Gladden longevity — Episode #21

Speaker 1:  Welcome to The Gladden Longevity Podcast with Dr. Jeffrey Gladden, MD, FACC, founder and CEO of Gladden Longevity. On this show, we want to answer three questions for you. How good can we be? How do we make 100 the new 30? How do we live well beyond 120? We want to help you optimize your longevity, health, and human performance with impactful and actionable information. Now, here's today's episode of The Gladden Longevity Podcast.

 The Gladden Longevity Podcast is provided for informational purposes only. It does not constitute medical advice. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The use of any information and materials linked to this podcast is at the listener's own risk.

Dr. Jeffrey Gladden: Welcome everybody to this edition of The Gladden Longevity Podcast. I'm going to be on today with a very interesting guest, Colleen Cutcliffe, who is a PhD, did her work at Johns Hopkins and her postdoc at Northwestern. She's involved with a product, actually, that we've come to really appreciate and enjoy using at Gladden Longevity. It's basically a probiotic that helps people control their blood sugars and then some of the downstream effects of that. So should be a very interesting conversation. Welcome to the podcast, Colleen.

Colleen Cutcliffe: Thanks so much for having me.

Dr. Jeffrey Gladden: Yeah. So tell us a little bit about your background, how you got to be here in the middle of prodrome and probiotics and all that sort of thing. What led you to all that?

Colleen Cutcliffe: Yeah. That's always the question. How did I get here? So my background, as you mentioned, is biochemistry and molecular biology. I actually got my first job and cut my teeth in pharmaceutical drug development. We were developing drugs for Parkinson's disease, and then I moved from there to an early stage DNA sequencing instrument company. That company went through some pretty rapid growth, went public, and on the other side of that, I started Pendulum.

The premise behind Pendulum was, really, I learned a lot in pharmaceutical drug development about how drugs are developed, and it always was interesting to me that efficacy was, of course, the number one goal, but, really, safety and thinking about the whole body as a system was not really a focal point in drug development.

So when I learned about the microbiome, I thought this was a huge opportunity where you could start to approach the microbiome using DNA sequencing data science. At the heart of the microbiome is really DNA sequencing technologies. So the idea was if you could marry DNA sequencing technologies and network data science with pharmaceutical drug development, you could, with the microbiome, create products that had the efficacy of a drug but the safety of a probiotic.

So to me, that was the really big opportunity of the microbiome. Probiotics have been on the shelves and yogurts have been on the shelves for decades, but there actually hasn't been any new ingredient innovation in the last 50 years. It's the same lactobacillus and bifidobacterium strains. So it seemed like an opportunity and a place that was ripe for innovation.

Then at the same time that I felt like there was a scientific and medical opportunity, I realized that there was a personal connection for me, which was that my first daughter was born almost two months prematurely and she was four and a half pounds. I got to hold her for a couple of seconds, and then she was put in intensive care, where the protocol is to give these preemies multiple doses of antibiotics.

What I noticed about her as she started in elementary school was that she had certain food sensitivities that the rest of us in our family didn't have. A big study came out around that time where they looked at, I think, 12,000 children and found that kids who were systematically exposed to antibiotics before six months of age were also systematically more prone to obesity and type two diabetes as they got older. 

That study has subsequently been repeated by the Mayo Clinic, and they're not only more susceptible to obesity and type two diabetes, but also things like Celiac disease, ADHD, all sorts of things because what's happening is when you take an antibiotic, you are decimating the microbiome, and in these tiny little babies, they now have to start back over again with a depletion of these microbes.

So for me, what I realized was that we had the opportunity to create products that could help millions of people around the world, including my own daughter. So that was the idea behind launching the company.

Dr. Jeffrey Gladden: Yeah. Nice. How old is your daughter now?

Colleen Cutcliffe: She's 15. So we have a whole new set of problems, but actually, I will say that I think her gut health, our focus on it, has been really instrumental for her. She can pretty much eat whatever she wants now for better or worse.

Dr. Jeffrey Gladden: So how did you rehab your daughter's gut? Because it's well-known that if people are on antibiotics, particularly at young points and age, this happens for kids with chronic ear infections and things like that, they get round after round after round of antibiotics, and it really does decimate the microbiome. Did you leverage some of your technology, some of your DNA sequencing technology and things like that to try to help her or how did that play out?

Colleen Cutcliffe: Yes. I mean, essentially, I'm the chef that gave the sausage to my kids. There are two, I think, really important pathways in the microbiome that we've been targeting using our DNA sequencing data, and one is the metabolism of fiber into butyrate, which is a really important molecule for variety of things, including the metabolism of sugar and fibers. Then the other is really the gut lining and the strengthening of that gut lining. So I basically gave her our product when it was still in dev stage and it worked for her.

Dr. Jeffrey Gladden: So let's talk about butyrate just so the audience understands how critical this is, sources of butyrate, why it's so important. Do you want to just launch into that a little bit?

Colleen Cutcliffe: Sure. Butyrate is a small molecule that's been known for quite some time to have a really important role in a variety of different things. I would say probably one of the most interesting things is that in your colon, your colon cells are the only cells in your entire body that use butyrate as their source of energy as opposed to glucose. Every other cell in your body uses glucose as a source of energy. So that makes butyrate particularly important in the colon.

So there have been a lot of studies showing that both in animal models, as well as human models that butyrate could play an important role in just a healthy colon. Additionally, butyrate is a small molecule that binds to these receptors in the gut lining and triggers the release of GLP-1 and ultimately leads to insulin and glucose response.

So we were really interested in butyrate for that mechanism. I think that it's quite well-known that butyrate is an important molecule and it's also really well-known that fiber is important. We all know a high fiber diet is really important for us, but the microbes that actually metabolized fiber into butyrate were never really known. So we're really just filling in the gap of this whole pathway that ends in this really important butyrate and GLP-1 signaling pathway.

Dr. Jeffrey Gladden: Yeah. We've heard for years that high fiber is good on multiple fronts, bulking up the stool for one, but it's also, just so the audience understands, the metabolism of that fibrate by the gut biome generates the butyrate that then actually feeds the intestinal lining, particularly in the colon, right? 

So this high fiber diet is not just so that you're not constipated. It's really about how do you keep the inner lining of the intestine healthy. That's a massively important thing that relates to, well, we'll get into it, but all kinds of things related to leaky gut or neurotransmitters or all host of things, quite honestly. 

It's fascinating that the butyrate is responsible for releasing GLP-1. Just so people understand, when GLP-1 is released, and correct me if I'm wrong here, it does signal the pancreas to release insulin, right? So if you're eating pure sugar, just a sugary drink or a sugary something or other and you don't have fiber with it, you're not getting that signal from the fiber to release the GLP-1.

In more of an evolutionary thought process, carbohydrates always came in with fiber. Pretty much, they were always associated with fiber, unless you were eating sugar cane, I guess, but other than that, and even there, you're chewing fiber, I suppose, but anyway, it always came with fiber.

So there's this natural way to bring carbs into your body in a healthy fashion, if you will, that helps you to metabolize them. It's also, interestingly enough, related to how many copies of the amylase gene you have that actually will increase the amount of amylase in your saliva that it also helps you process the carbs even starting in your mouth. 

So there's a whole host of things going on here to make that metabolism work properly, but it's interesting that the butyrate is actually helping to augment that. So if you are going to eat something sugary, make sure you do it with fiber. I guess maybe that's part of the take home message. So do you want to expand on that a little bit? Did I leave some things out?

Colleen Cutcliffe: No. It's absolutely right. I think the important thing is to know that we've evolved over time, to your point, to eat certain foods and certain pairings of different ingredients together. Through our own industrial evolution, we've separated these components out.

So really, what we're trying to do is give people back these components that they're missing. I think the other thing a lot of people don't know is that the fiber that's beneficial for you here, you actually don't encode for anything that can metabolize that fiber. It is entirely metabolized by your gut microbiome.

So if you're missing these microbes, that fiber is literally going right through you. All the good stuff you're trying to do is not having its benefit. So the idea is how can we give people back things that they've lost over time and through just the way that we diet and live in today's world.

Dr. Jeffrey Gladden: So have you been able to identify which of the microbes are responsible for metabolizing the fiber. The corollary question to that is, is this also true for resistant starch? Does the same microbes process resistant starch in a similar manner or are they two separate things?

Colleen Cutcliffe: Well, so first of all, I should emphasize that the microbiome is an early stage science. So we certainly don't know everything about it. We're just learning-

Dr. Jeffrey Gladden: For sure, for sure.

Colleen Cutcliffe: I think what we do understand is that there are microbes that help us digest these different types of fibers and there are different microbes. I think it's interesting. If you DNA sequence people's microbiomes and you try to compare them to each other, people have very different microbes in their microbiome, but if you try to bring it down to functions, people are actually quite similar in these functions.

So what ends up happening is if you're missing certain functions, that ends up being the problem. So there are microbes that have these functions. So really, it's not as much about the specific microbes as it is about these functions that you're trying to give back to people.

Dr. Jeffrey Gladden: Okay. So let me interrupt you for a moment. Would I be right in saying that different microbes can be associated with similar functions? So even if you have a different microbiome than your neighbor, you can still both be functioning optimally because you have the functions covered. Is that what you're saying?

Colleen Cutcliffe: That's exactly right. It's like a community, and in a community you can have let's say your doctors. One community has a different set of doctors than the other community, but they're performing the same health function.

Dr. Jeffrey Gladden: Got it. So this is important because there's a lot of misconception about the microbiome. For example, when stool tests are done by whomever is doing a stool test, they're always comparing the person's stool against a "ideal" stool, so to speak, and they're showing where you're up and down relative to that. In actual fact, there is no ideal stool.

So all of the testing is a little bit, you have to take it with a grain of salt. Any stool test you've done, if you've sent one in from home or you've done it at your doctor's office, you have to take the gut biome data with a grain of salt because there is no ideal stool. 

Back to your point, Colleen, it's really more about do you have the right functions. I don't know of any stool test that's actually reporting on all the different functionalities are being covered with your biome. I've never seen that kind of report. Are you aware of someplace where people can get that or we can get that?

Colleen Cutcliffe: I think it's very difficult to produce that kind of data. So just to give you a feel, you can get your gut microbiome sequenced for $100-$200. When we do sequencing of gut microbiomes where we're actually creating these functional maps, we spend about $2,000 to $3,000 per sample. So if you really want to get that functional map, it is a pretty deep sequencing exercise that you just don't get that kind of data from a consumer-priced sequencing project.

I think that one of the interesting things that's emerging is that this functional thing is very important, but there might also be some keystone strains. So I think of it like when we think about our genetics. P53 emerged as such an important gene that if you had a mutation in it, there are a variety of cancers that would come out of that.

Similarly in the microbiome, there are certain strains which appear to be emerging as these keystone strains. Akkermansia muciniphila is one of these, not to get too deep in the weeds there, but there are some key strains that I think are important.

Dr. Jeffrey Gladden: Yeah. That's great. Maybe we could get a list of some of those key strains from you and put them in the show notes. That would be great. I'd like to see that, too, because having those keystone strains enables us to look for those things. As I understand it, you can grow or shrink those populations based on what you're eating, of course. So if you're eating a variety of plant-based fibers, let's call it that, it's not all about just eating one source of fiber, but if you're eating a variety of fibers, you can be feeding the variety of those, let's call it keystone strains, and keeping that whole thing healthy. Is that correct?

Colleen Cutcliffe: Exactly right. Diversity is important everywhere.

Dr. Jeffrey Gladden: Yeah, exactly. Yeah. That's true for life, right? So well, that's very cool. So you go in, you do this DNA sequencing, you actually start to understand probably better than most people what the function is of these microbes. Even though you can't label each microbe with a particular function, you start to see the groups of functions that are happening. You identify some of the keystone microbes. Then from there, how does that take you into building your product to basically help control blood sugars? What's the story there?

Colleen Cutcliffe: Yeah. So we looked at people with type two diabetes and prediabetes and healthy people, and we were really trying to understand, are there functions that have a clear mechanism of action that are low or missing or maybe an overabundance in these individuals with diabetes? Then we did a twin study and these twin studies are extremely powerful because you can take a twin that is healthy in terms of their weight and then a twin that has diabetes and compare their microbiomes to each other. It eliminates some of the genetic component of these diseases, which there certainly is a genetic component to diabetes.

So when we did all of these, and I should say too, there was also research around the world happening at the same time where people were looking at this correlative and comparative data, it was really emerging very clearly for us that there was a mechanism of action that was missing in people with diabetes and prediabetes, and it pointed to these two key pathways. One was that they were missing these strains that could metabolize fiber into butyrate. This is a multi-step biochemical reaction. So some people were missing just the first half. Some people were missing the second half, but they were missing some component of that metabolism.

Dr. Jeffrey Gladden: Is that different microbes, different microbes are associated with different stages of that metabolism?

Colleen Cutcliffe: Exactly. Exactly. Microbiome is an ecosystem. So as one set of strains is producing one set of metabolites, another set of strains takes those and produces the next one. So you ultimately are creating butyrate.

Then the second thing was that they appear to be missing this keystone strain called Akkermansia, which is one of the only strains that actually lives in your gut lining and responsible for regulating that gut lining. So the idea was simply, "Okay. Well, if they're missing these, can we give them back and start to understand whether you could actually replenish a person's microbiome?"

We did our studies all telling people, "You don't need to change your diet. Don't go on any new medications. Just simply keep doing what you're doing. We just want to see if we can perturb the microbiome and then have this impact on A1C and blood glucose." We developed this the way you would a pharmaceutical drug. So starting in the lab in test tubes, and then moving into preclinical studies and then ultimately into clinical trials that have been published.

Dr. Jeffrey Gladden: So one of the things that we tend to think about with probiotics in general is that the probiotics don't actually seed the microbiome. They go in and through their own whatever mechanisms, they modulate the microbiome, but they don't necessarily seed it. It sounds like in this particular case that you're actually getting microbes to take root or to take hold or is it that you're accelerating the growth of a population that's already there? How do you conceive of that working exactly?

Colleen Cutcliffe: Yeah. In this particular way that we're doing it, we are delivering in a capsule, an oral capsule, this formulation of different microbes and the prebiotic that feeds them. So we actually have it in the capsule.

Dr. Jeffrey Gladden: ... and the prebiotic. Okay. That was a nice thing.

Colleen Cutcliffe: Yes. Actually, we found in our preclinical work that if you didn't have that prebiotic in there, you didn't have the same efficacy as if you had it there. Think about it like if you're going to drop me off on a tropical island, I would want to have also a cooler of sandwiches and beers. So really, we're giving them the food so that when they come to life, that's there.

We do know that for most people when they stop taking the pills, these strains actually went away. When they were on the pills that you can see the strains increase in their microbiome. There was a small percentage, though, about 15%-20% of people that after the washout period where they weren't taking pills for about a month, the strains were still in their microbiomes.

Dr. Jeffrey Gladden: Interesting.

Colleen Cutcliffe: So you ask people not to change their diet, but it is possible that people were feeding those microbes and in their diet there was a way for these things to colonize, but really, yeah, that's quite rare.

Dr. Jeffrey Gladden: Yeah. That's interesting. The microbiome also affects appetite as I understand it. So if you basically grow a crop of microbes in your intestine like sugar, then you're going to have more of a drive to eat sugar, right? I mean, it's not just you, it's actually you and your microbiome in synergy, right? So they're hungry. So they're actually stimulating you to eat sugar. I wonder if as you're replacing those with these butyrate-producing microbes if they're actually pushing you to actually change your diet suddenly. It's like all of a sudden that fiber looks good to me now or something, right? I mean, maybe that was some subtle piece that explained that. I don't know.

Colleen Cutcliffe: Oh, well, I wish I had been talking to you when we were designing our clinical trial because that was not a component that we had been thinking about, but since we've released the product, something like 60% of our customers have said they have reduced sugar cravings. So you're exactly right. It is affecting the craving.

Dr. Jeffrey Gladden: Exactly. Yeah. So that's fascinating, too, isn't it? Because not only are you getting the butyrate in a GLP-1, but you're also modifying somebody's appetite. So really, it's a three-step approach, although you probably don't claim that, but I find that really fascinating. So then with this probiotic, this is a refrigerated product as I recall, right? Why the refrigeration? Explain that to us. Can people travel with it or do they have to leave it at home or what do you recommend with all that?

Colleen Cutcliffe: Yeah. It's really around the stability of these strains. There are five strains in the formulation, and we've been working really hard to try to get them to all be room temperature stable, and we've succeeded in four of them, but we've got one diva that still needs to be-

Dr. Jeffrey Gladden: One diva, yeah, yeah. There's always that diva out there, right? She just needs to have the refrigeration.

Colleen Cutcliffe: Always one problem child. 

Dr. Jeffrey Gladden: "I can't go anywhere without my refrigerator."

Colleen Cutcliffe: Yeah, exactly. So for that reason, it still has to be refrigerated. People can travel. The formulation is stable for a few days at room temperature, but really, it's like take it on the plane with you, and then as soon as you get to your hotel, throw it in fridge.

Dr. Jeffrey Gladden: Put it in. Okay. Got it. Good to know. Do you want to rattle off the five strains that are in there or do you want us to just put that in the show notes?

Colleen Cutcliffe: We can put it in the show notes, but I can also ... It's Akkermansia muciniphila, Anaerobutyricum hallii, Bifidobacterium infantis, Clostridium butyricum, and Clostridium beijerinckii. So these are not lactobacillus, your typical-

Dr. Jeffrey Gladden: No, they're not the typical microbes, right? So they're completely different. Yeah. Nice. So who's the diva in the group?

Colleen Cutcliffe: The diva is the Anaerobutyricum hallii.

Dr. Jeffrey Gladden: Okay. You know I could tell. I thought that was the case. So tell me a little bit about the data. So you have people, I mean, what we see in the clinic as we put people on the product, Prodrome, basically, they drop their, or Pendulum rather, I'm saying prodrome, it's actually Pendulum. I don't know why I'm saying that, Pendulum, and we actually see them drop their hemoglobin A1Cs and things like that. It's really, really quite impressive. We've been pleasantly surprised and almost amazed at times at how effective Pendulum is. So what's your data? Do you have data where people can, if they start taking this, they can expect a certain drop in their hemoglobin A1C or something like that?

Colleen Cutcliffe: Yeah. So probably the initial trial that we did was published in BMJ, and it shows that in a placebo control double blinded randomized trial that people who were on the formulation versus placebo had an A1C drop of 0.6. So as you know, that can be the difference between having diabetes and not having diabetes. Then the lowering of blood glucose spikes was 33%.

So again, these are, maybe to your point, they're on par with some of the small molecule drugs that are out there, but this is a natural product. So there are other benefits that people get, and then there's also the side effects that they don't get with this product. 

So I think that it's always so great to hear a clinician experience those benefits. I think that we're in a world now where people are interested in what are the natural products that they can take to help, use in their toolbox. So I think not all physicians are forward-thinking enough to get outside of the regimen of drugs. So really great to do that.

Dr. Jeffrey Gladden: Exactly. Well, we've been outside of that for a long time, but yeah, no, I think that's fascinating. Were the people in the study, by any chance, were they wearing continuous glucose monitors or was this just based on office visits or how was that data collected?

Colleen Cutcliffe: When we did that trial, we didn't want to stray very far from the gold standard of how these trials were run. So unfortunately, that meant doing the in-clinic oral glucose tolerance tests and the blood tests in clinic, but we have done continuous glucose monitor studies with people. Of course, there's so much more data in there and you can really see the lowering of these blood glucose spikes more globally than just when they're doing the glucose tolerance test. I'll throw in there, too, I-

Dr. Jeffrey Gladden: Let me interrupt you for one second, I'm sorry, because we do two-hour glucose tolerance tests with insulin curves on everybody that comes in because we find that whether your hemoglobin A1C is 5.2 or 4.9, there are people that they don't respond well to a sugar load and they can be clearly diabetic for an hour or two, quite honestly. Sometimes we're stunned to see how much insulin they actually have to secrete to control the 75 grams of glucose, right? So I'm just curious, were you also seeing that it took less insulin to control, as well as a lower blood sugar when they did the followup glucose tolerance test? Is that what you saw?

Colleen Cutcliffe: We saw in terms of the insulin response an improved insulin response after the 12 weeks of being on product. Yeah.

Dr. Jeffrey Gladden: Okay. Interesting, because one of the drivers of cellular senescence is higher insulin levels. I think a lot of people realize that high blood sugar can cause problems. We'll talk about that in a minute, but also higher insulin, just like IGF-1, high levels of IGF-1 can basically promote growth. They promote cancer, particularly if they're not balanced with AMPK on the flip side, but you're actually aging yourself and people are actually aging more rapidly when they're forced to push out these high levels of insulin. 

Of course, they're exhausting their pancreas over time because you're asking the pancreas to do three, four, five, 10 times the work it normally would have to do. So then the beta cells burnout and then you're stuck at this point in time. So it's really a big deal. It's not just all about blood sugar. It's really as much, and that's why we do the insulin curve with it, it's really as much about how much insulin does it take to control your blood sugar as it is about the blood sugar itself. So if you're actually improving both those parameters, I mean, that's a massive win. That's really awesome. Yeah.

Colleen Cutcliffe: Yeah. I think just the starting data that we saw, this was more than 10 years ago, was that these fecal microbiome transplants can actually also result in these improvements. Of course, we wanted to get to a more refined product than stool.

Dr. Jeffrey Gladden: Yeah. Well, stool has its drawbacks, right? So yeah.

Colleen Cutcliffe: Yes.

Dr. Jeffrey Gladden: Cool. Well, that's very cool. So let's talk a little bit about neuroinflammation. I know that this is something that you're passionate about, too. Do you want to talk a little bit about this? Do you have any data to show that people that use Pendulum that they decrease neuroinflammation or anything along those lines, better cognitive function or anything?

Colleen Cutcliffe: Yeah. It's really interesting to me because, again, when we did our clinical trial, we weren't really thinking about some of these outcomes of glucose control that I wish we had measured many of these things in our trials, but what we're learning from our customers and from real life use of the product is that people are reporting reduced inflammation. They are reporting less brain fog, more sustained energy throughout the day, that post-lunch slump that goes away for people.

I, myself, I don't have diabetes or prediabetes, but I take the product because I wear continuous glucose monitor. I actually did a placebo control on myself and blinded. So I found on the other side of that that everybody has a glucose spike and crash when you consume things with sugar, and all of mine were minimized. I knew when I was on the formulation because my workouts were actually stronger.

So we haven't done a clinical trial around it, but we are getting a lot of these reports. Of course, there is a known relationship between managing your blood glucose spikes and neural inflammation, but there's also this gut-brain connection that is really interesting to us.

One of our strains is a punitive GABA producer. So we think a lot about what are all of these different systems that the microbiome is tied to and how are we impacting them, but the brain fog thing-

Dr. Jeffrey Gladden: Well, let me interrupt you for just a moment because this is really interesting, not that everything you've said isn't interesting, but this is particularly interesting to me in the sense that if you're using the product and you're actually increasing your ability to produce GABA, have you noticed that people are actually, and GABA is really, just so people understand, GABA's really the neurotransmitter that puts your brain into a rest mode. It precipitates sleep. It helps you sustain sleep. Glutamate is more the neuroexcitatory transmitter, if you will, but if you're able to increase GABA, are you showing that people are sleeping better? Do you have any data on that with their WHOOP, their Oura rings or sleep studies or anything like that?

Colleen Cutcliffe: Yeah. We haven't really been asking people about sleep so much as about general stress and anxiety. There we see some real improvements, and especially, I think, we've been all going through a pretty stressful period here over the last couple of years, and that's something that people are able to really talk about improvements on with stress and anxiety, but-

Dr. Jeffrey Gladden: Yeah. That might be interesting to look at would be to see if sleep improves.

Colleen Cutcliffe: Absolutely. Absolutely.

 Dr. Jeffrey Gladden: Yeah. Cool. So back to the neuroinflammation, so the sugar, so how are you actually monitoring and measuring changes in neuroinflammation? Is it more just the clinical data, people notice more energy and less brain fog and things like that or are there actual metrics that you're able to look at as well or where are you with that?

Colleen Cutcliffe: Yeah. Well, we haven't done a trial in it, but I think that what people are coming back with are their general inflammatory markers. Then these reports about the better energy, the reduced brain fog, the better cognitive capabilities, of course, there are tests that can be run to measure cognitive abilities. So we haven't done that yet, but I think that's definitely something that we are super interested in testing. I'm curious whether in your population as people start to improve their blood glucose spikes, do you see those cognitive changes as well or hear reports of it?

Dr. Jeffrey Gladden: Well, we haven't correlated it exactly. So we could do that, though. I mean, retrospectively, we could do that because we do cognitive assessments on every client also, brain function being, I mean, there's nothing, well, heart's important, too, everything's important, but your brain, if you have your brain, you've got something to work with.

So I think we might be able to go retrospectively and go back and look at that, but having this conversation with you, we can start to look at it going forward and make some correlation there. Also, we can correlate it with followup two-hour glucose tolerance test and see if there's improvement there both in the insulin curve and the glucose curve would be interesting for us.

We can also have people keep track of their sleep trackers. Most of our people are wearing something, either an Apple watch or WHOOP or Oura ring or Biostrap or something garment, and they're getting data on their sleep. So we could think about doing that, too. It'd be fun to see just how many parameters we're actually impacting by putting five strains into the microbiome, right? Pretty fascinating.

Colleen Cutcliffe: Yeah, absolutely. We'd love to help facilitate that. I mean, I think what's really interesting is thinking about blood glucose control outside of just people with prediabetes and type two diabetes. As we age, I don't think we need signs to tell us this. We all feel that our metabolism slows down and we have to really start watching-

Dr. Jeffrey Gladden: It does. It actually does slow down. Yeah. No, we measure that. It does slow down.

Colleen Cutcliffe: Exactly. Right. I think we all know that we have to exercise more and watch how we eat a lot more as we get older. So I think trying to understand how that's tied to this depletion in the microbiome and some of these things that help us metabolize those things, I'm super interested to hear your experiences in those readouts for people that don't necessarily have metabolic syndrome.

Dr. Jeffrey Gladden: That's interesting, too. We do resting metabolic rates on just about everybody also. I'm just thinking it might be interesting to actually correlate that also with this. For those that don't understand, a resting metabolic rate is basically you sit in a chair for about 20 minutes, let's call it, and you're wearing a mask and we're measuring how much carbon dioxide you're expelling, how much O2 you're consuming. From that, it's really a gold standard test in terms of accuracy at showing us what your metabolic rate is. 

Of course, that correlates with thyroid levels as well. We use it to actually determine whether or not somebody needs additional thyroid. It's one of the metrics that we use, but it would be really interesting to see if the resting of metabolic rate is improved as the gut biome improves, right?

So if it's raising, if it's like it's raising all ships, now you're decreasing sugar spikes, but you're also raising the metabolism on the other side. I mean, it'd be fascinating to be able to look at that. You could probably do this in a week or two. How long does it take for the Pendulum to work? It works pretty quickly, doesn't it? Within a couple weeks isn't it already having an impact?

Colleen Cutcliffe: Well, of course, as with anything else, it varies from person to person, but we do see for some people, it's as soon as, I mean, days for some people, but really, to see an A1C change, as you know, it's a 12-week process.

Dr. Jeffrey Gladden: Well, yeah, for sure, for an A1C because, just so the audience knows, it's a 12-week look back. So you got to have 12 fresh weeks, but if you did a two-week run in with the Pendulum, you could pretty, I mean, virtually, everybody would be having an effect and you could do some testing prior. You could do the run in, and then you could treat them for another week or whatever, and then test them again across these different parameters, resting metabolic rate, sleep, and all that, and see where they're at. It would be fascinating. We need to do something like that.

Colleen Cutcliffe: Absolutely. I would be curious, too. If people are wearing glucose monitors to really look at different foods that they're eating and do the test beyond just the hardcore glucose. One of the things that we noticed in one of our smaller trials with continuous glucose monitors was that people tend to eat the same breakfast every day. That's one of these that we're habituated to. So you could see over time people's glucose spikes for their breakfast were actually going down. I thought that was pretty cool because it's just practical information for your health.

Dr. Jeffrey Gladden: No, that is interesting. Yeah. Back to your variety, it's interesting that most people eat inside of 25 foods or 30 foods. I mean, you're really out there if you're eating 40 foods as a variety, right? I mean, you're really pushing the limit. Yet, there's literally thousands of foods out there to eat. So this whole idea of variety is interesting, too.

Colleen Cutcliffe: Well, yeah, and it's real catch 22 because if you haven't been having diversity in your diet, you don't have the microbes that metabolize that food. So then you go to try to eat something different. Many of us have experienced this. You travel, you're eating new foods, you're trying them, and you just get incredible GI distress because you don't have the microbes to help you with that, and maybe your gut lining is not as solid as it really should be. So I think there's this period where people have to accept it might be a little bit painful, but when you push through, you'll actually be improving your overall health.

Dr. Jeffrey Gladden: So that's a great point. So let's talk a little bit about the gut lining because when we started this, you were talking about butyrate production, but you were also talking about the integrity of the gut lining. Do you want to tell us a little bit what you found there with the product?

Colleen Cutcliffe: Yeah. I think about gut lining a lot. I don't know if you can see. I have a wooden fence in my backyard. When I first moved into this house, the wooden fence was amazing. All the planks were really solid and strong and lined up against each other and really keeping my garden inside and not exposed to the outside world.

In our gut, we have a similar type of fence, and it has literally this lining and these planks and glue that keeps all of that together. So what happens over time with my fence is with weather and rain and sun and all of that, it starts to wear and tear. So if you don't keep up your fence, planks will start to fall, and then all of a sudden you've got exposure.

It's the same thing with your gut lining. If you don't keep up that gut lining and that regulation of the mucin, which is the glue that keeps everything properly in place, you can start to see this depletion of the lining and then you get these what's called leaky gut, but these small molecules that are inside the gut can now go outside of it and vice versa.

So now, you're getting this exposure that shows itself up in terms of increased inflammatory responses or undesired immune responses. So what you find is that there is this correlation where people that have a variety of different diseases have these lack of regulation of their gut lining. This is where this keystone strain that lives in the gut lining is literally responsible for making sure that that mucin layer is properly regulated. That's a really important strain. So we included that and we know that if you don't have that strain in the formulation, you don't get the same level of glucose improvements.

Dr. Jeffrey Gladden: Oh, wow. That's interesting. So have you been able to do data to show that you basically decrease leaky gut and zonulin levels go down and things like that? Have you been able to show that or is this more hypothetical or was test tube data or where are you with that?

Colleen Cutcliffe: Yeah. It's really the hypothetical because we know that the strain is located at the lining, and our outcomes are really centered around A1C and blood glucose. We did not measure zonulin. We have customers that are measuring their zonulin levels and then, of course, the levels of this strain. So unfortunately, we haven't measured that.

Dr. Jeffrey Gladden: So you've got a little more homework to do on your product. I mean, it sounds like it's doing a lot. Now, you also spoke specifically about the colon. Do you want to talk about the small bowel at all? Is this having any impact on small bowel function or anything there?

Colleen Cutcliffe: We have not researched that. We do have some customers that are using it for SIBO and things like that, but for regulatory reasons, I can't say whether it does anything there or not.

Dr. Jeffrey Gladden: Right. Understood. Okay. I gotcha. Well, it's interesting. It's fascinating. It sounds to me like you've really latched onto something. As you're looking forward, are there continued things that you're looking at with your DNA sequencing and things like that? Other problems you're looking to attack or tell us a little bit about what's on the drawing board for you.

Colleen Cutcliffe: Yeah. I think within metabolic syndrome, there's still so much more to be uncovered. We started with this first product and we have other products that we are looking at not just continuing to improve the GLP-1 response, but also some of these comorbidities. So people with metabolic syndrome often have cardiovascular issues. So starting to look at whether the microbiome is an opportunity there so that you can really be tackling the complexities of metabolic and cardiovascular issues.

I think this gut-brain thing is super interesting. We have microbes in our freezer that are able to produce dopamine, serotonin, various neurotransmitters. I think there's a huge opportunity to think about. I started my research in pharmaceutical drug development for Parkinson's disease, and we were always focused on the brain, and gee, how do you get rid of these plaques in the brain and how do you break that blood-brain barrier.

I think one of the most fascinating things that's come out recently is understanding that you don't just have neurons in your brain. You also have neurons in your gut. Unlike the neurons in your brain, where once they die, you get what you get. Once they die, they're gone. The neurons in your gut actually regenerate. So you have an opportunity to always have new gut neurons, and that these gut neurons create these neurotransmitters that go directly to the brain, and that actually, these plaques that you see in the brain that are associated with Parkinson's and Alzheimer's, they show up in the gut first.

So this new hypothesis that it's really stemming in your gut and your gut neurons and that you can maybe do some preventative actions that will help with Parkinson's and Alzheimer's I think is really interesting. Then taking it to the other end of the spectrum, you're talking about young kids and some of these diseases that we've traditionally thought of as neuro diseases like autism and ADHD, is there an opportunity to create natural products to help them with their microbiome?

A lot of people have shown that with autism, in particular, and ADHD, dietary changes can impact those symptoms. So with your diet, you're most likely changing your microbiome. So I think there's a huge opportunity in that arena as well.

Dr. Jeffrey Gladden: Yeah. There's been studies done on autistic children and looking at their gut biomes, and they're very different from somebody that doesn't have autism, right? So it's felt that that's part of the spectrum, so to speak, of the disorders that are going on. So are you hypothesizing here that you could basically stimulate the gut to produce more dopamine, which would go to the brain, which would then mitigate Parkinson's syndromes? Is that what you're thinking about here?

Colleen Cutcliffe: Yeah. I mean, that is the theory, which is using the gut neurons to change the neurotransmission. Yeah.

Dr. Jeffrey Gladden: Yeah. So if that's the case, then that would be true for anxiety, depression, other disorders, too, where there's not enough serotonin or dopamine or that kind of thing. Are you also postulating that you could change the glutamate and GABA ratios? You've already spoken a little bit about GABA, but would it lower glutamate if you're doing this kind of thing? Is that what you're thinking, too?

Colleen Cutcliffe: I think that what we don't understand is what fraction of the neurotransmitters made in your gut actually make it to the brain, and then are they really received in the same way as neurotransmitters that are going between neuronal- 

Dr. Jeffrey Gladden: Across the synapses, yeah.