Latest Evidence and Clinical Applications of Akkermansia with Dr. Colleen Cutcliffe

Many of us in the functional medicine space are thinking about Akkermansia: what exactly makes this gut bug a keystone strain for health and longevity? I am excited to tackle this with a founder of Pendulum Therapeutics, Colleen Cutcliffe, PhD, an excellent scientist and a leader in biotech. Her passion to help her daughter, and many others, overcome food sensitivities inspired Colleen to use biotech and research to develop products that have the efficacy of a drug, but the safety of a probiotic. We cover it all, and then some! Enjoy, and let me know what you think. ~DrKF

How is Akkermansia associated with common health conditions? What is its role in microbiome and overall health and why is it so challenging to grow? In this episode of New Frontiers, we are joined by Colleen Cutcliffe, PhD, co-founder and CEO of Pendulum Therapeutics. Colleen brings a vast experience in leading biotech and pharma teams. She completed her postdoc research at Northwestern’s Children’s Memorial Hospital, received her PhD in biochemistry and molecular biology from John Hopkins University. Dr. Cutcliffe discusses what makes Akkermansia a keystone strain for microbiome and overall health, what it takes to grow an anaerobe in Pendulum’s first-of-its-kind facility, why butyrate-producing strains are better than supplements, the importance of prebiotics and polyphenols, plus so much more!

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Dr. Kara Fitzgerald: Hi, everybody. Welcome to a New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. And of course, today is no exception. I am so excited to be talking to one of the founders of Pendulum Therapeutics, Colleen Cutcliffe. She is the CEO and co-founder over at Pendulum.

She has over 20 years of experience managing and leading teams in biotech, pharma, and academia. Before starting Pendulum Therapeutics, Colleen served as the senior manager of biology at Pacific Biosciences, which is where she met her two co-founders. Prior to that, Colleen was a scientist at Elon Pharmaceuticals.

Colleen completed her postdoc research at Northwestern’s Children’s Memorial Hospital, received her PhD in biochemistry and molecular biology from John Hopkins University and received her BA in biochemistry from Wellesley College. Colleen, welcome to New Frontiers.

Dr. Colleen Cutcliffe: Thank you so much for having me. Super excited to get to talk to you.

Dr. Kara Fitzgerald: Yeah. Yeah. Finally. I’ve been paying attention to Pendulum since you launched. I think maybe even before you launched when publications were starting to be teased out into the world that somebody was figuring out how to stabilize Akkermansia. So I want to talk about that.

Anybody listening to this podcast, so savvy regular people, but a lot of clinicians in the functional medicine world, are thinking about Akkermansia in all of our patients. I mean, we see deficiencies all of the time. We know that it’s this incredibly important keystone organism in our gut. That means it plays a huge role, an oversized role in so many different processes associated with good health. But it’s an anaerobe and we can’t stabilize. And so we have always been looking at influencing, so we can’t stabilize it and put it in a probiotic, so we’ve always been thinking about, can we secondarily influence it with diet, et cetera, et cetera.

So I want to hear from you a little bit about your journey to deciding to work with Akkermansia, realizing its importance, how you figured out how to stabilize it and just… I just want to get some of the backstory because it’s exciting. I mean, it’s really transformative in the world of probiotics. I think it has a chance to have broad influence on, not just how we early adopters and functional medicine are using probiotics, but beyond that. And so just give us some of the backstory.

Dr. Colleen Cutcliffe: Absolutely. So maybe I’ll go a little bit further back to when we started the company, what the vision was and why we started it and then how we got to Akkermansia. And then as with anything else, you fall in love with something and you realize it’s not quite as easy to do as you thought it was going to be and how we kind of overcame some of those challenges.

My background, as you said, is in pretty hardcore science. And then I worked in this DNA sequencing company that went through some rapid growth and then went public. And on the other side of it, I was really looking for a way to get back into innovation. And I think that the microbiome is a relatively new science. So even though probiotics and yogurts have been on the shelves for decades, microbiome has only become a new science in the last decade or so.

And that’s because DNA sequencing technologies have become inexpensive and usable. And that’s the technology that’s enabled us to really survey what are all the microbes that are residing in our microbiome, and how do they interact with each other, and of course most importantly, how do they interact with us the host.

And so when we started this company, we had, me and my two co-founders, we had this deep DNA sequencing and technological understanding of how to create these maps of the microbiome for individuals, and how we could use those maps to identify novel interventions.

And then simultaneously when we were thinking about this company, which by the way, we’ve been around for almost 10 years. So I love that you’ve kind of been watching us. It takes a while to build real products and novel products. And so it takes patience. But one of the other things that happened as we were starting to understand the microbiome and it’s huge opportunity was that this paper came out in 2012 where they looked at 12,000 children and they showed that babies, infants who were systematically on antibiotics were more likely to develop obesity and type 2 diabetes as they got older.

And that study was actually just repeated by the Mayo Clinic recently where they looked at kids under the age of two and showed that kids who were on antibiotics were more prone to obesity, type 2 diabetes, celiac disease, allergies, ADHD, all of these myriad of things that we know are environmentally somehow linked but now are linked to the microbiome.

And for me, it struck home personally because my older 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 off to intensive care where she received multiple doses of antibiotics as part of preventative care for these really small fragile preemies. And my daughter was in elementary school at the time that we were thinking about this microbiome technology and she has food sensitivity. She had food sensitivities that the rest of us did not have.

So she’d be the kid in, I should say, Dairy Queen or Baskin Robins asking how much dairy is in the Sherbert. And so she just had to watch everything she ate. And I realized, for me it really clicked, that the gut microbiome and her early disruption in life is leading her to have these early symptoms of, okay, I have these food sensitivities that nobody else has in my family and it could evolve or devolve into some of these chronic illnesses as she gets older. And so it seemed like a no brainer. Like, we got to start this company. We could help millions of people, including my own kid. And let’s approach this using methodologies that allow us to create products that have the efficacy of a drug, but the safety of a probiotic.

And so that’s really what we set out to do. We are like, let’s disrupt the probiotics industry with novel ingredients. There are new strains that get discovered all the time but they really fall into the same category of strains that already exist. There hasn’t been anything really breakthrough because microbiome is a new science. And of course, one of the first strains that we came across and that was being early publications on was Akkermansia muciniphila. And there are a few super interesting things about this strain that make it a keystone strain. The first is that generally-

Dr. Kara Fitzgerald: Would you define keystone and then jump into the wonderments of Akkermansia.

Dr. Colleen Cutcliffe: Yeah. I think when we think about health, when we use the phrase keystone, by we, I mean sort of the scientific and medical community, I think when we use the word keystone, what we mean is that this is something that if you are low or missing it, it shows up symptomatically in a lot of different ways.

Dr. Kara Fitzgerald: Yeah.

Dr. Colleen Cutcliffe: So it’s not this sort of one-to-one where, oh, if you’re missing this, then therefore you have this problem. It’s like, you’re missing this and now it’s like… I would say immune modulators are one example of keystone molecules where like, okay, if you’re low in IL-6, you have all of these different immune and even inflammatory issues going on. And so when it comes to the microbiome, of course this is still an early science, but the idea is that if you’re lower missing this strain, man, it shows up for you in a wide variety of illnesses and conditions.

Dr. Kara Fitzgerald: I want to just point some of those out. We were talking about them beforehand just so people can appreciate this concept of keystone. Akkermansia has an outsized influence on everything. So yes, of course, locally in the GI, we can think about inflammatory bowel disease, appendicitis, but extra-intestinally profoundly. They’re looking at it in deficiencies in ALS patients and influencing the course of that just horrible neurodegenerative condition, cancers, different cancers, and of course diabetes. And we’re going to talk about your work in that arena and glucose control and obesity, et cetera.

So it’s almost as if Akkermansia can be sourced to many of, well, of both acute and chronic conditions that we’re dealing with in clinical practice. Would you say that there’s some truth in that according to your read on the literature?

Dr. Colleen Cutcliffe: Absolutely. And I would say we’re just at the beginnings of really uncovering and understanding how all of these different things are linked to the microbiome, but there’s very, very clear correlative data that’s come out globally from various clinics and scientific academic groups showing that a deficiency in Akkermansia is correlated to this just extremely wide variety of diseases and illnesses, which is what makes it a keystone strain and super interesting to study.

Dr. Kara Fitzgerald: In my research, I published a study looking at a diet lifestyle intervention on biological age. And so I’ve been in the longevity science. My head’s been wrapped around it. And it shows up there too, Akkermansia deficiency and sort of accelerated aging. Or robust Akkermansia and other players in the microbiome and longevity.

Dr. Colleen Cutcliffe: And I’m curious, when you think about Akkermansia or for patient care when people are low in Akkermansia, how do you currently help them boost that strain?

Dr. Kara Fitzgerald: Yeah. Well, clearly, as I was kind of fan-girling on you a little bit at the beginning, I’ve been tracking Pendulum for a long time, since I could see that there was some science developing around this. And I should point out, I have a background in a clinical laboratory. And we were the first lab to actually release a PCR DNA stool test. We were the first clinical lab to do that.

And so I understand, I appreciate, the leap from culture where you’re growing something out in an oxygen-rich environment to actually starting to, being able to look at the anaerobes, those organisms that grow without oxygen. And I mean, it’s such a massive leap.

So when we launched that test, I should say the arsenal of probiotics we have are all those that are anaerobes or facultative anaerobes. I guess I, you could almost say. And those are important probiotics. I don’t want to put them down, but they are born out of an earlier technology, right? They’re born out of sort of the world of culture, which is where we’ve been up until about 10 years ago. So our tools early on were limited.

There’s some evidence that certain foods might help influence the course of Akkermansia, of course, that we evolved with Akkermansia as a player in our gut. So clearly diet and lifestyle things were going to influence. We knew antibiotics could be harmful. We certainly see, I don’t know, maybe the majority of our patients, I can’t pull a percentage off the top of my head, but a significant number of folks showing up with a variety of conditions with Akkermansia deficiency.

So it’s something that we’re thinking about all of the time. For most of our patients, people who want to age healthy and well, we’re thinking about it as part of taking care of just a good lifestyle practice. So we want them on a whole foods diet. We want them on a lot of fermented foods, nuts, seeds, good oils, et cetera, cetera, some animal protein and legumes, et cetera, rest and digest all of the smart lifestyle things.

But I just want to say, again, it’s a game changer that you figured out how to stabilize this wildly important bacteria that we all need to have an abundance so that we can prescribe it directly. And it’s revolutionary. And I’m just, again, thrilled to be talking to you and to be able to participate in launching this information as far and wide.

So those are my thoughts on it. And I would say the team of nutritionists and physicians here in my clinic are all equally thinking in this way.

Dr. Colleen Cutcliffe: Yeah. And I totally agree with all of that kind of… First of all, I love that you launched the PCR-based mechanism. It’s almost like old school but there’s a lot of advantages to the old school way of doing things, which is that it’s quantitative. And even though I come from a sequencing background, to tell you the truth, when we do our clinical studies, we measure Akkermansia using PCR also.

Dr. Kara Fitzgerald: Do you really? Oh, that is very cool.

Dr. Colleen Cutcliffe: Yes. The sensitivity and specificity is just so much better when you know what you’re looking for, right? Sequencing gives you a lot of information, but if you already know I’m looking for this, you can get much more specific and sensitive data that way.

I think maybe to understand Akkermansia, like why it’s a keystone strain and why it might be involved in all these things is to sort of understand what does it do? And it lives in our gut lining. And so I sort of think about it like I have this wooden fence in my backyard. And when we first moved into our house, the wooden fence was brand new, amazing, It’s got all these planks that are perfectly positioned and keeps all of the things in my garden in my garden and all things outside, on the outside.

And your gut lining is the same way, where you’ve got the inside of your microbiome, which should be on the inside, and then the things on the outside, which are most of your, kind of, for example, immune responses, inflammatory responses that should be on the outside. And what Akkermansia does for a living is it sits there and it makes sure that fence is always in tiptop condition.

So my fence in my backyard over time, through seasons, starts to weaken, maybe a plank falls. And then all of a sudden you’ve got this exposure, this two-way exposure that’s problematic. And so Akkermansia’s job is really to make sure that lining and that fence is always properly regulated to keep-

Dr. Kara Fitzgerald: Let me ask you this to that point. So it’s Akkermansia muciniphila. Right? And so it’s eating the mucin on the lining. Is it like recycling it? It’s keeping it clean and pristine? I mean, talk about that and then go on with the extended mechanisms that you know about with Akkermansia.

Dr. Colleen Cutcliffe: Yeah. Again, I would say the science is early. So there’s still a lot to unravel here. But right now the idea is that, again, if we continue with fence analogy, if you needed to put up a new plank, first, you would clean all of your planks and then you would put the new plank up rather than just piling on and piling on.

And so the idea behind Akkermansia is that it actually plays in this regulation two roles. One is the consumption of the mucin, which is needed for that kind of turnover. And then kind of creation of mucin that allows you to have the solid fence. And so it’s a regulator and many enzymes and bacteria kind of do this where they can actually do, they can do the reaction in one direction and they can also do the reverse reaction. And so really, Akkermansia is a mucin-consuming strain. And that’s part of actually this regulation.

Dr. Kara Fitzgerald: That’s so fascinating. I mean, would you go as far as to say that any condition associated with intestinal permeability would benefit from additional Akkermansia? Because we know, looking at broadly autoimmunity, cardiovascular disease, probably any chronic illness these days we could trace to some gut disruption and specifically disruption of the intestinal wall. So it’s possible Akkermansia could figure in to a lot of these then.

Dr. Colleen Cutcliffe: Yeah. And I think you just nailed it. That’s exactly what people are starting to realize and trace back to then these initial correlative studies where, okay, these people are low in Akkermansia and then you could start to draw the line between, well, gee, they’re low in it now they’ve got intestinal permeability issues. And that’s leading to all of these other downstream myriad of diseases.

I think that’s why it’s emerging as this keystone strain. Exactly. That fundamental principle of intestinal permeability, we’re realizing is linked to not just gut disorders, but all sorts of different diseases.

Dr. Kara Fitzgerald: Yes. And again, accelerated aging, compromised health span, et cetera. And so then that causes endotoxemia. And then you can sort of measure in circulation, probably increased LPS. And that would be driving inflammation again of every kind of stripe, whatever that individual might be vulnerable to. Has there been any research on looking at Akkermansia to your knowledge and endotoxemia or circulating LPS or anything like that? Akkermansia deficiencies.

Dr. Colleen Cutcliffe: I don’t know. Yeah, exactly. There are so many publications coming out. I think also we do have to be, I’ll give the word of caution here as a scientist, which is that sometimes when you’re a hammer everything looks like a nail. There’s a lot of emerging publications around Akkermansia. They’re not all good. And so I think one needs to be careful of. And this as a clinician too, which is that you have to discern which of these are publications that I believe and which ones is it still very early.

And so for this specific question, I don’t know, but I haven’t seen something that really caught my eye or building of evidence around it. But again, we’re so early in this discovery. And actually the growing of Akkermansia, live Akkermansia is really tricky to do. So not a lot of people are even able to do that. And one of the things that as a company is really important for us is to help fuel and foster all those studies. So we are actually working with academicians where we just give them Akkermansia for free so they can start to run these studies and learn more what it’s doing.

Dr. Kara Fitzgerald: I appreciate that. I appreciate it. Just being sort of right there in the epicenter of launching using PCR and sort of starting in the clinical world the push away from relying on culture. I appreciate it. The fact that you have figured out how to stabilize an anaerobe. And I’m so appreciative that you’re supplying it freely to academia so they can continue to investigate it.

Any comments on that, on how you figured out how to stabilize it? It’s a really big deal. And encapsulated and have viable Akkermansia at expiration date. I mean all of that is a huge deal.

Dr. Colleen Cutcliffe: Yeah. I think to understand why it’s so hard to grow Akkermansia even beyond other strict anaerobes, I would say maybe three things to know about Akkermansia, it’s all got to do with where it lives. Of course, where people live tells you a lot about what their challenges are and who they are. Same thing for these strains.

So first of all, Akkermansia is in what we kind of call the gut microbiome. And the gut microbiome, as you pointed out, is where all of these microbes reside that are not really part of the current menu of options for probiotics that are on the shelves. And the important thing to know about where these are located is that there’s no oxygen in your gut microbiome where all of these strains live. And so that’s different.

That means that when you’re manufacturing, you cannot have a single molecule of oxygen enter that system or else the whole batch dies. And that means it has to be closed from end to end. The whole manufacturing chain has to have no oxygen coming in. Which is hard because oxygen is sort of a very big part of our air. And so you have to create this very closed system.

So the first thing is it’s sitting in this strictly anaerobic environment. The second thing about Akkermansia is, as I said, it is one of the only strains that literally lives in your gut lining. It’s living at the gut lining, which means that it’s adhered to something. It’s not just sort of free floating. And so that’s sort of a second, kind of, structural challenge.

And the third is what you also mentioned, which is that Akkermansia consumes mucin. And in the United States, you actually cannot sell a probiotic that has been grown in a meat-based media. And so mucin… This causes a real problem because it’s used to consuming what would essentially be categorized as a meat-based media product. And so you have to figure out how do I grow this in a vegetable or vegetarian based media when the thing is used to consuming mucin?

So those are sort of the three big challenges of growing Akkermansia and keeping alive. And maybe the fourth challenge is around this anaerobic thing, which is that for the most part, when people try to count colonies, they’re putting them on a plate and then they’re counting how many colonies grow. And Akkermansia is tricky to grow on plates because of the nature of how it lives.

And so we actually had to develop an entirely new technology called flow cytometry, which interestingly is actually used by the dairy industry, they’re ahead of the game compared to human health. But we measure viability of these cells using flow cytometry, where you can actually get really granular. Are they live? Are they dead? Are they half dead? Are they mostly dead? And so you have to figure out how to grow the strain and then also how to measure it’s viability.

And so I’d say the big breakthroughs for us were how do you create a closed system? I should say this. When we started this, we had no intention of manufacturing any of our strains. Probiotics are manufactured around the world. Right? We’ve had them for a long time. And so we would send out a small culture and then we would just get back dead stuff. And so we decided, okay, we’re just going to have to grow this ourselves. So we had to build a manufacturing plant with the anaerobic thing in mind. So everything is closed. And then the second thing we had-

Dr. Kara Fitzgerald: You had to figure that out. Is this a first of its kind facility?

Dr. Colleen Cutcliffe: It is a first of kind facility.

Dr. Kara Fitzgerald: You had to hire a bunch of smart people to just, kind of, all right, go into here and do this impossible thing.

Dr. Colleen Cutcliffe: Well, it’s funny because our manufacturing plant is in the heart of San Francisco, which is where our company started. And people always laugh at me. They’re like, you have a manufacturing plant in one of the most expensive cities in the world, why? And the reason is because we had to build this thing from scratch. And there were PhD microbiologists building this manufacturing plant. Right?

And so it was… And it’s sort of a fun challenge, right? How do you build something that no one’s built before and you get freedom to create something? And so I think that’s been really almost like more fun than anything else to be able to build that out. And then the second challenge was figuring out how do you grow this thing in a vegetable-based media so that it’s safe and can be sold in the United States.

Dr. Kara Fitzgerald: What about those?

Dr. Colleen Cutcliffe: And again-

Dr. Kara Fitzgerald: What about like encapsulating it? Was that a puzzler and making sure that it’s viable through expiration date? I mean, it seemed… Did you have to use a special capsule or like… Go ahead.

Dr. Colleen Cutcliffe: Yeah. So after you grow the culture, so you think about like a beer brewing thing where you’re growing these bacteria, then we actually freeze dry them. And once they’re freeze dried, then the bacterial cells are really stable. And so you get it… After you freeze dry, you’re in a powder format.

And then we use an enteric coded capsule, to your point. So we put it in the special capsule that not only preserves the integrity of the strain inside, but also allows it to get through the stomach acid and into the place where it actually needs to have activity. And all of these things have an expense associated with them. But at the end of the day, the most important thing is that the product has efficacy.

And so if a person is going to feel benefit or a clinician is going to see benefit from it, you got to have a viable strain in there, and it has to get to the microbiome, and it has to be able to revive and perform its activity.

Dr. Kara Fitzgerald: So let’s talk about a couple things. I want to talk about one of the major products of Akkermansia, which is butyrate. And then I want to talk about your research. So you are currently focusing on glucose control, which is so fundamental and important. And Akkermansia plays a role in it. And I mean it’s imbalanced. Poor glucose control, obviously underscores many of the chronic conditions that we’ve been touching on and even acute conditions like COVID and so forth.

So I want to talk about that, where you’ve zeroed in on your focus and some of the science you’ve found there, but let’s take a minute and just talk a little bit about butyrate as well.

Dr. Colleen Cutcliffe: Yeah. I mean, butyrate is a small molecule that has been known for a very long time to be super important. But I think one of the issues that we’ve had as a scientific community is that there are so many great preclinical studies on butyrate and it’s efficacy, but somehow it doesn’t always translate into humans, right? There are far fewer human clinical studies. And I actually don’t… I think it’s because it’s actually a delivery problem.

So butyrate, every cell in your body uses glucose as its primary source of energy, except for your colon cells. They use butyrate as their primary source of energy. And so if you take just simply a butyrate supplement, all along the way, before the supplement actually gets butyrate, gets to where it needs to get to have its activity, it’s being consumed by these colon cells. It’s sort of like, I think about it like if I was going to give you a million dollars, would you rather, I said, hey, Dr. Fitzgerald, I’m now going to knock on your door and hand you a suitcase with a million dollars. Or if I called you and said, hey, I just scattered it all over Highway 101. You would say, what the hell? Why’d you put it on Highway 101? Everybody’s going to pull over and grab my money.

And that’s really what butyrate is like. So if you can deliver it through Akkermansia, through these strains where the strain gets to where the butyrate is needed, you’re delivering the butyrate right where the receptor is for butyrate. Whereas if you take a butyrate supplement, those small molecules are just getting consumed all along the way the colon to where it needs to get to. And so I think it’s a localization problem.

And I think that’s also why the microbiome, these microbiome interventions that increase butyrate are going to be so much more effective. Butyrate is such an important molecule for anything colon related and metabolism related.

Dr. Kara Fitzgerald: Yeah. Yeah. Absolutely. So you’ve been able to demonstrate butyrate production after using Pendulum.

Dr. Colleen Cutcliffe: Yeah. So with Glucose Control, we actually, in our trial, we had people on the product for 90 days. And then we had a washout period where they stopped taking the pills. And what you can see is an increase in butyrate, not only in the stool, but also in the plasma. And so you’re really seeing that elevation in butyrate.

And then when people go off of it, this is sort of an interesting thing, too, most people, after you go off of it, you see the strains no longer are showing up and things like that. But there is a small handful of people where they actually get colonization of Akkermansia and these other strains, where even after four weeks of not taking the product, they still have the strains and the elevated butyrate. And I think that gets to the other half of the equation, which is, it’s not just what you’re putting into your microbiome in terms of the strains, but also what you’re eating that feeds those strains.

And these people who are able to colonize the strains, our hypothesis is that they’re eating foods that have the right prebiotics to keep these strains colonized.

Dr. Kara Fitzgerald: Any idea on what those are? Have you guys teased that out?

Dr. Colleen Cutcliffe: We haven’t done any clinical studies on it, but I think the two maybe leading scientifically-based foods or prebiotics, I should say, are inulin, which we know feeds these different butyrate producing strains, and polyphenols for which there’s quite a few studies showing that polyphenols can increase the levels of Akkermansia. And so we literally are launching into these studies where we tell people take the pill and then now add on these inulin fiber-heavy and polyphenol-heavy foods and see if you can really boost your strains.

Dr. Kara Fitzgerald: That’s awesome. Any specific polyphenols? I’ve got my pen.

Dr. Colleen Cutcliffe: Well, interestingly, there’s so many polyphenols out there. So one of the things that we did in our lab is we said, do we think that they can all kind of help Akkermansia grow? So this is all in a test tube. It’s not in a human. The human system is much more complex. But we actually found that not all polyphenols are equal. And in fact, some of them in the lab inhibit the growth of Akkermansia. So the ones that we’re super excited about are grapeseed polyphenols and pomegranate polyphenols, which appear to really enable Akkermansia to grow in the lab. And so now we’re trying to understand, does that also happen in a human?

Dr. Kara Fitzgerald: That’s so interesting. And what polyphenols inhibited?

Dr. Colleen Cutcliffe: I’ll have to go back and look at which ones were inhibiting. I can’t remember. There was such a huge panel.

Dr. Kara Fitzgerald: We’ll chase you down on that for sure, because I know-

Dr. Colleen Cutcliffe: I’ll follow up.

Dr. Kara Fitzgerald: Yeah, yeah, yeah.

Dr. Kara Fitzgerald: Folks, we’ll pop it in the show notes. So go to the webpage, you’ll see it in the show notes, what her answer is on that one. Everybody wants to know. It’s ridiculously interesting.

Dr. Colleen Cutcliffe: Yeah. You can see that. I focus on… I just get so honed in on. I’m like, this works, let’s move forward. Let’s not worry about –

Dr. Kara Fitzgerald: Right. Right. But I can tell you, because of being a clinician, and the many folks listening to this are like, okay, what are those? I’m going to write them down because I want to make sure I’m not overly prescribing them or are they having a negative effect? I’m going to take a look at the stool tests we’re doing, et cetera, et cetera.

So talk to me about your research around diabetes and Akkermansia and glucose control. You picked that as your focus and you’ve sort of launched your product under that heading. Although I think we’ve made it extremely clear that there’s a very broad indication for Akkermansia, but talk to me about that and some of the research there.

Dr. Colleen Cutcliffe: Yeah. I think there’s a very broad application for Akkermansia, and a very broad application for Glucose Control.

Dr. Kara Fitzgerald: Yes, that’s right.

Dr. Colleen Cutcliffe: So really, and we can get into that, but really, initially what we found was that, through our studies and actually I should say this is studies that have been done globally around the world, that people with obesity, prediabetes, type 2 diabetes, so people on the metabolic syndrome spectrum, which to be frank is sort of all of us who are in the aging process are lower or missing Akkermansia and some of these other butyrate producing strains.

And so the theory was actually a pretty straightforward one, which is like, oh, well, if you’re low in it, what if we gave it back to you? Would that help you? And the underlying mechanism of action that was interesting to us was of course this mucin regulation of the gut lining. But then secondarily, this metabolism of fiber and to butyrate. And butyrate is already known to be upstream to trigger GLP-1 and insulin and glucose responses.

And so because butyrate is already known to trigger GLP-1 and insulin and glucose response, and we knew that these butyrate producers were low in people with diabetes, it seemed very obvious that, well, gee, if you could give it back, this mechanism of action might play out really nicely. So that was the theory behind it. And essentially we developed this like a drug. We did in vitro lab work. We did preclinical trials. We did clinical trials. And we were super excited to be able to publish in BMJ that in a placebo controlled double-blinded randomized trial that people who were on Pendulum were able to lower their A1C by 0.6 percentage points and lower their glucose spikes by 34%.

And what’s been really fascinating is that since we’ve launched the product, only about half of our customers actually have diabetes. The other half, many of them have prediabetes. So they’re trying to avoid kind of crossing over into diabetes. But many of them are people who know and understand that if I can help my body metabolize sugars better, there is a wide variety of additional benefits. So what we hear back from our customers, 90% of our customers have lowered A1C and lowered blood glucose spikes, but 90% of them are also having better digestion and able to eat foods that they weren’t able to eat before.

60% of our customers have decreased sugar cravings. Which that one is super interesting to me because of the gut brain connection and the idea that you can actually change your cravings by altering your gut microbiome. And there’s a wide variety of people that are using it for improvements in reduced brain fog, increased energy, better workouts, things like that. And I would say I personally, the chef should always try their cooking.

Dr. Kara Fitzgerald: Yes.

Dr. Colleen Cutcliffe: So I personally did a placebo-controlled trial on myself. I wore a continuous glucose monitor. I don’t have diabetes or prediabetes but I’m 45. And I know that my metabolism is slowing down. I don’t need a doctor to tell me that, any clinical test to tell me that. And what I found is when I was on product versus placebo, I knew when I was on product because my workouts were stronger. But I also knew because once my CGM data came back, all of my spikes and all of my crashes were minimized when I was on product versus placebo.

We have so many customers who are very data-driven, they’re wearing continuous glucose monitors, and they’re also seeing these benefits, especially around certain foods that would cause them to really spike. And so Glucose Control is being used for diabetes. That’s what we put the product out for, that’s what we did the studies for, but also for a lot of other glucose related indications.

Dr. Kara Fitzgerald: Well, that’s amazing. So exciting. Digestion, I mean, what’s the mechanism do you think that it’s improving digestion? I’m curious about that. Because it’s acting locally and extra intestinally.

Dr. Colleen Cutcliffe: Yeah. Well, I think, first of all, Akkermansia is probably playing quite a large role in that just by improving the gut lining. And that is, you can imagine how that could help with GI symptoms. But I think it’s also well known that butyrate production also helps with GI symptoms. So Clostridium butyricum is one of the other key strains that’s in Glucose Control. And as you can tell with the name, it’s a butyrate producer – butyricum. And it’s actually been studied quite a bit in Japan, in the application space of IBS and IBD. And so I think these butyrate producers are really helping with things like diarrhea, constipation, bloating, pain, all of these GI symptoms that many people experience, especially when they eat certain foods.

Dr. Kara Fitzgerald: How are you dosing it? What’s the recommended, to get these benefits that you’re describing? How are people taking it?

Dr. Colleen Cutcliffe: The dosing is strictly based on the clinical trial. So in the trial, we asked people, and this is before we didn’t really know anything, is this thing going to work? What do we do to give it the best chance of working? In the trial, we asked people to take the pill in the morning and a pill in the evening. And that’s because we don’t know when these strains are actually going to… It’s not like an acute small molecule drug where you take it immediately has an effect.

With the microbiome, you’re asking this thing to get through the stomach, get to the colon, the pill opens up, the thing has to colonize and start performing its activity. And so we weren’t sure whether taking it in the morning or the evening would be better for the colonization. And so the recommendation on the bottle is really just exactly what was done in the clinical trial, take one pill in the morning, one pill in the evening.

And it’s the dose that was done in the trial that showed efficacy. We do have, and I’ll just say I myself, I take two pills in the morning because my morning routine is where this thing could get integrated. I don’t have a night routine around taking any pills. And so I take both in the morning and I saw this efficacy for myself. But really, the dosing is based purely on the trial data.

Dr. Kara Fitzgerald: I want to get back to the comment, the quick comment on GLP-1, of course. It’s in everybody’s mind these days with Semaglutide with the diabetes and now weight loss drugs. And you did point out that individual experienced a drop in cravings. I would imagine that a subset experienced some weight loss. Can you speak to how these might be acting like the class of GLP-1 agonists?

Dr. Colleen Cutcliffe: Sure. So we have not done a clinical trial around weight loss. And so we can’t make any claims around that. But I can tell you that our customers, the majority of them are losing weight on the product. And the way that GLP-1 is believed to affect that is that it’s quite well known that, and there have been studies around this, which is that GLP-1 increases your feeling of satiety.

Dr. Kara Fitzgerald: Yeah.

Dr. Colleen Cutcliffe: So you feel full faster. And when you feel full, you don’t continue to consume food. And therefore it’s sort of an easy path to weight loss. And since our product is upstream of GLP-1 and causes GLP-1 levels to increase, the idea is that it’s just following that same pathway. Increases your satiety and therefore you lose weight. And that’s related, I think, to these sugar cravings. You just don’t get this like need to consume.

Dr. Kara Fitzgerald: Yeah. Oh my gosh. That’s so interesting. Do we have anything else to talk about? We’ve covered a lot. We’re just heading into the home stretch here. What about… What’s next for you guys? What’s next for Pendulum? What other products are you looking at creating? Are you going to be working with other anaerobes? Where are you headed?

Dr. Colleen Cutcliffe: Yeah. I think I would love to come back and talk to you when we actually drop this product. But one of the things that we’re super excited about that is in the late stages of development, it’s going to come out before the end of this year, is a more affordable Glucose Control version. So really, Glucose Control was developed for type 2 diabetes. It’s relatively expensive. It’s $165 a month.

And what we realized is that we could create a product which could really cater to everybody. So not just people who are at the far end of metabolic syndrome, but as you’re on the path there, and you could use butyrate, producers and you could use Akkermansia, how could we create a product that could really fit into people’s kind of daily lives that don’t necessarily have type 2 diabetes.

And so we’re going to be coming out with that product towards the end of the year. And it’s going to be a lot more affordable and really much more geared towards how do you help your body metabolize sugars better. And I think sugars and carbs, we all think of as the enemy, but super hard to cut those out of your diet. Let’s be honest. We all have those cravings. We all want to eat those things. So how can we arm you with the right microbes to help you metabolize those more effectively and efficiently and kind of keep you in a younger kind of microbiome state?

And then beyond that we have other strains. So other strains that are sitting in the freezer that we’re pulling out and growing that are along the lines of Akkermansia where they have very unique functions, they appear to be emerging as keystone strains. So I’ll sort of leave it at that, but I’ll say I’ll suggest that they play a role in the gut-brain relationship. So we’re very excited about that.

Dr. Kara Fitzgerald: Good. All right. Well, I look forward to getting to talk to you again as you launch these. I do want to say, I know that there’s a little anxiety around the price point for a Pendulum, but I think you’ve articulated well. You have another product with a lower price point coming out, which everybody will be thrilled about. But the reality is you guys invested so much in building this company and inventing and developing it and launching it. And that’s a huge, huge investment. And thankfully, it’s worked and you’ve launched this and now you’re going to be able to figure out how to make it more affordable, like you’ve crossed that massive hurdle.

But again, I just want to commend you for your hard work. It’s been so fun to talk to. I look forward to talking to you again. And yes, folks, we will get citations. We’ll get more information on those polyphenols. We’ll get a look at that over onto the show notes for you. So circle over there and you’ll find all these goodies along with the full transcript.

Again, thank you so much for joining me on New Frontiers today. Colleen you are a pleasure.

Dr. Colleen Cutcliffe: Thank you so much for having me. And I have one more thing, which is that for all of your listeners, we have a special code, KARA20, which gets 20% off a membership of any of the products that we’re offering. So very excited to get to talk to somebody who’s so in the know about Akkermansia and blood glucose and the microbiome. And we’re just at the beginnings of this science. And I hope that all of your listeners get an opportunity to try our product and also just really think about how their microbiome is really impacting a lot of things that you wouldn’t even suspect in your health. So it’s an exciting time.

Dr. Kara Fitzgerald: Yes. Absolutely. Very exciting. KARA20, we’ll make sure we blast it in the newsletter. We’ll have that on the show notes. We should have set that at the very beginning, but that’s okay. We got a little carried away on other topics. All right. Thanks so much.

Dr. Colleen Cutcliffe: Thank you.

Colleen Cutcliffe is the CEO and Co-Founder of Pendulum Therapeutics. Colleen hasover 20 years of experience managing and leading teams in biotech, pharma andacademia. Before starting Pendulum Therapeutics, Colleen served as the SeniorManager of Biologyat Pacific Biosciences, which is where she met her two co-founders.Prior to that, Colleen was a Scientist at Elan Pharmaceuticals. Colleen completed herpostdoctoral research at Northwestern’s Children’s Memorial Hospital, received herPh.D. in Biochemistry and Molecular Biology from Johns Hopkins University andreceived her B.A. in Biochemistry from Wellesley College.

Pendulum

Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation

Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes

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