[Transcript] – The New Probiotic Strain That Allows You To Eat Carbs Again, How GLP-1 Peptide Actually Works And Why It’s Not Intended For Everyone, With Pendulum’s Colleen Cutcliffe.

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From podcast: https://bengreenfieldlife.com/podcast/colleen-cutcliffe-pendulum/

[00:00:00] Introduction

[00:00:45] Colleen Cutcliffe's extensive education and background in the fields of biotech, pharma, and academia

[00:05:18] The gut-brain axis plays a crucial role in how the microbiome influences factors like blood sugar levels

[00:12:19] Berberine, bitter melon extract, apple cider vinegar, and metformin use a different mechanism of action to regulate blood sugar levels

[00:15:32] Akkermansia muciniphila stimulates GLP-1 production. Where does it come from?

[00:27:25] Are there genetic variations in the microbiome that could predispose someone to an Akkermansia non-responder?

[0:32:00] Are there potential side effects, like bloating and gas, when using inulin and Akkermansia, especially in people with SIBO?

[00:38:15] Is there any connection between gut metabolism and Parkinson's disease?

[00:41:40] When is the best time to take Pendulum products?

[00:45:07] Ben's experience while taking Pendulum products while wearing a glucose monitor

[00:49:41] End of Podcast

[00:50:13] Legal Disclaimer

Ben:  My name is Ben Greenfield. And, on this episode of the Ben Greenfield Life podcast.

Colleen:  You don't just have neurons in your brain, you actually also have neurons in your gut. And, unlike the neurons in your brain, which is you get what you get, and when they die, they're gone forever. We all know that. You're not supposed to drink because once those neurons are gone, you never get them back. Unlike that, the neurons in your gut are constantly replenishing. So, there's new neurons being generated all the time in your gut.

Ben:  Faith, family, fitness, health, performance, nutrition, longevity, ancestral living, biohacking and a whole lot more. Welcome to the show.

Alright, folks. Well, my guest on today's show is Colleen Cutcliffe. Say that 10 times fast. She has a ton of experience, over a couple decades, managing and leading big teams in biotech, in pharma and academia. And, she recently started this company called Pendulum Therapeutics. It's this probiotic and bacteria-based company that we're obviously going to talk a lot more about on today's show. She has a Ph.D. in biochemistry and molecular biology from Johns Hopkins University, which means that she knows what she's talking about when it comes to all things biochemistry and biology. And, this company Pendulum is a biotechnology company that she helped to found to kind of bring forth these really crazy new probiotics you've never heard of for things that go way beyond just say, I don't know, helping you to poop better or strengthen the immune system.

So, Colleen, I've been checking out your stuff lately. I'm intrigued by this whole concept of, I guess what you might call it, the gut metabolism axis. So, welcome to the show.

Colleen:  Thank you so much for having me.

Ben:  I'm curious. I mean, I just want to jump right into some of the cool science on this. I think it was a few years ago. I was reading a study, I believe it came out of Israel, and it was showing that people who ate, I think they were, cookies and bananas had varying responses in their blood sugar reaction to those arguably sweet and starchy foods based on what I understood was their gut microbiome. And, they're even down to the probiotic balance in their gut. And, I think some people had a big response, big blood sugar response, some people had less of a blood sugar response, and they found out this was all due to their genetic diversity of the gut biome, I guess. And so, I wanted to ask you if what you do kind of stemmed from that study or if you're aware of it or your take on that whole thing.

Colleen:  Sure. Yeah, those studies coming out of the Weizmann Institute in Israel have been really foundational and they continue to do amazing work in the field of the microbiome. And, I think that at a high level when we think about metabolism, it's been a little bit confounding how does metabolism work, why do some people appear to have faster metabolisms than other people. There's a genetic component we know about our human genetics. And, there's certainly nutrition and exercise and all these things that we've all kind of learned about and debated over the decades, but I think what was new that they were one of the first people to really come out with and there have been several other groups also that have been really foundational in our understanding of the microbiome. 

What they realized was that there's this whole world of bacteria and viruses and fungi that live inside us in our guts and they are literally digesting all the foods coming into our system and they are a huge part of our metabolism. And, this is a huge unlock. As scientists or as people, we didn't even know that there was this whole real world of microbes there that we've co-evolved with over time and what a huge role they're playing in our metabolism. So, that's over the last 10 years, been just a real awakening and opening of data and products that can really help us in metabolism.

Ben:  So, you said it was the Weizmann Institute, I think, in Israel that did this research. Did you start Pendulum before or after all that research was coming out?

Colleen:  I think that research was coming out relatively concurrently. Some of the research that really sparked our interest was coming out of Lee Kaplan's Lab over at Harvard. And, they were doing some similar analyzes of the gut microbiome and particularly some of these strains that they thought were involved in metabolizing our foods and particularly helping us to metabolize sugars and carbs better. And so, some of the work coming out of there and then also some of the work coming out of University of Washington and St. Louis. Pete Turnbaugh was doing a bunch of work comparing obese and lean people and really doing all these pre-clinical animal studies showing that you could transfer microbiomes and make my skinny and fat, all just by changing their microbiome. So, all of that work was sort of happening around 2010, 2012. We started our company in 2012 and a lot of that stuff was really what made us believe there was an opportunity here in the microbiome.

Ben:  Okay. So, this is a weird question, maybe. I don't know if you've gotten this before, but I wear this continuous blood glucose monitor. I'm going to show them a video. By the way, if you want the video version of this podcast, go to BenGreenfieldLife.com/PendulumPodcast. That's BenGreenfieldLife.com/PendulumPodcast.

And, I've got this blood glucose monitor and I can hold my phone up to it. It's a Freestyle Libre. It'll tell me my blood glucose in real-time. And, I was thinking about the fact that gosh when I test this, this is measuring the sugar in my blood, but how the heck do you make the connection from a bacteria in my gut to the sugar in my blood? I think that it would be really helpful for me to wrap my head around this whole gut metabolism axis if you could describe how this actually works, what I eat, specifically the bacterial content in my food or the biome in my gut. It actually influences something like blood sugar.

Colleen:  Yeah. I think, at first, it's sort of non-obvious how your gut bacteria might be influencing your blood glucose spikes. And, I actually also wore a continuous glucose monitor to understand what impact the products we're having on my own blood glucose spikes. But fundamentally, everything we eat first goes into your stomach, you have all these stomach acids and they kind of break down your food to some extent. But, more importantly, as your food parts go down the digestive tract, they hit the gut microbiome. And, this is where the real metabolism of all of your food is happening. And, one of the things that we all know is that a high-fiber diet is really good for us. We're supposed to eat lots of fruits and vegetables. And, one of the reasons why a high-fiber diet is good for us is because when those fibers get to the gut microbiome, they get metabolized into small molecules called short-chain fatty acids. One of the most important is called butyrate. And, those small molecules that the microbiome creates after metabolizing our fibers actually stimulate GLP-1 production. And, a lot of people don't know this, GLP-1s are certainly starting to become more well-known but a lot of people don't know that GLP-1 is actually triggered in the gut microbiome.

Ben:  What's GLP-1 stand for?

Colleen: GLP-1 stands for glucagon-like peptide. And essentially, it is a small molecule that stimulates insulin response. And, it actually does more than that. So, on the one hand, it stimulates insulin response to help clear out the sugar in your blood after you've eaten a meal, but it also appears to have a very strong tie to our brains and our cravings and our food cravings. And so, people who take these GLP-1 drugs, which are designed for people with type 2 diabetes, not only see that their sugars are metabolized in their blood more effectively by releasing insulin but they also find that they have increased satiety. So, they just really don't crave foods as much. And so, that combination leads to kind of a really nice positive cycle in which you are metabolizing sugars better and then you're also craving less of the foods that kind of cause these high sugar spikes. And so, GLP-1, drugs like Ozempic and things like that, that's how they function and they're extremely effective in helping to lower blood glucose spikes and lower food cravings.

Ben:  Would you ever take those, I think they call them semaglutide peptides because now I know why I've heard that term GLP-1 before because everybody's dropping that is the way that these drugs or peptides if you want to call them like Ozempic actually work. What do you think of those?

Colleen:  I personally would not take them. And, the reason is because, first of all, they were designed for people with type 2 diabetes who are people that are actually unable to produce the right amount of GLP-1 in order to manage their blood glucose spikes. So, you're talking about people that have a disease that a drug was designed for. And, if you're a healthy person and you're able to make GLP-1, kind of adding a drug on top of that in general, there's going to be side effects that you're going to experience. But, maybe more importantly is physiologically what GLP-1, how it's supposed to work. So, how it's supposed to work is that you eat food, your microbiome digests that food and it tells your body, “We just ate a bunch of food, we need to the glucose out of the blood.” So, it stimulates GLP-1, GLP-1 gets released, it tells your body to release insulin, you clear the sugar out of your bloodstream.

So, actually, the levels of GLP-1 in your blood go like this, kind of similar to blood glucose spikes. When your body eats food, GLP-1 gets spiked in your bloodstream to tell your body to metabolize that sugar, and then it goes away. And then, when you eat again, it does the same thing. And so, you're supposed to have this cycle of GLP-1. What the GLP-1 drugs do is they increase GLP-1 consistently. So, you no longer have this cycle that your body is supposed to have, it's just high levels of GLP-1 all the time. And, while that can result in really nice immediate results, it's not the way your body is supposed to physiologically work. And so, when you disrupt cycles like that in your physiology and all kinds of other biochemical systems get disrupted, and so for me, since I don't have diabetes, I wouldn't personally take them.

Ben:  So, if you had the GLP-1 constantly being stimulated by these semaglutide peptides, would you have constantly high insulin levels or low insulin levels?

Colleen:  You would be high. So, basically, your body is constantly trying to metabolize all the sugar in your bloodstream even when you haven't eaten.

Ben:  So, you could almost induce kind of chronic hyperinsulinemia with these?

Colleen:  Not only that but these beta cells which are producing insulin, you're constantly stimulating them and having them going. And so, eventually, those betas–and, this is actually quite well known for people with type 2 diabetes. When you keep stimulating those beta cells that produce insulin, over time, the drugs become less effective because you're basically, it's like if someone were yelling in your ear all day long, in the beginning, you might have a reaction but after a while you're going to start to tune it out. And, our cells have a similar feedback loop which is to say that under constant stimulation, eventually they become less responsive. And so, that's what you're doing to your body, you're overstimulating a process all the time that's not supposed to be turned on all the time.

Ben:  Well, I mean, even though obviously being overweight or obese might have more risks than something like this peptide might present, it sounds to me like we would have to see a lot better long-term safety debt on something like pancreatic function or insulin sensitivity before saying that the average, I don't know, fitness enthusiast who wants to lose a few pounds or one of this anti-aging enthusiast who wants to keep blood sugar regulated effectively should use something like this.

Colleen:  100%. I mean, the long-term effects and safety of long-term use of the drugs in healthy people really hasn't been explored. They were developed for people with diabetes.

Ben:  Yeah. And, in contrast, it's my understanding that a lot of these so-called blood glucose disposal agents that a lot of people talk about like berberine or bitter melon extract or apple cider vinegar or I suppose a pharmaceutical metformin, those are acting differently, right? Those are triggering, from what I understand, the cell surface receptor, the glute transporter that would allow for glucose to be taken up into something like muscle rather than hanging around the bloodstream. It's a different mechanism of action, isn't it?

Colleen:  Well, to be honest with you, even though metformin has been out for a long time, I think there's still things being uncovered about it. And actually, there's a pretty strong set of hypotheses around metformin impacting the gut microbiome, and that being one of its mechanisms of action too. And actually, a lot of people theorize about apple cider vinegar as having kind of a similar thing. So, you're introducing something more acidic into the microbiome, you're potentially changing the composition of the microbes that are there. But ultimately, the microbiome is your natural way to metabolize these fibers and to help your body metabolize sugars and carbs by stimulating GLP-1 that that's kind of the natural system. And so, that's where the microbiome becomes really interesting because what people found is that people with obesity and type 2 diabetes are low or entirely missing these microbes that stimulate GLP-1. And so, that's where you start to have really interesting intervention opportunities.

Ben:  So, rather than taking GLP-1, you're actually allowing the bacteria in your gut to naturally produce GLP-1 all on its own. What kind of bacteria would actually do that?

Colleen:  Well, there's actually only one strain so far that's been known to do that. So, as I mentioned, there are these short-chain fatty acids like butyrate that get produced by the microbiome, and there's been evidence suggests that butyrate can stimulate GLP-1 production. There's actually only one bacterial strain that's ever been shown to directly be able to stimulate GLP-1 and it's a strain called Akkermansia muciniphila. And, this is a strain that you're really not going to see on labels and certainly probably most people haven't heard of it, but it is emerging as a keystone strain in the gut because it is the only strain that we know of right now that literally lives in your gut lining. And, its job all day and all night is to keep that gut lining regulated and it also is the only strain that is known to be able to stimulate GLP-1. And so, it really is becoming clear that this strain is super important. And, maybe I would say moreover the way Akkermansia started to make its way into this keystone string status is because there are a wide variety of diseases in which people are low in Akkermansia. So, there's obesity, type 2 diabetes, type 1 diabetes, bipolar disorder, inflammatory diseases, immune diseases. So, you start to say, well, gee, all these diseases that people have and they're also low, they're correlatively low in Akkermansia, why would that be? And really, what's starting to emerge is that Akkermansia is just playing a really core role in the gut lining as well as a production of GLP-1. And, that's how it's having all these outsized effects when you don't have enough of it.

Ben:  What was that word you said after Akkermansia like muciphila?

Colleen:  Akkermansia muciniphila.

Ben:  Okay.

Colleen:  I can describe a little bit more about mucin if you want.

Ben:   Yeah. The reason I ask is when you see probiotics named, you'll see Lactobacillus but then you'll see, I don't know, Lactobacillus reuteri, for example. So, maybe stepping back for a second, how are probiotics actually named? And, are there different kinds of Akkermansia in addition to this one that I'm going to butcher the name of again, the muciphilin Akkermansia?

Colleen:  Yeah. So, we all have to go back to, I think, seventh-grade biology when we learned about genus and family and that whole ordering of things. Things like Lactobacillus and Akkermansia are kind of the species' name. So, all different bacteria can be bucketed into one of these species. And so, the first word is the species. And then, the second word is more defining the strain. And so, within lactobacillus, you have Lactobacillus plantarum, Lactobacillus reuteri; these are different strains that fall in that Lactobacillus species. So, they're more similar to each other than they are to say something outside of the Lactobacillus family. But, they have some slight differences between them in terms of their functionality or maybe how much of them that people have or how they interact with other strains. And so, when we talk about Akkermansia, that's sort of the species. And then, Akkermansia muciniphila is the strain. And, there's even deeper ways in which people think about strains too. There might be different methylation of these strains that might make people say, well, actually these two strains are not the same. And so, that starts to get into a lot of very academic conversations on what is the definition of a strain. But, Akkermansia muciniphila is the full name and Akkermansia is a name of the species. Does that help?

Ben:  Yeah, it does. Where does Akkermansia muciniphila, if I said that correctly, actually come from?

Colleen:  Oh, my gosh, that's the million-dollar question. So, it's not exactly entirely known. Nobody has been able to find Akkermansia in any of our foods or beverages. You can find Akkermansia actually in mother's breast milk. So, it's believed that maybe some of the first Akkermansia we get comes from mom's breast milk, but it's pretty unclear where it comes from and how you get it. But, what's known is that there are a lot of ways in which it can become depleted over time. If we all kind of think back to a time when we could eat or drink whatever we want to do and you look in those sort of healthy almost teenagers, there's really large abundance of Akkermansia. And, there's a lot of things that can cause us to lose Akkermansia. One of them is simply aging. As we age, we start to lose Akkermansia. When we go through periods of intense stress, we start to lose Akkermansia. When women go through menopause, we lose Akkermansia. When you travel and your circadian rhythm gets messed up, night becomes day, day becomes night, you lose Akkermansia.

So, there are all these pressures that are happening around us in our environment that are causing us to lose this strain and yet we don't know how to get it back because we don't know any foods or beverages in which it resides. The only thing that we've seen is that if you eat polyphenols, so you increase your polyphenol uptake, that can stimulate the growth of Akkermansia. And, if you up your fiber intake, these are all prebiotics that feed into strains, feed Akkermansia. So, if you increase fibers and polyphenols, you can increase Akkermansia levels but really up until very recently, you couldn't even get Akkermansia or take it directly.

Ben:  Okay. And, maybe I'm a little bit confused here because last week, somebody sent me this white bottle and it says Akkermansia on the label. Is that actually Akkermansia or is it a bunch of stuff that helps you make Akkermansia yourself?

Colleen:  It's a white bottle, it didn't come from our company.

Ben:  Okay. Well, I mean, if I was at Walgreens or CVS and the label says Akkermansia, is it just a bunch of precursors? Kind of if you see the testosterone booster, it's not actually testosterone, it's Tribulus or fenugreek or whatever?

Colleen:  Unless it came from Pendulum, there is no other company in the world right now that is selling live Akkermansia that you can take directly. So, if they're saying Akkermansia on the label, it would be a prebiotic boosting Akkermansia unless it's from Pendulum.

Ben:  Okay, got it. Those bastards. So, how do you guys make it? Is it in a lab or something?

Colleen:  Yeah. We actually had to create an entire manufacturing plant to figure out how to grow this strain. I mean, to be honest with you, to be totally candid, when we started this, we just realized this strain was really important. We actually had no idea how hard it was going to be to grow this strain. But basically, this strain lives in your gut lining in your gut microbiome, which is strictly anaerobic. Meaning, there's not a single molecule of oxygen in there. And so, what we had to do was to understand how Akkermansia grows in our GI tract and then try to replicate that in a kind of outside the GI tract manufacturing setting. And so, figuring out how to grow Akkermansia was super hard. And then, figuring out how to keep it alive and then get it into these pills and deliver it to people and show that it actually took foothold in their microbiomes was also really hard. And so, our company's been around for about 10 years, that's always been a good amount of that 10 years trying to figure out how to do.

Ben:  So, how do you do it?

Colleen:  So, the key is that you have to create a manufacturing plant that end to end doesn't allow any oxygen into it. And so, I mean, oxygen is all around us in the air. And so, that was actually one of the hardest things to do. And, kind of the way that you do that is you're constantly pumping in other gases that will compete out the oxygen. So, we have tanks and tanks of nitrogen and CO2 and all these other gases that get pumped in to really pump the oxygen out. And then, the second thing is figuring out what are the nutrients that Akkermansia can live off of because it actually lives off of–it's called Akkermansia muciniphila because it munches on the mucin in your gut. So, maybe, I'll just take one second to explain how that kind of looks in the body.

Ben:  Yeah.

Colleen:  The way the gut lining is structured is almost like a fence. So, I actually have a wooden fence in my backyard. There are all these planks that are held together by glue. When I moved into the house, the wooden fence was super strong over time and through weather. Those planks can become weak and they can start to fall and the glue can start to get weak. And, our gut lining is actually exactly the same way. We have literally these planks, these cells in the gut lining and we have glue that holds those together that's called mucin. And, Akkermansia lives at that gut lining. And, Akkermansia's job all day and all night is to strip that mucin, to strip that glue when it gets weak, and to put new glue up when it's doing that so that that gut lining and that fence can stay really strong. And, the repercussions to not having a strong gut lining or a strong fence is that when one of those planks comes down or that glue gets weak, you now have these holes or these leaks as some people call them in which these molecules inside your microbiome can make their way into your bloodstream. And, that's what leads to kind of these heightened inflammatory responses, sort of miscommunication in the immune response. And so, Akkermansia muciniphila lives off of that glue, that mucin. And so, figuring out how to replicate that in a lab was sort of the second challenge, and figuring out how to grow these.

Ben:  Your lab sounds like a giant gut/farting factory with all the gases and the giant anaerobic tube. It's almost like you just replicated a human gut.

Colleen:  Totally. And, I'll tell you something funny which is that when we first started doing this, literally we're breathing in all of these. They're not noxious fumes that they really did not smell good. And so, we had to get all these air filtration systems just to be able to come into work and not feel like you're going to pass out.

Ben:  Yeah. My office sometimes also smells like a giant fart but for different reasons, obviously.

So, when you look at the ability, like you said, for you guys to be able to take this Akkermansia that you're making, keep it live, are you then putting other things in this Pendulum capsule like the polyphenols that you talked about or some sort of food for the Akkermansia to feed on?

Colleen:  Yes. So, we add inulin, which is a type of fiber in there which we know that this Akkermansia can feed off of. We put a very a small amount, which is really intended for the Akkermansia into the pill. 

We don't add polyphenols in with Akkermansia because as you just heard, it's a kind of a finicky sensitive strain. And so, in a lot of ways, figuring out what you can pack in the pill with Akkermansia in is important. Well, you want to make sure that you're maintaining the viability of the strain when you're packing other things in the pill. And so, we did some studies looking across different types of polyphenols and how they interacted with our specific Akkermansia strain. And so, we do offer polyphenols that specifically interact with this strain of Akkermansia, but they're in a separate pill because when they're actually in the pill with Akkermansia, they can affect the viability of the Akkermansia strain itself.

Ben:  That's right. This is sounding familiar because you sent me, I think, two bottles. And, I think one was Pendulum, but then one was to be taken in combination with it. I tested it, by the way, because I experiment with this stuff all the time like the apple cider vinegar. I've experimented with metformin, with bitter melon, with berberine. I haven't tried out any of those Ozempic semaglutide peptides yet for some of the reasons we just discussed. But, I did note that it seemed to very effectively keep my blood glucose low compared to a lot of these other blood glucose disposal agents that I was taking. But, you would take both at the same time, right, the Akkermansia, they need to take the polyphenol at the same time before a meal.

Colleen:  Yeah. You would take them together because basically, it's the double hit. You're giving yourself the actual Akkermansia strain and then the prebiotic that's going to help it grow.

Ben:  What if you take it after meal? What if you forget? How's the timing work?

Colleen:  Well, actually, unlike drugs, the timing of this is probably a lot more forgiving and complex. So, what you're asking this pill to do is to make its way into your GI tract to open up after it gets to that GI tract. And, we actually have special coating to make sure it doesn't just open up in your stomach. We sort of pay for this time-released capsule. So, it gets to your gut microbiome. That capsule has to open up, the freeze-dried strain has to then get rehydrated and come to life and then it has to start doing its activity. So, there's a lot of steps in that. And, taking it concurrently with a meal, that may be really important but it may be that you have to take it for a while for them to actually take a foothold in your gut and then start to have that activity.

Ben:  Yeah, kind of like that. I interviewed Dr. William Davis. I don't know if you know him. He has a great book. It's called the “Gut Fix.” And, he's big on Lactobacillus, the L. reuteri strain and he has this yogurt. I still make it. I make that yogurt or somebody in my house makes it every couple of weeks. Ever since I've done that podcast two years ago and I mix it with a little bit of gelatin afterwards to make it nice and thick, but he said you have to take it for a solid I think it was two to four weeks before you actually start to notice some of the bowel irregularity, the sleep enhancement, et cetera. And, I think it's for similar reasons. You have to build up these bacteria in your gut, right?

Colleen:  That's right. And, for some people, whatever the ecosystem that they have in their microbiome allows these new strains to come in and immediately take footholds. So, for some people, they can see a difference in a matter of days. And, for other people, it can take as long as 90 days, three months to really see a difference. It just depends on what your existing ecosystem looks like and how easy or hard it is for this particular strain to make its way into the system.

Ben:  Well, I mean, this kind of reminds me of what I was talking about earlier with that study in Israel about different people's biomes and cookie responders and banana responders and non-responders. What about something like Akkermansia? Could there be genetic variation in the microbiome that would be something that could predispose someone to be an Akkermansia non-responder?

Colleen:  Well, actually, one of the things that is in that study is they do show that different levels of Akkermansia are associated with your ability or inability to really metabolize these high-sugar foods. So, basically, people who are low in Akkermansia, not only are they not able to respond as well to these high sugar foods, there's actually been studies showing that if you're low in Akkermansia and somebody else is high on Akkermansia and you go on the same diet, so same high fiber, low-fat diet, if you're low in Akkermansia, you won't respond as well as that other person. So, Akkermansia is really a key strain that can even help you respond to dieting better. 

And so, I don't think we know whether there are people who are non-responsive to Akkermansia but we definitely know that when you start to give people back Akkermansia, they start to get these functions back and their blood glucose response starts to improve. It's awesome to hear that you observe that too because as you can imagine, the healthier you are, the harder it is to really see a response. And so, it's pretty amazing that you were able to see something.

Ben:  Yeah. I don't know if you know the answer to this question, kind of related to diet variation or if you know of any research about this, but a lot of people eat a low-carb or ketogenic diet and obviously, most of those people are going to have more stable blood glucose. Arguably, you could even theorize maybe they have less of a need for elevated levels of Akkermansia. Let's say somebody's been eating a diet like that and then they switch to a moderate to higher carb intake or start to introduce fruits or berries or honey or things like that, do you think that those type of people would, based on their diet not needing as much Akkermansia, actually go through a period of time where they had higher blood glucose responses once they started to introduce more carbs until they got more Akkermansia in their gut?

Colleen:  Yeah, that's a great question. I don't think that's been specifically studied, but it has been kind of shown that when you go on to a keto diet, you can actually increase your levels of Akkermansia. So, I don't really understand what– 

Ben:  That's kind of counterintuitive, isn't it?

Colleen:  Well, sort of, except that Akkermansia feeds off this glue, this mucin. And, actually one of the biggest producers of mucin is a meat byproduct. So, that might be the way that that's happening.

Ben:  Yeah, that makes sense. So, you said the Akkermansia, not the polyphenol product that is your separate Pendulum product but the Akkermansia product, you said, that has inulin and Akkermansia in it. Does it have anything else in it?

Colleen:  No. The pure Akkermansia product doesn't have anything else in it, but we also have some formulations. So, pendulum glucose control which was designed to help people lower blood glucose spikes and lower A1C, that one has Akkermansia plus four other strains which are involved in this metabolism of fiber into the short-chain fatty acids and help reduce butyrate. And so, that formulation has been clinically shown to lower A1C and lower blood glucose spikes in people with diabetes, lowered A1C by 0.6, and lower blood glucose spikes by 34%. So, super effective as a formulation. Some people are really just low in Akkermansia and so just adding Akkermansia can have an impact in and of itself. But, if you're looking for the full kitchen sink, Pendulum Glucose Control and Metabolic Daily have Akkermansia plus these other strains.

Ben:  Actually, that was the one that you sent me was the Glucose Control, but I didn't realize it had four strains in addition to Akkermansia. And, are these all strains that you came up with too?

Colleen: Three of those four strains, yes, we are also the people who manufacture them and identify them. One of them is a relatively common strain, it's called Bifidobacterium infantis. That one you can find in in lots of different probiotics. It is one of the steps, one of the biochemical steps in creating butyrate. And so, we have that strain in there, but we also have Clostridium butyricum, Clostridium beijerinckii, and Anaerobutyricum halai. You're not going to find those on any other labels. So, those and Akkermansia muciniphila, those are strains that we identified that we manufacture and they're all kind of these strict anaerobes where you can't have any oxygen in the manufacturing system.

Ben:  Got it. Now, it's my understanding that for people who are wanting to eat a low fermentation diet or who have maybe struggled with small intestine bacterial overgrowth that they're supposed to be careful with fibers, and a lot of times they'll get a lot of bloating and gas with some of these prebiotic fiber blends and even inulin. Have you ever found any issues to arise in people who have this kind of excess gas production in response to fiber intake when they're using something like the Akkermansia and inulin combination?

Colleen:  Disclaimer, we haven't done a clinical trial in SIBO or anything like that. But, we have a fair number of customers with SIBO who started taking our products, Pendulum Glucose Control or Akkermansia, and reported benefit. And really, what we think is happening for those folks is that there is a little bit of inulin in there. It's an incredibly small amount. So, it's not enough to sort of stimulate the response that these patients have. But what's actually happening for them is that when you have SIBO or when you have some of these kind of digestive issues, what people often end up doing is going on to a very, very refined diet. And, they're basically just trying to figure out what can I eat, what can't I eat. And so, they end up starting with bare minimum, bare bones. One of the big things is to reduce your fiber intake because that's one of the things that can kind of stimulate these unwanted reactions. 

What these strains are doing is they help you metabolize fiber. And so, the hypothesis for these people who have SIBO that are taking our products of why it's helping them is that they aren't able to eat fiber because they don't have the microbes that help them metabolize the fiber. Now that they're giving themselves the microbes to metabolize the fiber, they can start to eat these foods that they hadn't been able to eat before and not have those reactions. And so, we haven't done a clinical trial in it but it's been super interesting to kind of follow these customers and their journeys with SIBO.

Ben:  Okay. I got to try an n equals 1 now that you've said that because I didn't realize it could help you potentially to digest prebiotic fibers. There's this one company called Miracle Noodles that I love. They got fettuccine and angel hair pasta and spaghetti and done-for-you keto meals and it's all made out of this Japanese yam. And so, it's almost zero calorie, zero carbohydrate and it's just fiber. And, I got on a Miracle Noodle kick where I was doing a whole package with lunch every day. And, after about a month of that, I actually started to get pretty significant amounts of bloating and gas all the way up to and sometimes after dinner. So, I told my wife, I'm like, “Gosh, I don't know what to do. These Miracle Noodles I love, they're making me bloating now.” And, about two weeks ago, I quit eating all of them except they have one version called a Content Pasta, which is made out of a different form of fiber that my gut seems to agree with. But, I'm thinking now, maybe I should just pop a bunch of Akkermansia whenever I eat a high-fiber meal like that and see if it has any effect. You think something like that could work?

Colleen:  100%. I think you should totally run that experiment. I cannot wait to hear the results. But, I would say, be dosing yourself with Akkermansia. If you kind of went off of it for a second here, I would give myself four weeks on it, so 30 days on it, and then try the yam-based food again and see if works. Because you want to give your body a chance to kind of actually colonize the strain.

Ben:  Yeah, you're going to make a whole bunch of people with SIBO or SIBO tendencies who miss their salads and their fibers a lot happier with this information because this is actually something I haven't heard of before. That's the number one complaint I give people with SIBO like, “I like to have my big salads and everything. I can't because I get so bloated.” So, this is interesting. This is good information.

Now, what if I were building up my Akkermansia levels or are using Pendulum or something like that and I get an antibiotic? Is it just going to nuke everything and I got to start over?

Colleen:  Yeah. I mean, I used to think it made no sense to kind of take a probiotic alongside an antibiotic. Well, first of all, to answer your question, it's yes. So, an antibiotic is a nuke to your whole system. It really does kill almost every single bacterial strain in your body. And, I used to think that it didn't make sense to take a probiotic while you're on an antibiotic because it's just going to be killing the strain off. But, there was an interesting study that just came out that showed that people who were taking probiotics proactively before going on antibiotics but for many people, you kind of know when you're going to go on an antibiotic like if you're going to surgery or whatever. So, they started taking probiotic before they went on antibiotics. For those people who were on a probiotic before they started the antibiotic and they continued on the probiotic through the antibiotic treatment compared to people who were on no probiotic, on the other side of that antibiotic treatment, these people who had been on the probiotics were actually able to reconstitute their microbiome with these beneficial strains more easily than the people who weren't.

So now, I kind of changed my tune after seeing that study. We don't understand why that is, but I basically now tell people like don't go off of them, just keep taking them. I don't know why, but there's this data out there suggesting it's helpful.

Ben:  That must be a new study because so many functional medicine practitioners and nutritionists still tell you it's useless to keep taking a probiotic when you're on an antibiotic because it's going to nuke it anyways. Is this a pretty new study?

Colleen:  Yeah, that's a new study. And, like I said, I wouldn't agree with it. I mean, logically, it doesn't make sense to kind of have these two things countering each other. But, this new study, and it was well run, it really shows that there might be something more there than what we understand. There might be some, I don't want to call it like a memory but there's something there to continue to take from.

Ben:  That's interesting. Could you ever have too high of Akkermansia levels? Could you take too much? If so, what would happen?

Colleen:  Well, with the Akkermansia product that we have out, we've basically did all of the safety studies. I mean, you could down a whole bottle and you'd be fine. And so, no from that perspective, but I'll give the caveat, this is really still an early science. So, what we know today is nothing compared to what we're going to know 10 years from now. Akkermansia was only just discovered in the early 2000s. So, we haven't really known about it for very long. So, there hasn't been anything to show that if you administer Akkermansia at really high levels, you can have some detrimental effect. But, I'll give the caveat that we're still pretty early in it so you never really know.

Ben:  Yeah, yeah. This is interesting. I have a friend who has Parkinson's. And, I think six or seven months ago, I was listening to a podcast, I think it was, with somebody who had I think it's a probiotic compound called Sugar Shift, some kind of bacterial strain that can lower blood glucose. I don't know if it's working on the same mechanism of action as Akkermansia if you know of it, but they were alluding to the idea that some of these gut metabolism strains may have an impact on Parkinson's. And so, I'm curious if you're aware of that, if this is any strain, if Akkermansia plays a role or is there any link that you know of between gut metabolism and Parkinson's?

Colleen:  Yeah. This is super interesting. So, first of all, on a personal note, I started my career working in pharma and we were trying to develop drugs for Parkinson's Disease. So, when we were studying Parkinson's disease, it was all about the brain. So, one of the hallmarks of Parkinson's is that you start to get these plaques in your brain. There's these dark plaques in your brain. And, the biggest way in which people were trying to develop drugs for Parkinson's was to try to get rid of those plaques. And so, the hope was that if you get rid of those plaques, you could clear the brain back out and you could kind of at least elongate the progression of Parkinson's so they could help people. 

But, one of the most interesting things that's come out is that you don't just have neurons in your brain, you actually also have neurons in your gut. And, unlike the neurons in your brain, which is you get what you get and when they die they're gone forever, we all know that. You're not supposed to drink because once those neurons are gone, you never get them back. Unlike that, the neurons in your gut are constantly replenishing. So, there's new neurons being generated all the time in your gut. And moreover, those neurons in your gut talk to the neurons in your brain. There's this thing called the vagus nerve and these neurotransmitters can go directly from your gut to your brain. And basically, your gut produces things like serotonin, GABA, all these neurotransmitters in really high doses. And, we now know that those neurotransmitters can get sent to the neurons in your brain. And then, the third thing is so, first of all, you have neurons in your gut, second of all, they're communicating with the neurons in your brain, and the third super fascinating thing is that these plaques that show up in the neurons in your brain that are associated with Parkinson's and Alzheimer's, those plaques show up in your gut neurons first.

Ben:  Oh, wow.

Colleen:  So, you can actually see them show up in the gut first. And so, now, the theory is it actually starts in the gut, then you get this misfiring of signals, and then it goes to the brain. And then, once it's in the brain, you're kind of hosed. And so, really the right target to go after is not the brain, stop focusing on that, is to go after those neurons in the gut. How can you accelerate the regeneration of them? How can you get rid of the guys who are misfiring signals? It's a huge new opportunity to go after these brain diseases through the gut.

Ben:  Oh, this is super interesting. Have you guys actually done any studies on Pendulum as far as clinical relevance? I mean, you've shown a decreased blood sugar, but have you ever taken people with diabetes or overweight or obesity or MS or Parkinson's or Alzheimer's or anything like that and actually been able to do trials with Pendulum?

Colleen:  It is on our roadmap. So, we are in a deep collaboration with a professor at the Mayo Clinic really investigating this. I mean, it's super interesting and it could be potentially a huge unlock.

Ben:  Yeah, yeah. That would be really interesting.

Okay. So, talk to me about the dosage. You mentioned that building it up is a good idea, but how many times a day am I taking this stuff? Is it three times a day? Is it just a couple in the morning with food, without food or what's the best way to do this if people are listening and they get their hands on a bottle?

Colleen:  Well, we recommend on the bottle, you'll see it says take one in the morning, one in the evening. And, the reason we recommend that is because I'd only say to take it with food. And, the reason we say that is because everybody's kind of lifestyle is pretty different when people eat, when they're fasting, all of these things. And so, what we're trying to do is to hit you at the two points in the day that maybe give it the best chance of colonization. Then, the name of the game is colonization. So, we tell people take in the morning, in the evening because we don't really know people's lifestyles. And then, we recommend that people take it with food because some people are just sort of sensitive to taking supplements in general like the capsules or whatever, some of the stuff that's the components in it can cause people to feel sensitive. And, when you eat a meal, the acidity of your stomach, it basically becomes more basic. And so, that allows then the capsule to have a better chance of making it through the acid. Whereas, if you're taking in an empty stomach, it's kind of the highest acid stomach moment. And so, we tell people take it in the morning, the evening and with food.

Ben:   Okay.

Colleen:  Now, that being said, I take two in the morning with coffee. And, I saw my blood glucose spikes go down when I was doing my own placebo-controlled trial with a continuous glucose monitor. So, it really does vary from person to person. I'd say the most important thing, again, the name of the game is colonization. When can you remember to take it? Where does it fit into your lifestyle? That's the time to be able to fit it in.

Ben:  Well, don't laugh because a lot of biohackers are doing probiotic enemas like putting stuff up the butt and hanging upside down and using butyric acid. And, this is an addition to something like coffee enemas. Have you ever had anybody put Akkermansia up their butt? Have you seen any evidence besides that? You remember that Jeff Leach guy who went to visit the hunt the Hazda Hunter-Gatherers I think it was, he hung himself upside down the middle of the village and did a fecal transplant. And, I think Akkermansia was one bacteria that he saw elevated. But, besides that, any benefits to going up the other side?

Colleen:  Well, again, we pay extra for these capsules that help people get it through the stomach acid and to the gut microbiome. And so, there shouldn't be a need to go up the other side, but I can't say that I have investigated. We've certainly not done a trial going at the enema route. I don't know how effective that would be.

Ben:  Okay. Good to know with these titanium super bulletproof time-release capsules you're talking about, who knows, you might just cough up your capsule a few hours later and it comes out the other end. So, you might have the opposite problem. So, all things to theorize about.

Well, Colleen, this is super interesting. I'm going to put a link to this Pendulum stuff if you go to BenGreenfieldLife.com/PendulumPodcast, P-E-N-D-U-L-U-M, Pendulum Podcast. I think we have a discount code for you guys if you want to try the polyphenol, the kind of done-for-you blend with the five different strains in it. 

And, anything else you want to share with people about the form formula, Colleen?

Colleen:  Well, actually, I'm really curious to hear your story. So, you are on product, were you wearing a continuous glucose monitor when you were looking at your glucose response?

Ben:  I was, yep. I was.

So, I've been taking blood glucose disposal agents kind of cycling between everything, like I mentioned, from apple cider vinegar to berberine, to bitter melon extract. I generally see a restoration of my blood glucose levels to normal premium levels within a couple hours after a meal. And, when I'm using these agents, I generally don't see a rise anything more than 120 post-meal, even if that's a starchy meal. When I started taking the Pendulum, I quit taking these others. I didn't do a washout period first, but what I saw when I started taking Pendulum and I quit taking the other blood glucose disposal agents to compare was my results were similar. And then, when I quit taking the Pendulum, my blood glucose excursions would go north of 120. I would also get post-meal hypoglycemia but I only took it for a very short period of time. I think I did consistently for two or three weeks. So, I don't think I've given it a fair trial yet, I didn't understand the point about having the Akkermansia build up in the gut. So, I'm going to do a little bit more testing with this stuff and also test it with the fiber.

Colleen:  Yeah, that's awesome. I mean, I did a placebo-controlled trial in myself and I wore a continuous glucose monitor. I either took placebo or the glucose control product. And, I actually did it blinded so I told the team don't make them look the same like I don't want to know which one I'm on. And, I could tell when I was on the formulation because actually my workouts were stronger. But then, when I got the glucose monitor data back, I could see all my spikes and crashes were minimized. And so, the area of the curve for both of those was less. And, I was only on it for 14 days. I think a lot of us try to eat healthy, we think that we're metabolically healthy, but the microbiome is such a black box on how do you even get these strains back sort of going back to one of your first questions, how do you get Akkermansia that many of us who are doing the best that we can to be as healthy as possible could be depleted and that could be why you had a really rapid response. I also did too, it was only two weeks into it that I saw those changes. So, that's pretty cool.

Ben:  Yeah. And, by the way, that's interesting what you say about the performance. Are there any exercise performance studies on Akkermansia whether it's lactate or reduced rating of perceived exertion or strength or power or anything like that?

Colleen:  We haven't done those yet, but that's definitely on our radar and our list to do. And, as you probably know, when you can get your blood glucose spikes under control, for a lot of people, it shows up in different ways. It's more energy, better sleep, better workouts, you don't have that post-lunch crash. And so, I think for me, that was how it showed up. But, we haven't done any of those kind of studies to any clinical trials to really show those changes.

Ben:  Yeah, you've no doubt seen a few that have come out over the past few years showing that certain elite athletes have a markedly different biome than their non-athletic or their peers who aren't able to perform quite as well. It is a question which came first, the chicken or the egg, right, does intense training or competition change the biome, or does a certain biome predispose you to being better at certain sports or at certain performance metrics. But, it is interesting and it'd be interesting to see that repeated with something like Akkermansia.

Colleen:  Yeah. And, Akkermansia is one of those strains that those athletes are higher in. But, knowing whether actually giving yourself more Akkermansia helps improve your athletic performance that that's still yet to be done.

Ben:  Yeah.

Colleen:  So, thanks for sharing your story. And, I guess the only thing is that I think we do have a special code, GREENFIELD, for people who want to come try the product to get a 20% off their first bottle of membership, so they can trial the products.

Ben:  Cool. Well, I'm flattered you named your code after me. That's very nice of you. So, BenGreenfieldLife.com/PendulumPodcast. Sounds like the code is GREENFIELD, but I'll put it in the shownotes as well. And, you could also, at the shownotes, leave your questions, your comments, your feedback from me or Colleen. We check them all out and I love to see some interaction and be able to keep the conversation going over BenGreenfieldLife.com.

So, Colleen, thanks so much for coming on the show.

Colleen:  Thank you for having me.

Ben:  Yeah. I'm going to go have me some Miracle Noodles with some Akkermansia. Alright, folks. Well, have an amazing week. I'm Ben Greenfield along with Colleen Cutcliffe from Pendulum Therapeutics signing out from BenGreenfieldLife.com. Have an amazing week.

More than ever these days, people like you and me need a fresh entertaining, well-informed, and often outside-the-box approach to discovering the health, and happiness, and hope that we all crave. So, I hope I've been able to do that for you on this episode today. And, if you liked it or if you love what I'm up to, then please leave me a review on your preferred podcast listening channel wherever that might be, and just find the Ben Greenfield Life episode. Say something nice. Thanks so much. It means a lot.

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You might've heard me say it before: “The gut is the second brain.”

But what if that boundary is pushed even further, and you consider the gut not just as an influencer but as the master controller of the body? Perhaps the real biological is unfolding right inside that intricate microbial realm that could be the linchpin to peak health.

With over two decades of leadership in biotech, pharma, and academia, my guest on today's show, Colleen Cutliffe, is gut-deep :) in microbiome knowledge. Her path, spanning from the hallowed halls of Johns Hopkins University to groundbreaking initiatives at Pacific Biosciences and Elan Pharmaceuticals, showcases an unyielding curiosity about the mysteries of the human body. Now, as the driving force behind Pendulum Therapeutics, Colleen is charting new territories in the world of the microbiome.

Pendulum is no ordinary biotech outfit. It's a beacon of innovation, deeply rooted in family values and driven by a team that believes in the profound potential of gut health. From the streets of San Francisco, they're pioneering a new understanding of our inner biology, spotlighting proprietary strains like Akkermansia muciniphila and pushing the boundaries of what probiotics can achieve.

Akkermansia muciniphila, one of Pendulum's products, is a unique oval-shaped bacterium that thrives in the human gastrointestinal tract. This anaerobic microbe predominantly resides at the junction between oxygen-rich and oxygen-depleted zones of the intestines. Found in about 90% of healthy individuals, it constitutes 1% to 3% of your fecal microbiota. However, its prevalence can decrease with age or certain diseases.

In today's chat, Colleen unravels the enigma of the gut-brain axis and its monumental influence on the microbiome's functionality. She sheds light on the role of natural agents like berberine, bitter melon extract, apple cider vinegar, and even pharmaceuticals like metformin in regulating blood sugar. With insights into the importance of Akkermansia muciniphila in GLP-1 production and the captivating genetic variations within the microbiome, this conversation promises a comprehensive look at gut health like never before.

During our discussion, you'll discover:

-Colleen Cutcliffe's extensive education and background…00:45

  • Experience in managing and leading large teams in the fields of biotech, pharma, and academia
  • Co-founder of Pendulum Therapeutics (code GREENFIELD saves 20% off your first month's subscription)
    • Specializes in probiotics and bacteria-based products
    • Develops innovative probiotics with applications beyond traditional uses
  • Has a Ph.D. in biochemistry and molecular biology from Johns Hopkins University
  • Her work is influenced by research from institutions such as:
  • Freestyle Libre

-The gut-brain axis' crucial role in how the microbiome functions…10:40

  • The microbiome metabolizes dietary fibers into short-chain fatty acids, such as butyrate
  • Stimulates the production of GLP-1 (glucagon-like peptide) in the gut
    • Influences insulin responses, blood sugar regulation, and food cravings
  • GLP-1 drugs, like Ozempic, are designed for individuals with type 2 diabetes who struggle to produce adequate levels of GLP-1 naturally
    • Not suitable for healthy individuals
      • Disrupt the natural GLP-1 cycle and may lead to unintended side effects
  • Constant stimulation of GLP-1 by semaglutide peptides would lead to consistently high insulin levels
    • The body continually attempts to metabolize sugar from the bloodstream even when not actively eating
    • Overstimulation of insulin-producing beta cells could lead to:
      • Decreased responsiveness over time
      • Reduced effectiveness of the drugs

-Berberine, bitter melon extract, apple cider vinegar, and metformin to regulate blood sugar levels…22:48

  • Blood glucose disposal agents
  • Metformin
  • The microbiome is the natural way to metabolize carbs and fiber
  • Facilitate glucose uptake into tissues like muscle
  • GLP-1, or glucagon-like peptide-1, is a molecule that stimulates insulin responses
    • Aids in blood sugar clearance
    • Plays a role in food cravings
  • Probiotics can influence GLP-1 production naturally through the gut microbiome
    • Short-chain fatty acids, like butyrate, can stimulate GLP-1 release
    • People with diabetes and obesity are often low, or lacking entirely, in the microbes that stimulate GLP-1 production

-Akkermansia muciniphila and GLP-1 production…26:33

-Genetic variations in the microbiome…37:55

  • A study in Isreal: Personalized Nutrition by Prediction of Glycemic Responses
    • Associates different levels of Akkermansia with responses to high-sugar foods
    • Low Akkermansia levels may lead to poorer responses to high-sugar diets
      • There isn't enough data to confirm Akkermansia non-responders
    • Akkermansia can even help you respond to dieting better
  • A keto diet can increase Akkermansia levels
    • The relationship between diet and Akkermansia is not fully understood

-Are there side effects from using inulin and Akkermansia?…48:07?

  • Patients with SIBO reported benefits from taking Pendulum products
  • Providing the necessary microbes for metabolizing fiber can allow people with SIBO to reintroduce fiber into their diets
  • Miracle Noodles made out of Japanese yam (use code BEN to save 15%)
  • Akkermansia was discovered in the early 2000s

-Is there a connection between gut metabolism and Parkinson's disease?…52:37

  • Sugar Shift probiotic compound
  • Colleen's career started in pharma, working on drugs to treat Parkinson's disease
    • Research on brain plaques and how to remove them
  • We have neurons in our brain and in our gut
    • Neurons in our gut are constantly regenerated
    • Communication between the brain and gut via the vagus nerve
  • The plaques that show up in the brains of Parkinson's and Alzheimer's patients show up in the gut first
    • New field of work in studying and healing the gut rather than solely looking at the brain
  •  Pendulum is in the process of studying this

-When is the best time to take Pendulum products?…55:02

  • Take Pendulum twice a day with food (code GREENFIELD saves 20% off your first month's subscription)
    • Once in the morning, once in the evening
  • Colonization is key
  • Taken with food will reduce sensitivities
    • Food also creates a basic, rather than acidic, environment
  • Colleen takes two in the morning with coffee
    • It works for her
  • Take orally
    • There is no trial for this being used as an enema

-Ben's experience taking Pendulum products while wearing a glucose monitor…59:18

  • Cycles between apple cider vinegar to berberine to bitter melon extract
  • Sees a restoration of his blood glucose levels to normal pre-meal levels within a couple of hours after a meal
    • Generally doesn't see a rise to anything more than 120 post-meal
  • Started taking Pendulum, and stopped taking the above agents, and had similar results
  • When he quit taking Pendulum, his blood glucose would go above 120
  • Colleen had a similar experience, taking either Pendulum or a placebo while wearing a continuous glucose monitor
    • She had stronger workouts
    • Glucose spikes and crashes were minimized

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  • Couples Collective: October 25th – 29th, 2023

Couples Collective is an exclusive and immersive way to explore health, wellness, and mindset with your significant other. Jessa and I will be leading a health optimization and relationships workshop alongside many other awesome couples. This is a small event, and access requires you to interview with event-holder OWN IT to ensure a right fit. However, for those who are said fit, this event is designed to bring you into deeper union within your relationship and onward into greater connection with your life, love, health, and happiness. I'm looking for 6 to 7 powerful couples to come join me at the event – are you one of them? Learn more here.

Resources from this episode:

– Colleen Cutcliffe:

– Podcasts:

– Books:

– Other Resources:

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