Polyphenols, Novel Probiotic Strains & Metabolic Health: The Latest in Microbiome Science

How much do we really know about the microbiome? What does it take to identify new probiotic strains and their associated health benefits? When should we leverage precise single strains and when is it more effective to use synergistic blends?

I am grateful to talk again with the brilliant scientist and incredibly courageous entrepreneur, Dr. Colleen Cutcliffe. Colleen has over 20 years experience managing and leading teams in biotech, pharma, and academia — I just love picking her brilliant brain! She completed her postdoc research at Northwestern’s Children’s Memorial Hospital and earned her PhD in biochemistry and molecular biology from Johns Hopkins. In this episode of New Frontiers, we explore novel probiotic strains such as Clostridium butyricum, Clostridium beijerinckii & Anaerobutyricum hallii, discuss their synergy in producing short-chain fatty acids and their potential to stimulate satiety-inducing GLP-1, and so much more!

I commend Colleen and the team at Pendulum for their dedication to bringing new & challenging science and next-generation probiotics to the world. I sure learned a lot, and am sure you will, too. Let me know with a comment, review, and rating wherever you listen to New Frontiers! ~DrKF

The microbiome is an incredibly rich new field of study, where, with the help of DNA sequencing, we are able to identify entirely new strains that were previously unknown. But it is not just individual probiotic strains that play a key role in human health – it is their synergistic effects that confer the most benefit.

In this episode of New Frontiers, Colleen Cutcliffe, PhD, co-founder and CEO of Pendulum Therapeutics, explores exciting novel probiotic strains and how they interact synergistically to promote health. Dr. Cutcliffe introduces us to the newly discovered butyrate producers Clostridium butyricum & Clostridium beijerinckii, describes how these work together with Akkermansia muciniphila to produce short-chain fatty acids, explains why the microbiome plays an important role in cravings & satiety and more!

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. Of course, today is no exception. I am once again here with the amazing Dr. Colleen Cutcliffe. We have a previous podcast we’ll link to on our show notes. We also did an incredible webinar together, and I just love picking her brilliant brain. Let me tell you a little bit about her and we’ll jump right in. So, Dr. Cutcliffe is CEO and co-founder of Pendulum Therapeutics. Colleen has over 20 years of experience managing and leading teams in biotech, pharma, and academia.

Before starting Pendulum, Colleen served as the senior manager of biology at Pacific Biosciences, which is where she met her two Pendulum co-founders. Prior to that, Colleen was a scientist at Elan Pharmaceuticals. She completed her postdoc research at Northwestern’s Children’s Memorial Hospital, got her PhD in biochemistry and molecular biology from John’s Hopkins, and received her BA in Biochem from Wellesley College. Colleen, welcome back to New Frontiers.

Dr. Colleen Cutcliffe: Thank you so much. Always great to talk to you.

Dr. Kara Fitzgerald: So, we’re going to jump in and talk about some new probiotic strains. Once again, you guys are cutting the edge. You’re just bringing us new science. You’re bringing it to clinicians, to regular people, but I want to just do a little love fest on Pendulum and bringing Akkermansia to market. I mean, I wanted to talk to you. I wanted to talk to you as a scientist and just as an incredibly courageous entrepreneur in figuring out how to do it. So, if you can just snapshot the Akkermansia story and then that will bridge us into talking about some of the new revolutions happening over at Pendulum, that would be fabulous.

Dr. Colleen Cutcliffe: Absolutely. Well, just taking a step back and talking about the microbiome, I think this is incredibly rich new field of study, where we’re all using DNA sequencing to identify entirely new strains that were not identified before. Even just 10 years ago, we didn’t know most of the strains that were in our microbiome. Actually, I might argue even now today, we don’t know most of the strains that are in our microbiome. But what we’re starting to discover is that there are a whole wealth of these different strains and functions living inside us and on us that play a really important role in our health. We’ve co-evolved with these strains. It feels like we’re constantly trying to eradicate them with our use of antiseptic wipes, antibacterial soaps, antibiotics.

So, I think it’s really important to start to elevate, especially on the heels of a massive pandemic, what the important good strains are and good viruses are for our bodies. So, it starts with Akkermansia. So, the snapshot of Akkermansia is that it is the only strain that you can find on the market today that literally lives in your gut lining. It is there to make sure that the gut lining is regulated. When you don’t have a properly regulated gut lining, it shows up in a lot of ways, insufficient metabolism, GI issues, increased inflammation, reduced immune response. So, we’re starting to realize this is a keystone strain in your gut that was never known before. We’re starting to uncover a lot more roles of Akkermansia and the gut lining in overall health.

Dr. Kara Fitzgerald: Well, let me just add to that, because we know Akkermansia is present in abundance in healthy centenarians, so not centenarians. Well, we can see that morbidity and mortality can be associated with a drop in Akkermansia. So, we need this player around for the long haul. I want to say beyond what you just said, when you talk about it being such a keystone player, it influences systemic health and it’s essential to an intact gut wall. It’s essential to regulating and rebuilding, just as you and I were talking about, this mucin recycling, keeping that wall just functioning and beautiful and how it should be.

When that breaks down, it’s associated with really, what isn’t it associated with? What medical condition that we confront isn’t it associated with? I mean I’ve been researching recently for my slides for the Institute for Functional Medicine where I lecture on allergic disease. We’re nailing down what starts the food allergy phenomenon. Right there, of course, is intestinal permeability. So, immediately, one of our key interventions we need to use probably early on is Akkermansia.

Dr. Colleen Cutcliffe: Yeah, I mean absolutely. I would say when we think about food allergies and how that’s related to how our body metabolizes foods, it becomes clear how these things are connected. I’ll share a fun stat with you that I just saw this morning, which is that we’re constantly asking our customers of Akkermansia, “What are the health benefits you’re experiencing?” To your point, when you don’t have a strong gut lining or when you start to have a strength in gut lining, it shows up in a lot of ways. I just learned this morning that half of people who are on Akkermansia experience lower sugar cravings within 90 days.

I think that speaks to also this gut-brain relationship of what you’re eating can change your microbiome and can also change what you’re craving, which just ends up being in this cycle. We’ve all experienced that cycle without needing to be a scientist. I crave bad foods, I eat bad foods, I crave more bad foods. How do you get out of that cycle into eating better foods and just living a healthier longer life? I think it’s a really interesting cusp of new data that we’re just sitting on now.

Dr. Kara Fitzgerald: It’s absolutely extraordinary and it’s something that we can use. Then we’re going to talk about the new stuff, I assure everybody, but just for a minute, because as you know, as I talked about on our webinar, I had a similar experience. I noticed my blood sugar dropped. I talked a little bit about my history and my family history and all of us being on that cardiometabolic continuum in my family and talked a little bit about our history, where we came from and the epigenetic implications. I think most people in the United States will march on that cardiometabolic continuum unless we’re actively resisting it. I found that Akkermansia was incredibly helpful for me and definitely shifted my cravings.

To that point, I am using it and regularly prescribing it. So, one of the most challenging pieces that we confront as clinicians is the transition into a healthy diet, that first step. What I used to do and I actually still do it, but now we can use Akkermansia in conjunction, is I tell people, I advise them that they’re going to take this weekend to detox. I talk to them about the transitioning of the guards. I call it the transitioning of the microbial guards. So, you’ve gone from the standard American diet or whatever dietary pattern that they’re eating that’s not healthy. We’re going to move them onto a really individualized diet that we’ve designed here in my clinic based on that individual. They’re very specific needs, and that journey is going to massively change their microbiome.

I say, give yourself a good weekend, binge on Netflix, get a massage, really setting them up for success. Do whatever you want while you transition on that journey. Sometimes people will feel worse. I really try to advise them, but jumpstarting that journey with… I mean, we could go up to 90 days. You’re saying that people noticed a reduction in cravings in 90 days. My experience has been that it happens sooner, but Akkermansia can help that whole transition process, which we really haven’t had a lot of tools for other than binge on Netflix, get massages, get some foot massage, get some reflexology, buy yourself jewelry. Yeah.

Dr. Colleen Cutcliffe: Exactly.

Dr. Kara Fitzgerald: It’s an amazing tool.

Dr. Colleen Cutcliffe: Yeah, I love the idea of the jumpstart because you’re really moving the microbiome and this is giving your body the boost that can help it get there faster. The 90 days, to your point, there’s a spectrum along there. We have a lot of people that are pretty healthy and eat pretty healthily that are taking Akkermansia. So, you might expect that if you really haven’t had a very high fiber diet and now you’re switching to high polyphenols, high fibers that you might experience a much sooner benefit of Akkermansia. Or if you’ve taken a test and you know you have low levels of Akkermansia, you might experience a boost sooner than somebody else.

Dr. Kara Fitzgerald: Yeah, I think there’s definitely an individual component, but I’m certainly grateful for it. Just one of the other cool things I wanted to add and then we’re going to jump in and talk a little bit about Clostridium and its ability to produce butyrate and all of the amazing synergistic interactions, but the fact that you and your team were able to figure out how to produce Akkermansia. So, for anybody who doesn’t yet know, Akkermansia is an anaerobe, meaning it survives in an oxygen-free environment, it dies upon contact with oxygen. They just have a great story that Colleen shared with us on our first podcast, but they had to figure out how to do it themselves. There were no probiotic manufacturing houses at the time that they could hire.

So, they took it on to do that. They spent oodles of research dollars and time and energy figure cracking that nut to stabilize Akkermansia and produce it in a capsule that’s actually shelf stable and just really easy to transport. I was telling you that I’m packing to leave to Mexico tomorrow in the morning and gathering my supplements. Akkermansia is there and it’s nice that I can just throw it in the suitcase, but yeah, it’s badass of Pendulum for doing that work. So, thank you.

Dr. Colleen Cutcliffe: Thank you. Well, like anybody who’s endeavored to do something new, you don’t really know when you get into it what it’s going to entail, otherwise you would’ve never done it in the first place. So, I think-

Dr. Kara Fitzgerald: That’s a good point.

Dr. Colleen Cutcliffe: … we didn’t know, to be totally honest, I didn’t know it was going to be that hard, but I’m glad that we pushed through.

Dr. Kara Fitzgerald: Yeah, that’s a really good point. It’s game changer. It’s changed your career. It’s changed your life. I mean, it really was a game changing experience. You did not know what you were saying yes to.

Dr. Colleen Cutcliffe: Absolutely. Then also I would say our investors didn’t know what they were saying yes to. So, coming back to them being like, “This was actually a lot harder than thought it was going to be,” it takes a lot of people to get behind an idea for it to actually come to life. So, I think the most rewarding part now for all of us who’ve been involved in it, and for you too, is seeing the benefit that it’s conferring to other people. Just seeing how much you can help somebody boost all of these issues that they’ve been experiencing and make them healthier. I mean, that’s what we’re trying to do. That’s where we are now. So, it’s very exciting.

Dr. Kara Fitzgerald: It’s really exciting. It is like next generation probiotics, and I’ve been paying attention to the field for a long time. It’s just really, really nice you guys are contributing to the science and to the expansion of this field, both from the scientific perspective, but also just what we’re able to use in clinical practice. So, with that, let’s talk about continuing to think about species to introduce. So, what are you doing now? Who are you looking at? What’s going on at Pendulum in terms of where you’re headed and what we need to be thinking about as clinicians and as just regular people interested?

Dr. Colleen Cutcliffe: Yeah, I think it’s probably no news to somebody like you or anybody who’s been looking at the microbiome literature that the microbiome is an ecosystem. So, coming out with Akkermansia has been awesome and amazing, but Akkermansia is not a standalone character. You think about a community, it takes more than one character to get that community going. So, the microbiome is no different. So, we think about, “What are other strains in the community that are working with Akkermansia as well as independently to also bring different benefit to the microbiome and to human health?”

So, one of the strains that we’ve been really starting to get excited about is Clostridium butyricum. Now, there is a famous Clostridium out there, the most well-known Clostridium of all, which is a nefarious criminal of the microbiome world, Clostridium difficile. It’s most well-known for the infection that occurs when people have unchecked Clostridium difficile growing in their microbiome. It can cause people to come very ill. Ultimately, it’s actually fatal. Some of the first microbiome interventions have been targeting this infection of Clostridium difficile. But Clostridia is a species that has over 100 different strains that have been identified, only one of which is Clostridium difficile.

So, Clostridium butyricum is another strain, which as its name implies, butyricum, it produces butyrate. For us, it’s super interesting because it actually works with Akkermansia. So, Akkermansia can produce these short chain well, let me take a one step back. When we consume fiber, things like inulin, they are metabolized by our gut microbiome into short chain fatty acids. There’s a bunch of different short-chain fatty acids. Butyrate is probably the most well-known. Akkermansia actually produces two short-chain fatty acids called acetate and propionate. These two can be converted into butyrate.

So, Akkermansia converts your fiber into acetate and propionate, and then Clostridium butyricum converts that into butyrate, which has a bunch of health benefits that we can go into at any time, but the idea is these two things work together. We found in our clinical trial that if you just gave butyrate producers and no Akkermansia, you saw some health benefits. But if you added the Akkermansia and you saw even larger health benefits with regards to blood glucose spikes as well as A1C. Then we took that into the lab. We thought, “Oh, my gosh. Let’s look at this in vitro.”

Sure enough, if you just throw Akkermansia in or you just throw Clostridium butyricum in, you don’t get butyrate production. But when you put them in together, all of a sudden, they work together synergistically. So, this is part of putting the puzzle together of who works together, who’s needed in order to have maximum efficacy. So, we’re excited about Clostridium butyricum both on its own as well as in the context of this with Akkermansia.

Dr. Kara Fitzgerald: That’s awesome. So, I want to back up a little bit and make a comment on C. diff. C. diff colitis, which definitely is fatal and although it’s very treatable also and we’re ushered in the era of FMT, fecal microbial transplant because of C. diff, but it’s a phenomena. I mean, it’s an iatrogenic phenomena. I mean, it’s because of antibiotics that this massive overgrowth, to your point, it’s left unchecked. I mean, most of us have probably a handful of C. diff hanging around, but it’s just absolutely well controlled in a healthy gut. It’s a non-issue. It’s once we damage the microbiome, once we damage that synergistic interaction that we can just confront terrible and fatal diseases such as C. diff colitis.

So, it really illustrates your point C. diff overgrowth. Yeah, it’s a fallout of modern living, but I just love the elegance of Akkermansia acting on the fiber, producing the food for the Clostridium butyricum. I mean, it’s just so cool and this is happening, just interactions all over the place. For you to see that, to be able to demonstrate that essential synergism in the lab is also awesome.

Dr. Colleen Cutcliffe: It is really cool to see that. I think that we have known for a while that the diversity of your gut microbiome is a strong indicator for your overall health as well as healthy aging and all of that, but I think we haven’t fully understood… That’s a blended tool. Oh, you need a lot of diversity, but now it’s getting down to, “Why do you need that diversity and what kind of diversity do you need?” So, the whole field is just getting more sophisticated.

Dr. Kara Fitzgerald: Yes. Yeah, absolutely, it is. As I shared on our last podcast that the laboratory I completed my postdoc training at released the first 16S DNA stool analysis back in the day. We were hoping for those interactions. We were hoping to be able to have some insight that you’re sharing with me now, 15 years later or something, but it took a long time. As you opened up our podcast with, we still know we don’t know a heck of a lot. So, what else in this combination? I mean, are you thinking about other species to add to the Akkermansia and the Clostridium butyricum?

Dr. Colleen Cutcliffe: Yeah, I mean, we have a bunch of strains that we’ve been looking at. I mean, Pendulum Glucose Control has five different strains in it. We know that those have benefit for people with type two diabetes. So, we’re constantly looking at what are the deeper dive into how are these strains really interacting with each other and what other similar strains might be out there that we’re looking into. So, I think this is one of the interesting things that we’ve observed, which is with our customers, Pendulum Glucose Control, which is pretty pricey. Sort of, $165 to $195 a month for that.

Dr. Kara Fitzgerald: Let me just say, I mean, I’m sorry, I just want to give a shout out for people who are anxious about the price. Of course, I understand that it’s prohibitive for some people, but they did an insane amount of R&D. So, you had to walk through that for a little while. I would imagine there was no other way around it.

Dr. Colleen Cutcliffe: Absolutely. I think that creating a product that you could show clinical efficacy in a disease state for us was a really important first step in just establishing a foothold in this space. I think coming out with the same old step that everybody else is doing is not an interesting business to me. I mean, at the heart of it, I want to discover new things for people. So, I think we needed that, but I would say this, I mean, I understand out of pocket that’s a lot of money a month. I also think that there are a lot of people who are trying to manage the way their body metabolizes sugars, but they don’t have type two diabetes.

So, we’re super excited because one of the things that we learned from our customers is that they could take lower doses of the Pendulum Glucose Control and still get all of that benefit. In particular, if you have pre-diabetes or obesity or you’re generally healthy, but you’re trying to reduce your blood glucose spikes, some people could get away with just Akkermansia, but some people could get away with a much lower dose of Pendulum Glucose Control than we used in the clinical trial. So, we’ve actually just released Metabolic Daily, which is not just for people with type two diabetes. It’s literally the exact same formulation. It has all the same strains, the acetate, propionate, butyrate producers.

Akkermansia’s in there, but it’s all at a lower dose, which is really intended for anybody who’s trying to improve the way their body metabolizes sugars. It’s at a $49 price point because it’s a lower dose. So, very excited to help. I mean, the whole point of this is to be able to help people with their health. If the price is prohibitive, we’re not doing our jobs. So, I’m really excited as we progress our manufacturing capabilities, as we understand what is the dose effect for different people, we can start to create products that people can actually bring into their lives day after day and it’s not hindering on their wallet. So, I’m really excited about that because that’s actually how we’ll be able to impact health.

Dr. Kara Fitzgerald: Woohoo. It’s a massive drop. It is. It’s a massive drop. I mean, as people get better, they should be able to transition off of, or many, not all, but transition off of glucose control anyway.

Dr. Colleen Cutcliffe: Yeah. I mean, this is a terrible thing for me to say as the owner of Pendulum, but it’s true. I mean, if you are able to modify your diet to provide the foods for these strains, you should be able to get them to colonize. You don’t have to be on the product forever. And then everybody goes through cycles. So, then as you feel like, “Okay, I’ve reduced my polyphenol and fiber intake. I want to get a little boost,” you can come back to it. But I think a good diet and exercise and nutrition and all of that is key to sustaining a healthy microbiome.

Dr. Kara Fitzgerald: We need to talk about the other strains in this product, but along with craving control, people have lost weight. In fact, I would argue that it was the one variable that I had changed that helped me lose a little bit. I didn’t really need to, but it shifted how I was eating. Perhaps it influenced satiety a bit for me as well.

Dr. Colleen Cutcliffe: Yeah, I think that’s a really interesting thing because you probably have seen all of the flurry of interest in Ozempic. There are GLP-1 drugs that have been used for people with type two diabetes, and one of the things that those GLP-1s do is they induce satiety. As a result of that, people experience weight loss. Well, Akkermansia and the Pendulum Glucose formulation in its totality stimulate GLP-1. That’s actually why we got interested in the whole mechanism of action. Our chief medical officer was actually the chief medical officer of Amylin Pharmaceuticals. They developed the first four GLP-1 products to bring to the world. So, he’s like a huge rockstar in the space.

So, we know that this is a way to increase GLP-1, but it’s naturally and you’re also not taking a drug away from people who actually need it, who have diabetes. But I think that that whole pathway and the importance of GLP-1 is continuing to be elevated, not just for people with diabetes, but people who are trying to manage how their body metabolizes sugars and improve their satiety.

Dr. Kara Fitzgerald: Arguably, we’re all marching along this continuum. I mean, really, the statistics are astonishing for the number of us on the cardiometabolic continuum. I mean, as I said in the beginning, I think unless we’re very intentionally putting effort into not being on it, our path is towards high blood sugar, et cetera, and all the associated fallout. I think that we can’t rely on Ozempic and the GLP-1 agonists. We still don’t know long-term use for those drugs. So, as miracle as they are and they’re game changing, they’re extraordinary, we need to be thinking about alternatives that are without questions safe for long-term use. They’re part of our own microbial colony in a healthy gut. So, I think this is really essential work.

Dr. Colleen Cutcliffe: Absolutely. I think to speak to the whole weight loss thing, you probably know, we don’t talk about the weight loss thing very much at all. This may be more the pierce in me and less of the salesman in me. I know everybody’s looking for a quick way to lose weight, but that’s the problem. I think that there are so many different ways that people try to lose weight rapidly that are extremely unhealthy. So, I don’t want to harp on the weight loss part of it. I want to harp on the healthy microbiome and the function of these strains for folks. Once they’re on it, they can experience all these benefits. But I think if we talk about it as a weight loss pill, it takes away from actually the importance of having these strains in your microbiome.

So, yes, we do have a lot of customers, majority of them in fact, that have experienced weight loss and reported that back to us, but I think the thing to really focus on is, “What are the things that are missing your microbiome? What are the things that as you’re aging, you start to become depleted in? How can you bring them back into your system to experience better digestion, better metabolism, better immune responses, reduced inflammation?” Then all the ways that that shows up are benefits that every individual experiences that are different.

Dr. Kara Fitzgerald: Though I appreciate not wanting to dwell on weight loss. I absolutely, absolutely appreciate it, but what you’re showing is that it’s gut mediated. The obesity epidemic, this problem of willpower, et cetera, just blaming the individual is sourced to the gut. I think the literature, scientists have been pointing towards that.

I know some very interesting case reports looking at fecal microbial transplants, and sometimes gaining weight with this change and sometimes losing weight, probably more often the latter, losing weight, but just showing really clearly that you radically change the microbiome. For better or for worse, you can absolutely change metabolism. You’re just really more granularly teasing it out. I think it can bring relief to people who’ve been struggling, who’ve spent a lifetime struggling with weight issues.

Dr. Colleen Cutcliffe: I think the cravings is a really important part of the story. That’s why that’s one of the questions that we ask people to share back with us, because I agree with you, this is something that people are blamed for. You don’t have the willpower, you don’t have the discipline, it’s your fault. The fact is that none of us has the willpower. These bugs are actually helping us have that willpower.

So, I think that if you can start to give yourself more of these tools, the whole gut-brain axis is a whole new world that can help us understand how do what we eat affect our mood, affect anxiety, stress, cravings, all of these things. So, again, it’s not something we’ve really understood. So, then I think the tendency is to blame the individual, but we’re starting to uncover what are the things that are driving these emotional and these desires.

Dr. Kara Fitzgerald: Yeah. All right. Talk to us about the other strains involved in the product.

Dr. Colleen Cutcliffe: Okay. So, they’re actually five strains that are in the formulation of Glucose Control and in the formulation of Metabolic Daily. Of course, we’ve talked about Akkermansia muciniphila. There is Clostridium butyricum, which we’ve also talked about. There’s also another Clostridial strain, Clostridium beijerinckii, and this is also a strain that helps produce butyrate. One of the things that we don’t fully understand is, “Why do people have such diversity of strains?” If you were to look across 10,000 people, they could all be healthy and they could all have different strains, but they actually have very similar functions in those strains. So, there’s probably something about individual microbiomes that allows people to grow certain strains and not other strains.

We just really don’t understand what’s going on there. So, we included two of these strains that basically perform the same function in order to understand, “Are there certain people who have an uptake of Clostridium butyricum versus Clostridium beijerinckii?” We have Bifidobacterium infantis in there. This is the only strain that actually we don’t produce and you can actually find Bifidobacterium infantis in lots of different products. It’s quite well known to have a bunch of health benefits, including short chain fatty acid production. It’s actually one of the first strains that shows up when you’re born.

So, I think that to your point about the immune response, understanding how things that we experience in our childhood in the microbiome affect us later in life is important. I’ve shared my personal story about my daughter and what got me into the space and thinking about kids and how we can help shape them for healthy lives and not these chronic illnesses. So, Akkermansia, Clostridium butyricum, Clostridium beijerinckii, Bifidobacteria infantis, and then Anaerobutyricum hallii. All of these strains except for the Bifidobacterium are all strict anaerobes. So, we’ve had to grow every one of them ourselves.

They have this problem of not being able to grow with any oxygen around. So, Anaerobutyricum  hallii is another one of these. It’s also been shown to play an important role in metabolism. I would say we know probably the least about that strain, so still learning more about it, but healthy people have a vast abundance of it and we know that it helps to contribute to glucose control.

Dr. Kara Fitzgerald: Have you looked at them, at their synergistic interactions as a collection?

Dr. Colleen Cutcliffe: Yeah. I mean, one of the things that we were most interested in, of course, was what’s the minimum viable product in order to be able to help people with type two diabetes when we came out with this product. So, both in the lab and then also in our clinical trial, we were doing subsets of these different strains. We also did preclinical work where we did subsets. We even did things where we included the prebiotic inulin, took out the prebiotic inulin. So, trying to understand how do these things function together?

At the end of the day, it really was the composite of all of these five strains with a small amount of inulin, which is used to feed those strains that had the most benefit. Even when we went into our clinical trial, which is a pretty expensive thing to do, we still were trying to figure out, “Is the minimum viable product just butyrate producers?” What we found was if you just increase your butyrate producers, yes, that’s helpful, but it’s the entire consortia that actually benefits and they really are working together in this multi-step biochemical reaction to metabolize fiber into butyrate.

Dr. Kara Fitzgerald: Why do they normally select strains for products? It doesn’t seem like there’s as much attention to the interaction. I mean, you’re describing something that I’m not sure I’ve really encountered in product design. Is that true? I mean, would you know?

Dr. Colleen Cutcliffe: Well, I think that first of all, every other probiotic that’s available to consumers today is using the same strains that have been available to us for 50 years. So, I do think that they’ve been studied in combination by themselves, but I mean, they’re just all Lactobacillus and Bifidobacterium. So, there’s only so much diversity you can get in function. As we start to explore this new world of microbiome, we can start to understand how do these things interact with each other? So, I think that in microbiome science and certainly academic publications, people are constantly thinking about the consortia and fecal microbiome transplant is the ultimate consortia.

So, now, how do you take the kitchen sink and start to pull out what are the things that are actually working together to benefit? But it’s a lot of work. It means you have to understand the entire genetic composition of things. We’ve been doing DNA sequencing since the early days. We have never released a diagnostic test because we spend so much money doing deep sequencing. We’re assembling genomes. We’re understanding how do these genes interact with each other. Therefore, how do these strains interact with each other? Really mapping out the microbiome and using that to select what are things that actually work together to help with a known mechanism of action. That’s really the deep science that’s going into creating the next generation of probiotics.

Dr. Kara Fitzgerald: Right, okay. Yeah, that’s interesting. So, there’s only so much tweaking you can do when you’re dealing with the aerobes, the ones that we’ve been using for so long. But since you developed this technology to be able to actually produce anaerobes and plus your commitment to the science of interactions, it’s not just building product after product and hoping for the best. It’s actually really intentionally designing those products. Very cool.

Dr. Colleen Cutcliffe: It’s likely cooking with corn and water for the last hundreds of years, and all of a sudden, now we’re introduced to sugar and salt and pepper. So, I think that all of a sudden, you have all these new combinations, you’re like, “Oh, these actually fit together. We just didn’t have any of those tools until recently.”

Dr. Kara Fitzgerald: That’s so fascinating. So, it really must be exciting in your company when you’ve got a new chunk of data to review and explore and see what’s happening. I know you’re working with polyphenols as well. You’re interested in polyphenols and I’m sure you’ve looked at polyphenols. Maybe there’s some suggestions that you’ve identified for how people should eat to support these strains.

Dr. Colleen Cutcliffe: Absolutely. I mean, you’ve probably been saying this for your entire career, but certainly foods that are high in fiber are really important, but foods that are high in polyphenols are also super important, specifically for supporting Akkermansia growth. We actually looked at a wide variety of polyphenols and how they interact with our Akkermansia strain. We released a combination of pomegranate, grapeseed and… What is the third one? It’s a combination of three of them that actually helps support our Akkermansia. It’s going to come to me later, and then I’m going to shout it out like somebody with Tourette’s.

But anyway, that work with our Akkermansia to support it, because I think that you can get polyphenols, of course, from a pill, but there’s also a ton of amazing foods that have them too, like dark chocolate and red wine and all the things that we want to have in our diets anyway. So, it is really about the prebiotics, the foods that feed these strains, and then enable them to really produce the postbiotics, which are the small molecules that are helping confer all this benefit.

Dr. Kara Fitzgerald: So, what’s next? Can you share with us any of the future, where you guys are thinking about going to continue to evolve the science? I mean, I know this wasn’t in our agenda to talk about, but I mean I can’t help but think about it with all of the data that you’re mining and the clinical studies that you’re doing and this big picture forward thinking revolution that’s happening in Pendulum.

Dr. Colleen Cutcliffe: Yeah, I think there’s a few things we’ve been thinking a lot about. Well, of course, we’re always thinking about, “How do we make these products more accessible to people?” So Metabolic Daily for me is a very exciting product, because it’s definitely making it more accessible for people to be able to get access to these. We also are thinking about how other supplements that have data behind them that show improvements and not only in blood glucose control, but other health benefits, how they might be interacting with the microbiome.

We think about like, “Oh, vitamin D is doing this over here and chromium is over here doing this and Omega 3s are here and then there’s the microbiome,” but how do these things all actually fit together? Is there a way to combine them to actually get, again, this synergistic effect? So, we’ve been thinking a lot about what are some of the other credible, clinically supported supplements out there that are not so obviously involved in the microbiome that might function well with these strains. Then on the other side, we talked a little bit about food cravings. I think this is a fascinating opportunity.

I think that when we think about cravings and how those affect our behaviors and then how those things in turn affect our mood, I think this is really important. I think we all know that coming out of this pandemic and now living in a pretty deep recession, it’s a time in which a lot of people and even young people who are just starting to come out into the world and experience their first jobs, this is a time of a lot of stress and anxiety and ultimately depression. If there’s anything that we can do that’s targeting the gut microbiome to be a new tool for these individuals, I think that is a really compelling health initiative to go after.

So, we’ve really been focused on metabolism and of course how to battle that pandemic in the world, but I think trying to understand how can we help impact mood is the next big health issue that the world is facing. The funny part is that your metabolism and your mood are actually intertwined through your microbiome. So, I think this is a really exciting new space.

Dr. Kara Fitzgerald: Oh, it’s such an exciting new space. It really is. It’s essential. I’m really happy to hear that you are thinking about it and sitting at the front of it. I mean, I have the podcasts on psilocybin and some of the other cutting edge interventions, but we know that the gut plays a massive, massive role. I don’t think that that nut hasn’t been as cracked as it needs to be. So, I’m really glad to hear you’re going into that space. Awesome.

Well, Colleen, Dr. Cutcliffe, it was awesome to chat with you and really glad that the new product is out and that it’s affordable. So, Glucose Control, so there’s the Akkermansia that I’ve been taking for a long time. There’s my bottle here. This is shelf stable, but then there’s the Glucose Control and then now you’ve got Metabolic Daily, which is less than half. It’s like a third of the price.

Dr. Colleen Cutcliffe: Yeah.

Dr. Kara Fitzgerald: That’s amazing. Less than a third. Amazing. All right. Well, bravo to you over at Pendulum and I just want to give you a moment. Any last thoughts, any words to leave us with?

Dr. Colleen Cutcliffe: Well, I am always so grateful to get a chance to talk to you and love our chats and excited for people to get a chance to try the new products. We have a discount code, which is KARA20 for 20% off the first bottle of any membership. You can buy our products at our website, pendulumlife.com. But we also sell on Amazon, Walmart, Target, all of those different marketplaces if you are shopping for a bunch of other stuff and you want to add this to your cart.

So, again, I think for us, we’ve been doing all this science, we’ve been nose down in the lab, we’ve come up with these products, and now the big challenge for us is, “How do we get these into everybody’s homes? How do we educate people?” So, my ask for everyone who listens to this is to share the information out, help us really bring this to the world, and share back with us what benefits you’re experiencing.

Dr. Kara Fitzgerald: Awesome. Awesome. You also have a clinician wholesale account available for folks as well, right?

Dr. Colleen Cutcliffe: Yes, we do. So, if you are a clinician, we have a whole separate portal for you to go into and you get access to information that’s helpful for you and your practice, as well as different bulk ordering opportunities.

Dr. Kara Fitzgerald: I know we did great. I know when we did, clinicians were really, really excited about our last couple of conversations. So, in the show notes, folks, will be our last webinar (we did with Pendulum). It’ll be a link to the discount code. It will be access for professionals for your own portal and just all of some of the cool stuff that we’ve been talking about today will be in this portal. So, Colleen, again, thanks for joining me.

Dr. Colleen Cutcliffe: Thank you.

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

Previous New Frontiers with Dr. Cutcliffe

Previous All About Akkermansia webinar (replay)

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