GOLDILOCKS, FUNCTIONAL MEDICINE, AND THE MICROBIOME AS ITS OWN SCIENCE
Megan: I feel like so many things in our body, we’re learning, are literally just about this Goldilocks homeostasis space. Like, stay right here in this line.
Kara: Yes. I think that’s where functional medicine, and integrative medicine, has really been helpful. It’s taking us out of this very black and white system of saying, okay, your labs have to be in here, or you have to have this, whereas someone might not feel great even within a normal range. And I think that’s where the microbiome has become such a functional medicine topic. Where I worked in allopathic GI, they didn’t know anything about the microbiome. Maybe we’ll have MD stand for “microbiome doctor” one day. I do think it’s its own science. Microbiologists will agree with this. It’s sort of its own world, and we are understanding so much more about how to manipulate these ecosystems to better our health.
Megan: Isn’t that sort of the goal? If we’re going to be playing with this, the research we can do is to make it grow in a health-promoting way, versus just for funsies, like, let’s put some glitter in a pill and swallow it. I don’t think that’s helping any of us if we’re screwing around with the microbiome. Sorry, what were you going to say?
Kara: No, I agree. And I think that’s why the research, and challenging companies to do research, is even more important.
HOW RESBIOTIC TESTS ITS PRODUCTS: ORGANOIDS AND FINISHED-PRODUCT VALIDATION
Megan: It is, and you guys are doing awesome research. I was reading through some of your research on organoids, which are so incredibly exciting, and I wanted to see if you could explain what that even means. From an outside perspective, someone’s like, what’s an organoid? How do you even look at a lung cell or a gut cell or an ovary cell? What does that look like for you guys?
Kara: This is one of the things I was so excited about when I joined resbiotic, the level of scientific rigor. Our founder, Dr. Vivek Lal, is a neonatologist, a super fascinating guy. He was also an early NIH-funded researcher, and his group, among a couple of other groups, was one of the first to discover that the lungs have a unique microbiome. They were doing research in the NICU, trying to better understand why babies in the NICU developed secondary respiratory distress. That is the leading cause of death in the NICU. And it led them to the lung microbiome.
Our lung microbiome is much smaller than our gut microbiome, but we understand these different gut-organ axes. Your gut sends signals to every part of the body, and other parts of the body can also impact the gut, so it’s a bi-directional relationship. From gut to brain, to nose, to eye, to lung. This sent him down a very long path in his research and career of looking at how we can influence lung resiliency, not just in babies but in people, through microbiome modulation. He actually has a pharmaceutical company, and he was looking at something inhaled. When he launched resbiotic, it was more like, no, we can have a direct impact through the gut, sending those signals directly to the lungs. That is how we started. We launched with a lung probiotic.
Because he comes from a very traditional background, he’s not a supplement guy. He probably would have told you five years ago that supplements are snake oil. I’m a dietitian, and supplements have always been part of my practice, but he did not believe it. He saw a gap. What the pharmaceutical industry does very well is finished product validation, which is evidence, but it’s not affordable and not always accessible. What we see lacking in the supplement space is finished product research. So we took the same R&D roadmap that pharmaceutical development would go through, and we basically rinse and repeat when it comes to our supplements.
Because we’re bringing these strains to market, our scientists use very state-of-the-art technology. They are highly trained, and not all scientists know how to do this. We use different organoid models. They take human lung cells and grow them out in petri dishes. It’s not a human, of course, but this is how we’ve been able to see the system-specific impact of our strains.
Our scientists are highly trained in this specialized technique where they grow out human cells related to specific systems of the body. That way we can take our individual strains, or those postbiotics or probiotics, and see whether they’re having that system-specific impact. We look at a marker called MMP9. A lot of practitioners actually measure this. It’s an enzyme expressed in various tissues of the body, related to tissue breakdown and inflammation. If we can see that a strain or a blend of strains reduces that in those specific organ cells, then we know it’s having a direct impact. If we took our postbiotic and looked at kidney cells and saw no impact on MMP9, we would not use that for a kidney-specific postbiotic or probiotic.
We not only do that on the biotics themselves, to make sure we’re seeing system-specific outcomes through what we call the Gut-X Axis, our platform for gut-organ communication, we also do it for anything we blend into the formulation. Our lung probiotic, for example, is three different probiotics that we combine with vasaka, holy basil, and turmeric. We run the same organoid testing on the blend, because you want to make sure there’s compatibility and synergy. And then we do it on the finished product, because this is how we mirror drug development rigor: if the finished product doesn’t have the greatest impact, then something in there is not enhancing the benefits. We want to put enough of the biotic, the herbs, the vitamins, and the minerals in there to make sure the finished product has the greatest impact on whatever biomarker, organ system, or outcome we’re looking at.
We then follow everything up with human clinical trials. That’s where the pharmaceutical-level rigor comes in, not just quality in the sense of an efficacious product, but making sure we’re putting in enough of a dose that you’re seeing a clinically meaningful impact, so we’re not putting in too much or too little. This is not a common thing in the supplement space, and it’s where we built resbiotic to fill that gap, so we can provide products with real-world impact. We have not just clinical confidence, but confidence that the product you’re taking is going to have a meaningful outcome.
BLENDS, COMPETING STRAINS, AND FINISHED-PRODUCT RESEARCH
Megan: I think that’s the big thing right there, meaningful outcome versus we just threw a whole bunch of lactobacilli in because that’s what everyone is talking about, slapped a label on it, put it on an Amazon truck, and it’s fine.
Kara: Yes. And the interesting thing in the probiotic space is that in one of our studies on our lung probiotic, we combined three different lactobacilli strains, and we found that the blend outperformed any individual strain. Whereas there’s been previous research, and research I’ve done at previous companies, where researchers found that you can have two strains that are individually impactful, but when you combine them, they wipe each other out. Bugs can compete. I was looking at a house this weekend where there were a hundred other people looking at that house. We’re all competing for that space. It’s the same thing in the microbiome.
So when I look at a probiotic that has a bunch of strains thrown into the capsule, my first question is, I wonder if all those strains are actually doing something. The reality is they probably aren’t all doing something. So does the product become more of a marketing product, because we combined so many strains, or how are we actually seeing that each strain is intentionally put in and having an impact? That’s a lot of science, and most companies are not doing it, which is why I think finished product validation is key. At least then you have some human or finished product outcome where you can confidently say, yes, this product is doing something, even if maybe not everything in it is, because they didn’t do this pharmaceutical-level rigor from the lab all the way to humans. At least there’s some human outcome. That’s where I start a lot of the time, because I get confused walking down the aisle, so I imagine a lot of people do.
Megan: It’s so overwhelming when you think about all of the options, and whether things are third-party tested, and just access. Is this seven-dollar one actually worse than the twelve-dollar one or the fourteen-dollar one? Sometimes the seven-dollar one is great. It just depends on who’s making it and what they’re putting in it. So I love that you guys are testing that, and you’ve done several human trials. You did the GLP-1 one, and aren’t you also running a trial with your perimenopause postbiotic?
Kara: This is our R&D process on every product. We have five products, and we do this extensive organoid and in vitro lab testing to make sure we’re seeing system-specific effects. That’s how we formulate. All of our products are targeted to systems, from lung to digestive to perimenopause to bone and joint to metabolic health, and we have clinical trials on every single product. We’re in publication review for our GLP-1 postbiotic. I did get a sneak peek at our perimenopause data, and that’s wrapping up. We’re in data analysis for our bone and joint postbiotic, and we actually have two human trials on our lung probiotic.
Megan: It feels like you’re getting all of the systems that start to really break down after midlife. Your lungs, your bones, your microbiome blowing up, your metabolism, your hormones, everything just tanking.
Kara: As we get older, yes. And your hormones.
THE ESTROBOLOME, PERIMENOPAUSE, AND THE POSTBIOTIC FORMULA
Megan: I’m very curious about this. When we think about all of the changes in our estrobolome and what’s happening in perimenopause, the research on the perimenopause gut is basically showing a lack of diversity. Her neighborhood is just getting less diverse. Everyone looks exactly the same, and that is one of the big problems. With this hormone step-down, estrogen is not feeding the diversity, and we’re having a slowdown in motility. How did you guys think about structuring your postbiotic? There are also some really great herbs in there, and I know there’s magnesium glycinate. So there are other things contributing to this ghost-biotic product, if you will.
Kara: I love talking about the estrobolome because it is a very complicated process. I think it’s even more fascinating that yes, we’re losing diversity, and we’re losing functionality of this group of bacteria that is very necessary and essential in putting estrogen back into circulation and excreting the right amount. It’s dynamic, kind of like a seesaw. It’s a Goldilocks effect. When our estrogen is low, the estrobolome is going to put a little more estrogen back into circulation to maintain homeostasis. And if our estrogen is a little high, then it works the other way. Again, in perimenopause our hormones are going up and down day by day, minute to minute, which is why we can’t be faulted for how we feel.
Megan: Get a hall pass for the entire decade. It’s fine.
Kara: It’s the Dr. Jekyll and Mr. Hyde kind of thing. Like a toddler. I feel that way with my toddler right now.
Megan: Sometimes I feel like a toddler right now. Can I regulate myself? No, I need you to do it for me. Thank you.
Kara: What’s fascinating to me, and this could be a whole other conversation in and of itself, is that the postmenopausal microbiome, after we get through that one day where we’re like, okay, I went 12 months with no cycle, actually resembles the microbiome of men.
Megan: Yes, isn’t that bananas? That just makes my brain explode.
Kara: Pretty full circle, right?
Megan: But then I guess the question is, once we get to that point, is that a pro or a con? Do men have worse microbiomes without this diversity? Are we just taking a hit in functionality there?
Kara: That could be a very esoteric conversation. But yes, I think it’s really fascinating. And I truly think it’s not even so much that we lose diversity, which we do, but that we lose function. It’s like my neighbor stops being the friendly neighbor. They’re not going to give me the eggs that I want, or maybe some houses become abandoned, and we don’t get a robust production of short-chain fatty acids, these very important compounds that are far-reaching. We don’t get the efficiency within the estrobolome. When we have an imbalanced, dysbiotic microbiome, that’s where we start to see other systems of the body affected, like metabolic health and bone and joint health. Estrogen plays a key role in those too. That’s the other parallel: estrogen plays a key role, but your microbiome also plays a key role. That’s really the foundation of resbiotic. We wanted to offer solutions that are very targeted, improving specific systems, but at the foundation they’re all through the lens of the microbiome. Whether you have COPD or asthma or you’re constantly getting sick, your microbiome is playing a role. Whether that condition changes the neighborhood, yes, or the neighborhood itself is decreasing resiliency to that system, yes. It’s bi-directional. So how can we bring more targeted support?
When we were thinking about our perimenopause postbiotic, a lot of the initial research we did was looking specifically at the estrobolome, because we know the estrobolome is central not just to what’s happening during perimenopause, but to why symptoms can become so intensified. It isn’t always because you are low in estrogen or high in estrogen, which can be a player. It’s that the estrobolome isn’t regulating this very fine-tuned process. So we started looking at beta-glucuronidase, the enzyme that basically unties the bow to put estrogen back into circulation. We measured things like estradiol, because in the functional provider lens we sometimes look at beta-glucuronidase as being bad, and it’s not necessarily bad. We can have a high level, which means there’s potential for too much estrogen getting put back in, but we also need beta-glucuronidase to regulate it. So what we really focused on is how to bring that homeostasis back, not necessarily raising or lowering beta-glucuronidase. There are other things that can help pull beta-glucuronidase out of the gut, like calcium D-glucarate, which I love, but how do we establish more equilibrium within the estrobolome?
We looked at that with our postbiotic, and we saw in vitro, because we grew out human ovary cells and looked at that specifically. And then we thought about which bioactives, which herbs, vitamins, and minerals, would be synergistic and compatible with this postbiotic to target those symptoms and enhance the benefits. So we added black cohosh, chasteberry, magnesium glycinate, L-theanine, a little bit of B6, and a little bit of B12. Again, we looked at whether the blend does the same thing, and then of course the finished product. It offered a really exciting opportunity, and in fact we’re in data analysis for a clinical trial and we’re seeing some of our most statistically significant results. I can tell you from personal friends, I’m 39, I’ve got lots of people in my life who are all entering that next season, my sister-in-law called me the other day and said, I actually think this is helping.
Even if you’re taking hormones, everything still goes through the liver and still has to get packaged for excretion, so everything still gets sent to the gut. This is unrelated to anything you’re taking exogenously, like hormone replacement therapy. It’s making this process, which is naturally working day in and day out, more efficient.
HORMONES, HRT, AND THE GUT AS A FOUNDATION
Megan: I think that’s such an important piece of this puzzle, because I work with so many women who come in and say, well, hormones didn’t work for me, and I’m like, hold on. Did the hormones not work, or did someone not take a look at your entire picture? This woman is pooping twice a week. She clearly does not have supportive ways to balance her microbiome if she’s not clearing everything out, and beta-glucuronidase might be upregulated or downregulated, we don’t know. But if she’s not taking care of that, then that’s a problem.
Kara: Yes. How do you know?
Megan: Right. How do we know the hormones were the problem, rather than her gut being out of balance? That’s a really big part of this picture. This is sort of a synergistic product. You could take your hormone replacement therapy with or without it, and this is going to work whether you want to be on hormones or not, because it’s regulating the system that is actually in flux right now. You’re not adding to the system, you’re making it more efficient, as you said.
Kara: Yes. I’m microbiome-first. When in doubt, I start in the gut, because upstream from there we get to figure out what falls back into place. If we can use some of these targeted microbiome supports, or adjust the diet, or do the things we know influence this ecosystem, then maybe, like you mentioned, the hormones start to be processed better. Maybe our food cravings start to shift. For me, it’s a really important tool in the toolbox, but it’s not the only tool. It’s kind of a universal tool, though, because no matter what we’re struggling with or trying to prevent, and this is what the last 15 years of research has really shown, there’s not one condition that’s not linked back to the health of the gut microbiome.
Even in the pulmonary space, for people who suffer from COPD or asthma, there are only a handful of pharmacological agents. There really aren’t that many, and getting new drugs into the pulmonary space is a very long, hard process. So if we know someone with COPD naturally has an imbalanced microbiome, is that microbiome decreasing resiliency? How can we bring in supportive tools that aren’t interacting with, or necessarily impacting, the medication or the hormone replacement therapy or the GLP-1s we’re taking? It’s a foundational process. That’s how I view the microbiome. It is like the foundation in your home. You can have the most perfect newly built home that has everything you’ve ever wanted. But if you have cracks in your foundation when that hurricane comes or that earthquake comes, your structure, your house, might not be so resilient, even though it’s perfect and beautiful and has all the bells and whistles and is new. So how can we start to patch up those individual cracks?
