RHR: The Microbiome Approach to Better Probiotics, with Colleen Cutcliffe

In this episode, we discuss:

• The current probiotic marketplace—novel strains and formulations are starting to be discovered after not much new development since the 1970s
• The difference between aerobic and anaerobic strains and the emerging biotherapeutic agent Akkermansia
• How the gut microbiome influences everything about your health, and what Pendulum has discovered about these connections
• The gut–brain neurotransmitter relationship and the potential of novel strains in the treatment and prevention of Parkinson’s disease, Alzheimer’s disease, and autism
• Results of clinical trials with Akkermansia showing significantly lowered A1C and stabilized blood glucose levels
• The challenges to taking the microbiome approach, including the difficulty in manufacturing anaerobic strains and connecting microbiome science with actual health solutions
• Recommendations for taking the Pendulum line of therapeutics

Show notes:

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Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. Probiotics [have become] a huge and growing industry as people have realized the importance of the gut, and specifically the gut microbiome, for their health. We have thousands and thousands of published scientific studies on this topic, and we see articles about this on the cover of popular magazines and mainstream online publications. Even the average person on the street is aware of how important their gut health is to maintaining their overall health and longevity, and probiotics have been a hot topic for the past several years as a way of modulating the gut microbiota and repairing some of the damage that modern lifestyle causes to the gut. The problem is that many probiotic companies are using strains and formulations that date back to the 1970s, when our understanding of the gut microbiome was still in its infancy and we didn’t have modern DNA sequencing and proteomic testing techniques that have shed much more light on what’s actually living inside our gut, which species are there, which species are the most important in terms of contributing to gut health, and how we might be able to leverage those species therapeutically.

The issue is that we have learned an enormous amount about what’s happening in the microbiome through modern testing techniques, but our interventions and therapeutic approaches have not caught up to that research. That’s what I’m going to be talking with Colleen Cutcliffe about today. She’s the CEO and co-founder of Pendulum Therapeutics, a leading microbiome solutions company. She has over 20 years of experience leading and managing biology teams in academia, pharmaceuticals, and biotech. Prior to starting Pendulum, she was the senior manager of biology at Pacific Biosciences and a scientist at Elan Pharmaceuticals. She has a PhD in biochemistry and molecular biology from Johns Hopkins, and a BA in biochem from Wellesley College.

We’re going to talk about the problem with current probiotics, novel probiotics that have proven efficacy but have not been available due to significant manufacturing challenges that have recently been solved, what the future of probiotics might look like, given our new understanding of what’s going on in the gut, and how we might be able to modulate the gut microbiome with these new interventions. We’ll [also] talk about some of the challenges and risks that scientists face in implementing these new solutions for human health. This was a fascinating episode for me. I learned a lot, and I hope you do, too. Let’s dive in.

Chris Kresser:  Colleen, welcome to the show. It’s a pleasure to have you.

Colleen Cutcliffe:  Thank you so much for having me.

Chris Kresser:  Let’s start off with a little context here. Probiotics have become a big industry, and for good reason. There’s a lot of therapeutic potential with probiotics. Gut health is a major issue that many people are struggling with, and we now know from abundant research that the health of our gut is directly linked with our overall health, and basically every chronic disease that we know of at this point. The stakes are high, and it’s a really important area of focus. But as is often the case, when there is a proliferation of new companies trying to address a problem, particularly in the supplement world, there [are] some high-quality products and some approaches that are based in science and then there’s, let’s just say, stuff that’s not high quality or based in science. What’s your assessment of the problems with the current probiotic marketplace, if you will?

The Current Probiotic Marketplace

Colleen Cutcliffe:  I think you’re right to start with all the big opportunities around the gut. I think probiotics have always been a part of our lives, probiotics and yogurts. But people are starting to realize that there’s more opportunity beyond just what’s out there. One of the things that people don’t necessarily know about probiotics is that there hasn’t really been a new ingredient in the last 50 years. There have been a lot of new strains discovered, but they’re very similar to the strains that are already on the shelves. What’s happened over the last decade is [that] there’s this entirely new science that’s emerged called microbiome science, where you’re tackling the microbiome as its own organ, looking at all the different microbes that are in there, probiotics or bacteria, one of the types of microbes, and trying to use [those] data to identify novel strains or formulations that can be used to tackle diseases.

There are a handful of companies that are really at the forefront of trying to identify what I think [of] as next-generation probiotics. And there [are] two challenges. One is, how do you discern between the probiotics that are on the shelves today? Ones that are really giving you high-quality, truth-in-the-bottle kind of products. Then, how do you discern what all the new stuff coming out [is]? Is it actually new? What does it do for me, and what can I expect from this next generation of probiotics that are derived from microbiome science?

Chris Kresser:  [Who] are some of the candidates of that next generation, from your perspective?

Colleen Cutcliffe:  Well, speaking with personal bias, I think Pendulum is definitely among the small handful that are really generating novel formulations and novel strains. I’ll say that the reason microbiome science has only become a science in the last decade or so is because DNA sequencing technologies have only become affordable and usable in the last decade or so. That’s really the technology that’s at the heart of creating maps of your microbiome and identifying these novel strains. Then the second thing is using [those] data to identify how you isolate these strains and how you grow these anaerobic bacteria, which is a unique characteristic of these strains.

Almost every company that is using data-driven, DNA-sequencing-driven analytics and creating anaerobic manufacturing capabilities [is] going after pharmaceutical drugs. Pendulum is really the only company that is applying that toward direct-to-consumer products. So I like to say [that] we don’t really have any competitors at [this] exact moment.

Chris Kresser:  Well, let’s talk about that because I’m happy to talk a little bit more about Pendulum as we go. I was thinking more along the lines of the strains, or new probiotic interventions that you’re exploring like Akkermansia. If you could explain for the listeners the difference between aerobic and anaerobic organisms, the history of probiotics and what has mostly been the focus, and then why there’s an opportunity for anaerobic organisms and why that’s been a challenge to create probiotic supplements that have those strains.

Aerobic vs. Anaerobic Organisms and the Discovery of Akkermansia

Colleen Cutcliffe:  I think to explain the anaerobic thing, it really again gets back to this microbiome science. Your gut microbiome and all these key microbes that are responsible for your health are located in an area that has no oxygen in it. That’s essentially [the] definition of anaerobic. Anaerobic means there’s no oxygen; aerobic means there is oxygen. All the probiotics on the shelves right now are aerobic or partially aerobic, so you manufacture them and oxygen can be in the system, and it’s no big deal. But my prediction is that all the next-generation [probiotics] that are going to come from microbiome science are going to be anaerobic. That means that you have to manufacture them without any oxygen. Literally, one molecule of oxygen in the manufacturing plant and the whole batch is dead. So it’s a real challenge to develop a methodology for being able to grow these strains, but these are the key strains for our health.

I can talk about some correlative studies [that] have been done over time showing that people with metabolic issues from obesity [due] to type 2 diabetes are low [on] or missing some of these key anaerobic strains. You could also look [at] some of the gut microbiome tests that are out there right now. Most of the things that they’re listing that are important are these anaerobic strains. One of the keystone strains that’s been starting to emerge is called Akkermansia muciniphila. If you look at the labels of probiotics right now, you’re going to see a lot of Lactobacillus and Bifidobacterium. You’re not going to see anything with Akkermansia, and that’s because it’s a pretty new strain that’s been discovered. But what’s been discovered about it is that it is low or missing in microbiome testing reports for people with a wide variety of conditions. Not just obesity, but also inflammatory issues, immune issues, [and] skin disorders. So this strain in particular is super interesting, and [I’m] happy to go into more detail about it.

Chris Kresser:  I’ve seen a lot of the research on Akkermansia. It is fascinating, and I agree that, to some extent, a lot of the probiotics that we have available to us now have been a result of how challenging it is to create products with anaerobic strains. Not necessarily because the aerobic strains are the best ones, although I think they have some benefit, but because of the manufacturing challenge. And possibly because before we had DNA sequencing and the comprehensive gut microbiome and analytics available to us, we weren’t as clear on these relationships that you just mentioned.

Before we go on to more about Akkermansia and what it seems to do for us, are those correlative relationships where you see lower levels of Akkermansia in conditions like obesity, inflammatory bowel disease, etc., cross-cultural? Because I know that in the case of Bifidobacterium and some other strains, there [are] some contradictory findings, where, in some cultures who have very healthy guts, like the Hadza in Africa, bifidobacteria is pretty low. Whereas in Western cultures, high bifidobacteria is correlated with positive gut health. Is the Akkermansia relationship consistent across all cultures? Or is that mostly in Western populations?

Colleen Cutcliffe:  I think, not speaking for some of these isolated tribes, where they’ve really had the perk of not having to interact with anything Western, generally speaking, low Akkermansia does appear to be an issue worldwide. There have been studies in the [United States], certainly, but also in Asia, as well as Europe, showing the correlation between low Akkermansia and a variety of disease states.

Role of the Gut Microbiota in Health

Chris Kresser:  Great. Let’s back up a little bit and talk about some of the gut health relationships that have been fleshed out with DNA sequencing and some of the innovations that have come about through Pendulum. I’m thinking about things like the connection between short-chain fatty acids and glucose regulation. We could maybe call that the gut–metabolic axis. I’m thinking about beta-glucan regulation and modulation of the inflammatory response. And then, of course, the gut–brain axis, which has been known for well over 100 years, but I would say in the last 20 years is getting a ton more attention to the point where we now have a model of understanding depression, like the gut inflammatory cytokine model of depression, where it’s an inflammatory condition that starts in the gut. Tell us a little bit about what you’ve been able to learn about these pathways between the gut and the other parts of the body.

Colleen Cutcliffe:  Sure. I think [that] when we think about the gut and the role it plays in a variety of different diseases, you can find thousands and thousands of these correlative studies. And those were interesting, but that’s not the same as causation or having therapeutic potential. There are fecal microbiome transplants, which are exactly what they sound like. You put stool from one person into another. And while they’re not exactly fun dinner or cocktail conversation, [those] have been really effective in demonstrating that if you change a person’s microbiome by putting somebody else’s microbiome into [them], you can change their disease state. So we think about the gut–metabolic axis here. There have been studies showing that if you transplant stool from a healthy person into a person with diabetes, you can improve their insulin response. That tells you that there’s something in that gut microbiome that, by itself, ought to be able to improve this.

When you dig a little deeper into that, one of the key pathways involved is the metabolism of fiber into short-chain fatty acids, and particularly butyrate. We all know a high-fiber diet is really good for us, [and] we’re supposed to be eating lots of fruits and vegetables. One of the benefits of these fruits and vegetables is that when they’re metabolized by our gut microbiome, they get metabolized into these short-chain fatty acids. Butyrate, when it gets produced, binds to these G-protein-coupled receptors, which then triggers [glucagon-like peptide 1] (GLP-1) response and insulin and glucose control. When you don’t have these microbes, the fiber you’re eating is literally going right through you. So these microbes that we’ve really honed in on are involved in that pathway of metabolizing fiber into butyrate, understanding that butyrate is the key to increasing GLP-1 production. That’s one of the key pathways along the gut–metabolic chain. Around the inflammation world, and really even beyond that, is this idea of your gut lining. Many people may have heard about leaky gut, which is to say that your gut is like a fence and, without care, it can start to get holes in it or fall apart. When you have that problem, you have the ability for small molecules that are supposed to be inside the gut [to make] their way into your bloodstream, [and] that results in a heightened inflammatory response. But then conversely, you also have molecules that can make their way into the gut that are really not supposed to be there.

So having an appropriately regulated gut lining is important as sort of the heart of gut health. This is what makes Akkermansia muciniphila so special. It’s the only strain that’s been identified that lives in the gut lining. It lives in that mucin layer of the gut lining, and it is responsible for regulating how thick or thin that mucin layer is, and therefore the integrity of your gut lining. So when you lose it, you lose the integrity of your gut lining, and now you have all these inflammatory issues. For different people, inflammation shows up in different ways, ranging from how you feel on the inside to what shows up on the outside on your skin.

Then the third one that you alluded to, the gut–brain axis, is certainly one of the most fascinating ones. I think [with] depression and anxiety, there is a clear connection between the small molecules that your gut can generate and how your body responds. Interestingly, one of the things that we found with our product is that we’re really focused on the gut–metabolic and the gut–inflammatory axes here. But [in] people who are on glucose control, so they have the ability to increase butyrate production and improve their gut lining, 60 percent of our customers have reported fewer sugar cravings. We don’t totally understand that. [We’re] trying to unpack that. But clearly, there’s something about your microbiome’s ability to change the way that your brain is creating cravings.

Chris Kresser:  I would imagine that’s some kind of feedback system, [in] the same [way] that we get when our metabolism is functioning optimally [and] there’s hormonal feedback between ghrelin and leptin and all those hormones when we eat that sends a signal to the brain saying, “Okay, we’re done for now. We’ve got what we need.” I’ve always suspected [that] with strong sugar cravings and disrupted metabolic function, there’s a strong gut component there, as well. So that’s not surprising to me. I mean, it would be fascinating to find out what the real causal chain or the mechanism [is there]. But just anecdotally, and in terms of my clinical work with patients, that doesn’t surprise me at all.

Colleen Cutcliffe:  I should have talked to you before we designed our clinical trial because it’s not even one of the things we measured. We didn’t realize that connection.

Chris Kresser:  And that’s a big deal because people struggle with that. There’s a vicious cycle, I think, with metabolic issues like diabetes, or even prediabetes or high-normal blood sugar, where there is a tendency to have more sugar cravings when you’re in that state. That becomes a vicious cycle where the more dysregulated your blood sugar becomes, the more sugar cravings can intensify, and then it becomes very difficult to get out of that cycle. So it’s exciting to have a therapeutic intervention that can not only help with the measurable—actually reducing blood sugar and increasing short-chain fatty acids and doing all those things—but on a more behavioral level, help with people making choices that are more supportive for their health and healing. That’s pretty exciting.

Colleen Cutcliffe:  Absolutely. And I think that to contrast being in that vicious cycle, where you’re craving more bad foods, and then you’re eating more bad foods, and then you’re craving more, in this case, it gives people a little bit of a jumpstart to a healthy lifestyle. They can feel good about making good choices, and then you start to get on this virtuous cycle, which I think is really nice. One of the other things about Akkermansia is [that] from the genes, it has putatively, it can help increase [gamma-aminobutyric acid] (GABA) production. I think that also has potential real benefits.

How Akkermansia and Other Interventions Can Influence the Gut–Brain Axis

Chris Kresser:  Yeah, that’s a fascinating connection; maybe we can linger on that a little bit. Because, as some of my longtime listeners will know, there’s 400 times more serotonin in the gut than there is in the brain, and 500 times more melatonin in the gut than there is in the brain. There’s also a lot of GABA in that whole system. When you think about that, it becomes pretty clear that the gut [is important]. Some researchers and scientists refer to the gut as the “second brain” or as the “enteric nervous system.” I know this hasn’t necessarily been the focus for you in your research [and] you focus more on metabolic issues, but have you learned anything more about the way [the gut] is interfacing with the brain and how Akkermansia and other interventions can influence that?

Colleen Cutcliffe:  Yeah, I think as with many things in life, you end up on a path by accident. I think you’re right; we started looking at the metabolic relationship and then got really curious about this gut–brain thing that we were starting to observe in the form of cravings and people reporting reduced anxiety and things like that. I think that one of the most interesting R&D sets of experiments that we’re doing are centered around the gut–brain axis. We’ve been doing this in collaboration with Johns Hopkins, and it’s around neurogenesis. I didn’t know this, but you have neurons in your brain, and when they die, they’re done for. But you have neurons in your gut, also, and, when they die, new ones generate. You have this constant neurogeneration that’s happening in your gut.

I started my career working in pharma, [and] we were trying to find small molecule drugs for Parkinson’s disease. We were super focused on the brain and these plaques in the brain and how we get things in there to reduce these plaques. Well, it turns out that your neurons in your gut also develop these plaques, just like they do in the brain. And in Parkinson’s disease, it appears that they develop first in the gut before they show up in the brain. So the current hypothesis is that it’s actually the neurons in your gut that start to have the issues, and then they misfire these neurotransmitters to the brain, [moving] the problem from the gut neurons to the brain neurons. Some of the exciting work that we’ve been doing with Johns Hopkins is identifying strains and formulations that can increase that neurogenesis [and] increase that turnover in your gut in order to keep your gut neurons fresh and young and [keep them] from degenerating. I think that has implications across a wide variety of what we thought of [traditionally] as brain-specific diseases. [There’s] a huge amount of opportunity there as we think about, “What does it mean to age healthy? What does it mean to try to prevent the onset of some of these diseases?”

Pendulum Therapeutics is disrupting the probiotic industry with a novel microbiome approach and an innovative manufacturing solution for anaerobic strains. Learn how they’re creating better products through cutting-edge science and technology in this episode of Revolution Health Radio. #chriskresser #probiotics #microbiome #guthealth

Clinical Trials with Akkermansia

Chris Kresser:  We know from observational research that there’s a correlation between Akkermansia and various disease states. What do we know so far about clinical interventions with Akkermansia? Because it’s one thing to see a correlation, [but] it’s another thing to see a causal relationship, and it’s still another thing to develop a treatment or an intervention that alters that causal relationship.

Colleen Cutcliffe:  Absolutely, and I think that one of the things that we’ve been really excited about at Pendulum is the ability to run clinical trials with formulations that have Akkermansia. One of our key trials was a placebo-controlled, double-blinded, randomized trial that was published in [the] BMJ, that showed that people who were on this formulation with Akkermansia versus placebo saw their A1C lowered by 0.6 percentage points and their blood glucose spikes lowered by 33 percent. That is the first and only clinical trial [with] that formulation that has shown that kind of improvement. We brought this product to market about 18 to 24 months ago and have been super excited to see that 90 percent of our customers see lowered A1C and blood glucose spikes. And it’s not just people with type 2 diabetes, which is what we did our clinical trials in. It’s also people with prediabetes. You have people [who] are able to move from the diabetic state to the prediabetic state and from the prediabetic state to the healthy state, simply by modifying their microbiome, which is pretty cool.

Chris Kresser:  That’s amazing. In that trial, was that the only intervention? Or was it combined with any other treatment?

Colleen Cutcliffe:  Most people in that trial were also already on metformin. So this was on top of metformin, which is a pretty effective intervention in and of itself.

Chris Kresser:  They didn’t start or stop any other treatment. If they were already taking metformin, they continued and then just added the Akkermansia.

Colleen Cutcliffe:  That’s right. You couldn’t change your medications, and also, we asked people to not change their diets because we wanted this to be independent of any dietary changes.

Chris Kresser:  Yeah, that makes sense. That’s pretty significant, particularly a 30 plus percent drop in post-meal glucose spikes. We know that post-meal glucose excursions, as they’re sometimes called, where your blood sugar ventures into undesirable territory, can be really damaging for metabolic health even if you have normal fasting blood sugars. There are cases I’ve seen in my clinical experience where that’s the sole problem. People can have normal fasting glucose but still be experiencing these post-meal glucose spikes, and that can put them at risk for a whole bunch of complications down the line. So it’s interesting to me that there was not only a change in A1C, but [a] change in those glucose spikes.

Colleen Cutcliffe:  I’d be curious to hear your thoughts about other benefits that people experience when they’re able to lower their blood glucose spikes, even if they don’t have diabetes. I myself wore a continuous glucose monitor and did a placebo-controlled trial [because] the chef should always eat their cooking. So I did this, and I knew when I was on intervention because my workouts were stronger. For me, this showed up as better workouts. But when I looked at my continuous glucose data, I could see that all my spikes and crashes were minimized when I was on the intervention. And I don’t have diabetes or prediabetes. So I am curious to hear what one [would] expect [to see], if they don’t have diabetes [and] if they weren’t measuring with a glucose monitor.

Chris Kresser:  I think the two biggest things in my experience are stable energy and stable mood. Everyone who’s listening to this has had some experience in their lifetime of a blood sugar drop. I mean, “hangry,” right? That’s a word that we have in our culture that I think everybody has had at least one experience with, and particularly anyone who has kids has been on the receiving end of hangry experiences. So hangriness is one, which is a combination of energy and mood, [and] the other would just be stable energy levels throughout the day.

One of the most common experiences that I hear from people who switch from a Standard American Diet with massive intake of refined carbohydrates to a Paleo type of diet, or even further, like a low-carbohydrate or ketogenic diet, in response to that change is, “Wow, I have stable [energy]. I can go all day. I used to have these incredible crashes after lunch, where I would feel like I was a zombie, and I couldn’t work or do anything, or I’d have to take a nap in the afternoon. Now I feel like I can power through the whole day and still have energy to spare at the end of the day.” Likewise, people can often go longer without eating without getting hangry. They can miss a meal and still not feel like the world’s coming to an end. Those are probably the two main ones that I see.

Colleen Cutcliffe:  Yeah, and it makes sense because you’re not on this roller coaster ride all day long of highs and lows. You’re stabilizing it. One of the other things we’ve heard people reporting is reduced brain fog. I wonder what you think about that link.

Chris Kresser:  Yeah, for sure. One of the number one benefits that people report from a keto or low-carbohydrate diet is mental sharpness. As most people listening to this podcast know, ketogenic diets are often used for lots of different brain conditions [like] epilepsy, improving memory, dementia, Alzheimer’s [disease], [and] Parkinson’s [disease]. There [are] improvements with [a] ketogenic diet, so there’s definitely something going on there with the glucose regulation in the brain being impacted with metabolic dysfunction. Some people refer to Alzheimer’s [disease] as type 3 diabetes. But we’re not talking necessarily about that scale of problem. Even just brain fog could have something to do with impaired glucose processing in the system, including the brain. When that is evened out with more stable blood sugar levels, it makes sense to me that that cognitive function would also improve.

Colleen Cutcliffe:  Yeah, and again, you’re not surprised by any of this, but it was surprising for me, who was trying to tackle diabetes, to understand [and] now have a deep appreciation for the fact that improving the way your body metabolizes sugars is at the heart of so many things that don’t feel like they’re related to diabetes at all. Your energy levels, your brain fog, your cognitive function, neuroinflammation, all these things that all of us experience as we get older, are linked to our reduced ability to manage how our body processes sugars.

Chris Kresser:  Even things like skin health because diabetes affects blood flow, which can lead to peripheral neuropathy, and that can impact circulation, which is why people get edema in their legs. They can have retinopathy and issues with the eyes. I mean, it really affects every system of the body. I think we’re still learning the extent to which metabolic function [and] blood sugar regulation impact every system of the body. We haven’t even talked about hormones yet, like cortisol, and sex hormones like progesterone and estrogen, and how closely they’re linked to blood sugar regulation. That’s another major influence that maybe in future studies you might explore.

Colleen Cutcliffe:  It’s interesting, too, because there have been a reasonable number of studies showing that when women go through their menstrual cycle or go through menopause, their microbiome is changing, and [they’re] particularly having depletion in some of these key strains that we know are associated with blood glucose management.

Chris Kresser:  Absolutely. What else have you learned in this process that’s been surprising? Maybe something that wasn’t really part of your focus or protocol, but that has been useful.

Challenges of Taking the Microbiome Approach

Colleen Cutcliffe:  The whole building of this company and these products has been one surprise after another. I think discovering that, when we talk about the probiotics that are out there right now, we are only talking about a fraction of a percentage of all the strains that exist in our microbiome. That tells you there’s so much left to uncover and understand.

I think the second challenge, besides understanding how vast this microbiome science is and is going to be, is understanding how to manufacture the strain. This whole anaerobic thing and having to create an entirely closed manufacturing plant. The way you keep oxygen out of your manufacturing system is you pump nitrogen in. Oxygen is everywhere around us, so you have to be replacing it with nitrogen. We had to put some safety systems into our plant to measure the oxygen levels in the air for our employees because the people on the manufacturing floor are also getting exposed to less oxygen. Having to make sure that it’s only the bacteria that’s oxygen [depleted] and not the people. So, manufacturing was another challenge.

The third, and you alluded to this earlier, is [that] there’s the science and the theoretical. There’s the reality of, “How do you actually change a person’s microbiome, and how do you change it in a way that helps them with their health?” Drawing that line between the microbiome science and actual health solutions has been, I think, an important one for us to focus on. I think I’ve been surprised, particularly with type 2 diabetes, [that] there’s definitely not going to be one [solution]. I’m an advocate for the microbiome, but I don’t think that’s going to be your one solution. It’s such a complex disease, and what leads us to have such huge obesity problems, both in the [United States] and globally, is much more complicated than just your microbiome, or your GLP-1, or anything like that. So when we launched our product, [we introduced] complimentary nutrition coaching.

To be totally frank, it started as sort of a marketing thing. But what I’ve come to realize is that people stay on our product. We have very high retention, and it’s even higher when they have nutrition coaching because they’re learning what foods are beneficial for them. More importantly, they’ve got somebody in their corner helping them through trashy times, and helping them get through that. The mental state of mind and the role that plays with your behavior and then with your microbiome [are] so tied to each other. I hadn’t appreciated it as much, that emotional support, and that the food is the fuel for your microbiome, which is the engine, and how all these things are important to pull together in totality. And again, you’re probably not going to be surprised by that concept at all. But I was.

Chris Kresser:  Yeah. I don’t know if you know this, but we have been training [health] coaches for the past few years. We’ve trained over a thousand coaches in 50 countries. So I’m a big believer in health coaching, obviously. And I think you can’t really supplement yourself out of a bad diet. [A] probiotic or any other supplement could certainly help if you’re eating a poor diet, but it’s not going to have nearly the impact that it would if you’re also eating plenty of fermentable fiber and nutrient-dense whole foods, things that provide the nutrients that the gut needs to thrive and function optimally. Those things go hand in hand for me.

On that note, is there any difference between anaerobic species of bacteria and how they interact with fermentable fibers with Akkermansia? Is it a synbiotic product? Is it just a probiotic? What do you recommend for people when they’re taking Akkermansia in terms of fermentable fiber?

The Pendulum Line of Therapeutics

Colleen Cutcliffe:  We definitely recommend that people increase their fiber in their diet. I mean, generally speaking, that’s good for you. But in particular, with these strains, that is their food. The product itself is actually a synbiotic. We do have some inulin in there, but it’s a very small amount. It’s not a therapeutic amount. It’s designed to feed the strains. When we did our first preclinical study, we delivered the formulation with and without inulin, and we found that you only had efficacy when you had the inulin in there with the strains. I kind of liken it to, if you’re going to drop me off on a deserted island, I’d rather you drop me off with a cooler of sandwiches and beers so I have something to sustain me. So we’ve included the sandwiches and beers for these strains in the pill itself. But if you can increase your dietary fiber, that’s also going to feed them. There’s been some good studies showing that increasing polyphenyl consumption, like [eating] cranberries, can also help fuel Akkermansia growth. Those are some of the things that we recommend.

Chris Kresser:  Yeah, and sometimes people with a sensitive gut can have issues with inulin and [fructooligosaccharide] (FOS) and the more typical prebiotic fibers [like galacto-oligosaccharides] (GOS) [and] resistant starch. Whereas people with [small intestinal bacterial overgrowth] (SIBO) and some other gut issues tend to be able to tolerate polyphenols a little bit better in many cases. So that’s just a consideration for folks. I know we have a lot of folks in our audience who have sensitive guts, and it sounds like the amount of inulin that’s in the Pendulum product is not likely to cause those kinds of symptoms, because it’s mostly there to provide food for the organisms. But if you’re actively trying to incorporate more prebiotics, and you’ve had trouble with inulin and FOS, it might be worth trying more polyphenol intake.

Colleen Cutcliffe:  Absolutely, and it is a very small amount, about 100 to 200 milligrams [of inulin] in each dose. But [in] people who are sensitive, sometimes even that is enough to trigger responses. We actually launched a third product very recently, which we call GI Repair, and it’s a step-in solution. It starts with just one strain, and no prebiotic in it. It’s just Clostridium butyricum. And by the name butyricum, you can tell what it does. It’s a butyrate producer. This strain has been studied in Japan for quite some time and [has] been on the market there for [irritable bowel syndrome] (IBS) and [inflammatory bowel disease] (IBD). You start with just that strain, [and] if that’s helping and you’re able to manage that, then the second formulation adds another strain. So we’re slowly getting people’s microbiomes reconstituted. You don’t go straight to five strains plus a prebiotic if that’s going to cause a jolt in the system.

Chris Kresser:  I think that’s smart and I wish more companies did this. To be fair, a lot of the patients that I treat are pretty sick. I don’t have a general care, family medicine type of practice. It’s pretty specialized. But one of the most challenging parts of my clinical career has been finding products that my patients can tolerate. It can be a big problem, especially if you can’t titrate the dose in any way, if it’s a type of capsule that can’t be opened and where you can’t cut the dosage in half or a quarter. So I’m glad to see that you’re taking that approach because it’s very common in my experience for patients who have pretty significant gut issues to not tolerate probiotics or prebiotics.

Colleen Cutcliffe:  Yeah, and this was a response to people saying, “This is too much.” We’d say, “Well, go from two pills a day to one pill a day [to] one pill every other day.” And [then] we were like, “Why don’t we just make a formulation that steps people into it?” I think that’s helpful for people with sensitive guts. What I hadn’t fully appreciated was [that] there are so many people with sensitive guts, and it feels like that’s a growing population. As we go through the stress of everyday life and all the crazy stuff we’ve all been through, we know that stress reduces your microbiome, and you start to get depleted in certain strains. I think that aging and stress and all these things are causing more and more gut issues. So it’s actually more common than not that somebody has a sensitive gut.

Chris Kresser:  Absolutely. That’s the reality that we’re living in now, and that’s a product of a number of different influences. Everything from excess antibiotic use to increase in cesarean sections to decrease in breastfeeding to a whole bunch of other medications to a switch to an industrialized diet that’s high in acellular carbohydrates and processed and refined foods, lower fiber intake, etc., etc. So yeah, I would say virtually all of the patients I’ve treated over the past 15 years—not all, but 80 percent—have some gut issues, even when it’s not their main complaint. When they fill out the questionnaire, they’re checking off a lot of boxes in the gut category. And that, of course, can be contributing to something that is their main complaint. Even something like cardiovascular risk factors. I’ve talked about this on my show before, but very often, if somebody has high cholesterol and we test them for SIBO and other gut pathogens, and we find something and we treat those issues, their cholesterol will come down, even without doing anything at all that’s explicitly for cholesterol reduction. So I think there’s a lot of exciting territory still left to be explored there.

Colleen Cutcliffe:  Amazing. Speaking [of] antibiotics and things like that and the way people are born and breastfeeding, I think we also don’t realize how much early life shapes the microbiomes that we have. You don’t really feel it until later on in life, but it’s really shaped early on. There was this study that came out that was recently replicated by the Mayo Clinic that showed that kids under two years of age who were systematically on antibiotics were also systematically more prone to obesity, type 2 diabetes, allergies, ADHD, celiac disease, all these things that don’t show up until you’re a teenager or you’re in your 20s, 30s, and 40s, but really got seated in the early stages of life.

For me, actually, that was one of the big reasons we started the company. My daughter was born prematurely. She was on antibiotics right out of the gate, even though we had a vaginal birth [and] I breastfed her. She got multiple doses of antibiotics in intensive care. And when she was in elementary school, she had major food sensitivities. She was asking how much dairy was in the sherbert at the ice cream store. She’s been on our product, and for better or worse, she’s a teenager now and she can eat whatever she wants to. I think that it became clear to me that this early microbiome depletion was potentially setting her up for a lifetime of chronic illnesses.

Chris Kresser:  Yeah, absolutely. And often, that’s not anybody’s fault. It’s not by choice of [the] parent or any decisions that were made. It’s just that confluence of factors, which sometimes cannot be avoided. But it’s good to know now. Over the past few years, there’s [been] more research on how to overcome those early life deficits. I think this is fairly new territory where we’re able to now intervene, not just with aerobic organisms, but with anaerobic organisms. That’s, of course, particularly important since the colon is an anaerobic environment and that’s where most of the gut microbiota live. It’s always made sense to me that we would get here, and it’s great that you are innovating and doing fantastic work in this area. Where can people learn more about Pendulum and what you’re up to?

Colleen Cutcliffe:  You can go to our website, which is PendulumLife.com. We talk about all the different products on there and the science behind them. All the links to our publications are on the website, too. If people purchase, they can use [the] code Kresser20 to get a discount off of their first membership purchase.

Chris Kresser:  Great. That link for anyone who’s interested is Kresser.co/Pendulum, and you can check it all out. Again, if you’re super sensitive, you might want to start with the GI Repair product we mentioned that is a little bit easier to take and helps with butyrate production. The reason that’s a good starting place is that butyrate is anti-inflammatory. So if you can increase butyrate production, you can calm the system down, in my experience. In fact, just [as] a side note, when we have patients with really severe [gastrointestinal] dysfunction, particularly IBD, sometimes we will use butyrate enemas. That’s in the scientific literature. There’s a long history of butyrate being used for these kinds of issues. So it’s great to see that’s a possibility here.

Colleen Cutcliffe:  Yeah, it’s interesting. Straight up delivery of a [butyrate] molecule has varying results. I don’t know if you’ve seen that at all. Butyrate is a super powerful small molecule. [I think it’s really] a delivery problem. Essentially, all the colon cells use butyrate as their primary source of energy, unlike every other cell that uses glucose. When you’re delivering this butyrate, it’s being absorbed by every cell along the way that wants it before it gets to the actual receptor you’re trying to get it to. With the strains that are butyrate producers, you get the strain into the colon in the right location, and then they’re producing the butyrate in close proximity to the receptor. You end up helping with that variability of delivery.

Chris Kresser:  Yeah, that’s always been the issue with butyrate. It’s not the molecule itself, but [rather] how to get it to where it needs to be. If you take it orally, it often just gets digested and absorbed before it gets to the colon. Implanting by enema has different downsides and challenges. So obviously, the way that makes the most sense is the way that it’s normally produced—by the colonic bacteria. [It’s] so great that you have this option, for sure.

Thank you so much for coming on, Colleen. It’s been a fascinating conversation. I’m excited to see where this goes, what we’re going to learn over time about additional anaerobic strains that have therapeutic value, and even additional benefits that Akkermansia has. Because it sounds like, as you said, you set out to create a blood sugar regulation product and address diabetes, but you’re finding that, “Oh wait, this could have impacts for depression, anxiety, all kinds of cognitive and mood and behavioral issues and other things that [we] weren’t even thinking of, just by the nature of how closely connected gut health is to every other aspect of health.”

Colleen Cutcliffe:  Absolutely, it’s just the beginning of all the learnings and, hopefully, we’ll be able to bring more [opportunities] to help people in the future.

Chris Kresser:  Great. Kresser.co/Pendulum [is the link] and the code [is] Kresser20. It’s a pretty fascinating and promising new development. Particularly if you have blood sugar issues, it’s really worth exploring because there’s a lot of evidence now to back up this connection. Thanks, everybody, for listening. Keep sending your questions in to ChrisKresser.com/podcastquestion, and we’ll see you next time.

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