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Colleen Cutcliffe
Well, my background is in biochemistry and molecular biology. I have my PhD in that from Johns Hopkins. I did a pretty traditional postdoc, and then I actually started my career in pharma. We were developing drugs for Parkinson’s disease, and that was a really important part of my kind of understanding how pharmaceutical drugs get developed and what people really think about when they’re developing drugs in that industry.

After that company, I joined a startup company. It was a DNA sequencing instrument company that went through rapid growth and went public. And on the other side of that IPO, I started Pendulum. And really, the inspiration behind Pendulum was that probiotics and yogurts have been on the shelves for decades, but they haven’t really been premised in microbiome science. Microbiome science is actually relatively new because we needed DNA sequencing technologies to become affordable enough that we could actually use them to understand what are all the microbes. There’s a hundred times more genes in the microbiome than there is in the human genome. And so it was this sort of really big data problem to be able to be tackled. And so for me, it just seemed like there was a huge health opportunity to go after the data underlying the microbiome and try to find entirely new strains and pathways that play a role in our health.

And then, kind of at the same time that I was learning about all of this, I realized that there was a very personal connection for me, which is that my first daughter was born two months prematurely. She was four and a half pounds when she was born. I could literally hold her in one hand. And she spent the first month of her life in intensive care where she received multiple doses of antibiotics. And one of the things that I started learning about was that there are these great studies that have come out showing that infants and toddlers who are on lots of antibiotics are more prone to issues later on in life compared to kids who aren’t. And these things are things like obesity, type 2 diabetes, allergies, asthma, celiac disease, ADHD, just a whole host of different things that you are more prone to and more susceptible to because in this early start to life, you have completely decimated your microbiome. And at the time that we started this company, which is a little over 10 years ago, my daughter had food sensitivities that nobody else in the family had. And it immediately clicked for me that that early start to life was setting her up for this terrible kind of deficit in her gut microbiome that was starting to show itself already at a very young age in terms of sensitivities to foods. And so I thought, oh my gosh, I could create a company that could help millions of people metabolize their foods better, including my own daughter. Let’s give this thing a shot.

Kalea Wattles
So you were doing all of this work and then you had a personal connection. At what point did you start really investigating how specific bacterial strains could really make a difference in our health outcomes?

Colleen Cutcliffe
That was from day one. I mean, really, the whole mission was, let’s get out of Lactobacillus and Bifido, two of hundreds of thousands of strains sitting in the microbiome, and let’s start to explore this vast number of other microbes and other genera, and what are they doing and why do we have them? Which ones are so-called good? Which ones are bad? What are the pathways that are really important? What is the gut-brain axis? What is the gut-metabolic health axis? And who are the big players here? So from the get-go, it was all about, who are the players that nobody has known about before?

Kalea Wattles
Let’s talk about, I’m gonna call it a VIP player because you’ve been doing some groundbreaking work looking at a specific bacterial strain that’s found in the human gut. It’s Akkermansia! Tell us a little bit about Akkermansia—some might call this an intestinal symbiont—and how it’s beneficial for our gut health, why we should be paying attention.

Colleen Cutcliffe
Yeah, Akkermansia is probably the most important strain that almost nobody has heard about. And so it really is emerging as a keystone strain. And it just got discovered like in the early 2000s. So if you haven’t heard about it yet, there’s no reason to feel bad about it. It really is a newer strain. And over the last 10 years, there’s now over like almost 3,000 publications around this strain and its importance.

And the reason it’s important is, first of all, a healthy gut has…about 1 to 3% of it is Akkermansia. So that just goes to show you like how prevalent it is in a healthy gut. And the absence of it, or being low in it, has been associated with a wide variety of indications, ranging from obesity and metabolic issues to GI issues to even neurodegenerative issues. And so really understanding, what is this microbe and what is it doing that’s so important has been at the heart of not only our research but lots of other people’s research.

And here’s what it does kind of in the most fundamental state. It keeps your gut lining strong. And so, when you think about our gut lining, I think about it like I have a wooden fence in my backyard. And when you first have a wooden fence built, you have all these planks that have to stick together and they’re really strong. But what can happen over time, just through aging and seasons and wear and tear, is that glue between those planks can start to deteriorate and those planks can start to fall. And your gut lining is exactly the same. You have these planks, these cells that are forming your gut lining, and you have this glue, this mucin layer that is holding them together and keeping that structure really solid. And you need a structure that is solid because all the things being made in your gut gotta stay in there. You don’t want them leaking across and into the bloodstream creating havoc on your immune and inflammatory responses.

And so Akkermansia is the only strain that we know to date that lives in the gut lining, and its only job all day and all night is to make sure that that glue is solid. It strips away the old mucin when it gets old, it puts new mucin in when it’s needed, and it keeps that gut lining solid. And so that’s why it becomes known as this keystone strain, because if you don’t have that solid foundation of that fence, then all the things your gut microbiome is doing are either leaking out or other things are leaking in. And so it is so important to have a strong gut lining, and therefore, it is so important to have Akkermansia.

Kalea Wattles
Well, Colleen, I’ve been noticing over the last few years, when you go to PubMed now and you search for “intestinal permeability” or even “leaky gut,” you have so many search results. And I think this is really gaining traction in our medical field, so it’s really exciting that now we have Akkermansia that can really support that gut barrier integrity. It’s kind of paralleling this increased interest in intestinal permeability. So we know that, let’s say even just a leaky gut barrier can contribute to systemic inflammation in so many chronic diseases. If we have low levels of Akkermansia, what are some of the outcomes we might witness?

Colleen Cutcliffe
Yeah, I think that some of the things that, and now I’m not a clinician by training, and so I’ve actually been learning a ton from folks at IFM and then other clinicians that are sharing with us what they’re seeing. But essentially, if you are experiencing things that are related to kind of this gut permeability, you might be feeling, at a very fundamental level, GI distress, poor digestion, food sensitivities, like you can’t eat foods that you used to be able to eat. But then, Akkermansia also plays a role in metabolism. So the other things beyond that is if you’re feeling like, again, the foods that you used to be able to eat, you can’t eat anymore and that you’re gaining weight more easily, your blood glucose spikes are going up, you have brain fog, you’re kind of experiencing this rollercoaster ride throughout the day in terms of energy, you have a post-lunch slump, your sleep is disrupted. These are all now being tied back to you fundamentally don’t have the strongest gut lining you could have.

And so a lot of those things I just listed like, oh, I can’t eat like I used to, or I can’t sleep as well, or I have more anxiety, or I have post-lunch slump. A lot of people sort of chalk that up to, well, that’s just aging and shrug their shoulders and say, “Well, we all just have to go through that. That’s life.” But it’s not true. You don’t have to accept that because it could be that you’ve just lost some of these keystone strains, and we know that you lose Akkermansia as you age, and we know that centennials have more Akkermansia than their counterparts. And so there is this reason why you’ve lost it, that is the reason why you’re feeling these things and you can actually get it all back.

Kalea Wattles
Well, that’s a message of hope if I’ve ever heard one. That’s so exciting. We connected a little bit, and I always apply everything back to my patient population, which is fertility patients. And I’m just thinking about how beneficial this could be because I see intestinal hyperpermeability causing so many issues with conception, implantation, even ovulation when we see this systemic inflammation that can affect our ovaries, affect our endometrium. So I’m feeling very excited about utilizing Akkermansia to support that barrier integrity.

Colleen Cutcliffe
Absolutely. And I don’t know if you remember, there was a time in which people were doing fitness and workouts and they never talked about the core. And there was this big epiphany that happened where all of a sudden it was like, oh my gosh, if you have a strong core, you can do any workout. And if you just worked on your core, you could go run that marathon that you’ve always been wanting to run. Do you remember that movement?

Kalea Wattles
I sure do.

Colleen Cutcliffe
That big epiphany, and I think we’re living that epiphany now in the microbiome, which is to say that if you have a strong gut, which really is your core, all of a sudden, there’s all these other things that you can do, and I think fertility falls right into that bucket, which is that your gut plays a really important part in all these other systems in the body. And I mean, I’d love to hear from you how you think about just glucose control and what the role is that that plays just in general health and especially fertility health.

Kalea Wattles
Oh, I think about this all the time for fertility patients for so many reasons. But we know, for example, that when we have a high glucose load, that upregulates our inflammatory pathways, and then we see the effects of systemic inflammation. Really, it’s fertility and beyond into our cardiovascular system and really every organ system. But then we also know for patients who are already on this metabolic spectrum, metabolic dysfunction spectrum, we have this dysregulated glucose that can cause more testosterone production in our ovaries, which can inhibit ovulation and cause all kinds of downstream effects. So I think that’s actually the next big deal in the fertility community is glucose control. And I know that Akkermansia has some real benefits for supporting our metabolic health. Will you tell us a little bit about that?

Colleen Cutcliffe
Absolutely. And I think this has really been at the heart of what we’ve been focused on since the beginning, which is what is this gut health/metabolic health tie-in? And really starting to understand the, such an important role that metabolic health plays in all of these systems in our body. And so, Akkermansia, one of the other, like, there’s two really fascinating things about Akkermansia that have recently been discovered. One is that Akkermansia is able to stimulate GLP-1 production. So essentially, when you eat food and it’s metabolized in your gut, your gut then stimulates GLP-1 production, which then results in insulin secretion and your body’s ability to manage the sugar that you just ate. And that’s all kind of a timely thing, right? Your GLP-1 levels in your bloodstream have a wide range, and it kind of spikes up if you’ve eaten and then goes back down. And so, this is what these GLP-1 drugs are trying to mimic. They’re essentially trying to give your body that GLP-1 to stimulate insulin secretion. It’s a little bit of an issue because of the timing of it. You really are supposed to get a spike in GLP-1 right after you’ve eaten a meal. And so it’s hard to kind of have a sustained high level of GLP-1. And what Akkermansia does is it’s the natural strain that after you eat, it stimulates GLP-1 production. And so there was a paper that came out in Nature showing that in fact, Akkermansia by itself was able to stimulate GLP-1 production, and that’s one of the main ways in which it acts.

And we had always had this sort of weird thing that was happening with our customers that we could never really understand. 70% of our customers on Akkermansia say that they have reduced sugar and food cravings, and that’s actually why they’re on the product. And we’re always like, that’s sort of a weird thing. We don’t know what to make of that. And now we really understand, it’s through this pathway that also GLP-1 plays an important role in satiety that Akkermansia is actually helping people to naturally produce more of.

Kalea Wattles
It’s so fun to hear about these emerging interactions between microbes and the host. And I like it when we have these unexpected outcomes and then it allows us to remain curious and ask these questions. So are there certain foods that we can eat to support the Akkermansia levels in our gut?

Colleen Cutcliffe
Absolutely. There’s been several clinical trials showing that polyphenols can increase Akkermansia levels in the gut. We actually sell a polyphenol formulation that we tested a bunch of different polyphenols with our Akkermansia to figure out which ones are the most compatible. And so, but foods rich in polyphenols are fantastic. And then, of course, anything that is high in fiber is also really important for creating the prebiotics that are going to feed your bugs that produce butyrate. And so Akkermansia, of course, does not act alone. It acts in conjunction with other strains. It’s able to produce propionate and acetate, which are upstream molecules of butyrate. And so feeding your body fibers can also enhance Akkermansia by enhancing those guys who take that acetate and propionate and convert it into butyrate. And so high-fiber foods, high polyphenol foods are all great for boosting Akkermansia.

Kalea Wattles
Polyphenols. I think that is such a hot topic right now in the world of functional medicine. So we’re gonna eat polyphenols, we’ll eat fiber-rich foods. Are there any other nutritional or lifestyle factors that we should be thinking about to ensure that our Akkermansia population remains strong? You mentioned that this population will dwindle as we age, so how can we protect it as much as possible?

Colleen Cutcliffe
Yeah, I mean, I think the proactive things that we can do are to have a diet rich in fibers and polyphenols. Obviously, kind of trying to have more of a plant-based diet or more plants in your food is super important. But unfortunately, the bad news is that even doing all of that great behavior might not be enough. We don’t exactly understand why is it that when you age, you start to lose Akkermansia, but we know that that happens. We also know that when you go through periods of intense stress, you actually lose Akkermansia and other strains. And when we women go through menopause, we lose Akkermansia. When our circadian rhythm changes, like if you travel and night becomes day and day becomes night, that can cause you to become depleted in Akkermansia. So there’s all these things that are just part of life that somehow causes depletion. And so I meet, all the time, super healthy people, people who are living healthy lives that are depleted in Akkermansia. And as soon as they start taking Akkermansia, they get back all of these functions that they didn’t know that they’re missing. And it’s really through no fault of their own that they’ve started to become depleted in the strain. So the high-fiber, high polyphenol diet is really important, but then it’s also important to recognize that you might lose this strain just through being a human being.

Kalea Wattles
Well, I guess that’s where some supplementation comes into play. Sometimes this question I’ll get, people will say, “Okay, I’m so excited to take this probiotic supplement. Is this something I need to do forever?” Do you have any advice about setting some expectations for the timeline of Akkermansia supplementation?

Colleen Cutcliffe
Absolutely. I think, and hopefully my investors don’t watch this, but I don’t think you have to be on it forever. I think that the truth is that if you’re depleted in these strains or these functions, what’s most ideal to do is to introduce them into your system, and different people introduce them different ways. So we have Pendulum Glucose Control, which is a full formulation, which contains Akkermansia and other strains that are involved in butyrate production at very high levels, the clinical level dose. And you know, for some people, that’s the place that you wanna start at. For other people, they wanna start with a much more minimalist approach. And maybe they have a sensitive GI tract, so maybe they’re gonna start with Akkermansia and they’re gonna have a pill every other day. So this is really where the physician becomes such a, the healthcare provider becomes such an important part of this regimen, really understanding where the patient’s starting point is and where to begin.

But I think the first thing to know is that you’re trying to bring new strains and functions into an already existing ecosystem of the microbiome. So we’re not telling people like, go take an antibiotic and clear everything out and then take this probiotic. It’s really, how are you introducing new strains into the system? And so some of the things that can be beneficial are giving it 90 days. I always say take a 90-day challenge. And the reason I say 90 days is because if you were to change your diet, so if you went from being an omnivore to being a vegetarian, it takes eight weeks for your microbiome to restabilize to that vegetarian diet. So if it takes eight weeks for like this whole haul change, give yourself another 30 days for these strains to really be introduced into an existing ecosystem. The second thing is that there might be things that you observe right away. So sometimes, people within the first few days can notice GI improvements, and then it takes, of course, at least 90 days to see an A1C improvement. And so the 90 days is a great starting point for, try it for at least 90 days and know that many people will start to feel something earlier than that.

And the other thing that can be really helpful is to take these prebiotics that are gonna boost these probiotic strains. So in Pendulum Glucose Control, and in the Akkermansia pills, we actually have a little bit of inulin, not a very high dose, but it’s really intended to be there to feed the strains. But simultaneously, if people are increasing their dietary fiber and their polyphenol intake, that can help also jumpstart these strains and give them a chance to really take foothold in the microbiome. And then after 90 days, I would actually say, if you haven’t felt anything, it’s possible that you weren’t depleted in those strains. I want people to feel something. And it doesn’t have to be that you felt, most people can’t feel if their blood sugars change, but feeling differences in your energy, feeling differences in your digestion, feeling differences in your workouts, feeling differences in your sleep, all of these are things that you’ll notice and that you aren’t necessarily tying back to your gut. But if you start to notice those things, that’s great. And then after three months or six months, you can start to maybe just stick with just the prebiotic foods that are feeding those strains and see how long that can sustain the strains. Because the truth is that once the strains are in your gut, if you’re feeding them the right foods to keep them alive, they’re gonna stay there.

Kalea Wattles
Feels really approachable. That strategy feels really approachable. As you’re talking about, you get the Akkermansia colony established and then you continue to nurture it. I’m thinking of how you feed a sourdough starter. It feels very similar to that, that there’s a nurturing, but then it’s more sustainable. So I’m really interested in the typical use of this product. Are you having, or are you seeing that patients are using Akkermansia standalone or they’re also taking a more broad-spectrum probiotic supplement concurrently?

Colleen Cutcliffe
Well, we have people that are doing both of those. I think that it’s really about what is the problem that you’re trying to solve and also what kind of philosophically is your approach to life in general. So we have a lot of people who are just taking Akkermansia because they think, I’m low in Akkermansia, I’m trying to solve a GI issue, an inflammatory issue, and that’s all I think that I’m missing. And so they’ll just take Akkermansia.

Kalea Wattles
I think this field of microbiome science will continue to grow and grow. And I’m interested, since you are so involved in the field right now, where do you see the future of microbiome research and the therapeutic use of probiotics? Where do you see that going over the next few years?

Colleen Cutcliffe
Well, I think there’s still a lot to be learned about the gut-metabolic health axis. And I think that there’s still a lot to be educated around that axis. But some of the interesting things are I think around the gut-brain axis. And so we know that our gut produces more serotonin than our brain. Our gut also produces GABA. And via the vagus nerve, those neurotransmitters can go straight from the gut to the brain. And we know that we have also neurons in our gut that can start to show signs of these inclusion bodies that you usually see associated with Parkinson’s and Alzheimer’s disease. They actually show up in your gut neurons before they show up in your brain neurons. And so the new theory is, hey, if you can tackle the gut neurons, then you can avoid kind of the misfiring that happens that then takes it from the gut to the brain. I think there’s some really interesting work there.

And we recently showed that Akkermansia has the ability to produce GABA. It has all the genes to produce it in there, and we now know that it is actually producing GABA. And so, again, when people think about stress and anxiety and the gut-brain connection, I think we’re only gonna learn more and more about that. And then I love the fertility angle. I think that is a huge growing problem that many people are facing. And so, if there was a way to think about the gut and its role, again, this gut-metabolic-fertility health triangle might become something that is a part of everybody’s regimen at some point.

And then I think it’s really just about this inflammatory role. We have dermatologists who are using Akkermansia with their patients to fight acne and rosacea and atopic dermatitis. And the skin axis, I think, is also just really interesting. But at the core of it is really the inflammatory system and how that interacts with our gut. There’s so much exciting stuff that’s gonna be coming out over the next 10 years.

Kalea Wattles
Wow. I’m picturing in my mind as you’re going through all of these conditions that could benefit, I’m picturing the functional medicine matrix, which is a foundational tool we use here at IFM that is essentially a map of all of your body systems. And you’ve touched on so many of these body systems, our inflammatory mechanisms, our cardiovascular system, the gut-brain axis, hormones. It’s just really endless. And I’m thinking for fertility, that is so important. But even, I think longevity in general is very prominent right now. And it seems that there’s certainly a role in longevity medicine where Akkermansia has a huge benefit in supporting us as we’re aging.

Colleen Cutcliffe
Absolutely. And I think that longevity role is founded in this glucose control premise, which is to say that if you can manage the way your body metabolizes glucose, that helps with healthy aging. And we know that the microbiome, we now know that the microbiome is central to that. And I think functional medicine and integrative medicine eventually will just become medicine because really understanding how all these things are integrated with some of the more traditional drug therapies is also really important. And how does the microbiome interact with these different drugs? And I think that one of the like more interesting things that we’ve observed is that certain strains, including Akkermansia, can actually interact with checkpoint inhibitors. And so we have now learned about oncologists who are trying to incorporate Akkermansia into their practice because what they’re seeing is that their patients are responding to immunotherapy better when they have a strong gut. And so it’s really just making its way across all these systems, and certainly longevity and cancer and glucose metabolism, they all kind of come tied together through the gut.

Kalea Wattles
Beautifully said. And one thing I appreciate about the availability of Akkermansia is clinicians, we can prescribe this or recommend this. It’s not some strain that’s only used in a research setting and it’s inaccessible. This is something that we could use in patients right now.

Colleen Cutcliffe
Yeah, and I hope everybody at least tries it. I think one of the things that’s been really important for us is we can’t run a clinical trial and every idea that pops into our head, but the clinical practices have the ability to think about, hey, if I’m trying to treat this patient, what’s the right way in which I can incorporate Akkermansia into my clinical protocols? And I think that’s where we learn a ton. And then, on the heels of that, we are starting to make investments on trials that have been born out of actually functional medicine physicians telling us how they’re using the products. And so now we’re going out there and saying, all right, let’s create some clinical trial data behind this. And so it all starts with people who are in practice and seeing patients and believing that the gut plays a role and then generating the preliminary evidence that there’s a role to be played here through the gut.

Kalea Wattles
The functional medicine community is particularly well-suited to take on this challenge. So this is a great question. If we have practitioners who are utilizing Akkermansia in clinical practice, is there a mechanism by which they can feed back some of their results and outcomes so that you can collect that data?

Colleen Cutcliffe
Absolutely, so on our website, pendulumlife.com, we actually have a separate section, which is for healthcare professionals. And so that is a way in which everybody can actually also get access to additional resources. So publications, white papers, protocols that we are getting from you guys, we actually just post them there for everybody to be able to see and use and exchange information there. And then we also have information about our clinical trials on there too. And so it’s kind of like a special place for HCPs to really go and share information with us and for us to then share information back out. We’re also on Fullscript and Emerson. And so that’s another place in which people can share data. But we’re super excited to get to hear from folks. And so we’d love to hear how people are using it in their practice and what they’re seeing, and if people wanna do trials with us, we are running those and really interested in working with practitioners on that.

Kalea Wattles
Right, so there’s also this commitment to building the functional medicine evidence base, which is one of IFM’s priorities as well. That’s so exciting. Colleen, what do you hope our listeners will take away from this episode about gut health, about Akkermansia specifically?

Colleen Cutcliffe
I love when everybody kind of listens to this and walks away that they really think about and start to research Akkermansia and learn, what is this strain, what is all the data out there, the evidence out there? And to think about how it could be applied in their practice. And then, of course, to share back with us if things are working and if there’s any interest in doing trials. I mean, that’s something that we’re always interested in and sharing even case studies. It doesn’t have to be, I tested 3,000 people. Even just understanding at an individual level where benefit is being had. That’s stuff that we’d love to learn, but I think the most important thing is going out and getting super educated on Akkermansia and then being able to think about, how can that knowledge be used to help patient care?

Kalea Wattles
Absolutely. Well, I know I’ll be hitting PubMed after this to learn even more about Akkermansia. I’ve learned so much already in this episode. Thank you so much for spending time with us and sharing your insights. I can’t wait to see where this research goes. Thank you so much.

Colleen Cutcliffe
Thank you so much for having me.

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