Gut Health and Your Microbiome: Separating Facts from Fiction

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  Speaker 1:
  Hello everybody. Welcome to the webinar today. My name is David Shapiro, Managing Partner with Alumni Ventures. I am super excited to be joined by two CEOs in our portfolio, both Leo Grady and Colleen Cutcliffe. We’ll come to you both in a moment. Just to orient everybody, this is gut health and your microbiome. We’re going to get into a lot of detail. Go really quickly. We’re going to separate some facts from fiction. That’s kind of the goal here—to really make this educational for folks on a super important, complex, and rather mysterious topic, namely everybody’s microbiome. So, super psyched to be able to welcome everybody to it. And with that, let’s just jump right in.

  This is for informational purposes only. Just so everybody knows what we’re going to cover today, I’m actually really not even going to preview Alumni Ventures and our Health Tech Fund.

  We have a Health Tech Fund. Anybody interested in learning more about venture capital and how to invest in it? Reach out. Reach out to me directly, David at AV VC, or lots of ways through our website. But with that, I’d rather focus on the roundtable discussion and get into it with Colleen and Leo.

  So, jumping right in. Really pleased to have them join. So what I’ll do first is just maybe offer a chance to have Leo and Colleen introduce both their companies and a little bit on themselves. So maybe Leo first if you want to highlight a little bit on Jona  and really what was your journey and how you got to be an expert in the microbiome. And then Colleen, you can do the same after that.

  Speaker 2:
  Sure. So thank you, Dave. Thanks for organizing everything here. I started off my career as a PhD in AI 20 years ago, and I spent my whole career building AI systems in conventional medicine for radiology, for cardiology and cancer. And these were FDA-approved AI systems that we were mainly selling to doctors. And there was a big gap between the technology that we were building and the actual end patient and the actual end user. And that was very challenging sometimes to get really great feedback on exactly how our technology was impacting patients, which is really ultimately what we were after.

  For me personally, gut health is interesting because I’ve had a number of my family members with Crohn’s disease, with colitis, with celiac, with undefined gut issues, and just seeing their struggle as they tried to understand what was going on and tried to get answers—and really struggling to get some of those answers from their doctors and bouncing around to lots of different medical professionals.

  And ultimately, many of them settled in functional medicine or doing testing themselves. And I saw some of the benefits they derived there. I got interested in the gut microbiome because every aspect of your health has been linked to the gut microbiome. It’s not just gut health—skin health, obesity, mental health, cardiology even, and cancer. But there’s a tremendous complexity with the gut microbiome. You’ve got 30 trillion organisms in your gut, which is this complex ecosystem. And every single month there are more than 2,000 studies published on the microbiome in PubMed. Nobody can read them all.

  So what we did is we built an AI system to read all of those papers. We offer a gut microbiome test—it’s a stool sample. You send it off to the lab, we do deep sequencing, identify everything in your gut down to a strain level, and then the AI matches the patterns in your personal gut to every study that’s ever been published.

  So we can say for you, your microbiome fits the pattern of everything from bloating and brain fog and fatigue all the way to psoriasis or Parkinson’s disease or even early cancer signatures. Then the AI takes the next step and looks at ways to change your microbiome through diet, lifestyle, supplements, and does an analysis of what would happen if you went vegan or went keto or took the supplement—and virtually makes all of these changes to your microbiome through a digital twin. And based on all of that analysis, pulls together an action plan for you that’s personalized to your own biology, your own body, and ultimately allows you to make changes to achieve your health goals.

  Speaker 1:
  Excellent, thank you. And we’ll come back to some of the bits related to Jona , I’m sure, as the questions go forward too. So thanks.

  Colleen?

  Speaker 3:
  Hi everyone. Thanks for organizing this, Dave, and thanks to everybody for joining us. I’m super excited to talk about, I think, Leo and my favorite topic—the gut microbiome, or microbiome in general.

  My background is in basic science research. So I have a PhD in biochemistry and molecular biology from Johns Hopkins. I did a postdoc at Northwestern, and then I started my career working in pharmaceutical drugs. We were developing small molecule interventions for Parkinson’s disease. Then I joined a startup DNA sequencing instrument company called Pacific Biosciences. That company went through a lot of growth while I was there and went public.

  And on the other side of that IPO, I started this company, Pendulum, with two co-founders. We all worked together at that DNA sequencing company and we’re all very technical. So I’m a biochemist. Jim is a biostatistician. John is a biophysicist. And the whole idea of—and this is about 11 or 12 years ago now—but the whole idea of microbiome science is really founded in being able to use DNA sequencing technologies to create these metabolic maps of the microbiome and understanding how do all the functions of the microbiome interact with each other, and then also interact with, of course, the human host, and how might you change the microbiome in order to impact human health.

  And that was really, I think, a big interesting data problem as well as biological problem. And if you could merge those two and really approach this from a systems biology approach, you could create interventions that had never been seen before that could really help people with a wide variety of diseases.

  And we honed in on metabolism. From a personal standpoint, I got really interested in the microbiome when a paper came out by Martin Blaser from NYU. This was in 2012. He looked at 12,000 infants and showed that infants who were on a lot of antibiotics were more prone to chronic illnesses, including obesity and type 2 diabetes as they got older.

  And that study was actually repeated by the Mayo Clinic, and they showed that if you’re under two years old and you’re on a lot of antibiotics, you are more prone to not just obesity and diabetes when you get older, but you’re also more prone to things like allergies, asthma, ADHD, celiac disease.

  And so all of these things that are kind of on the rise really might have at their root cause a microbiome deficiency. And I personally had my first daughter born—she was born two months prematurely. And so she was on a lot of antibiotics as kind of the protocol in the ICN. And as she started to get older, I noticed that she was having food sensitivities that the rest of the people in our family don’t have. And it’s sort of those food sensitivities that are the beginnings of this march towards bigger and more significant chronic illnesses.

  And so from a personal standpoint, I felt like, well, if we could create a company that could help millions of people, including my own daughter, why not give it a shot? And we created Pendulum. And we spent about eight years doing R&D work, really focused on how does the gut microbiome impact metabolism—what role does it play there?

  And we have created a series of different products that have been on the market for a few years now, which all target the gut-metabolism axis, ranging from products that are for people with type 2 diabetes that are clinically proven to be able to lower your A1C and blood glucose spikes, to products that can specifically increase your GLP-1 hormone, to products that are for people that are generally just trying to improve their metabolic health.

  And so happy to go into any of those today as we go into our conversations. But the microbiome is this incredible opportunity to create interventions that can help us with a wide variety of diseases, and I’m excited to dig into what some of those opportunities are today.

  Speaker 1:
  Great. Well, thank you both for that—clearly experts in the domain. Alright, let’s just jump right in. I’m not going to start with “what is the microbiome,” let’s go right past it. I want to talk a bit more about the whys.

  So why is it important? Why should people care about their microbiome, right? We’ve been living, we’ve been eating—until a couple of years ago, nobody knew what the term even was. So maybe Colleen, why should people care about their microbiome and care about keeping it in balance?

  Speaker 3:
  Well, I think when we think about our health, we generally kind of classically think of these 11 organs in our organ systems, in our body. So any medical textbook talks about these different organ systems, and we think about them when we think about our health—our cardiovascular, endocrine, all of that.

  Well, it turns out that at the center of all of that is actually your gut microbiome, and that your gut microbiome is linked to every one of these systems in really profound ways.

  And so you at some point have a real strong diversity in your gut microbiome that allows you to have a bunch of different functions that are tied to all these different systems. And what can happen through a variety of reasons is that you can start to become depleted in some of these functions.

  And so we know that, for example, if you go on antibiotics, that can significantly deplete your microbiome functions. We know that depending on your diet, you might be missing certain functions. We know that as we age, our microbiome can become depleted. We know that when we go through periods of intense stress, that can deplete our microbiome. We know when women go through menopause, our microbiome becomes depleted.

  So there are all these things that are just part of being a human that can cause our microbiome to become depleted.

  And the problem with that depletion and that loss of function is that it shows up in a wide variety of diseases. As Leo mentioned, it can range from GI disorders to metabolic disorders to skin disorders, to even things that we traditionally thought of as brain disorders like Parkinson’s and autism.

  And so really the idea here is that you might be experiencing symptoms or be trying to manage diseases for which the gut microbiome is an opportunity to intervene—and you didn’t even know about it. And many of us didn’t know about it.

  This is a new science; this is new medicine being uncovered now as we speak. But it’s a major opportunity in health and medicine to be able to impact disease that there’s really not that many products or tools out there for us today.

  So the reason you should care is because if you have any health issues whatsoever, your microbiome might be part of the problem—or part of the solution.

  Speaker 1:
  Alright, that’s going to tee up some calls to action later and it’s great. So thank you.

  But you also touched on something I want to bring to Leo, which is: why now? What has led to so much research and information now versus five, ten years ago? Everybody’s talking about the microbiome—nobody used to. Was there some seminal event a few years ago, or why now?

  Speaker 2:
  I think it’s a combination of several factors. So if we think back 20 years ago, about all we could do to study the gut microbiome was to culture organisms in Petri dishes. And the only organisms that we could look at were the ones that were culturable, and that we knew how to survive in an oxygenated environment and we knew how to grow them.

  Today we can do DNA sequencing—shotgun metagenomics. Before that, other types of sequencing: 16S and so on—that have allowed us to analyze these organisms at a much more comprehensive level.

  And by knowing the DNA, we can both understand the composition of all these different species at a much greater level—and not just bacteria, but also fungus and viruses and protists and archaea and so on.

  But we can also, by looking at their DNA, understand what sort of proteins they’re able to generate and what sort of metabolic pathways they’re able to impact.

  So now that gives us a tool to really analyze what’s going on in people’s gut microbiome at a much broader level.

  And the cost of sequencing has continued to go down every year, which makes it easier and easier to more comprehensively measure somebody’s microbiome.

  And then at the same time, the amount of data that gets thrown off by doing this analysis is really enormous. If we look at the amount of data that you get out of one stool sample—even at a moderate level of sequencing depth—maybe eight gigabytes for one person. Whereas a cardiac CT image—a CAT scan—would be about one gigabyte. So it’s like eight times the information that you would get in a CT or an MRI scan.

  And so the ability to process that data with, again, compute power—cloud—has been much more recent as well.

  AI today—now we can, with these language models, actually read this entire bolus of literature that is out there and be able to consume that and leverage it into doing both the analysis and advancing the science.

  So it’s really these trends of greater sequencing capability, greater compute capability, and now with AI, really being able to understand and take advantage of this information at a greater level.

  Speaker 3:
  Great. Yeah, and I would just add to that if I could. I think it is all of the tools and technology and informatics and now AI that Leo pointed to that have been instrumental in being able to uncover new discoveries in the microbiome.

  But at the same time, there’s been, I think, always an inherent belief by people that your gut and your gut microbiome are important for human health. So I think because people inherently believe that, when all this data starts to emerge, it really is the convergence of the fundamental belief that this is an important system with the data supporting that—what’s really launched the gut microbiome and gut health into such a popular concept.

  I mean, we even have phrases like, “Oh, what’s your gut instinct on this?” or “I’ve got butterflies in my stomach.” I mean, there are things that have been around since the beginning that really point to people feeling like the gut is important.

  And so I think when you have that belief and the data support it, now everybody’s like, “Okay, tell us what to do, Leo. Tell us what to do.”

  Speaker 2:
  Social media to get that message out too.

  Speaker 1:
  Yeah, for sure. I’m thinking about—I want the Oura Ring for the gut microbiome. We’re going to come back to that. Just lots of insights related to it since everything you just said, Colleen, we’re waiting for that.

  Okay. I have one question before we broadly—which is a topic—antibiotics. It’s actually not even a question. That’s just a dot, dot, dot. But you two probably have some thoughts and opinions or something worth sharing. So let me just start with that, and whoever wants to go first: antibiotics—how should people think about that vis-à-vis their microbiome?

  Speaker 2:
  So I can go first. Antibiotics were a miracle cure when they were invented with penicillin initially. And now we have a whole range of antibiotic tools, and they’re nothing short of miracles when you have certain infections and a lot of historical scourges.

  At the same time, antibiotics are broad spectrum, meaning that they kill all of the bacteria in your gut. And I think for a long time, the prevailing view was, “Well, germs are bad. It doesn’t matter if we kill them. I’ll just take an antibiotic even if I’m not sure that I need it.”

  And I think we’re now realizing that because of the important role of the microbiome, if you take an antibiotic unnecessarily, you can actually increase risks for a whole range of different diseases.

  There’s a study in Korea not long ago—they took the entire population of Korea over their whole lives, the last 20 or 30 years. They cut them into four groups and looked at the people who had taken the most antibiotics, the people who had taken zero, and the two groups in between. And there was a linear correlation between the number of antibiotics that they had taken and obesity rates and BMI.

  We know, for example, that farmers will feed antibiotics to their animals to make them fatter and to generate greater meat from them. And so the idea that antibiotics have no risk or that they should be used sort of casually—I think we’re now understanding that that’s just really not the case.

  Antibiotics are important when you need them. But sometimes you are not sure, or you don’t, and you really want to stay away from them in those cases.

  And when you are forced to take antibiotics, when it is really important, studies are showing that really paying attention to your diet directly after a course of antibiotics can make a huge impact in how well your gut reconstitutes.

  There are actually conflicting studies on the use of probiotics post-antibiotics, with some probiotics being found to enhance recovery, and other probiotics have been shown to actually make recovery harder and worse and cause problems. But diet directly post-antibiotics is something that seems to have a really big impact.

  Speaker 1:
  Colleen, anything to add on the topic?

  Speaker 3:
  Well, I mean, I broadly agree with everything that Leo said. And I think one of the challenges with antibiotics is the fact that most of the antibiotics that we have access to now are broad spectrum.

  So it’s sort of like if you had a weed in your garden and you wanted to get rid of that weed, you threw bleach all over the whole garden and killed everything.

  And so it would be nice—and I think that we are going to head there eventually in antibiotic therapeutic treatments—to be able to actually just kill that weed and everything else can continue to live. But until that time arrives, you’re kind of stuck with this bleach treatment in order to get rid of this weed.

  And I think that this question about how detrimental that is to the microbiome—well, it’s not a question. I mean, you’ve really decimated the whole thing.

  But the good news is I think that’s an opportunity to replant a new garden.

  And so how do you avoid some of these outcomes that are associated with antibiotic use, like obesity? It’s to really, as Leo says, use this as an opportunity to refresh.

  So if you can move to a high-fiber, high-polyphenol diet—that’s basically when you walk into your grocery store, all the things in the produce section—those are really going to help you to reconstitute your microbiome with some of these strains that are known to be important for metabolism.

  And then another kind of interesting study that came out showed that if you start taking probiotics before you’re on an antibiotic—so let’s say you’re going to go into surgery, you’re going to go on antibiotics—if you start taking these probiotics ahead of time, that somehow, and this is something that was sort of hard for me to believe, but it looks like somehow taking it beforehand and then going on an antibiotic enables you to then reconstitute your microbiome on the other side better.

  And it’s a little counterintuitive, because if you’d asked me five years ago, “If I’m going on an antibiotic, should I take a probiotic?” I would’ve said, “No. That’s the point—you’re just going to kill your probiotic by taking the antibiotic.”

  But there’s now some emerging evidence that there’s some kind of ability for certain either strains or small molecules to be able to sustain through that antibiotic treatment that does enable you to do better on the other side of it.

  So if you have to go on an antibiotic, first of all, don’t ask your doctor to go on an antibiotic. Only go on it if you have a bacterial infection.

  If you have to go on it, it’s an opportunity to start with a probiotic ahead of time that is focused on metabolism—obesity is one of the bigger outcomes from antibiotics—and then to use this as a refresh to get into that good diet you always wanted to do.

  Speaker 1:
  That’s great.

  Total separate note to me—there’s an interesting point of view of, why—we won’t cover today—but why antibiotics were developed as drugs to be basically broad-scale, whereas many, many other drugs are so, we’ll honestly, point solution, right? But they’re very focused on a very specific mechanism of action. But here we are. So that’s a question for some life science folks.

  Okay, GLP-1s. Let’s get into that a little bit. So first 1A and 1B questions to Colleen. What is it, and how is GLP-1 connected to and influenced by the microbiome?

  I know you did a great video with us not that long ago, and I thought your description of it was fantastic. So maybe I thought I’d ask you this.

  Speaker 3:
  Oh man. Okay, well, I don’t remember what I said in that, but let’s give it a go here.

  GLP-1 is a small molecule that I think most people hadn’t heard of even a few years ago, but it’s really become a mainstream known molecule because of Ozempic and Wegovy and semaglutide. These are all small molecules that are meant to mimic your body’s natural GLP-1 hormone.

  And so the natural way that things are supposed to work in your body is: you eat a meal. You have, of course, these trillions of microbes in your gut microbiome—they each have a job—and this sort of factory that’s metabolizing the food that you just ate.

  There’s one department that is responsible for metabolizing this food and then triggering your L-cells to release GLP-1.

  And there are two strains that have been published to date to show that they can directly stimulate your L-cells to secrete GLP-1.

  And so what happens when you eat food and your microbiome signals to secrete GLP-1 is: GLP-1 will go up in your bloodstream.

  And that has two really important consequences. One is it stimulates your insulin pathway to metabolize the sugars in the food that you just ate.

  And the second is it signals to your brain: “Hey, we just ate. We are full. We don’t need to eat anymore.”

  And so those two things are incredibly important for you to be able to have good eating patterns and to metabolize the sugar in the food that you just ate.

  What happens is then eventually your GLP-1 levels will go down, you get hungry again, you eat a meal, signals—GLP-1 goes up. So you’re supposed to be on this cycle of GLP-1 kind of going up and down that helps you regulate your hunger as well as helps you metabolize the sugars in the food that you just ate.

  The GLP-1 drugs are chemical mimics of your GLP-1 hormone, and so you inject them directly into your bloodstream.

  And so what you’re doing is you’re just having really high levels of GLP-1 at all times. And so it’s basically constantly telling your body: metabolize the sugars, we’re not hungry; metabolize the sugars, we’re not hungry.

  And so people get this very dramatic, immediate response on these drugs. But then once they go off the drugs and they’re not getting that signaling, you get this immediate rebound, because you haven’t really taught your body how to make its own GLP-1 hormone.

  You’re just sort of injecting it in this other form factor.

  And so I think the two kind of issues that we will foresee are: one, if you don’t teach your body how to make its own GLP-1, you’ll forever be dependent on this drug. And there are ways that you can actually help your body increase its natural GLP-1 production.

  And then the second problem is that if you’re dependent on this drug—it’s like if I was talking to you through a loudspeaker, a megaphone—you would definitely be able to hear me better. You would hear me, you would respond to me.

  But over time, you’d go deaf if I’m always talking to you through a loudspeaker.

  And actually, our beta cells, which produce insulin, are very similar. Which is to say that if you keep hammering at them, they can become deaf to the signaling pathways.

  And this is actually a problem even with insulin drugs. Over time, you’re actually almost having this converse effect on your body, which is really negative in terms of being able to have all the benefits of the food noise reduction as well as the sugar metabolism.

  And so I think that what we’ll find over time is that people will start to realize that the drugs maybe have certain side effects or maybe aren’t going to be as effective over time as you once wanted them to.

  And so you’ll want to be able to either instead of, or in conjunction, help your body make its own GLP-1 hormone, which you can do through probiotics that we’ve been investigating and brought to market, as well as through certain dietary changes.

  Speaker 1:
  Excellent. There’s a fact and fiction we’re going to come to, and I think I can now answer it myself. So I’ll be the first one to answer that.

  Leo, question for you—related from your vantage point, particularly Jona  having AI basically pull in and curate so much research and science out there—what are interesting new insights you’re seeing relating to GLP-1?

  Speaker 2:
  Well, there are a lot since the introduction of Ozempic and these other GLP-1 agonists. The fact is that we’ve had several challenges with them. Colleen mentioned some of them.

  One challenge is that about a third of people don’t respond well to them. Some people who do respond have side effects. And then last, when people are on them for a long time, sometimes it’s a challenge to come off them and still maintain any benefit.

  And so what we’re seeing is the microbiome can play a role in all three of those areas.

  In particular, there are emerging studies showing that the person’s microbiome composition prior to taking one of these drugs is actually predictive of who’s going to respond and who’s not going to respond to these drugs.

  So now there are several studies—they’re all relatively small—but they’re showing that it is possible to predict who’s going to respond or not to respond to these drugs.

  And as that science continues to build out, it may be possible to say, “Hey, look, you shouldn’t go on this drug if we know that your microbiome isn’t suited for it or is predicting that it’s not going to work for you,” because all you’re doing is risking side effects and it’s very costly.

  And it may then be possible to change your microbiome and get it in a shape that would actually make you more likely to respond to one of these.

  On the flip side, there’s also evidence on exogenous production of GLP-1 by the microbiome—that your microbiome can produce GLP-1 itself in some circumstances with some substrates—and there may be, as a result, pathways for getting someone off one of these drugs and still being able to maintain those benefits.

  Speaker 1:
  That’s great. Okay, cool. Thank you.

  Let’s move to—I have a bunch of fact or fiction on rapid fire, right? We’ll just go through ’em real quick. I’ll call ’em out, and we will just hit them. And I get to do the first one. So I jotted a few of these down.

  And the first one—fact or fiction: I can only get GLP-1 from Ozempic.

  Fiction. I can get that now from your answers, I put on there. I think it’s important for a lot of people out there that think—I have a feeling that people are equating GLP-1 with Ozempic, right? And, “Oh, that is GLP-1.”

  It’s not. GLP-1 is a hormone produced by the body, mimicked by semaglutide and other drugs. And it’s important for people to just maybe first start with that understanding.

  So again, that one’s fiction.

  Okay, well, you guys have touched on it, but I’ll ask it anyway.

  Maybe Colleen—fact or fiction: GLP-1 drugs have no downside?

  Speaker 3:
  I think that that’s definitely fiction. For any drug in general, there’s a long laundry list of side effects that you’ll notice come alongside any drug. And GLP-1 is no exception to that.

  Speaker 1:
  Yeah, good. In fact, I’ll put a little plug for those that are interested more around this specific topic—Peter Attia just did a great podcast, I think, all on sort of many, many questions and his latest thinking on GLP-1.

  And he talks about side effects he’s noticed with some of his patients. So for anybody interested, I’d sort of point them there.

  Fact or fiction: I can just eat yogurt and fix my microbiome. Right?

  Leo?

  Speaker 2:
  Fiction.

  Speaker 1:
  Wait, what if it’s Greek yogurt?

  Speaker 2:
  No. There’s no one thing that you can eat that’s going to fix anything.

  There are general guidelines for people, but at the end of the day, your microbiome itself is very individualized. And there’s a lot more variability from one person to another in their microbiome than there is in their genetics.

  And as a result, what’s really needed for you is going to be dependent on your biology, dependent on your microbiome, depending on the rest of your biology.

  And as we’re learning more and more about how to move your microbiome in one direction or another through diet, having a good understanding of where you’re starting and really profiling, analyzing your gut microbiome helps you make those choices.

  As a rule, yogurt’s great. Other fermented foods are great. And there’s good evidence on this for many people. But nothing is perfect for everybody. And there’s no one-size-fits-all for any food or any lifestyle change.

  Speaker 1:
  Okay. A healthy gut microbiome is essential for a strong immune system.

  Leo, what do you think?

  Speaker 2:
  A healthy gut microbiome is essential for pretty much every aspect of your health.

  Seventy percent of your immune cells are in your gut lining, and there’s a very strong crosstalk between the microbiome and the immune cells.

  And it makes sense, right? Every time you eat a food, it’s not sterile. And if your immune system responded to every microbe that ends up in your body, it would be constantly firing—constantly inflamed.

  But then if it didn’t respond when you needed it, then you’d have a different kind of a problem.

  And so it’s critically important to your health that your immune system knows which of these organisms to react to and which ones not.

  And as a result, there’s a very strong crosstalk between these. And in some ways, you can think of your microbiome as training your immune system and providing it information so that it can respond appropriately—and almost as a unit that can help keep you safe.

  Speaker 1:
  Yep.

  Probiotics—fact or fiction: Probiotics are beneficial only to those with digestive-related issues like Crohn’s or colitis.

  Maybe Leo—I know this is close to what you do with Jona  too, so your thoughts there.

  Speaker 2:
  Fiction also.

  Again, the microbiome impacts way more than just inflammatory bowel disease like Crohn’s and colitis.

  And as a result, getting the right probiotic for the right individual can have a big impact on acne, eczema, mental health.

  There’s a lot of different aspects of your health that can be influenced by changing your microbiome through probiotics or other ways.

  Speaker 1:
  Okay. Fact or fiction: The diversity of the gut microbiome can influence mental health and mood.

  Colleen?

  Speaker 3:
  Yeah, I just wanted to add to Leo’s last answer about probiotics.

  Most of the probiotics that are on the shelves—if you start reading labels—they’re all really quite similar to each other.

  So they start with things like Lactobacillus or Bifidobacterium.

  And so there’s a limited scope of tools that people have access to in the probiotics market today that represents a very small fraction of the total number of types of gut microbes that you have.

  And therefore, you’re not really getting all the different functions that you need.

  And so I think that it’s important for people to know that what we have access to today—even though the shelves feel like they’re lined with a million different probiotics—they’re actually not that different from each other.

  And so when you start to read labels, you’ll see they’re not that different.

  But the hope of the future, and what we’ve really been building at Pendulum, is bringing in all these other types of strains and species that have functions that are beyond just what we’ve got on the market today.

  Speaker 3:
  And I would say when we think about mental health, that’s no exception. There are a variety of different strains which are known to generate neurotransmitters like GABA, serotonin, dopamine.

  And so as we advance microbiome science and advance the ability to not only cultivate these strains, but also to then deliver them into people, we’re going to see an entirely new category of probiotics start to enter the market—either as therapeutic interventions, drugs, or as consumer products.

  I just think there’s so much more yet to come that it’ll be hard for me to tell anyone right now, “The solutions are out there.” I think there are some solutions out there, but I think so much more effective stuff is on its way.

  Speaker 1:
  Excellent. Alright. And I’ll build, and sort of—the answer is fact, which is: the microbiome can influence mental health and mood.

  And maybe it’s worth a quick comment on the gut-brain axis as well?

  Speaker 3:
  Yeah. So as I said, the gut microbiome actually produces a ton of these neurotransmitters, and there’s literally a direct connection between the gut and the brain—the vagus nerve.

  And so these neurotransmitters have a way to actually make their way to the brain.

  And probably one of the more fascinating things I think that’s been discovered is that we all would know we have neurons in our brain, and that once they die, they don’t come back.

  But we also have neurons in our gut. And unlike the neurons in our brain, the neurons in our gut actually regenerate—they’re regenerating all the time.

  And so the question is: why do you have neurons in your gut? And so the answer I think is still being unveiled.

  But really the idea is that you have neurotransmitters being generated in your gut microbiome, you have neurons in your gut microbiome, and you have neurons in your brain.

  And somehow all these things are really talking to each other and connecting with each other.

  And I started my career working in Parkinson’s disease. We were very focused on how do you get rid of these plaques that show up in the brain that are associated with Parkinson’s and Alzheimer’s.

  It’s now been discovered that you can see these plaques showing up in people in their gut neurons before they show up in the neurons in their brain.

  And so there’s this really, I think, amazing opportunity to really target the gut neurons. And so the hypothesis is that you have some kind of misfiring that’s happening in your gut first, and these plaques show up there, and then that signals to your brain, and then they start to show up in your brain.

  And so the big opportunity is maybe you could tackle the gut microbiome and hit it earlier, before any of these signals make their way to the brain, as the thing to target for Parkinson’s.

  And so now you look at the gut microbiome as a new target beyond just the brain—and it’s way easier to target the gut than it is to target the brain.

  So yes, there’s a fact—there is a connection between the gut and the brain. And then even more than that, I think it’s a target of opportunity for developing interventions.

  Speaker 2:
  And on the Parkinson’s question—I mean, to support what you’re saying, Colleen—there have been these studies where people have had their vagus nerve cut.

  And what they find is that your chance of getting Parkinson’s disease goes way down if you’ve had your vagus nerve cut.

  Which—there are a whole lot of other problems you have if you have your vagus nerve cut—but your chance of getting Parkinson’s goes way down, which really suggests that somehow it starts in the gut and travels up the vagus nerve into the brain.

  I think one way to think about the gut is as a big sensory organ. I mean, we think about eyes, ears, touch, smell, taste—and the retina in your eye is small. It’s loaded with receptors that react to light.

  But if you think about the whole GI tract, it’s full of receptors that respond to temperature, to pH, to different chemical compositions.

  And as a result, you release neuron firings, but also hormones and other kinds of responses to whatever comes through your GI tract.

  And so in many ways, it’s like one enormous sensory organ that is responding to whatever goes in your mouth.

  Speaker 1:
  Mouth. I love that actually. It’s great.

  Alright, one last fact or fiction, and then I’ll summarize some things for a moment—which kind of ties into some of, well, all we’ve talked about.

  Maybe I’ll point this one back to Leo:

  Fact or fiction—diet has a more significant impact on the gut microbiome than genetics?

  Speaker 2:
  We’re still understanding the role of genetics in the gut microbiome.

  There’s certainly some evidence that suggests that genetics play a role and can impact things like pH level and whatnot in your gut and can affect the microbiota.

  But at the end of the day, these organisms need to eat something, and they need to consume something.

  And what you choose to put in your body from a diet standpoint is going to have a direct impact on what can grow and what continues to grow and survive in your gut.

  So generally speaking, diet has a very strong, very important impact on your gut microbiome.

  There does seem to be some role for genetics, but I think that’s being understood and seems to play a lesser role.

  Speaker 3:
  And just to add to the role that your diet plays on the microbiome—I saw there was a question in the chat box about fasting.

  And similar to antibiotic treatment, fasting is an opportunity to actually reestablish your microbiome.

  And so I always tell people—fasting, of course, there’s a lot of studies, pros and cons to various lengths of fasting and how frequently to do it.

  But the fact is that what you’re doing in fasting is you’re actually starving your microbiome.

  And so when you get to breaking your fast—or your breakfast—you have all these microbes that are sitting in your gut that are food deprived.

  And what you choose to put into your body that minute that you break the fast decides who gets to thrive and who doesn’t.

  And so that first thing that you put in when you’re breaking your fast is actually super important.

  So if you can get things that are high in fiber and get things that are high in polyphenols, that is going to, I think, be really important as you’re breaking your fast in order to make fasting as effective as possible.

  Speaker 2:
  And I should say on the subject of fasting, there are a lot of studies now that have shown intermittent fasting, longer fasts—how that impacts people’s gut microbiome in general.

  And so you can take a population of people who don’t fast, a population of people who begin with intermittent fasting, and you can see the changes in their microbiome pre and post that intervention of intermittent fasting.

  And so we know characteristically certain organisms are going to go up and certain organisms are going to go down if you engage in fasting practices.

  Whether that’s good or bad for you personally is going to depend on where your microbiome is starting before you engage in that fasting.

  So the way that we try to analyze that for you on a personal level at Jona  is: when we measure your microbiome, we test your microbiome and we see where it is today, and the AI has read all of those studies on intermittent fasting.

  What we do is we virtually apply those changes from the intermittent fasting to your microbiome in a way that says, “Okay, well if we know these certain organisms will go up and others are going to go down,” we digitally apply that to your microbiome and see what the impact on your health is going to be from taking that action.

  And based on that analysis for you, we can tell you whether it may be something that’s beneficial or even potentially harmful for you.

  Speaker 1:
  Cool. That actually leads to my next part, which is: I want to focus a little bit on what can we all do about it.

  But before we do, maybe I’ll summarize. Here’s what I’ve heard—a couple of quick things:

  So first of all, the microbiome is touching far more than just digesting foods.

  It’s affecting your skin, it affects your immune system, it affects—and there’s a direct line to your brain.

  It can affect mood all the way to Parkinson’s, right?

  So for everybody out there, it’s more important than just digesting what we eat.

  It has direct impact on many, many other functions—much like, as Leo pointed out, kind of a sensory organ in and of itself.

  Part one.

  Part two—well, we can do something about it now. We can measure it.

  I think in the years past we all would’ve said, “Well, that’s cool, but so what? I’ll just try this mushroom and hope for the best.”

  Well, now we can measure it, right? We’ve got tools—which we’ll come back to in a moment.

  So that’s an interesting development that’s important.

  And then three, I think what I also took away: no, it’s not one-size-fits-all. Not everybody’s microbiome is the same, nor are probiotics the right thing for everybody in the right way.

  You can’t just blanket-apply these things. So everybody needs to better understand their own personal microbiome, and you can develop some personalized tools related to that.

  But don’t discount it—do something about it.

  So with that, maybe calls to action. I want to make this helpful for folks.

  And so the first one is kind of, Leo, you just mentioned it, but if I was to ask us: what can people do to better understand or measure their microbiome?

  Right? We couldn’t in the past—now we can. I know it’s a bit of a softball, but go for it.

  Speaker 2:
  Well, you can measure it now—and it’s really easy.

  I mean, with my company, Jona , we can ship you a kit to your house. You take a stool sample, you send it off to the lab. It’s a really painless process.

  And then based on doing deep sequencing of all the organisms in your gut, you can profile them down to a strain level.

  And then based on that complete compositional analysis of your gut microbiome, the AI can then read all of the literature and figure out what’s going on there and whether or not your microbiome looks off in any way—looks off in everything from a bloating or a fatigue direction to depression, to Parkinson’s, to acne or whatever—based on all of these signatures that have been discovered in the literature.

  And then through this digital twin analysis, figure out what’s going to work for you to make the changes to your microbiome that you want to make in order to change your health.

  So those tools exist today—they’re recent—but now people have the ability, just like your Oura Ring, to actually measure themselves and use that information to make concrete changes to improve their microbiome and improve their health.

  Speaker 1:
  Excellent. Thank you.

  So Colleen, what can people do to affect and alter their microbiome? Also, I know you have some product there, so you must have some thoughts.

  Speaker 3:
  I do—and I don’t want this to be a sales pitch.

  So what I’ll say is that I think while there is a personalized component to the microbiome, I think that’s a matter of optimizing your microbiome.

  There are some fundamental things—functions—in your microbiome that appear to be important for everybody.

  In fact, there was a paper that just came out in Cell where they’re really looking at these guilds and these particular functions of the microbiome that appear to be associated with being healthy.

  And that’s not the first reporting of some of the functions that are just fundamental to a good microbiome.

  For example, your ability to produce short-chain fatty acids.

  So having microbes that are able to convert fiber into short-chain fatty acids, and particularly butyrate, has been known for a long time to be really important for your gut health and your human health.

  We also know that having the microbes that help you stimulate your natural GLP-1 hormone production are also really fundamentally important.

  And so when we think about what are some of the tools that we have at our disposal to try to increase these strains that help us produce short-chain fatty acids and butyrate and GLP-1—

  The first thing is actually nutrition.

  So as I said, this high-fiber, high-polyphenol diet—that’s really important. So the more of those foods that you can get into your diet, the more that you’re providing the prebiotics that feed those strains that can form those functions.

  The second thing is: anything you can do to increase your diversity of your microbiome is actually really beneficial.

  So not always eating the same fruits and vegetables, but trying to diversify—that can get you access to additional different microbes that do these functions.

  And then the third is sort of a fun one, which is that there was a paper that came out showing that people who have dogs have more diverse microbiomes than people who don’t.

  And so if you are ever thinking about getting a dog, you should get one now.

  And if you have a dog, you should go home and hug that dog—they’re increasing your microbial diversity.

  And then lastly, what we’ve really been working on at Pendulum is: how can you increase very specifically these strains that can produce short-chain fatty acids and butyrate and can stimulate GLP-1 production?

  And so we have a variety of formulations that are clinically proven to be able to increase your short-chain fatty acid production, your butyrate production—not only in your stool, but also in your bloodstream.

  And we know that there are clinical outcomes associated with increasing butyrate and increasing GLP-1.

  And so if you’re really interested in, “How can I maximize that?” I encourage you to go to our website, pendulumlife.com. We have a lot of literature on there and information.

  And to really check out Pendulum Glucose Control—this is the highest-dosed formulation that was shown to increase GLP-1 and butyrate, lower A1C, lower blood glucose spikes.

  This is what Peter Attia is on. This is what Halle Berry is on. This is what I’m on—probably the least significant of those three people—but it’s because this is the clinically proven formulation that these guys are also seeing have clinical outcomes for them.

  And so I encourage everyone to go to pendulumlife.com to learn more about these interventions.

  Speaker 2:
  Cool. Thanks Colleen.

  I know we’re going to break soon, but I did see there are a couple of questions on chronic fatigue syndrome and some of these chronic diseases affected by the microbiome.

  And I should say that we don’t fully understand the origin of a lot of these diseases, and we don’t really have good diagnostic pathways for many of them.

  At the same time, there are telltale signatures that have been identified in the literature of particular configurations of a person’s microbiome that have been strongly linked with, say, chronic fatigue syndrome or a whole range of other chronic conditions or autoimmune conditions.

  So if you are curious if your microbiome has that configuration or that signature, it is something our AI looks for in trying to analyze the composition of your microbiome. And if it does, we can tell you the specific changes to your diet, lifestyle supplements that have been shown to change your microbiome and a way to change that signature.

  Speaker 1:
  Cool. Thank you for picking that up, Leo. That’s great. I have just one last question for both of you.

  Okay—if you look out over the next couple of years, 2, 3, 4 years, what do you see in this space? It’s broad, but help us see around the corners, really—to both.

  So maybe Colleen first.

  Speaker 3:
  Yeah, I think what we’re going to see—it’s already starting to emerge—but what’s really around the corner are two things.

  I think first is the increased sophistication of being able to analyze a person’s microbiome—and, as Leo has really made a lot of headway on—being able to therefore predict and give you something actionable from that data.

  And I think that’s really the key thing: not just can I tell you what’s happening, but can I now tell you what to do in order to change or improve your health?

  And so I think the analytics and the tools that are available to us, and the AI platforms that Leo’s working on—we’re going to see those become more and more sophisticated as we learn more and more about the microbiome, and really give us actual things we can do.

  On the intervention side, I think we’ve started breaking out of just things that are good for your digestive health into things that can improve your metabolism.

  And I think we’re going to see new next-generation microbes that can help you.

  I really believe that we’re going to start to see them focus on some of these neurodegenerative diseases, or things that we’ve typically thought of as brain diseases. I think that is around the corner.

  And there are a lot of amazing academics and companies that are working on this problem.

  And so I just think it’s going to be amazing to have an entirely new tool to tackle those things early on.

  And part and parcel of that is that what the microbiome—and all of this data and these tools and these interventions—enable us to do is to transform the way that we think about health from “I’m already sick, and now I have to solve the problem” to “How can I ensure that I have all the functions in my microbiome to really realize the vision of preventative medicine?”

  And when you think about it in that way, it’s a huge opportunity for all of us to intervene before we get diseases in order to actualize preventative medicine.

  And the microbiome is just such an amazing opportunity for that.

  Speaker 1:
  Edison 3.0. It’s perfect, right? So I love that idea.

  Which, in fairness, it’s Peter Attia—so I’m quoting him.

  But Colleen, you just touched on it.

  Leo, over to you. What are your thoughts on kind of seeing around the corners? You’re seeing so much data and so much from the AI—what does it tell you? What does it foretell?

  Speaker 2:
  Well, first of all, I agree with everything Colleen said there.

  We have 2,000 studies a month—more than 2,000 studies a month—being published in PubMed on the microbiome. And that’s just continuing to accelerate and increase.

  So the breadth of knowledge and the depth of knowledge that we’re gaining is really tremendous.

  And the ability to operationalize that—not only to analyze somebody’s gut microbiome, but then to take concrete action—is new. And that power is only growing every month.

  And as Colleen also mentioned, many probiotics we’ve had for decades have been really very similar, because they were based on culturing off of fermented foods—organisms that were sort of easy to get.

  But that’s limited the set of organisms that we’ve been able to get in probiotics.

  And with some of Colleen’s work and Pendulum’s work, we’re now being able to break out of some of those more traditional organisms and do new things.

  There are a few other things I think that we’re seeing as well.

  One is—getting back to the antibiotics question—away from broad-spectrum antibiotics.

  People are working on antibiotics that can really target some specific organisms, whether it’s phage therapy or other kinds of therapy that can really allow us to be much more selective in antibiotics.

  I think that trend is really exciting and growing.

  And I think there’s also a mainstreaming of the microbiome—not only in the public, but even within clinical medicine.

  I have yet to meet an MD or doctor who’s not excited about the microbiome or doesn’t believe in it.

  I think there’s a variance of opinion on when it’s going to be mainstream and part of routine clinical practice, but there’s zero difference in opinion on the importance and the excitement around it.

  And I see every day more and more doctors are incorporating this sort of information in how they analyze patients and really how they treat them.

  Speaker 1:
  That’s fantastic. And it’s an optimistic note to wrap up on, I guess I’d say.

  And that makes—it’s optimistic for me.

  I mean, not that long ago, I would’ve been the pessimist that said, “Doctors would never believe that adjusting a microbiome or taking a probiotic can actually affect mood or Parkinson’s or something so far afield.”

  And it’s great to hear that not only is that the sort of field of research, but that hopefully it becomes part of clinical discussions and practices too.

  So—great.

  Alright, with that, I think it’s great to wrap.

  Super happy we could do this.

  So thank you, Leo. Thank you, Colleen. Great information. We covered a lot of ground.

  If anyone has questions out there, by all means, reach out to Alumni Ventures—part one.

  Or part two—Leo at Jona Health, and Colleen at pendulumlife.co. Or on—

  Speaker 2:
  Instagram or LinkedIn or—get in touch with us. Please feel free to reach out.

  I know I didn’t get to all the questions exactly, so happy to continue the conversation.