Interviewee: Good evening. Thanks for joining us, everyone, and it’s been a heck of a couple of days here, hasn’t it? And hopefully we’ll put our minds on some different topic tonight. Those of us who may be – those Americans who may be joining us from Canada especially, welcome. Tonight we’re going to talk about genetic immune-cell and microbial interactions in inflammatory bowel disease, celiac and some other GI disorders. This is a huge, huge topic.
I just came back from Harvard, where Alessio Fasano invited me to attend the 20th-year celebration of the Celiac Treatment and Research Center that’s at Mass. General that collaborates with some other institutions at Harvard. And at that occasion, he and the other heads of the other centers that are collaborating in this –
area spoke a little bit about the past 20 years and what they’ve – what’s transpired in this field, and it’s quite a lot. We’ll touch on some of that by way of review here. The thing that was also interesting is that they spoke about future research, and the future research that they see is this topic, genetics, immune-cell interactions with the gut microbiome and the metabolome.
This is to say, therefore, that the topic is – it’s a new horizon. It’s extraordinarily broad. The findings that’re coming out are coming out very, very quickly, and it’ll be something that I think will guide medicine for some time to come. The purpose of this presentation is to give a little bit of a foundation to the basic concepts, and some of the research that we’ve been involved with –
with some of the institutions like Yale School of Medicine with respect to the food component of this equation and see how the pictures emerging that puts these things into juxtaposition with one another and kind of make sense of it.
The gut microbiome is – it’s like another organ system, in a way. By the way, I just wanted to start here. I’ll explain this in a moment. There’s about 1,000 times more genes in the gut microbiome as there are in the human host. We have fewer than 30,000 genes in the human genome, but there’s probably 50 times that in the microbiome. So, they all interact with one another. We have a symbiotic relationship.
The human provides a home and safety for the microbes, and the microbes provide services, provide the synthesis of short-chain fatty acids for foods for enterocytes and synthesis of vitamins that are used by the host and also are involved in educating the host’s immune system. And they continue to interact with the host’s immune system, and that’s kinda what we wanna talk about a little bit here.
What we do is to try and bring a framework to this is offer some testing that helps clarify when a patient presents with gastrointestinal symptoms which direction to go, which kind of diagnostic procedures to follow. Do they need a referral to a specialist?
How likely or unlikely are they to progress to celiac disease? Do they have celiac disease? What’re the interactions with foods and Crohn’s? Why is Crohn’s there? What can we do about it? There are things that we can do about it that are noninvasive.
So we have an assay that we call the CICA for short, the Celiac, IBS and Crohn’s Assay, which has a number of different markers in it. And some of those, as you see, are genetic markers for identifying risk if a person is at risk for developing celiac disease and then other genetic markers for looking at risk for Crohn’s disease. And it’s kind of interesting is that as we move along, and I’m gonna touch on some examples, particularly with the Crohn’s, some of the reasons that we thought those genes were risk factors for the disease are becoming expanded upon as we go deeper.
And just recently there’s an interesting article in Science just in July that identifies a new role for these genes in the etiology of Crohn’s disease. And I think as we move along, we’ll see – we’ll dive deeper and see more of these things coming to light, and we’ll understand even further about this very complex constellation of this interaction between the symbionts or the host and the microbes.
Of course, we can gain insight by looking at serological markers that can tell us whether or not there’s an active disease process going on with celiac. And, of course, we add to that as an option a cellular test, the ALCAT test, which we won’t have time to –
review in much detail today, but the – this company, Cell Science Systems, which sponsors the Cell Science Collegium, is known for having developed this test. And I’ll just mention a little about the company now in that regard.
We’ve developed this test over a period of 30 years, and this Cell Science Systems is a laboratory, federally licensed and state-licensed, but it’s also a medical-device manufacturer, and we manufacture the instrumentation for carrying out the cellular assay, as well as all the reagents and buffers that are used in the process. That means the food extracts and so forth are – we go to Whole Foods, buy the foods, bring ’em here, lifealise ’em and then process them and use them in the assay. And we do this all under a quality program –
that’s supervised by the FDA and compliant with ISO medical-device manufacturer standards, which keeps our certification. And that’s good, because we have some more then control over this process, and it allows us to really understand a bit more. We can run experiments very easily.
We’re fully independent. We’re fully integrated so we can run more experiments and understand a bit more about how the cells, the leukocytes, the peripheral immune cells, interact with dietary components and other environmental components. So we’ll touch on that a little bit, especially since there’s recently been some report about clinical findings and technical findings about the cellular measurements that the test exposes.
The CICA report’s easy to follow if there’s homozygous positive or negative.
We have either very low or very high or elevated risk or somewhere in between if we’re heterozygous. It’s for both the genes that relate to celiac, as well as the genes that relate to Crohn’s. Let’s focus in a little bit about why – what those genes are. We look at the human lymphocyte antigen DQ2 and DQ8 genes, as most people do, and I wanna speak for a few moments about why we do that. What do those genes do? Why do we measure those just for an overview, so that’ll give us a little bit of a basis for understanding the progression to celiac in those individuals that have that susceptibility or why there is something called non-celiac gluten sensitivity.
So, this is an old but, I think, very useful –
graphic that’s borrowed from Scientific American from Dr. Fasano’s article some years ago that he called “The Inside Story,” and it shows here, of course, the enterocytes, in this case probably a damaged enterocyte that’s probably kinda leaky. So we have pericellular transmission of cellular products, as well as dietary products, in this case gluten fragments that are able to penetrate into the lamina propria, where we have 80 percent of the immune system is resident in the gut. And so, there’s a lotta stuff going on right here. So, in the pathogenesis of celiac, which is what this graphic is showing, is the first – the trigger of gluten fragments that can bind with tissue transglutaminase.
So you’ll notice when we look at the particulars of the testing that we do is that we measure antibodies against TTG, tissue transglutaminase, to see if it’s present.
Why? The clinical significance is that TTG is produced from damaged enterocytes. It, on the one hand, indicates that there’s a disease process going on, so if a person has the celiac genes but they don’t have TTG, well, they still have to avoid gluten, because they have those genes, and it could erupt if other co-factors present themselves, which could be microbes or other factors. So, we wanna look for the presence of the deaminated gliadin peptides, which we know are toxic, and of course in this illustration there’s a leaky gut, so they have more access into the lamina propria and then to the general circulation.
They can bind with TTG and become immunogenic, meaning that they’ll be recognized by an antigen-presenting cell.
That complex will be taken up by an antigen-presenting cell, most commonly a dendritic cell, and brought into sort of a lysosome. The peptides are broken down and bound to a molecule that translocates to the surface and then presents it to a T-cell that will recognize that molecular conformation and only a T-cell that recognizes, and that’s why we’re talking here about the adaptive immune response or the specialized cells, the T-cells.
The mediator here, of course, is this molecule that picks up the peptides and translocates it. That’s called a major histocompatibility molecule or MHC Class-2 molecule. Now, if that interaction does not occur, which we see depicted here, the T-cells don’t get involved or much less so.
And then we don’t have the progression of the cytotoxic T-cell lymphokines causing the damage that we see here to the enterocytes. We may have irritation. We may have other disorders, which will broadly characterize as non-celiac gluten sensitivity, which could give rise to symptoms that we call IBS, but we won’t have that progression to celiac, and that’s why it’s interesting to look at the presence of those genes. If the genes are not present, the molecule doesn’t exist, and the presentation of the antigen and the antigen-recognition process does not occur.
And so, therefore, everything on this side of the graphic doesn’t happen. We don’t get the T-cell communication to the B-cells to produce antibodies. We don’t get the activation of the T-cells and the transformation of the T-cells into cytotoxic T-cells that then cause this damage.
So that’s why we test the human lymphocyte antigens for those genes.
Now, of course, the antibody test against the deaminate gliadin peptides has been documented very well, and sometimes different people, particularly younger versus older, vice-versa, will have more of the IGA isotype present and less of the IGG and vice-versa, so they should both be present in the evaluation.
Looking ahead now just a bit to the other part of the equation, microbiome, when we start off there’s not that much of one, really, and of course natural childbirth will help inoculate with beneficial, hopefully beneficial, bacteria from the mother.
A C-section will abrogate that, so, when possible, natural childbirth, natural anything seems to have probable benefits to living organisms. And then there’s a change over time in the composition, and there’s really only about – there’s really only four phyla that comprise the majority of the microbiome. Bacteroides and firmicutes are about 75 or 80 percent of it. And that composition changes over time, and of course it becomes much more individual over time. We have more, greater diversity and less individual variability as we age.
So, why do we care? Of course, we hear about it every day.
As I mentioned, at a minimum the gut microbiome contains at least 500 to 1,000 different species. It’s very, very, very diverse. And these guys, they can be friendly, can be commensal. They can be pathogenic and everything in between. The microbiome composition will vary significantly in abundance and the type between individuals, within the individual, depending upon the location inside the GI tract. In fact, the types of microbes that tend to colonize in areas where there’s inflammation are different. Now, we don’t know if that’s a cause or effect, but we’ll find that out as time goes on.
Purpose-wise, they help synthesize vitamins. They are involved particularly in carbohydrate metabolism. They manufacture short-chain fatty acids, which is fuel for the enterocytes.
They help the immune system mature, both locally in the gut and throughout the whole body. We’ve all heard now about the hygiene hypothesis that there’s more atopy, there’s more – meaning allergy and asthma amongst children that grew up in a more sterile environment. So the early inoculations that we experience not only during birth and breastfeeding but throughout exposure to the environment in a natural way help develop tolerance.
Then, of course, the pimensules will – they wanna survive like everybody else, so we have good bacteria there. They will help exclude the colonization or the expansion of colonies of pathogenic bacteria.
And there’s also other communication that takes place not only with the immune system but also with the nervous system. So, they’re critical, it’s like a whole new orien.
In animal models, IBD, that’s what we wanted to talk about, actually, in this presentation. They play a role. These microbes can be protective, or they can be pathogenic. And it’s all contextual, and contextual means how the immune system has been programmed and our genetic factors. And that’s what I wanted to address in a moment. We know that when you manipulate the microbiome through a fetal transplant – fecal transplant, sorry. I don’t wanna transplant fetuses. I apologize for that. It changes.
It changes the phenotype. So, that’s not a surprise. Antibiotics have been shown in some experiments to reduce gut inflammation, but one must be cautious. Obviously using antibiotics, it will drastically reduce maybe by 50 percent. A course of antibiotics can reduce by 50 percent the abundance of microbes in the gut.
An area we particularly wanna focus on is that the microbes impact not only – we’re talking about antigen presentation through the innate branch of the immune system or the dendritic cells, which are professional antigen-presenting cells that sort of sit in the middle between the innate and the specific immune system, as we saw in that graphic moments ago, but the microbes talk to the T-cells.
That not only influences T-cell function and immunity but also factors that impact the barrier function of the gut. And that’s critical, and that’s a very complex area that we should delve into entirely on its own because it is so interesting.
So, it leads us to conclusions that we have our genetics, but does genetics and even knowledge of the microbiome also – is that sufficient to explain phenotype of symptomatology or disease or health? No, it’s suspected other factors are environmental, and of course that would primarily be diet. I mean, food is the biggest exposure that we have to the environment.
Now, foundational to any understanding is the microbiome studies have shown that IBD – [coughs] excuse me. IBD results from a dysbiosis. So, what dysbiosis would that be? First of all, in looking at a review paper fairly recently, metagenomics studies have shown that in IBD there’s an upregulation or an expression of genes, an upregulation of genes that are responsible for oxidative stress pathways for information and reduction in the expression of genes that are associated with normal metabolism.
The reduction in bacterial diversity is a hallmark feature of IBD.
Particularly there’s a decrease in firmicutes, which is the most – normally the most prevalent phyla, and particularly in a reduction in faecalibacteriun and prausnitzii. And here’s something that, of course, is just a reference. We won’t go through this right now, but in CD, also Crohn’s, ulcerative colitis, we see in surgical biopsy in stool consistently in CD and UC a reduction in the faecali/prausnitzii almost across the board. And in the others, they’re kind of mixed, but that’s a critical one, so that’s one that you may want to look at. We don’t do that. We don’t look at the microbiome right now, but we have some assays in development, but there’re labs out there that do have that.
So, although the precise cause of IBD remains unknown, what makes most sense or the most acceptable hypothesis is there’s an aberrant immune response against the microbiota, which can be triggered by environmental factors, meaning, to me, mostly, food, and that in a genetically susceptible host. Now, we looked at the genetic antecedents that are associated with celiac disease, so let’s look a little bit at the genes associated with Crohn’s. Most of you might know that the Nobel Prize in medicine this year was awarded to Dr. Ohsumi for his discoveries of the mechanisms of autophagy.
Now, autophagy is a normal process that’s very critical to homeostasis. Autophagy, as the name suggests, is the eating of self. That means debris that comes from damaged organelles or other physiological components. It’s like phagocytosis. When it’s disrupted, it’s quite a problem. You can imagine if you had human corpses lying around, they would spread disease. On the microscopic levels, you don’t want that happening, either. You don’t want dead organelles hanging around.
So, that’s an interesting perspective when we start looking at the disease antecedents or the genetic antecedents associated with Crohn’s disease. So, here’s two of ’em.
And these are the markers that we test for in our CICA assay. ATG16L1, that’s a gene which is associated with autophagy, formation of the autophagosome. NOD is one of the several classes or several types of pathogen – repeat – sorry, it escapes me at the moment that the things that recognize repeat patterns on the cell walls of pathogens.
So, the NOD1 and 2 will sense – and that’s intracellularly. We have these sensing molecules that can activate innate immune cells in –
defense against pathogens, both on the surface of the cells and on the surface of enterocytes, on the surface of immune cells, and they’re both on the surface and also within the cytosol in the event that a pathogen penetrates into the cell. So, the NOD1 and 2 are involved in sensing those repeat-pattern molecules inside the cell. And what they’ll do is they’ll recruit the ATG16L1 to the site of bacterial entry, and that triggers autophagy. So, in this review, these authors conclude that the close connection between NOD2 and ATG16L1 suggests the importance of this pathway in the pathophysiology of Crohn’s disease. And that’s why we test for those.
Now, you can’t explain it just by genes, because we have our genotype, and that may express itself, or it may not, depending upon epigenetic factors. And most of those factors – and they cover the whole range of everything that we think, that we breathe, that we come into contact with, that we eat, our internal physiology. So, certainly what we eat is a major factor. But just actually in July there was an article in Science that takes our understanding about these genes, these autophagy genes and these NOD-like receptor genes to a deeper level to explain a nuance that wasn’t understood in quite the same detail.
And what that was is that the immune system, again, mediated by the dendritic cells, culminating in activity of the lymphocytes, the specialized cells, the T-cells, is impacted by at least one commensal bacteria called Bacterioides fragilis. And what this microbe does is express in what’s called its outer membrane vesicle a substance called PSA. Now, it’s not important to remember what those substances are right now other than that they have to do ultimately with recognition by the dendritic cell, communication then with the T-cell in the same –
fashion that we saw just a moment ago, again, a dendritic cell communicating with a T-cell, but in this case instead of a food particle, think of a microbe. I’m sorry that I don’t have a graphic for that, so we’ll have to make do with that.
And that PSA that’s expressed in the – by the microbe and which is sensed by the dendritic cell then communicates messages to the T-cell, which causes the T-cell to upregulate its production of interleukin 10, which is anti-inflammatory. So, what we have here is a pathway, where polymorphisms in the susceptibility genes promote disease through defects in sensing the protective signals from the microbiome, in this case it’s the PSA –
expressed by the Bacterioides fragilis through its outer membrane vesicles coming into direct contact with the dendritic cell, which then communicates with the T-cell and kind of modulates the T-cell activity in such a way that it inhibits or doesn’t allow for the production of a very critical inflammatory-suppressing cytokine, interleukin 10. So, that’s another model explanation of the pathogenesis of your inflammatory bowel. And from that study – it’s a wonderful study. You can look at that reference in Science. I recommend it.
Just one of the illustrations here is levels of IL-10, interleukin 10 –
measured in the plasma of mice who’re either normal, wild-type, or have that mutation, the same mutation we’re looking at in our assay. So, what we can see is that with control there’s not that much difference. PBS is just a control, just a buffer, but in the wild-type mouse, the stimulus from the outer membrane vesicle causes a high level, relatively high level, of the production of this beneficial interleukin 10. In the genetically impaired mouse, very little is produced there.
So you can see if you short-circuit that and deliver the PSA directly without going through that pathway to the T-cell, you also get the –
production of the IL-10, which shows it’s not the T-cell that’s defective; it’s the pathway, which involves a dendritic cell. So what we’re talking about are these genetic antecedents in the dendritic cell, which, again, is modulating the T-cell.
What can we do about this? Well, there’s a number of things. Probiotics help. There’s been a number of studies that show various probiotics are effective with inflammatory bowel diseases. And this is a good reference to look at. And they’re equivalent in mesalazine in many cases, which is a nonsteroidal anti-inflammatory. Or, on their own they’re maybe even more effective. So these’re all the studies that are looked at for the different – this is a form of combination of probiotics.
Now, of course, probiotics require prebiotics.
I’m just gonna pause on this for a moment. Prebiotics, of course, can be given as supplements, but the best prebiotics are the right kinda foods. And the foods that nurture the beneficial commensals are things that contain a lotta fiber. And, in fact, the firmicutes, which is very beneficial, has been shown to be – represent a greater preponderance of the microbiota of children who eat a – it’s called a natural diet, children in villages in Africa, versus Bacterioides that’ll predominate in children that eat diets that are high in refined foods.
So, the fibers is the best prebiotic we can use. And we see we can use supplements as we want. We can do both, but I think the diet is the best way to go if you can do it.
I wanna segue now just a little bit into some of the research that I think is going to help set some new directions for understanding the effects of food on the immune system or the interactions between food and the immune system. This is a paper presented a couple years ago, and I suspect it’s probably too small to see the reference here, but it’s on our Web site. It shows that there’s an upregulation of a particular molecule on the surface of T-cells when there’s exposure to a positive food, and CD11b is a molecule, which is –
an adhesion molecule, and, well, we won’t do it again, ’cause we’ve looked at a lot. The graphic, if you – well, we’ll just keep that in mind as we move forward. Yeah, just let’s keep that one in mind.
So, CD11b is expressed more on immune cells when there’s exposure to an ALCAT test positive food. More recently just this year there’s been a constellation of studies that are done – technical studies done at Yale at the digestive-diseases laboratory there, that show a couple of interesting findings. One finding is that the positive foods are the cellular responses associated with certain mainstream immunological pathways. And we’ve looked at those, and the particular ones that are involved there are Protein Kinase C and NF-kappa B.
And they’re related to each other, so that makes a lot of sense.
And, of course, NF-kappa B, probably people have heard about it a lot in the context of chronic inflammation. It upregulates. It translocates from the cytosol when it gets activated, migrates to the nuclei and causes the upregulation of various inflammatory genes. So, that is taking place, so we can begin to look at the beginnings of a framework for when we’re looking at gross changes in cells as we do in the ALCAT test that there are understandable pathways that we know result in inflammation being activated.
One of the other things we see, as indicated by the title, is that a positive food is associated with increased levels of –
DNA fragments in the supernatant of the sample, where the positive foods and the cells have interacted, much more so than a negative sample. And that’s significant because obviously the DNA, whether it’s coming from the mitochondria, because that’s been damaged, or the nuclei, because that’s been damaged, doesn’t belong outside the cell. It belongs inside the cell. And when it gets outside the cell, it creates problems, and we’ll go into that in just a moment.
And which cells are involved? Well, there’s probably a number of different markers that can be looked at to determine activation of cells. One almost universal activation marker of inflammation is called CD63, and that’s almost always upregulated in eosinophils. Eosinophils are cells that are associated with allergy.
Micrograph of an eosinophil shows there’s the nuclei and a number of different granules that contain various chemicals that are either inflammatory or non-inflammatory like IL-10 or eosinophilic cationic protein or EPO. That can be very, very inflammatory. And if we look here at what the eosinophils do and why we say they’re associated with allergy, allergy is sort of our – we’re talking about classical allergy, not delayed allergies, not a food sensitivity or – we’re talking about a Type One hypersensitivity reaction. That’s our defense against worms. And, of course, I hate to be this poor guy. I mean, these eosinophils are just ripping him apart and digesting him.
So, that’s something that I think kinda gives us a little bit of insight as what’s going on when we see in an ALCAT test cells getting activated. I’m gonna go out on a limb here for a second and say probably when you see cells getting activated you’re looking at something that shouldn’t happen. The immune system’s there when it needs to be there to protect against danger, but you don’t want it getting triggered every time you have a meal.
Let’s go back for one second. This was from a study from Harvard from Fasano’s lab in cooperation with several labs in NIH looking at lymphocyte biology. And here we see this is a section of the gut from an experimental animal that’s been exposed, and in this case they’re exposing it to gliadin – pepsin, trypsin, gliadin –
so it’s predigested the way it would be if it gets down to the gut – and comparing the cellular response, sorry about that, to, whoops – the cellular response to a control and also a known experimental substance, FMLP, formylmethionine-leucyl-phenylalanine, which is a peptide that occurs on the walls of bacteria. What we’re seeing here is the activation of these neutrophils in a transgenic mouse, where they’ve been treated so they will fluoresce so we can see what’s going on. And after a little bit of time, they’re kind of exiting from the small vessels into the tissue.
So, here again, think about the Yale finding of the upregulation of CD11b, which is allowing for that process to take place. We’re beginning to see a picture emerge there.
This is what it looks like in vitro, where we’re looking at FMLP in this panel, which you’d expect to start activating neutrophils, causing migration – gluten versus a control, where we don’t actually see that taking place. Here we go again. So, again, gluten is causing at least ex-vivo and in-vitro, which we’ve seen in the previous slide, activation of cells.
Now, is it only gluten that can cause the activation of the innate immune cells and lead to these issues that –
may or may not advance to activation-specific immunity or just stay as a sensitivity like non-celiac gluten sensitivity? Here’s an interesting video, and this comes from a clinic in Kiel. And this patient’s presenting with – he’s got a lotta problems, but you could see he’s got some skin problems, periorbital rashes and so forth, and he’s talking about mainly his terrible GI problems. They investigated this guy, went through blood tests and scratch tests to look at reactions to common allergens and the antibody tests, and this in-vivo test, the scratch test didn’t show anything.
So, they did something very experimental. Using a probe, they were actually looking for the – and we’ll see this in a moment, the response of the enterocytes or the –
gut to the presence of direct injection or direct exposure of different common food allergens. These’re in German, of course: milk, soy, wheat and yeast. They’re injecting a gordial contrast media so that they can with a light see which substances, when they’re exposed directly into the gut, into the large bowel, are producing a greater transmission of light kind of analogous to TEER, decreased electrical resistance, in other words, greater intestinal permeability, and they’re trying soy. They’re trying milk. They tried wheat, and no result yet. But when they get with the yeast for this patient, of course we’re all different, they see the screen light up. So, we see that breakdown in the intestinal permeability, in this case because of the yeast.
Now, it’s interesting, because yeast is a living organism. Now, of course, we’re not necessarily testing it while it’s still alive, but it still has that conformation just like the FMLP. It’s not shown here. I apologize. I don’t have a reference for that right at the moment, but we know that antibodies against yeast are associated with Crohn’s disease, and that’s why we also include in our CICA assay or our Gut assay anti-saccharomyces cerevisiae antibodies.
Now focusing back again on the same constellation of studies from Yale – I apologize. This was in German.
Because of the election, I didn’t have the opportunity to translate it back into the English, but we see here that there’s a much greater release of DNA from the cells when exposed to an ALCAT-positive food versus no food or a negative food. And in their presentation, this poster – the investigators say that this is the first demonstration that specific food items – and these can be and these are food items other than gluten and yeast, which of course are biggies, but it could be anything, can result in release of DNA by peripheral blood leukocytes, and, further, these items can be identified by the ALCAT test. This finding may provide a mechanistic rationale for the reported findings of clinical improvement in patients using the ALCAT test.
And further research should be warranted.
Now, let’s put that in perspective. There’s a lot of studies now that show that when cells, neutrophils and other granulocytes, other innate immune cells, including monocytes and macrophages and eosinophils, become activated, one of the strategies that they can implement in a little bit of a later phase is the production of what’s called an extracellular trap. If it’s from a neutrophil, it’s a neutrophil extracellular trap or net, but these nets or extracellular traps are produced by other granulocytes as well, and they’ll trap pathogens.
And what do they contain?
They contain proteins and enzymes from the cytosol but also chromatin and DNA particles from the nucleus that merge with the cytosol and then form these – along with the membranes, both inner membranes and cell-surface membranes from these net structures to trap the bacteria. And the DNA is actually quite toxic to the bacteria. That’s all well and good. What happens to the debris? Well, we have an enzyme system that will clean that up. DNA’s one. But what happens if there’s too much of it? We don’t have enough of that enzyme. Or, if we don’t produce enough of that for genetic reasons, then we have too much of this DNA fragmentation and chromatin circulating around. And it’s been shown to be a factor, a major factor in inducing autoimmunity, particularly lupus and RA.
And here’s a nice report that just came out in July called Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance. So, when you have obesity from diet, it actually also promotes excess release and diminished clearance of nucleic acid. So, it also promotes that, but it also is a side-effect of that. The DNA actually will cause – induce metabolic problems. So you get into this cycle, as well as the generation of auto-antibodies. So we don’t want that DNA floating around outside the cells.
And to make it even more complicated, and I’m getting close to the end right now, is some research that comes out of the School of Public Medicine at Harvard, where they’ve identified something called six-transmembrane protein of prostate 2 –
which was first discovered in the prostate, which exists in the membranes of the adipocytes. And it provides a counter-regulatory mechanism so that when you have a high-fat diet or high-carbohydrate diet, where you’d naturally promote inflammation, this counter-regulates that. But you know what? If there’s, again, a genetic deviation, and at least in the case of experimental animals – it has not been demonstrated in humans yet, but when you have STAMP2-negative mice, they do not have STAMP2 in their visceral white adipose tissue, in their adipose tissue around the tummy, you get problems with transport of glucose.
And that’s also expressed in the other adipose tissue subcutaneous.
So, we’re beginning to see kind of a pattern emerging here that is a very, very, very intricate and finely tuned balance between our genes, our exposures to the types of food, the macronutrient composition of the food, the individual components of the food, our microbiome and our immune system. And it is so complex, and that’s why I think that the people at Harvard have identified it as being the focus of their study for the next number of years.
And just to conclude here, also in the experimental mice in the visceral adipose tissue and in the subcutaneous adipose tissue, the animals that are – these’re the wild-type mice –
but the animals that are lacking in the STAMP2 genes, they don’t have the STAMP2 molecules, they produce a lot more inflammatory cytokines and also Haptoglobin. And it’s interesting. Haptoglobin, too, is Zonulin, which causes gut permeability. So, there’s a lot to think about in these findings, and I hope that’s been helpful, and we’ll open up to questions right now.
Interviewer: First, thank you very much for that very engaging presentation. We are at, I guess, the top of the hour, so we’ll just keep it to two questions. First, for those health care providers who are, I guess, getting exposed to this topic perhaps for the first time, can you recommend any good resources for those who are, I guess, enthusiastic to dive deeper into the topic?
Interviewee: Nature Immunology just had several review papers –
published, and I’ve saved those, and I think they’re open-access. And if that’s what you wanna do, that’s what I’d recommend. Shoot me an e-mail, and I’ll send them to you.
Interviewer: Great, and maybe we can include that in the follow-up to this presentation.
Interviewer: The second was a question with regards to T-cell signaling in antibiotics and if you’re aware of any research or science that might show that one – that antibiotics interfere with the T-cells’ signaling capability.
Interviewee: None that I’m aware of off the top of my head directly, but obviously antibiotics are really gonna change the composition of the gut microbiota, and that’s gonna impact on the cells that modulate T-cell function. So, indirectly there will be many of them, and there’s probably so many different pathways that, again, that’ll be something else that’s contextual in the light of the person’s genetics and other environmental exposures.
So, I can’t say there’s anything specific that I’m aware of, but, again, the approach is kinda holistic. Let’s eat the right diet and avoid the food triggers or other environmental triggers that we know cause aberrant immune reactions. And the right diet, I mean certainly one that’s healthy for the microbiota and compatible with our unique genetically determined biochemistry.
Interviewer: Well, I wanna thank everyone for attending tonight. I wanna thank you for your presentation, and for those who wanna catch this again, we will be providing this – the video, transcript and slides of this presentation in about a week from today. Thank you very much. Goodnight.
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