[00:00:00] Carl Lanore: [00:00:00] Hey, Hey, welcome back to another episode of super human radio. Today is Monday, November 16th, 2020. For those of you listening to this show a hundred years from now and realizing that this audience knew a lot more than anybody else did, uh, we have a fascinating show today. We're going to discuss the microbiome during the first hour.

[00:00:19] You know, that's a favorite of ours to talk about. Uh, Hmm. Then later in the show, we're going to talk about a method of determining whether or not. Rheumatoid arthritis. Drugs will actually work therapeutically for people who suffer from RA. Uh, there's a way to figure that out before you even get started in a therapy, uh, which is also very interesting, uh, before we do any of that, we have to thank our title sponsor, legendary foods.

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[00:01:08] For those of you are new to this. The tasty pastry is basically a pop tart that has had all the sugar removed is gluten-free and has high quality, high protein, a high leucine protein in it. In the case of the hot fudge sundae, it has 15 grams of protein, zero sugar, and I think it's got like two or three impact carbs.

[00:01:33] It's got a little bit of fiber in it. They taste better than real pop tarts. The kids will love them. You'll love them. They can't keep them in stock. So please go to eat legendary.com. Use the coupon code SHR and, and save 10% off and enjoy yourself. Enjoy yourself. And, uh, without further delay, I'll bring my guest on now.

[00:01:55] And he is Kirk dr. Kirk Bergstrom. How are you doing Kirk?

[00:02:00] [00:02:00] Dr. Kirk Bergstrom, Ph.D.: [00:02:00] I'm doing great.

[00:02:02] Carl Lanore: [00:02:02] Thanks for being here. So, uh, for those of you who were looking at the show and going well, where where's the doctor Legion Shaw, he had problems connecting. Uh, so dr. Bergstrom has jumped in here, uh, to help us out. He is also, uh, one of the people involved in this recent paper that looks at, uh, some new information about the microbiome.

[00:02:24] So Kirk, uh, to, to get started with this discussion, Why was this study needed? What did this study springboard off of? Uh, what work was done before, and it could be by your, your group or other colleagues that these questions still needed to be answered.

[00:02:40] Dr. Kirk Bergstrom, Ph.D.: [00:02:40] Sure, sure. So, uh, yeah, Carl, you know, the study really, um, Was built on a need that to really define the relationship between our microbes in the gut and the copious mucus that's produced.

[00:02:56] And I can really elaborate on that if you want.

[00:02:58] Carl Lanore: [00:02:58] Yeah. So when you say the [00:03:00] copious mucus, this has become a more interesting topic because the mucosal barrier is, is implicated in everything from leaky gut syndrome to, uh, actually the ability for. Uh, things to get into the bloodstream that trigger auto-immunity.

[00:03:16] So, yes, please, please talk about that. That mucosal barrier.

[00:03:20] Dr. Kirk Bergstrom, Ph.D.: [00:03:20] You bet. You bet. So, you know, mucus is not the most glamorous thing to talk about. It's uh, you know, when people think about it, they think about snot coming from your nose and sickness and gross, the sticky gooey stuff, but it's really fascinating.

[00:03:34] Carl Lanore: [00:03:34] It's definitely, it's definitely fascinating to guys, not so much girls,

[00:03:37] Dr. Kirk Bergstrom, Ph.D.: [00:03:37] right? Yeah. Yeah. Girls. Interesting. Um, so I have, uh, you know, some researchers, uh, in my lab who wanted to study female researchers and I'm all about. Empowering women researchers. And so, um, but you know, mucus is, uh, you know, it's, it's, uh, one of the most complex molecules I think you'll ever come across.

[00:03:58] Um, it's, uh, [00:04:00] it's made of amino acids about, you know, three to 5,000 immuno acids.

[00:04:05] Carl Lanore: [00:04:05] So technically, so technically mucus is a protein.

[00:04:08] Dr. Kirk Bergstrom, Ph.D.: [00:04:08] Mucus is a protein more specifically, it's a glycoprotein. Okay. Yeah, exactly. Oh, it's got tons of sugars on it. So, um, it's 5,000 meter West is long and it's got this domain called a mucin domain, which are.

[00:04:24] It's of attachments for sugar structures that we call Oak, like glycans and these Oak like heads they form, uh, they're basically, uh, short chains of sugars that form made up of about five to six different monosaccharides linked together and all sorts of ways they could form, um, you know, up to a hundred different structures on the mucin.

[00:04:46] Um, And so it makes it extremely chemically and biologically diverse molecule. And then on top of that, so that changes its size from. A couple of hundred kilodaltons to now in the mega Dalton range, right? [00:05:00] So it's extremely large and chemically complex, and then it forms this massive polymer it's linked together.

[00:05:08] And this was done by an amazing researcher in Sweden, a good our Hansen's lab. It really defined the polymeric structure of the mucus. Um, and it, it, it's now in the. Hundred megadalton range. Like it's a really enormous molecule. So the problem with that, it makes it kind of, uh, it's uh, it's just a huge headache to study because of its complexity and some normality.

[00:05:33] Um, so it's just as fascinating as it is, uh, as much of a headache to study

[00:05:39] Carl Lanore: [00:05:39] the difference between studying yeah. Struck studying structures and looking at a house which is complex, but now looking, but now looking at an entire metropolitan area,

[00:05:49] Dr. Kirk Bergstrom, Ph.D.: [00:05:49] you could think of it that way.

[00:05:51] Carl Lanore: [00:05:51] Yeah. Interesting. Okay. So, so the mucosal barrier serves a purpose, right?

[00:05:56] Is the purpose exclusively, uh, to [00:06:00] line the stomach and keep the things in the gut from getting directly out into the bloodstream? Or are there other purposes for the mucosal barrier?

[00:06:08] Dr. Kirk Bergstrom, Ph.D.: [00:06:08] Sure. So, you know, one thing to maybe clarify as what you mean by the, the mucosal barrier. So the mucosal barrier is actually a collection of several things.

[00:06:19] So the mucus is part of that mucosal barrier. Then you have your epithelial barrier as well, which is a single layer of epithelial cells. Um, that also is a part of that mucosal barrier. And what they do is prevent. Limit the microbes from interacting with immune cells and the lemon appropriate that are poised right there to attack any sort of invader.

[00:06:44] And so the mucosal barrier, um, if you're referring just to the mucus, uh, that, that is what I'm our, you know, our research is focused on,

[00:06:54] Carl Lanore: [00:06:54] right? No. And, and, and, and, and the mucosal barrier is held in place by, uh, like, uh, [00:07:00] what do they call them cilia or some sort of, uh, uh, Tissue that actually has, uh, like tendrils and it kind of, it creates, uh, a rebar if you will, for the mucus to hold onto, right?

[00:07:14] Dr. Kirk Bergstrom, Ph.D.: [00:07:14] Yeah. Actually in the airway, um, you, mucus is produced, um, in large amounts in the airway and certainly the Celia are more pronounced there than they are in the gut. And so that, that function you just described as is definitely reminiscent of what you'd see in the airway where the Caelian, you could just work together to push the capture material on the celiac, push it up into the airway.

[00:07:36] And that's what you cough up as like sputum. Okay. Um, but in the gut, it it's a little, it's a little bit different scenario. So in the gut, the mucus, um, actually it's quite remarkable. It's made of, uh, one particular mucin called  too. Mucin tibia. We just short shorten it for muck too. And it really has two completely diverse roles that [00:08:00] it, that it plays, um, simultaneously.

[00:08:02] So one, um, it forms what's called, uh, This tradition called the outer layer and forms a niche for the microbes. So the microbes love to colonize it and they feast on it on the glide hands and the sugars in the mucus. Okay. And, and we don't know exactly what the mucus is doing to those microbes, but it's certainly we think helping to keep them happy.

[00:08:25] But at the same time, while it's attracting the microbes, it's also forming a barrier to keep them away from the tissues. And so it's kind of a form of social distancing. You can sort of think of it that way. And, and so, um, it's kind of remarkable a couple that the, the mucus system, as we're starting to call it now, because that's a pretty accurate term for it.

[00:08:48] And this was coined by a actually the Swedish group I mentioned earlier, um, The mucus system is it does those two things, um, totally, uh, diametrically opposed [00:09:00] things at the same time, it attracts the microbes and keeps them away from the tissue. And so that, that's kind of our understanding, but like how it does that, um, is still very much an open question.

[00:09:11] And that's where our study kind of comes in.

[00:09:15] Carl Lanore: [00:09:15] Okay. So talking back about the mucosal barrier, just for a second. Sure. Acid doesn't affect it, right? The acidity of the stomach. Uh, does it play any role in pre preservation in modulation and effecting the mucosal barrier at

[00:09:34] Dr. Kirk Bergstrom, Ph.D.: [00:09:34] all? I see, that's a really, really good question, Carl.

[00:09:37] Um, so the stomach that the mucus is a little, uh, again, different from the rest of the intestine, the mucus system really changes as you go through the GI tract. Um, the stomach it's much more neutral, meaning that there's a lot less acidic sugars on it. Um, And the reason is because the stomach is so acidic, the pH in the stomach could go down to [00:10:00] like pH one, a one to two.

[00:10:02] So that's extremely acidic. And so what the mucus does in the stomach, it helps to create a buffer between the harsh acidic. Environment of the aluminum, the tissue, and it plays a really, really important role in, in creating that very steep, um, pH gradient between the stomach and the tissue, which is really over the pH increases as you go through the intestine, um, And in, in the colon, in the larger tests.

[00:10:30] Yeah, probably around pH six, roughly. And so, um, so actually the mucus is much more acidified in the stomach. Believe it or not, they have these really interesting monosaccharides called silak acid and also these, uh, sulfate groups that contribute to this acidity, the acidity and negative charge. And so the mucus has a, uh, Pretty much a, quite a different role in the colon compared to the stomach.

[00:10:55] Carl Lanore: [00:10:55] So, um, does the mucus play a role in [00:11:00] keeping microbes from inhabiting areas of the digestive track that they're not supposed to be? So we have a lot of people talking about small intestinal, bacterial overgrowth, and I kinda think that is happens to be tied to, um, as we get older, the acidity. Uh, drops.

[00:11:19] Obviously the pH goes up and it allows microbes to inhabit areas that they shouldn't does the mucosal barrier, uh, protect or, or create an environment that is either beneficial or not beneficial to microbes, uh, from taking up space in places that they're not supposed to.

[00:11:38] Dr. Kirk Bergstrom, Ph.D.: [00:11:38] Uh, absolutely. Um, so what's really interesting, Carl is that there are certain parts of the intestine where the actually the tissue really likes the bacteria.

[00:11:49] Um, the proximal colon actually is a, is a place where microbes are routinely interacting with the epithelial cells, even going deep into [00:12:00] these episodes structures called Crips and like really in close. Contact with the host tissue and not causing disease. And so that part of the tissue, for reasons we don't completely understand, but seems to be very well adapted to the microbes.

[00:12:15] So it kind of, it's totally fine with having this complex community set in such close contact, but the distal colon though, Uh, it doesn't have that relationship with the microbes. Uh, it, it appears to want to keep them away. It is not adapted. And that tissue is very susceptible to bacterial induced inflammation.

[00:12:35] So you're talking about the descending, colon, the rectum and the people. And in mice, you know, we, we do a lot of work in, in mice as pre-clinical models. It's the same thing that region of tissue is extremely susceptible to. Um, microbial Doost inflammation. So that's where the mucus plays a role in what's called the biogeography of the microbiome microbiomes.

[00:12:56] It keeps them segregated and in the lumen where, [00:13:00] um, That's where the tissue is most happy to have them, but in the more proximal regions, the mucus serves other roles. It's probably more feeding the microbes, but not necessarily keeping them away from the tissue because in the approximate call. And that's where you get these, the most beneficial effect of the microbes with producing these anti-inflammatory metabolites through fermentation like short chain fatty acids, which can have a direct.

[00:13:27] Uh, impact on the, you know, on the immune system,

[00:13:30] Carl Lanore: [00:13:30] you iterate things like that, right?

[00:13:32] Dr. Kirk Bergstrom, Ph.D.: [00:13:32] Yeah. Propionic acid acid. Yep.

[00:13:35] Carl Lanore: [00:13:35] So talk about your study. How was your study design?

[00:13:40] Dr. Kirk Bergstrom, Ph.D.: [00:13:40] So, um, the study itself was designed. It that's, uh, Kind of a, it's a big question. You know, a lot of the platforms that we needed to support our hypothesis were developed in our previous publications of previous studies.

[00:13:55] So these include the, the animal models we use to sort of support and [00:14:00] prove our hypothesis in vivo, um, and some of the imaging techniques. And so as we designed the study, we basically relied on. No three, three or four major platforms. And so one is, you know, genetic manipulation of the mucus system and the mice.

[00:14:17] Um, and again, we've developed these mice and previous, but we had to actually generate a new model, um, in this study as well. And then some imaging techniques, um, Nor to really look at sort of the big picture what's going on in the whole tissue. We had to develop sort of an imaging technique where we can look at the whole what's going on in the entire colon.

[00:14:39] So, um, this is, you know, uh, an eight to 10 centimeter structure. Um, we wanted to be able to see what's going on at one time so we can understand what's happening with the mucus system as it's being produced, um, throughout the entire colon. And so we had to develop a new imaging platform. And then, um, [00:15:00] we took advantage of gnotobiotic, uh, most models and germ-free mice as well.

[00:15:05] And then we took, uh, also with, with our collaborators in Los Angeles, where to class data scientists, uh, John Bryan and David Casero. We, we did some of the most cutting edge, um, microbiomics that we've ever done. And so in order to really understand what the mucus system is actually doing to the microbes.

[00:15:26] So I'm happy to elaborate on it.

[00:15:28] Carl Lanore: [00:15:28] Well, I, I do that because my next question was what makes the mucus, so it sounds like do microbes do specific microbes, make the mucus.

[00:15:36] Dr. Kirk Bergstrom, Ph.D.: [00:15:36] That's a awesome question. So what we discovered in the study, um, so is that basically the cells. Specialized epithelial cells of goblet cells.

[00:15:49] These are kind of your mucus factories. Their whole purpose is to, well, their major purpose. Actually some studies have come out with they have different purposes, but their major purpose [00:16:00] is to produce, uh, the mucus system. That's secreted into the lumen that interacts with the microbes. And so, but where our study really, uh, you know, Provides clarity on this, on what they do is the fact that the it's actually the mucus in one part of the gut, the more proximal colon is what's contributing to most of the mucus that you see.

[00:16:25] And then the, the distal colon produces a totally different subtype that contributes little to the overall barrier function of the mucus. Um, But it does contribute to a new subtype of mucus that we discovered in this study.

[00:16:39] Carl Lanore: [00:16:39] But this is the part, this is in the colon. What about in the gut itself? What about the stomach?

[00:16:43] The stomach has mucus lining it as well. Is it the same tissue? The same size that make the mucus in the stomach.

[00:16:53] Dr. Kirk Bergstrom, Ph.D.: [00:16:53] So in the stomach they have. Uh, sort of mucus cells that we don't necessarily call them goblet cells in the [00:17:00] stomach. They should just call them more, more mucus cells. Uh, but yes, they do the same thing, but they produce a different type of mucin called MK five AC.

[00:17:09] And so this, this is related to MK two that you see in the small intestine and the colon, but it's a, it's a different, it's a different molecule. Okay.

[00:17:21] Carl Lanore: [00:17:21] But it does have a similar structure. So does it provide, um, uh, what's the word I'm looking for? You know, environment specific protection that you need in the gut because of the highest acidity versus downstream where the acidity is lower.

[00:17:36] Is it it's it's that? Yeah. The difference

[00:17:40] Dr. Kirk Bergstrom, Ph.D.: [00:17:40] in the stomach, you mean?

[00:17:41] Carl Lanore: [00:17:41] Yeah, the stomach to the colon, let's say wa yeah, it's a different type. Gotcha.

[00:17:46] Dr. Kirk Bergstrom, Ph.D.: [00:17:46] Gotcha. So, so let me let let's walk through the whole GI tract real quick. Okay. So starting in the stomach, you have this MK five AC produced by the mucus cells and it promotes, it produces this very [00:18:00] neutral, uh, type of mucus.

[00:18:02] Um, there's not much, uh, acid component and that forms that, that sort of buffer zone that contributes to that pH gradient for that low pH to that more, um, You know, uh, physiologic pH that are cells are more used to, and that's the purpose of the mucus really in the stomach is to, to pervade that buffer zone between the, the acidic, um, gastro juices that was, he moved to the small intestine.

[00:18:30] Now you're getting to the goblet cells. And so the small test, it is quite different from the colon. Small intestine has these structures called Villa. So these like stick out like fingers, of course, you know, into the lumen and goblet cells are produced, um, along the epithelium part of the Villa. And so they, they also produce mucus.

[00:18:51] Um, and here the mucus cooperates with. Um, the epithelial cells, which secrete anti-microbial molecules that [00:19:00] bind to the mucus, um, and also through Panis cells in the small intestine that also these will bind to the mucus and contribute to anti-microbial activities of the mucus. But the mucus doesn't form really a barrier in the small intestine and forms.

[00:19:14] It just stringy mass that. Um, that really isn't much of a barrier at all. And so, so we think probably the anti-microbial component of that mucus is able to, you know, compensate for the lack of barrier function there. Um, and so, but what, then you get into the colon, which doesn't have belie just has these sort of these Crips structured are these invaginations right.

[00:19:42] And so, um, that's where you get this really strong. Thick barrier structure that we are, it's now sort of a classic structure that you would see in the, in the colon of these mice. And that that's where the mucus is main function there is [00:20:00] to, um, promote. Both it's supposed to, to feed the microbes, uh, but also to separate them from the tissue perform a barrier.

[00:20:10] So it's really more about the microbes in the colon and in the stomach, more about the acid.

[00:20:16] Carl Lanore: [00:20:16] Right. Okay. So do all of these cells that produce the different types of mucus use the same raw materials? To make mucus, like, I've heard that if you, if you want to, re-establish the mucosal barrier of the stomach take glutamine.

[00:20:37] Um, what does, what do they, what do they use to make mucus?

[00:20:42] Dr. Kirk Bergstrom, Ph.D.: [00:20:42] So to make mucus, you're going to need a whole lot of amino acids. You need a whole lot of sugars and whole lot of enzymes. So, um, if you want to, to boost your, um, Too mucus. You, you gotta, uh, so you're going to need [00:21:00] the course, the, the gene to be expressed the muck to gene, for example, in the colon, but that's not all, um, you're going to need enzymes that are going to decorate the mucus with those sugars.

[00:21:11] So as the mucus is being translated to the protein, that's getting processed and then post translationally processed, moving through the golgi apparatus. Now you, you have to have a lot of, uh, glycol seal transfer phrases. These are the enzymes that will add the, uh, sugars. So unique monosaccharides to, to the mucin and build on those glycogen chains, those, uh, telling you.

[00:21:39] And so they need to be present and active. And so, um, it's actually, we don't know. It's what it is, as it moves through to like that, and shades get built and then you get, um, at some point as once it moves through the golgi, it gets packed into these mucin granules [00:22:00] after it's been glycosylated, and then it forms this polymer and then that probably Mer within these granules is then released.

[00:22:07] So, so really what you need to understand when you, if you want to boost mucus is you want to understand the, not just the. Mucin gene itself, but you need to understand all the glycosyl transfer is that the mucin gene normally interacts with to make a normal mucus.

[00:22:26] Carl Lanore: [00:22:26] Yeah, because it's fascinating to me because there's a, there's an emerging evidence that as we age, it could be age or as we live longer and expose ourselves to things in our diet, in our environment, we even know that RF is affecting microbes in the gut now, um, This mucosal, the protective barrier of the gut seems to thin and, and, and, and it leads to, um, uh, things that are in the gut that shouldn't be in the blood, getting out of the [00:23:00] environment and into the blood and hence autoimmunity, but also just ulcers and IBS, and even some say colon cancer, uh, as a result of the inflammatory, um, The inflammatory impetus in areas where you don't want inflammation.

[00:23:18] It seems to all come back to this, you know, this dielectric, this, uh, this protective barrier that seems to go away as we age. Is there anything evidence that there's a way to re-establish these, uh, uh, an a, maybe a dietary or supplementation, a combination of both, a way to improve the protective barrier that's in our digestive tract.

[00:23:43] Dr. Kirk Bergstrom, Ph.D.: [00:23:43] Um, again, I really appreciate your questions, Carl. So, you know, one of the things our study is we found is the mucus production is really controlled by that microbes. So, um, we take germ-free mice. [00:24:00] What was remarkable is that the, the mucus system was very rudimentary. Um, there's not much of a barrier at all.

[00:24:08] And even though he's my sort of high fiber diet, um, you can see the fibers you're scraping along the mucosal tissue and they, the tissue is perfectly happy. It wasn't damaged. Um, and I was a bit surprised by that. Um, so it's really, when you only added back microbes, even just one microbe. Um, now you've got the production of this mucus and.

[00:24:34] You get this. Um, and in the, mainly in the proximal part of the colon, and so the microbes really control the mucus production. So, uh, that I think gives us a lot of insight into how we could, you know, envision a way to boost it,

[00:24:49] Carl Lanore: [00:24:49] which microbes, which microbes were, were implicated in this process.

[00:24:54] Dr. Kirk Bergstrom, Ph.D.: [00:24:54] So we, we just, we, we looked at a complaint community.

[00:24:58] So in that case, it's hard [00:25:00] to nail down a particular one, but we did a study of gnotobiotic study and, uh, back to radio state over to I'm, a crime was one. Bacteria that was able to induce it on its own, although a slower dynamics than it, than a complex community. So even a single micro could do it. Yeah.

[00:25:18] Carl Lanore: [00:25:18] I mean, so, so you, what you're talking about here could be the Holy grail and helping people with disorders like IBS and so on.

[00:25:26] Um, that's right. So we did a show a couple of years ago that showed that, um, That, uh, certain, uh, carbohydrates, grains most specifically seem to, um, cause flare ups of IBS and it, and I wonder sometimes, you know, I keep thinking, I keep going back to our diet, right? Because look, you're talking about fiber right now.

[00:25:50] Dr. Kirk Bergstrom, Ph.D.: [00:25:50] Hmm.

[00:25:51] Carl Lanore: [00:25:51] We have a fiber four to five foods where we probably shouldn't have fiber is people are getting a ton of fiber that they may or may not need today. We [00:26:00] don't know what this is doing to the gut. In fact, uh, dr. Leslie Aiello, who used to run the winter Grande foundation in Manhattan, and I had a few conversations about this, and she said that as we evolved as humans, we have, we have consumed less and less fiber.

[00:26:16] Our guts got smaller as a result of that. And our brains got bigger. Now that's a very over-simplistic, uh, progression over millions of years. But the point is that we've gone back to eating fiber. Like it's, you know, like we're supposed to, and I often thought to wonder if the fiber isn't somehow causing, um, some unwanted changes in the microbial diversity of the stomach.

[00:26:41] So would this, uh, this bacterial Adidas, what was it called? Bacteria data's watt. 

[00:26:47] Dr. Kirk Bergstrom, Ph.D.: [00:26:47] or if we just call it  data for short.

[00:26:49] Carl Lanore: [00:26:49] Okay. So, so how did that, how does that respond to the, uh, soluble and non fibers? Does it do anything with them?

[00:26:57] Dr. Kirk Bergstrom, Ph.D.: [00:26:57] So that that particular bacteria is, [00:27:00] is what's called a, um, sort of glycogen generalist.

[00:27:03] It, it has, I think, uh, for last count, um, maybe close to a hundred different. Enzymes are basically groups of genes that can utilize pretty much any, almost any type of, uh, glycogen. So it can harvest an act on plank like hands, um, any sort of like hand. A monosaccharide and linkage that you see in there, all the different sugars that are in the fibers, but could also act on the host like hands too, which are quite different from the plant glide can, so not, not too many, uh, bacteria have that same degree of flexibility

[00:27:42] Carl Lanore: [00:27:42] that shows, and that shows us the importance of hierarchy that, that it's so adaptive.

[00:27:48] It can adjust to whatever it's being given to do its job.

[00:27:52] Dr. Kirk Bergstrom, Ph.D.: [00:27:52] That absolutely. That actually, that, that study was published by, uh, Jeff Gordon's lab, um, back in [00:28:00] 2005, which basically that was one of the more transformative studies for me. Um, and so, uh, Justin Sonnenberg has his own lab in Stanford and leading, um, Sort of electrologists and also glyco biologist as well.

[00:28:13] Uh, you know, he's also a, co-author on the study we're talking about today, but, uh, yeah, that, that was one of the defining things about that is that, that. Bacteria is able to adapt to its changing environment

[00:28:27] Carl Lanore: [00:28:27] generally. Uh, uh, uh, uh, what's the word I'm looking for important. Uh, if, when it's that it's that flexible that it knows it has to do its job.

[00:28:36] Uh, so it's going to use all sorts of fuel forms to, to, to, to be able to do that. We have to take a quick commercial break. When we come back, we're going to get back to, uh, what you discovered. Uh, in this study, we're talking today with dr. Kirk Bergstrom. He's filling in for dr. Lesion. She sh I'm sorry, Shaw, uh, who had difficulty, um, Logging on to our video system.

[00:28:57] We're going to take one quick commercial break. We'll be right back [00:29:00] with more super human radio station.

[00:29:09] welcome back. You're not going to want to miss tomorrow's show when Shannon Pennett comes on and gives us two different low carb recipes for Turkey stuffing. This is a big frustration of mine for, for Thanksgiving. I want to eat stuffing too, but I don't want all that carb the carbs. I don't want the bread.

[00:29:28] I don't want the pro-inflammatory grains in my body. Well, we have two recipes, one with a low carb keto bread that you have to make first. And then the other one using cauliflower. So don't miss this show because you're going to want this in your bird. Figuratively speaking this year, getting back to one other thing I wanted to mention, uh, dr.

[00:29:50] Bergstrom is I did a show probably about six years ago on how a cellular carbohydrates I E flour, [00:30:00] anything made into a flour from a grain corn, a cellular carbohydrates feed. Um, The wrong gut bacteria in the stomach, because they're already there. They're broken down. So small, typically you'd, you'd have to digest them and they wouldn't really start to become a problem until later down the journey out of the body.

[00:30:22] But because they're available right in the stomach for these microbes to eat, it actually changes the diversity of the gut to those that are. Uh, less energy intensive and, and more, um, uh, w have a higher ability to extrapolate, uh, or extract nutrition from food, which leads to obesity. And I thought that was fascinating too, because it's these, uh, these, these unwanted microbes get fed by flowers, any kind of flour, not, not almond flour, but most of your starchy flowers.

[00:30:58] Okay. So what, [00:31:00] what, what exactly did you learn? Uh, I don't think I can hear you. Are you muted? They are good. You don't, you don't have to mute. I mute you on this end. So Coco, so talk about the study. What, what really jumped out at this study? What is the, the thing that's really reshaping our understanding of the gut microbiome that was derived from this

[00:31:19] Dr. Kirk Bergstrom, Ph.D.: [00:31:19] study.

[00:31:20] I think the biggest thing is just really how our guts handle this vast community. So, um, you know, I think the, the thinking before was that, you know, we have this microbes that exist in our gut and, you know, it's hard to sometimes picture we'd maybe have this picture that the microbes are just, they're maybe floating around there, you know, attached to components of the diet.

[00:31:44] Maybe not super organized. Um, And it's just this continuous thing going on in the gut. And so, you know, we, we think about the gut, we think about the microbes and we maybe have this picture, um, you know, of a mucus, [00:32:00] for example, separating them, but we don't really have this, you know, the big picture of what, what is really, really happening.

[00:32:08] And so, um, You know, one of the, what our study is showing is that you have this massive community, that your mucus in your first part of your colon, uh, the first part is your lead and test dine. So, uh, that the proximal colon is, um, I should clarify the first popular that is actually your Seca. And then you move to the proximal part of the colon that mucus in the proximal colon is actually secreted.

[00:32:38] Into the lumen and as it travels down, it's somehow, um, we're reads, we don't understand completely yet, but it, it encapsulates that microbial community. So it wraps itself around that that entire,

[00:32:53] Carl Lanore: [00:32:53] um,

[00:32:54] Dr. Kirk Bergstrom, Ph.D.: [00:32:54] like mess in the sort of mass units, I guess you could call it. And so it forms [00:33:00] this barrier that is pretty.

[00:33:02] Effective, uh, keep sequestering the microbes altogether in the community and keeping them from escaping that community.

[00:33:11] Carl Lanore: [00:33:11] So these days, so they almost become biofilms. It sounds like we're talking about here, right? It creates almost like a biofilm because a lot of biofilms are designed to sequester, um, unwanted things in the digestive track.

[00:33:23] Right.

[00:33:25] Dr. Kirk Bergstrom, Ph.D.: [00:33:25] I think biopharma, I wouldn't necessarily call it a biofilm. I would basically, when you think of your, your, your fecal mass, that, that we'll have probably some biofilms within it may have little micro colonies and things, you know, attached to, you know, some of the fibers that are also going to be encapsulated in this, by this mucus.

[00:33:47] Um, but it's really, it's basically. Taking that whole community and kind of helping to, to, to wrap it all up into a distinct sort of, uh, mass. [00:34:00] And then that basically community doesn't seem to. Be able to escape that. I mean, it's not absolute, you're always going to see a situation where somebody goes escape, but,

[00:34:11] Carl Lanore: [00:34:11] um, by and large, it becomes like a virus vault.

[00:34:15] If you will, on your computer, like for some reason, the body doesn't want those microbes to come in contact with the tissue in that area. So it sequesters it. Yeah.

[00:34:24] Dr. Kirk Bergstrom, Ph.D.: [00:34:24] Okay. So,

[00:34:25] Carl Lanore: [00:34:25] so, so when, when that process goes awry, then do we see the types of, um, uh, anomalies, uh, to the colon, you know, IBS and, and irritable and all these other, and even colon cancer.

[00:34:40] Do we see those being triggered by the failure of the, of the mucus to sequester those microbes?

[00:34:50] Dr. Kirk Bergstrom, Ph.D.: [00:34:50] I would answer yes to that. And I can base, I could totally base that on, um, uh, you know, elaborate on that. So, uh, in [00:35:00] animal studies, absolutely. Um, once you mess up that ability of the mucus to encapsulate, um, that microbes now are able to have unrestricted access to, to the tissues.

[00:35:12] Um, as it, as that fecal mass moves through the colon and. That unstuck assets will lead to chronic, um, sort of inflammation, chronic inflammation. It, it, it, it, it will hyperactive inflammatory pathways, um, and just keep them on, on an always on sort of situation leading to this chronic inflammation. And that inflammation itself creates a pro-Trump Magenic environment and which can transform normal cells into tumor cells.

[00:35:45] And then it just basically. From there, it's just, uh, really creates a perfect storm. And then you get these, you get the tumors and the cancer, and that's the actually study we published back in 2016.

[00:35:58] Carl Lanore: [00:35:58] Wow.

[00:35:59] Dr. Kirk Bergstrom, Ph.D.: [00:35:59] So, [00:36:00] so

[00:36:00] Carl Lanore: [00:36:00] yeah. And I'm no, no, go, go, go.

[00:36:02] Dr. Kirk Bergstrom, Ph.D.: [00:36:02] So, so what our state does really, it, it, it really puts a re-interpretation though of a lot of the previous studies, including including our own, where we're understanding what's happening.

[00:36:14] To the microbes. Um, and as you see them, that sort of that host microbe interaction dynamic, our study really helps to now turn it from like this continuous idea that we're kind of used to seeing to actually, it's a very discreet communities that are moving through the corridor at one time, thanks to the, to the mucus largely.

[00:36:36] And so, um, it creates these masses of communities and in between them, it's very, it's a ver it's. Microbiome rich communities. And in between these fecal masses that are in Canada escalated, you have very bacterial poor zones. So it's a much more discreet communities that you see rather than this continuous micro colonization of, of the, of the tissue that [00:37:00] we, or of the, of the mucous along the tissue.

[00:37:02] So the mucus is actually the previous model was, um, That we're, you know, we're challenging, um, is that the mucus is not necessarily produced locally and attached to the tissue. It's a very highly mobile structure. Um,

[00:37:18] Carl Lanore: [00:37:18] that could you, could you, could you, could you use isotope, uh, glycans to see where the mucus goes?

[00:37:28] You know what I mean? Kind of tag it and then you say, Oh, this, this started here and it went here and then it went here and then could you do that?

[00:37:34] Dr. Kirk Bergstrom, Ph.D.: [00:37:34] Actually, we did something very similar to that in this study. So we did a metabolic labeling study, um, using the sort of bio orthogonal approach where we've, uh, used this technology, uh, by Carolyn Potosi.

[00:37:48] And she's the one who sort of, uh, you know, Brought this out into the limelight, a boat over 10 years ago now, but it's, I'm using click chemistry. So you can use this  can, you [00:38:00] could, you know, checked into the mouse and it gets a corporated very easily into the mucus. And then, uh, you can afterward if, once you collect the tissue from the mice, you can do the chemical reaction right on the tissue, and you can show you exactly where that label glycogen, um, You know, w where it is.

[00:38:21] And, um, we used it basically to analyze the secretary response.

[00:38:26] Carl Lanore: [00:38:26] Um,

[00:38:27] Dr. Kirk Bergstrom, Ph.D.: [00:38:27] but from that information, we were able to get some insight into where it was actually being produced.

[00:38:34] Carl Lanore: [00:38:34] So, yeah, whenever we talk about the gut, we talk about the microbes, but they're also fun guy and that live in the gut. And from what I understand from a show that we did years and years ago, I'm going to get these terms, right?

[00:38:47] One is a U Kara site and the other one is something else. One has a nucleus and one doesn't microbes don't have a nucleus, but fungi do so th they actually a step higher, uh, or, uh, organism than, than [00:39:00] microbes. And we also know that fun guy. Um, use microbes the way we, the way we ranch, you know, cattle and sheep and chickens.

[00:39:10] Uh, one, one, a fun guy can gather 10, 20, a hundred different microbes that it uses because these microbes, uh, when they eat something, they poop out something to fund guy likes. Uh, so they, they, they like little, little micro Branchers, if you will. Do when, when you study the microbial diversity and the effects of the gut microbiome, do you look at the fun guy and what they are contributing to a lot of this stuff as

[00:39:40] Dr. Kirk Bergstrom, Ph.D.: [00:39:40] well?

[00:39:42] No, I think you should. Um, this study really focused on, on the bacteria, right? Um, the bacteria component of the microbiome, but certainly, you know, our study has ramifications for all, all the other aspects of the microbes, including the fungi and the viruses and the eukaryotic [00:40:00] sort of micro organisms to single cell animals that you may see in there.

[00:40:03] Even some of the worms, all components of the microbiome. Um, are going to be wrapped up in this mucus, not just the, not just the bacteria. So it's interesting to see, uh, what's happening to those, um, components as well. And, um, what was interesting in our study was that even though we, we discovered, you know, the microbes induced this mucus in their own central.

[00:40:28] Uh, encapsulation, the mucus itself is it's sugars. Also modulating the microbiome. So you have this sort of counterpart to that. And so it shifted the community and it, it influenced their, uh, their metabolic output. Um, and so we, again, we focus on the microbes by, it'd be really interesting to see what the SSA, capsulation and its effect on the community is happening to the other members of the microbiota, [00:41:00] as you mentioned, like the fungi.

[00:41:01] Carl Lanore: [00:41:01] Yeah, because I kind of feel like looking at the gut and strictly looking at the. These microbes, but not, but not also looking at the contribution to all these other things that you just listed. You know, we, we could be making assumptions and we could be really far off without taking into account how they attenuate and modulating the effects of these microbes and, and, and what they put out.

[00:41:28] Dr. Kirk Bergstrom, Ph.D.: [00:41:28] Sure, absolutely. And that's where he could take advantage of, um, Things like the metogenomic data that we regenerated in, in this study. So we, we did, uh, um, shotgun, uh, measure. And so now we have basically all that information, at least on the genetic level. Um, see what. Types of, you know, the fungal species that are there, the viruses, and even potentially, um, you know, some of the, the functional potential that they have by looking at the genes that the fungi would have in there [00:42:00] as well.

[00:42:00] So we, we could, we could still go deeper in the study. I mean, uh, and, and use some of that data. We generated to actually address those very questions.

[00:42:10] Carl Lanore: [00:42:10] We're going to take a, uh, last commercial break for this interview, uh, and wrap up this discussion. I have a couple more questions I want to try to get covered.

[00:42:18] Then later in the show, we're going to be talking about a new way to determine whether or not. Uh, certain drug treatments for RA will actually work for you. They can actually now help identify you as a candidate, um, for some of these, uh, potential therapies. Uh, so stay tuned. You're listening to and watching superhuman radio.

[00:42:37] We'll be right back.

[00:42:43] welcome back to super human radio. We're talking with dr. Kirk bergs

[00:42:46] Dr. Jesmond Dalli Ph.D.: [00:42:46] from.

[00:42:48] Carl Lanore: [00:42:48] And we're talking about your microbiome. You know, the microbiome is kind of like out of space, you know, we think we know a lot about it. We don't know a whole lot about it. We're learning all the time. [00:43:00] So, um, was other than the key findings, was there anything that jumped out at you that you didn't expect when you did this study?

[00:43:10] Dr. Kirk Bergstrom, Ph.D.: [00:43:10] You know, um, one of them, things that I mentioned before was just the, uh, that really intimate association of the mucus response to the microbes and not to other components of the diet. I mean, we only really tested this with, with one sort of high fiber diet. So we can't say the other diets, you know, wouldn't have an impact on the mucus, for example, in a germ-free system.

[00:43:33] Um, but that, that was quite striking to me. Um, it really. It goes against this idea that, you know, the mucus barrier is just, you know, a pass. The, the barrier effect is, is passive to the Luber, you know, passive consequence of the need for lubrication as the stool moves through the colon. But really it. The microbes controlling.

[00:43:53] It indicates it's, it's more than that. It's more of a barrier. And that, that new I was talking about earlier in the [00:44:00] study. So that was really interesting. Um, the other is how the mucus is apparently constructed. So that the model before was that it seems to be, it was constructed locally in the tissue, by the goblet cells.

[00:44:13] It sits on the surface and then, um, it's linked to the surface and then it. Moose and gradually produces that nice layer from the barrier. Um, our study is showing that it seems to be constructed more in the lumen, um, itself, once it's secreted and. That. So how that barrier is actually forming is, um, it's still an open question.

[00:44:35] So that was really surprising. And then maybe how the microbes responded as well. Um, so we mentioned that the bee feta earlier, um, what was surprising is that, um, that microbe, when, when we lose the glycans, that microbes actually went up. In terms of its relative abundance, I would thought because it, it really likes the host [00:45:00] glycans.

[00:45:00] It would probably go down or at least, um, but it actually seemed to improve. And so, um, that was a bit, a bit surprising.

[00:45:10] Carl Lanore: [00:45:10] That sounded like a reactionary. Like if the, if the, if the, if the mucosal barrier is thinning, the body goes, we need to make more. So it establishes more of those, uh, B feta, uh, microbes, perhaps.

[00:45:23] Dr. Kirk Bergstrom, Ph.D.: [00:45:23] You know, it that's very true. And one way to test that hypothesis would be to, um, you know, remove the, both the host glycans as we do genetically in the mice and also remove the dietary glide. Maybe give them a, um, a diet that is, uh, devoid of these complex, uh, dietary plant polysaccharides, more simple sugars and see how the bacteria is response there.

[00:45:48] And that will, that will tell us whether. It that ability to improve when the host glycans are lost, they're actually, um, it's, uh, it's a, uh, adaptive response of the [00:46:00] microbiome in that situation. Um, but I guess it was just surprising, um, because it, it kind of gives an idea that even maybe the hosts like hands are actually.

[00:46:09] You know, limiting somehow, maybe I don't know, directly, or maybe indirectly, but it's affecting other species, the ability of that particular microbe to, to thrive in a normal, in a normal mucus environment. So that to me was a bit, was actually quite surprising.

[00:46:24] Carl Lanore: [00:46:24] So diet has the greatest. So when, when I first started to study the microbiome for shows eight to 10 years ago, we started talking about it.

[00:46:35] It was just fascinating. Cause I thought, Oh. Especially when you look at things like fecal transplant, the dramatic effects of a fecal transplant. I mean, some, some of the stories are astonishing and you go, Oh, so you just have to change your microbes to change your health. But as I've gone down this path, um, I've learned that the, that the microbes are more of a remnant.

[00:46:59] Of your [00:47:00] diet. And we've done shows that show that microbiome diversity can change in as little as 48 hours just by changing the diet. And we see this in, um, We see this in people who go to extreme elimination diets, and especially in response to emerging autoimmunity. We know that people who give up a lot of plant-based foods and go keto or carnivore or ultra low carb, they see almost a remission of a lot of their symptoms.

[00:47:36] And over time they, they seem to get better. And it's, this is, this is, um, Not in any equals one thing. We have millions and millions of people in this country that if someone took the time to set up a website and get their stories, we'd probably have some really statistically significant information out there that would lead to other studies.

[00:47:54] So with that being said that the diet changes the [00:48:00] microbiome and the longer you alter the diet, the deeper those changes go and take. Have you found anything? That seems to be contraindicated, or that seems to disrupt the development of this needed a mucosal barrier in various places in the gut, but most importantly in the colon,

[00:48:22] Dr. Kirk Bergstrom, Ph.D.: [00:48:22] uh, well, we haven't really looked at that specifically to be honest.

[00:48:26] Um, but I know other researchers, um, have, um, I know, uh, Justin Sonnenberg, for example, has shown if you're too. Change the diet, you can impact the microbiome over generations. Um, you can lose particular members and some of these changes can be compounded as the mice propagate. And they,

[00:48:46] Carl Lanore: [00:48:46] so the transgenerational you're saying that those changes are transgenerational.

[00:48:50] Dr. Kirk Bergstrom, Ph.D.: [00:48:50] Those are transgenerational

[00:48:52] Carl Lanore: [00:48:52] and it makes sense. The mom gives a lot of the mom gives a lot of the microbes to the offspring. So that makes sense.

[00:48:58] Dr. Kirk Bergstrom, Ph.D.: [00:48:58] Yeah. Yeah. But, [00:49:00] but the diet will impact that. And then the, the combination of the diet and then the transfer of the microbes over time will compound those changes originally introduced by the diet.

[00:49:12] Carl Lanore: [00:49:12] Interesting.

[00:49:13] Dr. Kirk Bergstrom, Ph.D.: [00:49:13] Yeah, that was very, very, very good. Interesting. Actually

[00:49:16] Carl Lanore: [00:49:16] the pro the problem with it, the problem with dietary interventions for, uh, issues related to microbial diversity is that. Some of these microbes that can we remember that these are evolutionary leap, adapted species of microbes, and some of them will become spores.

[00:49:34] They don't die. They just go into suspended animation. And as soon as you start eating the crap food, again, you cut all your problems return. So you can't, it appears to me that once the microbial diversity of the gut has been changed for the worse. You can't diet your way into fixing it, but you can die your way around symptoms if that makes any.

[00:50:00] [00:50:00] Dr. Kirk Bergstrom, Ph.D.: [00:50:00] Yeah. Yeah. I, I think I would agree with that. Um, so certainly some of the species, you mentioned, the sport formula, clustered and species, um, that that's a dynamic of the microbiome that is still really poorly understood. Um, and you can get at that through. I think that the evolution of microbiomics, which is getting now into the meta transcriptomics versus just the metagenome.

[00:50:26] So instead of just looking at what genes are present you, uh, you're looking at what genes are actually activated within a bacteria. So this is, uh, Curtis, uh, Hutton Howard has been huge at this. And, and, um, and so John Bryan or collaborative study also has been on this. So. Um, so that that's certainly one way to get at it because you can see if the species is present, but not transcriptionally active that may indicate they're dead, or maybe they're in some sort of a spore state or some inactive state.

[00:50:57] And so I think it's a, it's a totally [00:51:00] different dynamic of the microbiome that we need to understand.

[00:51:03] Carl Lanore: [00:51:03] Last question. Sure. Is there a way to test for the accumulation of the, um, mucosal? I don't even want to call it a barrier because it's more of a, I don't know, a player in, in, in the colon. That seems to be the culprit that could be leading to chronic inflammation.

[00:51:22] Is there a way to like ultrasound the goal? My God, you've got none of that mucosal lining. We need to do something about it.

[00:51:29] Dr. Kirk Bergstrom, Ph.D.: [00:51:29] That was one of the most exciting outcomes of this study is that the mucus system that's that. We are normally used to looking inside the tissue actually is attached to the fecal mass.

[00:51:47] And so the, you can now analyze the mucus now in the, on the feces.

[00:51:55] Carl Lanore: [00:51:55] Um,

[00:51:56] Dr. Kirk Bergstrom, Ph.D.: [00:51:56] you get a lot of insights and so this, this [00:52:00] answers, uh, Really addresses a lot of problems past problems with the mucus and that now you can get access to it, um, and non invasive way. So you don't have to, this reduces the number of mice maybe you need to use.

[00:52:14] Um, if you want to look at the impact of the mucus, but you also get access to the mucus, um, Through the fecal material. Now you can extract it. We've shown the study. You can extract it the same way as you can it from tissues and do glycol mix on it. And things like this, um, just from the fecal matter itself.

[00:52:32] So what this does is open doors for, um, clinicians, for example, and patients are, you know, people are interested in the mucus, what's happening to it. For example, if you have inflammatory bowel disease, like ulcerative colitis, you can look at the fecal material and you can see what's happening to the mucus just by looking at the feces.

[00:52:52] And so this opens up the door for not only non-invasive, um,

[00:52:57] Carl Lanore: [00:52:57] sort of analysis

[00:52:58] Dr. Kirk Bergstrom, Ph.D.: [00:52:58] of the mucus, but also. [00:53:00] Biomarker analysis

[00:53:01] Carl Lanore: [00:53:01] too. Very fascinating. Very fascinating.

[00:53:04] Dr. Kirk Bergstrom, Ph.D.: [00:53:04] Yeah.

[00:53:04] Carl Lanore: [00:53:04] This is exciting. Hey look, uh, Kirk, I want to thank you for jumping in, uh, uh, we're we're was unfortunate that we couldn't get, uh, adopted, uh, lesion Shaw on the show because of technical difficulties, but I think you've covered everything fantastic.

[00:53:19] And I will, um, I'm advanced, uh, inviting you back as you learn more, uh, you just email Elisa. We'll get you right back on the air because this is. This is really important stuff. When we talk about the gut, because I am convinced that, uh, just about all diseases of modernity, start in the gut and understanding.

[00:53:39] Uh, what makes the gut thrive and what makes the gut sick is probably going to lead to a lot of other diseases, uh, being eliminated in the population. So thank you so much for being here today. Okay. Tell me one more thing.

[00:53:52] Dr. Kirk Bergstrom, Ph.D.: [00:53:52] So yeah, I just want to really acknowledge a lesion shot. So he's. Uh, the study was driven by Oklahoma, [00:54:00] Oklahoma medical research foundation.

[00:54:01] That's where I did my post-doc and this is where it started. And lesion is an absolutely excellent mentor has tremendous instincts for science. Um, and so he's, we, the stay was, was driven. Uh, By myself and, and Legion. And so, uh, I just want to give a shout out to, to him and also a cold lead author, uh, Dylan shad, who did a tremendous amount of, uh, work as well on the study.

[00:54:29] Um, it's a very talented post-doc there. So I just want to make sure that that, uh, Just acknowledge them. Excellent. Excellent.

[00:54:36] Carl Lanore: [00:54:36] All right. We're going to take a quick commercial break. When we come back, we're going to switch up. We're going to talk about rheumatoid arthritis, which is a big problem, uh, in, in today's environment.

[00:54:44] Uh, and so stay tuned. We'll be right back with more supervision.

[00:54:48] Dr. Kirk Bergstrom, Ph.D.: [00:54:48] Thank you. Thank you.

[00:54:50] Carl Lanore: [00:54:50] Is the superhuman channel doing reps with the weight of the world?

[00:55:01] [00:55:00] Welcome back to superhuman radio. We're going to be talking about a new study that shows that there may be a way to predict whether or not a particular treatment will be beneficial for those who suffer from rheumatoid arthritis. We're talking today with dr. Jasmine Dolly. Did I pronounce your last name?

[00:55:21] Dr. Jesmond Dalli Ph.D.: [00:55:21] Proper that's correct.

[00:55:23] Carl Lanore: [00:55:23] Thank you. Thank you for being here. So, um, let's start with why this study. What, what, what, what. Was happening before this study that required this study to be done. D do these rheumatoid arthritis, uh, remedies not work for a large portion of it? The suffers?

[00:55:44] Dr. Jesmond Dalli Ph.D.: [00:55:44] Yes. So, so, uh, in many countries, uh, and I I'm currently based in the United Kingdom, but, uh, this was also true for the United States and many other countries in the world.

[00:55:55] Um, Patients with rheumatoid arthritis are treated in a [00:56:00] somewhat prescriptive manner. So that means that there is a, there's a procedure that's followed that it's not necessarily based on whether you're likely to respond to a drug, but more because the drug is usually cheaper. Um, to, to access. And so, uh, physicians are so somewhat obliged to provide the cheaper drug first and see what happens if you respond, then that's all very well.

[00:56:27] Yeah. And in

[00:56:28] Carl Lanore: [00:56:28] the United States, we call that the standard of care, correct. The standard of care.

[00:56:33] Dr. Jesmond Dalli Ph.D.: [00:56:33] Right. Um, and if you not, if you don't, then you've suffered four additional months, potentially you've been exposed to, uh, some of the side effects of some of these drugs, as we all know, nothing is a hundred percent safe in the world.

[00:56:47] Um, and so, uh, this also means that your disease would have progressed to potentially an even worse. State before you might be able to be assigned the drug that works for you.

[00:56:59] Carl Lanore: [00:56:59] And, and on [00:57:00] top of that, uh, what happens quite often in this type of an approach where we will, okay, we're going to try this drug, if that doesn't work, going to try that drug, you know, uh, when, when your body is, when you walk into the doctor's office, you're sick, you have it, you have an ailment, you want treatment for it and, and you manifest certain, um, unwanted undesirable symptoms.

[00:57:21] And then they put you on a drug. That doesn't work, but give you a host of new symptoms. And now you don't even know if the next drug is just getting rid of it. It's just a cessation of what you stopped taking, or the next drug is actually working. And it's very sad because patients who don't respond quickly to the first therapy could end up chasing new symptoms that were a result of this merry-go-round of drugs that they use.

[00:57:47] Dr. Jesmond Dalli Ph.D.: [00:57:47] Correct. That's very, very correct. And, and so, so, and, and this is, this is, uh, an unfortunate situation that we find ourselves in because we don't fully understand how, how many of the [00:58:00] diseases occur. What. Makes these diseases of care. And also how, uh, inf affecting some of the pathways that the drugs tends to target will influence the disease progression in different patients.

[00:58:14] And in some cases, because we don't understand because each patient is different and most people don't only have, say rheumatoid arthritis. Some people may have diabetes on top of it. Some people may have. Cardiovascular disease. Some people may have some weight issues, obesity linked issues. So, so you know, us as a scientist studying, sorry, I think in a laboratory where everything can be made in an ideal case scenario, and then going to the real world.

[00:58:41] When top of everything we have stresses, we are all very familiar with during these times. Uh, all these aspects tend to influence our ability to respond to a specific drug. Um, and today it's been our, our ability to predict whether someone is, is going to respond or not to actually to evaluate very [00:59:00] early on.

[00:59:00] Um, you know, w we're not talking about a magic ball here. Um, it's really trying to understand what the mechanisms of the disease that are, that there is of interest in this particular case arthritis, um, are involved in how these particular mechanisms are. Regulated differently in different people. Um, it, it, we, we've not necessarily quite got to that level of granularity.

[00:59:25] And this is, I think what has hindered us in understanding and being able to tell where the one patient is more likely to respond to the drug or that they're being prescribed or not. And, and so this is the aspect that we we've been very keen on, uh, on addressing over the very many years. Okay.

[00:59:44] Carl Lanore: [00:59:44] Uh, I'm I'm sorry.

[00:59:45] I'm sorry. I'm sorry. And,

[00:59:47] Dr. Jesmond Dalli Ph.D.: [00:59:47] and so, so, you know, we are my laboratory. Um, and, uh, and, and my, my mentors, the poetry were trained, uh, at Harvard medical school and the Brigham and women's hospital. Uh, he's there, there's, there's a level of [01:00:00] pioneering, um, of

[01:00:02] Carl Lanore: [01:00:02] new biology

[01:00:03] Dr. Jesmond Dalli Ph.D.: [01:00:03] where, uh, we're looking at how the body regulates the immune system and immune system regulates itself.

[01:00:11] In both, uh, diseases like rheumatoid arthritis, where you have a, what is generally referred to as a style inflammatory response, but also in infections. And we know that these checks and balances in, in many of these conditions become, um, become lost, or at least they don't work as effectively. And so we wanted to base.

[01:00:31] Uh, the, this, this potential of understanding whether a person is going to respond to a drug that impinges on these pathways, as we also found out, um, based on how D how well these pathways are expressed, these particular molecules are, he was by the buddy.

[01:00:48] Carl Lanore: [01:00:48] Okay. So how was the study designed?

[01:00:53] Dr. Jesmond Dalli Ph.D.: [01:00:53] So, so the study design, uh, was based on first of all, uh, methodologies [01:01:00] that were pioneered in my laboratory.

[01:01:03] And then we refined using mass spectrometry to measure molecules that we discovered, uh, in the peripheral blood. So in blood of patients that were diagnosed with rheumatoid arthritis, But were not given any of these disease modifying anti-rheumatic drugs. So this is the very early stage and we were very lucky to have a fabulous collaborator in professor  who had, uh, uh, through no, no little effort managed to establish a patient cohort, um, where.

[01:01:37] That we could obtain blood from these patients before they went on to the treatment of care.

[01:01:42] Carl Lanore: [01:01:42] Right? Exactly.

[01:01:44] Dr. Jesmond Dalli Ph.D.: [01:01:44] Which, which is very difficult because you can appreciate to obtain, and this allowed us to really be able to test this hypothesis to an a, to a large level. And then, uh, apart from using these methodologies and this unique cohort, um, we [01:02:00] also layered on top of it, the, you know, an expanding body of literature that is based around, um, uh, artificial intelligence and machine learning.

[01:02:10] So the ability of, of, of, uh, of a computer based system, if you will, to, um, to, to churn through chunks and chunks of data, to identify patterns, That are reliably reproducible.

[01:02:25] Carl Lanore: [01:02:25] And what was the molecule that you discovered?

[01:02:28] Dr. Jesmond Dalli Ph.D.: [01:02:28] So, so this is a class of molecules that are called specialized pro resolving mediators.

[01:02:34] And these are molecules that are primarily produced from omega-3 fatty acids. You know, the, the, the fatty acids that th that our parents always told us, you got to eat your fish, eat your fish. And this is one of the reasons why you gotta eat your fish, because these, these fatty acids, these essential fatty acids are the precursors.

[01:02:54] For the production of molecules, the specialized pro resolving mediators that are [01:03:00] important to our, for our body to regulate inflammation.

[01:03:02] Carl Lanore: [01:03:02] So let's talk about that for a second, because it's a very important distinction. What we're talking about here and CEDS, uh, corticosteroids, they stop. Inflammation, but they stop healing.

[01:03:16] Cause inflammation is telling the body, Hey, come fix me over here. And so when we talk about inflammation, there's two things that you can do. You can halt inflammation, which isn't really a good thing because you can't halt it forever or you can help it resolve. And by resolving, we mean to go through the complete process injury resolution healed all better.

[01:03:40] These molecules found in a mega threes actually SPI. And the truth of the matter is people who take large doses of Omega threes that have been also shown to, um, uh, affect, uh, be effective as well. But these molecules don't just stop inflammation. They speed up the healing process. Correct.

[01:04:00] [01:04:00] Dr. Jesmond Dalli Ph.D.: [01:04:00] That's very correct.

[01:04:01] Uh, I couldn't have explicit expresses better myself.

[01:04:05] Carl Lanore: [01:04:05] So, so, so how so, how so, how is it that these people who are suffering from this chronic inflammatory disorder are producing, uh, their own SPMS from their diet? Is it actually helping them or do they just need larger doses?

[01:04:21] Dr. Jesmond Dalli Ph.D.: [01:04:21] So, so there's, there's there's this is that an aspect that they actually were currently actively actively engaged instigating.

[01:04:27] And it's a fantastic question because the, the, uh, the disruption and what leads to chronic inflammation in this case, for example, rheumatoid arthritis could be from two aspects, the inability of your body to produce these molecules early on enough to stop. The inflammation from becoming uncontrolled.

[01:04:49] And then once, if you can imagine this as a, as a train, right? If you pull the brakes at that at an early time, you can stop the train from going, uh, [01:05:00] out of control. But if it gathers enough speed, then the brakes just don't work anymore. And even though your body produces these SPMS, the system has become so disrupted that you need a reset, a strong reset button.

[01:05:14] Now. The other sign that could actually be disrupted is not just the ability to produce them, but these molecules require proteins on the cell surface or on the surface of cells known as receptors that can sense their prisons and then, uh, convey the biology. That they're meant to convey to stop inflammation.

[01:05:37] So if the, if the expression of these receptors is, is happens to be out of tune out of sync with the production, or there are, there are defects in, in either the way the receptor and the signaling that it should they're listed downstream or the X or the, the, the X. The confirmation of the receptor is incorrect, then that, [01:06:00] that defeats the production in any way, because you have the molecule, but you don't have what it, what is required for it to be conveyed into a biological action.

[01:06:10] So there are two aspects here that could be different. It

[01:06:13] Carl Lanore: [01:06:13] actually, I'm going to submit a third one. Okay. Maybe you could put my name in the next study. So, so, so here's, here's the third one. Um, I've done shows on rheumatoid arthritis now for pretty close to a decade, and we know that, uh, rheumatoid arthritis has a autoimmune component to it.

[01:06:35] And we know that autoimmune diseases by and large are a result of. Um, things in the stomach getting out into the bloodstream that looked like bad actors, the immune system goes after them and then they go, Oh, it also looks like thyroid tissue. So let's go up to the thyroid too, or let's go after the meniscus and the, and the joints and the chondrocyte.

[01:06:56] And so could it be the third [01:07:00] possibility that these receptors are occupied by something that has a greater affinity to them? And so that the, the SPMS can even attach and do their job.

[01:07:11] Dr. Jesmond Dalli Ph.D.: [01:07:11] It is, it is also possible. Um, you know, it's, there is this receptors, have a Mo uh, have multiple functions. There's not one.

[01:07:21] I like, and for one receptor, because otherwise biology would, you know, we would require it in a numerous number of our, that's not how biology works. Right. So it's likely, what's been, what's been known for some of the receptors and many of these receptors. We're still really learning, uh, you know, the basics of their biology, but for the ones that we've been studying for a little bit longer, we know that one receptor can signal both.

[01:07:48] Pro-inflammatory so, so molecules that activate the immune system versus the pro resolving mediators that dampen the immune system and the downstream signaling pathways that elicited are also, [01:08:00] um, uh, not just mediated through the ligand, that's binding to the receptor, but how the receptor dimerizes so forms multiple, multiple complexes, right.

[01:08:10] With other receptors. So, so is there is that is, that is a valid point and it could actually be also an aspect that, that, that requires testing. I would, I would submit that it's potentially more endogenous ligand. So other molecules that are inflammatory that might interfere with the ability of SPMS, but, but you know, we, we know that some of the SPMS, for example, regulate bacterial function.

[01:08:35] And, and this is known, this has been known, for example, some of the SPMS regulate quorum, sensing mechanisms. Um, in, in, in some, in, in pathogenic bacteria. So, so there's no, there's no reason why it shouldn't be the other way around. And actually some of the receptors that we're studying are also activated by formulated peptides that are characteristic of [01:09:00] bacterial species.

[01:09:00] Uh, bacteria tend to have older. Proteins are formula formulated. And so, so there is, there is potential cross dock too, for this.

[01:09:09] Carl Lanore: [01:09:09] This is very fast to me because it's my, I have so many thoughts running through my head. Like, uh, I have a attention deficit, a deficit syndrome. So, and, and the, and then the other thing, as you kind of pointed out with the, the multiple ligands, uh, activating receptors is the mosaic of receptors can be selectively.

[01:09:28] Uh, domains can be selectively activated, and other domains can not be activated, which throws a whole different. Curve ball into the, into the, into the discussion now, anyway, so when, when, um, so, so just talk more about your study. So once you discovered the prevalence of these SPMS in the blood, what was the next step?

[01:09:52] Dr. Jesmond Dalli Ph.D.: [01:09:52] So, so the way we conducted the study was it was in two phases. The first phase was to identify potential [01:10:00] biomarkers. So, so in the first phase of your thing, blood, from a group of patients that we knew retro retrospectively, that they had either responded to the drugs being given or not. And so what we did to here was using these machine learning methodologies.

[01:10:18] We queried whether there were specific molecules that were diagnostic or sorry, prognostic of, um, uh, of, of treatment outcomes. So whether there were molecules that linked with whether some person, a person responded or did not respond to that treatment doc, um, and then by, by, by in the second phase of the study, we obtained.

[01:10:42] More plugs from completely different patients and question whether these. Molecules that we found in peripheral blood were indeed prognostic. So using completely different patients. Could we still classify someone as a, as a responder or [01:11:00] non-responder based on the concentrations of these molecules in their blood.

[01:11:04] And we found that we could do it with an accuracy of about 89%. So that means that we could get. Um, nine out of 10 patients in the right category, um, based on their, the levels of these molecules in peripheral blood. And the other interesting thing that we observed is that we could not only tell whether these molecules were predictive of what, of, whether someone was going to be able to read what was going to respond or not to these drugs, but also the type of disease that they had.

[01:11:34] So rheumatoid arthritis, and this is work that's been done by collaborators. Um, Has it been classified into different partner types, so different sort of if you will forms of the disease. Um, and, and this is based on, on the, the pathology, the, the, the way that the joint looks under a microscope, um, when people take biopsies from the joint and it's linked with whether [01:12:00] the immune system, which part of the immune system in a way it becomes disrupted, whether it's the innate part, whether it's the

[01:12:06] Carl Lanore: [01:12:06] learning.

[01:12:08] Dr. Jesmond Dalli Ph.D.: [01:12:08] More of a, of a, of a strong apart.

[01:12:11] Carl Lanore: [01:12:11] And we could

[01:12:12] Dr. Jesmond Dalli Ph.D.: [01:12:12] tell from what's happening in the peripheral blood, whether. A patient was more of one category type and versus another category. And that's important because we know, um, that different types of disease, different flavors of this disease respond better or worse to different types of treatments too.

[01:12:33] So, so together, it, it, it starts to tell us it's, it's starting to tell us that, um, we can start now to break down. RA patients into more of a unique person, uh, response, and a more of a, uh, a designed

[01:12:50] Carl Lanore: [01:12:50] treatment

[01:12:50] Dr. Jesmond Dalli Ph.D.: [01:12:50] approach rather than you have arthritis. So you need to go down this route.

[01:12:55] Carl Lanore: [01:12:55] Yeah. It's it w you're you're moving towards individualized medicine, which is actually the [01:13:00] goal of medicine today.

[01:13:01] Correct. So the first question that comes to my mind is, um, There are, there is actually companies out there that sell SPMS. There's a company that has a patent, uh, here in the United States called Metagenics. I actually take SPM. They could, they have a particle SPM active. It's a distilled portion of Omega threes.

[01:13:23] That is a very rich in the S the, um, uh, uh, form. So. Why not just give people SPMS as a PR. Cause because we know that Omega threes don't just act as an analgesic, but they actually turn genes on and off that help shut down inflammation while resolving inflammation at the same time. Why not just give people SPMS instead of these other drugs?

[01:13:50] Dr. Jesmond Dalli Ph.D.: [01:13:50] Wow, uh, that, that that's, that's where we aiming to be. Good. So, so the product that you mentioned, um, really helps [01:14:00] feed the production of, of the, of SPMS of pro resolving mediators. And it does so because, so, so these poses are, the mediators are produced via the conversion through enzymes of. Substrate into bioactive molecules.

[01:14:14] And th th the advantage of that product is, and I should say, I see what you're saying.

[01:14:20] Carl Lanore: [01:14:20] I see. It's not really an SPM. It's the, it's the raw material for your body to make jumpy.

[01:14:26] Dr. Jesmond Dalli Ph.D.: [01:14:26] It's actually a step above that jump start. So it skips part of this. Was because, because it it's formulated in a way to provide an, improve the conversion to SPMS over into the sort of general, um, or mega threes, I would say.

[01:14:41] Um, so, so that's, that's, that's the advantage now in terms of providing SPMS, you know, that's sort of the, the, the clinical

[01:14:49] Carl Lanore: [01:14:49] I see, I see where you're going. You take, so I think the SPM comes from the DHA portion. Of the, of the omega-threes. So what you, what you, what your group hopefully will end up [01:15:00] doing is taking that.

[01:15:02] And putting it through the enzymatic conversion where you actually have SPMS and a capsule to give somebody. Correct.

[01:15:09] Dr. Jesmond Dalli Ph.D.: [01:15:09] So, so, so it's not just the ha I should add it's it's DHA and three TPA of the omega-3 version of the  acid. All three fatty acids contribute to SPMS. Right? So what we're actually interested in and the aim of where we're, you know, uh, from a drug perspective, I'd say th th the supplementation perspective is very important.

[01:15:30] And I think it's, it's critical because there is evidence in the literature that providing omega-3 including recently, um, in a very big trial in cardiovascular disease, where people were given a refined. Form of, of EPA in the reduce it trial. There, there, there was clear evidence for benefit in reducing cardiovascular events, severe cardiovascular events.

[01:15:54] So, so, so I'm not saying that the supplementation point is, is not important. I think there is evidence [01:16:00] for it and, and it is an Avenue that we're also exploring. But the other side, I think that in those conditions where the enzymes become disrupted and we've shown this. That for example, in some patients and specific cohorts of patients with vascular inflammation, the enzyme activity is lost.

[01:16:18] So in that, in that case, you need to go with the mediator, the molecule itself to reset the system. Right? And so in that case, the way we're exploring it and Stu to actually produce these using a total organic synthetic approach. So you get a refined molecule that

[01:16:36] Carl Lanore: [01:16:36] has the biology

[01:16:37] Dr. Jesmond Dalli Ph.D.: [01:16:37] of interest. That we can target to help reset the system and then, you know, press that reset button really.

[01:16:44] And then once you've reset the system, you can go to a supplementation approach.

[01:16:48] Carl Lanore: [01:16:48] So talk about the enzyme for a second. Is this enzyme something of save the cytochrome people have 50 cascade and the liver is, and what is the enzyme?

[01:16:58] Dr. Jesmond Dalli Ph.D.: [01:16:58] So there's multiple enzymes. We [01:17:00] know, we know when we've characterized and these enzymes have been studied for many decades.

[01:17:05] Um, uh, some of these, but they're still unknown. So the ones that we know of are the oxygen needs. The family, the cyclo oxygen, his family in particular cycle oxygen is two. And there is a contribution of the cytochrome P four 50 enzymes too, as well as the soluble epoxide hydrolase enzymes and the boxer hydrolyzes.

[01:17:27] So there is multiple families and then there's also,

[01:17:34] there's multiple enzymes. The family of molecules contains over 70 members. Uh, and some of the pathways overlap and some of the pathways are separate. Um, and the, the, the, the interesting thing is that the pathways and the enzymes are shared with those molecules that are classically thought to be inflammatory, uh, the, the, the prostaglandins and the Lucas Trane.

[01:17:56] Right. So, and we think that this is also why in [01:18:00] some aspects, especially the chronic admin of inhibitors to these enzymes can have detrimental effects because maybe in acute settings where you have overproduction of say prostate prostaglandins, you will break that production. And it's it's. It's protective, but over a longer period of time than you're influencing the pro resolving mediator pathways.

[01:18:20] And that's, that starts to lead to side effects.

[01:18:23] Carl Lanore: [01:18:23] This is fascinating stuff. This is exciting to me because if you can actually produce the final end result molecule that's missing and you don't require enzymatic conversions or anything else that could go awry in the, from the precursor to the final product, then you can treat them.

[01:18:43] Um, uh, rheumatoid arthritis and a bunch of other pro-inflammatory diseases, I'm sure with something that is more holistic and natural for the body.

[01:18:52] Dr. Jesmond Dalli Ph.D.: [01:18:52] Correct. Correct. And that's the aim. So our, our, our, our aim, or at least the hypothesis that we're working [01:19:00] with is that if we can engage protective pathways that are geared towards, um, towards doing specifically that terminating inflammation, repairing damaged tissues, we've, we've shown in the past that for example, some of these pockets can regenerate bone in the periodontium, even in large animals.

[01:19:20] Um, in many pigs, for example. So, so if you can, if you can engage these pathways, um, Without disrupting. And this is the other interesting aspect of the biology that they do not suppress the immune system. So we've shown that they're not only protective in, in, in say rheumatoid arthritis, but also in infection.

[01:19:42] So it suggests that you're not, uh, pro um, interfering with the ability of the body to deal with another inflammatory in stock or an infection infection with their eyes. You're just. You're just reprogramming it. You're just getting it better so that it doesn't overshoot. Um, [01:20:00] and, and this we think would, will help a lot in minimizing side effects from treatments.

[01:20:06] So

[01:20:06] Carl Lanore: [01:20:06] very exciting stuff. And I, this, and I love it because it's, like I said, it's, it's a natural, you know, it's something that we should be getting from our diet. As you said, by the time the train has run away, you, the brakes don't work anymore. So you can actually kind of go in there and rescue the person.

[01:20:23] With purpose. That would be wonderful. Listen, this is fascinating stuff. I hope as you get closer, you'll agree to come back on the show and talk more. Wonderful. Yeah, this is really good, dr. Dalley. Thank you so much for being here today.

[01:20:36] Dr. Jesmond Dalli Ph.D.: [01:20:36] Thank you very much. Take care.

[01:20:38] Carl Lanore: [01:20:38] Bye bye. And we're going to actually pull the plug on the show.

[01:20:41] We're all done. Uh, we hope you enjoyed it. We hope you got some good information. Please share the show because. The gut autoimmunity, rheumatoid arthritis. This is all great stuff. You can help a lot of people. If you share the show, please share the show. We'll see you tomorrow with more superhuman radio.

[01:20:56] Talk to you then. [01:21:00]