the citrullination which is making the lab test positive. So we need to really take a more comprehensive look at this and not just throw symptom-mediating agents at it after the disease is manifested.
If we use these proactively, then we can predict the risk of falling ill in individuals. We can project a probability of what disorder they may develop, when they may develop it. We may look for the triggers that we know, get them out of the mix, whether it’s foods, whether it’s bacteria in the gut, whether it’s stealth pathogens, viruses, whatever they may be, and institute lifestyle programs that may stop them from ever getting the disorder.
So in the end, what are the assessment and interventions for autoimmune disease if you want to be cutting-edge proactive? Detect and remove opportunistic pathogenic GI bugs. You can do something like the GI map that I talked about from diagnostic solutions lab or other labs that do other types of stool testing. Detect and eliminate food sensitivities, or I would rather say activation of the inflammasome by foods. With that, there’s no better choice than using cellular response tests from cell science systems, known at the Alcat Test.
Do predictive auto-antibody testing, particularly in patients who you suspect may develop it because of family history, because right now, these tests are being used conventionally, but generally only to confirm a diagnosis that’s already been made. So it’s being used after the fact. Check for toxins and support detoxification because toxins, particularly things like mercury, for instance, can alter your host proteins, making them haptens, causing an autoimmune response, but many toxins can do this.
Checking vitamin D status and optimizing it. Quenching excessive inflammation and oxidative stress with a whole-food diet, directed by Alcat testing. Nutritional interventions. There’s a lot of great anti-inflammatory botanicals, fish oils, low arachidonic acid diets, gastrointestinal restoration with a normal 4R program, and stress reduction, because cortisol and other stress hormones can down-regulate the immune response. I hope you learned something today. I thank you for your time. I’m Dr. David Brady, with the Division of Health Sciences at the University of Bridgeport. Thank you for being with me today.