Reframing Microbiome Support for Functionality, with Dr. Heather Zwickey

I first met Dr. Heather Zwickey when she was my immunology professor in medical school and we’ve stayed in touch ever since. Her command of the microbiome literature is frankly unparalleled. Join me in this New Frontiers conversation about the latest perspectives on the microbiome: Find out how we’re moving beyond the era of Lactobacillus and Bifidobacteria probiotics, and how postbiotics (and their functionality) are arguably even more important than specific species. Not only that, Dr. Zwickey argues that we need to consider what we “feed” probiotics to create a desired postbiotic effect – this changes if you’re targeting the immune system vs nervous system, for instance. All this is going to evolve how we evaluate, and prescribe for, the microbiome. Smart, timely, and always engaging – I know you’ll think so too. ~DrKF

Reframing Microbiome Support for Functionality, with Dr. Heather Zwickey

The microbiome has a profound impact on our health, and our understanding of the complex mechanisms at play between microbes and host continues to evolve. For instance, did you know that different species of microbes can produce the same metabolites, making the pattern of metabolites (or “postbiotics”) even more relevant than simply looking at species and strains?

In this podcast, Dr. Heather Zwickey discusses the latest research as it pertains to the microbiome, through her lens of vast experience.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And I’m really excited to tell you that today I have one of the very tippy, top, top, top, top best minds in our field. As you can see, Dr. Heather Zwickey is here with me. And before I jump into her amazingness and we get into our great conversation today, I want to just give a shout out to the two diamond companies that make this podcast possible day in and day out, year in and year out. I think we’re going on year seven now, and that is Rupa Health and it is Biotics. So Rupa Health, it has made functional laboratory testing, which is notoriously complicated for the patients and also for us clinicians, a completely smooth ride. They have revolutionized access to this extraordinary body of testing. I am grateful for it. My patients are grateful for it. The other clinicians in my practice, absolutely love Rupa Health.

And Biotics has been around forever. Many of us lean on Biotics and rely on Biotics because they have such high quality products. I actually have my Biotics curcumin. I went upstairs and grabbed it. I am, by the way, I haven’t mentioned it. I’m outside, we’re live. I’m in Baja Mexico. And anyway, my Biotics curcumin pretty much goes where I go. So, thank you both Biotics and Rupa for just taking good care of New Frontiers and Functional Medicine.

And with that, I will move over to telling you about Dr. Zwickey. So not in her bio is that she came to my alma mater NUNM, National University of National Medicine when I was a second year student, and she was our immunology professor. And she came to us from Yale where she was conducting incredibly, interesting research on T-cells, we were doing some work with T-Cells, I believe, right?

Dr. Heather Zwickey: Yep.

Dr. Kara Fitzgerald: Our class was standing room only because not only did the entire student body want to hear what she had to say, all of the teachers, the faculty wanted to hear. I don’t know if you remember back then, it was just this packed, exciting… She brought an electricity and an excitement to the school, and then she went on to start Helfgott Research Institute. And that’s just a really premier research institute these days, and it’s the place that we conducted our study. But let me hush and just tell you about her and then we’ll jump right in. Dr. Zwickey is an inspiring researcher and educator. She breaks down complex science into stories that everyone can understand. She bridges integrative medicine and western science describing mechanisms that underline many natural medicines. Heather earned her PhD in immunology and microbiology from the University of Colorado Health Sciences Center with a focus on infectious disease and vaccine development.

Dr. Zwickey went on to complete a postdoc fellowship and teach at Yale University of Medicine, where she worked on immunotherapy for cancer. She launched the Helfgott Research Institute and served as its director for 17 years. She established the School of Graduate studies at NUNM, developing programs in integrative medicine, research, nutrition and global health among others. Dr. Zwickey currently co-leads an NIH funded clinical research training program focused on training the next generation of integrative medicine researchers. She teaches at many universities and lectures at conferences around the globe. Heather, it’s great to see you and welcome to New Frontiers.

Dr. Heather Zwickey: It’s great to be here. Thanks for having me.

Dr. Kara Fitzgerald: Let’s jump right in. So we’re going to talk microbiology today. We’re talking the microbiome, prebiotics, probiotics. So since, when I graduated NUNM as you maybe recall, I went over to a clinical laboratory. And we were the first clinical laboratory to release a DNA stool test, the first PCR for clinical access outside of the research setting. And I remember back then thinking, “Okay, we’re going to be able to prescribe pinpoint probiotics to move the microbiome.” And it was pretty fast that I realized that I was completely wrong. In fact, this level of insight was showing us that we need to chew our food, that we need to eat a whole food. Sort of, it was very validating to what I learned of in naturopathic medicine. But I mean, just talk to me about where we’ve come in the science. What do we know about our microbiome today? Is there an optimal microbiome that we all want to achieve, or is it everything unique?

Dr. Heather Zwickey: Yeah, it’s a great question. And I hate to remind you, but it’s been almost 20 years since you embarked on that journey, and I embarked on it with you. But we have learned an immense amount about the microbiome in 20 years. One of the big papers, I think that is seminal in this field came out a couple years ago in 2019 from a group called Visconti. And what they showed is that between any two individuals, the microbiome may only be between four and 40% the same.

Dr. Kara Fitzgerald: Wow.

Dr. Heather Zwickey: The low end being four and the top end being 40%. What is the same between individuals are the metabolites that the microbes make, and those are highly conserved between 80 and 95% conserved. So you and I might have different microbes, but our microbes are making the exact same metabolites or the fermentation products that they make are the same between us. They’re shared.

Dr. Kara Fitzgerald: Oh, that’s ridiculously interesting. So then, well, I guess I have a couple of questions. I mean, I’ve been interested in looking at epigenetics and biological age, longevity, et cetera. And there’s definitely, I mean, healthy centenarian and unhealthy older folk’s guts have certainly been investigated, and there are some keystone bacteria. It appears like Akkermansia is hanging out in a lot of healthy centenarians and I want your thoughts on that. But what you just said suggests that maybe it’s not correct for us to be looking at the microbiome at all. So talk to both of those.

Dr. Heather Zwickey: Okay. So first of all, there are definitely keystone species, and those keystone species may not be the highest in number but their function is critical to health and longevity. So Akkermansia’s one that has appeared. It’s interesting because it shows up in a lot of people who are older or who have survived a longer period of time. It also shows up in people who are leaner. However, if you hit the ground and you start talking to nutritionists who are ordering all sorts of microbiome testing now, they’re finding plenty of Akkermansia in people who are obese as well. So it’s not as clear as a single microbe. And it probably never will be because our microbiomes are so different from each other. Now, this question of, should we be measuring the microbiome? I think is a good one because one of the things that we’re finding is that especially people who have ailments. So we find people with Parkinson’s disease are missing certain microbes. And it’s not an individual microbe, it’s a class.

So it’s not like we’re saying, “Oh, lactobacillus is gone.” And it’s not. But what we’re saying is, the microbes that produce short-chain fatty acids are reduced. So there’s a whole series of 10 to 15 microbes that across hundreds of people with Parkinson’s, you’re going to see reduced. And those are the ones that produce something that would reduce inflammation and specifically neuro-inflammation such as short-chain fatty acids. Now, where that starts to become really interesting is when we say, let’s look at people with Parkinson’s versus people with rheumatoid arthritis versus people with multiple sclerosis. And it turns out different microbes are missing in different disease populations. And again, it’s less about the microbe and more about the functionality of that microbe. And what is that that microbe supposed to be producing and has another microbe stepped in and produced it instead? Because remember, there’s flexibility. We also have to remember genetically microbes are different than human cells, right? In that they can transfer their DNA from one microbe to another.

So just because one microbe is missing doesn’t mean that that functionality is necessarily gone. But in individuals who have a disease population or who are diagnosed with a disease, what we’re finding is the functionality is gone. So what I think we’re going to see is that we’re going to see a movement to measuring microbial metabolites as opposed to measuring the microbes themselves.

Dr. Kara Fitzgerald: Yeah, that’s exactly what I was thinking.

Dr. Heather Zwickey: It’s starting to happen. Yeah, it’s happening at the lab level. At this point as a researcher, I can measure microbial metabolites. I can send samples out and get a big list of metabolites back. As a clinician, it’s still a little expensive for you to do that.

Dr. Kara Fitzgerald: Well, and have they established ranges that would be useful within the clinical setting?

Dr. Heather Zwickey: Certainly there are. So first thing we need to understand is while we talk about 300, 400 different types of species of microbes in your gut, we’re talking about metabolites in the thousands, right? So, now identifying which metabolites are critical to health is also going to be important. We know from an immunological perspective which metabolites are important for the immune system, and we know neurologically which metabolites are important for the nervous system and for the cardiovascular system, et cetera. What we don’t know is which combinations are going to ultimately lead to longevity or lead to disease yet, but we’re getting there. Yeah. It’s amazing to me how fast this field is growing.

Dr. Kara Fitzgerald: It’s extraordinary. It’s incredibly interesting. And I’m glad to hear that we’re getting there, and it’s just nice to have a little bit of a snapshot into next generation stool testing. If the PCR was next generation 20 years ago as you said. Yeah. Now we’ll be looking at the microbial metabolome, that’s awesome. When then we’re going to be looking at proteome and the human metabolome, et cetera, and the epigenome as we’re doing. I think then, this is tangential, but I know you’ll have some thoughts on it. We’re going to have to be leaning heavily duty on AI to help weed through the potentially hundreds of thousands of compounds. What are you thinking?

Dr. Heather Zwickey: Oh, you’re absolutely right. It’s something that frankly, 20 years ago we probably didn’t have the technology to do it, but today we do. And so you’re going to start to see, it’s a lot of data to crunch. And when we do clinical trials to even look at that data, when you’re comparing 1800 data points from person one to 1800 data points from person two. And now you’ve got a clinical trial of a hundred people, how to do that data analysis gets really complicated.

Dr. Kara Fitzgerald: Yeah, yeah. I was at A4M conference in December, and Peter Diamandis spoke. And he said something about, you’ll be out of business as a clinician if you don’t start embracing… Well, I mean AI is not ready for the clinical setting for most cases that I’m aware of. There are some places that it’s being used, but it’s amazing that we’re closer. For many years we’ve been thinking about it, but we’re actually right at the door, would you say?

Dr. Heather Zwickey: Yeah, we’re absolutely getting there. And what it will mean ultimately is people will have a lot more control over their own personal health journey because they’ll know what’s happening at any point in time, they’ll be able to tell. I think the other thing that’s really fun to put together with all of this, all the new wearable devices that are coming out. So people can actually say, “Okay, here’s what’s going on internally, and then I can wear my Oura ring or I can wear my wristband, or whatever it is so I can track how that’s having an effect on my mood and my heart rate variability and all those other things.”

Dr. Kara Fitzgerald: That’s awesome. You’re absolutely right. It’s very exciting, and I want to be an early adopter or continue to be early adopter of where we’re headed because it’s awesome. All right. What else do we want to talk about? So most of us are taking probiotics, obviously, we’re prescribing them routinely. Primarily Lactobacillus and Bifido, I think are the big players. We’re using Akkermansia as well. There’s always a lot of energy, a lot of emphasis on viable until expiration that the contents need to be alive and thriving, et cetera. I mean, what are your thoughts on that? I mean, I know you have some big thoughts on that so I wanted to just set you up with that question.

Dr. Heather Zwickey: I have big thoughts on that.

Dr. Kara Fitzgerald: All right. Go.

Dr. Heather Zwickey: I’m skeptical that the microbes need to be alive until they hit the gut. So that is my first piece. There’s been quite a few studies that show that many probiotics are not alive when they hit the gut. And that I think, makes people nervous. They’re like, “Oh my gosh, that it’s not going to work.” That’s not what the research says. The research says that those microbes don’t have to be alive, and they can still be effective, especially in the immune system. Right? So it may be different for cardiovascular system. It may be different depending on what effect you’re trying to encourage with a probiotic. But at least for the immune system, the microbes don’t have to be alive.

Dr. Kara Fitzgerald: Well, let me just stop you and I want you to pick right up. But you just said something kind of provocative that that’s true for the immune system, but might not be for the cardiovascular system or the central nervous system. Do you have any inclining, whether it’s true or not? We need them alive in one setting, but not in another. I’m just curious.

Dr. Heather Zwickey: Well, so keep in mind that cells of the immune system have receptors on them that are called toll-like receptors or TLRs.

Dr. Kara Fitzgerald: Sure.

Dr. Heather Zwickey: And they can bind to a microbial cell wall, and the microbe doesn’t have to be alive, and it will still stimulate a cell of the immune system. So if you just have a microbe cell wall, you’re going to stimulate the immune system.

Dr. Kara Fitzgerald: That’s right. Oh yeah.

Dr. Heather Zwickey: Exactly. And now I don’t think that’s what’s happening. I actually think it’s more complex than that. But regardless of whether a microbe is alive or dead, it can stimulate the immune system. Now, what I think is happening with a probiotic is that when we make probiotics, we put food in the bottle to feed those microbes so that they don’t die, right? But the microbes in the bottle are eating that food and they’re producing metabolites. And so when you’re taking a probiotic, you are simultaneously taking what we call a postbiotic. You are taking the metabolite that the microbe made. The reason that I say we know this works for the immune system is that we know that if you have lactobacillus in the bottle and you feed it an inulin like psyllium husk or some other fiber, it will produce short-chain fatty acids.

And when you take that probiotic, you are taking short-chain fatty acids in addition to taking the lactobacillus. Do you need the lactobacillus at that point, or could you just take the short-chain fatty acids? Hard to say because nobody’s doing that research yet. However, what we don’t know, and the reason I say I don’t know if this is true yet for the nervous system or the cardiovascular system is for example, we know that one of the metabolites that a bacteria makes is neurotransmitters. It makes dopamine, serotonin. It makes some GABA, right? So the food that you have to feed a microbe to get serotonin is tryptophan. Did we put tryptophan as a food in the probiotic bottle? If we didn’t, we’re not getting serotonin on the other end. Did we put tyrosine in the bottle as a food for the microbe? If not, we’re not getting dopamine on the other end.

But we are putting inulin in the bottle, and so we know we’re getting short-chain fatty acid, so we know we’re feeding the immune system. Could we also feed the nervous system if we put the right food in a substrate? I think we could. I just think nobody’s there yet. They’re not doing that yet.

Dr. Kara Fitzgerald: That’s ridiculously interesting, Heather.

Dr. Heather Zwickey: Right.

Dr. Kara Fitzgerald: I mean, we could revolutionize probiotics by really manipulating their substrate, their cocktail. Whoa.

Dr. Heather Zwickey: What we’re starting to see now is we’re starting to see some very forward thinking companies put polyphenols. So substances from plants like spices into the bottle and seeing if they’re getting in a different effect with their probiotics. Specifically, they’re looking for anti-anxiolytic effects, anti-anxiety, lowering stress, lowering depression, using some of the things that we know have an effect on stress if we feed you them normally, not as a probiotic. So I think it’ll be really interesting. The other thing is that there are lots of companies now that are looking at postbiotics, so they’re not looking at the probiotic or the prebiotic. They’re saying, “Why bother with those steps, because so many people have microbiomes that are dysbiotic, they’re just out of balance. So what if we just feed them the metabolites themselves?” Now you can find butyrate, which is one of the metabolites on the market. Yet if you look at the clinical trials with butyrate, they’re woefully, woefully negative. Butyrate, we have to..

Dr. Kara Fitzgerald: You mean not negative? Not active,  Yeah. Okay.

Dr. Heather Zwickey: So you would think that butyrate would be an anti-inflammatory, because we know that when butyrate is made in the gut it’s anti-inflammatory. But if you feed butyrate, we don’t see any evidence of reduction of inflammation. So what’s going on there is that the butyrate is not reaching the gut. What’s happening, we don’t know. What we do know is that usually butyrate is made in ratio with acetate and propionate. There’s three short-chain fatty acids. And usually it’s three acetates to one propionate and one butyrate. So if you feed butyrate, you completely throw off that ratio. So it’s entirely possible that when we’re trying to exogenously add a single metabolite, we’re doing more harm than good.

Dr. Kara Fitzgerald: We’re actually inhibiting synthesis. So those particular producers are they, they stopped producing?

Dr. Heather Zwickey: Sure. So now you get feedback loop. Mm-hmm, yeah.

Dr. Kara Fitzgerald: Okay.

Dr. Heather Zwickey: Now, there are products out there that are a complete set of microbial metabolites. They’re complete postbiotics. And they are essentially the equivalent of a sterilized fecal transplant. Where they take someone who’s healthy, who has a full set of microbes, who’s eating an organic diet, who’s eating more than 30 plant-based foods per week, who’s eating all sorts of polyphenols, and they’re making all of these microbial metabolites in their gut. And then that is packaged into a postbiotic. And when you use a postbiotics that is complete like that, then we start seeing major differences in health. Mood differences, neurological differences, immunological differences, GI differences, like it is truly having an overall effect on human health.

Dr. Kara Fitzgerald: Wow. It’s the complete package.

Dr. Heather Zwickey: It’s the complete package. And it’s also makes sense-

Dr. Kara Fitzgerald: And even are the bacteria and the viruses there? Or they’re dead?

Dr. Heather Zwickey: They’re dead.

Dr. Kara Fitzgerald: Yeah. So you’re still getting that information from them. They’re providing some kind of information, even if they’re not viable.

Dr. Heather Zwickey: Even if they’re not viable, they can be providing part of the story. Absolutely. Now, the whole field has been moving towards a postbiotic for a long time. It was starting in Europe because they wanted to be able to add things to foods like orange juice. And if you try to add a probiotic to orange juice, the acidity kills it. So the field started moving towards postbiotics because they wanted something that you could put into a food product. And as a result, the first thing that they were called is parabiotics. Where we heat kill the probiotic and we get a parabiotic. And now we’ve got this thing that’s a postbiotics, which is we’re sure the metabolites are there. So the postbiotics, we know that there’s metabolites, parabiotics has the heat killed microbes and you can have products that have combinations of parabiotic and postbiotics, and you could do a combination of a probiotic, prebiotic, parabiotic, postbiotic, et cetera. But it might also be why fermented foods have had such a positive effect on people for so long in that they’re essentially the whole package.

So there was this really interesting study that came out last year, actually, this is 2023. It came out in 2021. So I forget there’s just one passed year. Anyway, it was looking at fermented foods, and it was showing that the only thing better than eating 30 plant-based foods per week is to add fermented foods to your diet.

Dr. Kara Fitzgerald: Wow.

Dr. Heather Zwickey: And I think that it’s really telling. There was something a little funny about that study too, in that when they first did the research they had all of these people who had added a fermented food to their diet and they weren’t that healthy. And they went back and they said, “Well, maybe we need more than one.” And so then they changed it to two or more fermented foods, and they got huge amounts of what we’re looking for, which is beta diversity of the microbiome. It turns out, if you’re just looking at one fermented food, most of the people we’re talking about beer. If you’re just adding beer to your diet, not that healthy.

Dr. Kara Fitzgerald: That’s awesome.

Dr. Heather Zwickey: But if you add two or more, then we’ve added things like yogurt and sauerkraut, kimchi, kombucha. So yeah, one fermented food might just be beer or wine. But two or more, we’re usually talking about adding some healthy foods.

Dr. Kara Fitzgerald: Oh, isn’t that? That’s great. That’s good. So let me ask you about this postbiotics. So actually doing a pre-killed FMT product. So you’re getting the parabiotic and you’re also getting the postbiotics metabolites, and you’re getting the whole kit and kaboodal from an extremely healthy individual. That’s absolutely amazing. I guess we’re live, did you hear that or no?

Dr. Heather Zwickey: I didn’t hear it.

Dr. Kara Fitzgerald: Okay. Fabulous. Then there was-

Dr. Heather Zwickey: But that’s okay because-

Dr. Kara Fitzgerald: It’s live.

Dr. Heather Zwickey: We’re just getting a thunderstorm, which we never get in Oregon. I’m like, it’s thundering outside.

Dr. Kara Fitzgerald: How weird though, in January? Yeah. That’s not-

Dr. Heather Zwickey: Yeah, I know.

Dr. Kara Fitzgerald: Okay. But ultimately so this, so I can see and I know that you have some case reports around using this postbiotics, this post and parabiotic product. And I’d love to hear. It’s extraordinary and I’m incredibly excited about it. But I can’t help but think we want to more than just feed them this nutrition, we actually want to restore the microbiome so they start doing it themselves. So can you speak to how to… So is that the gateway to restoring the microbiome? Are you seeing that phenomena happen also? So ultimately they can transition off of using that?

Dr. Heather Zwickey: Yes.

Dr. Kara Fitzgerald: In conjunction, I’m assuming with a full functional pros should diet changes, et cetera, et cetera. But yeah, talk about that.

Dr. Heather Zwickey: Yeah, so you nailed it. If they don’t change their diet, then eventually they’re just going to go back to where they were. Although what we find for a lot of folks who come in who have extreme dysbiosis, it’s because they’ve had to be on antibiotics for a long period of time, and now they’re finally off the antibiotics but they can’t seem to get their gut back. And this is one of those ways that you can start to restore your gut. So I think one of the things that we tend to forget is that the metabolites that your microbes make also serve as the precursors for secondary metabolites. Right? So if you don’t have the initial set of metabolites nor do you have anything downstream. So if you are able to feed a postbiotic and get that initial part of metabolism taken care of, then all the downstream effects start to fall into place. And you start to put all of the feedback loops back together.

And so what we’re seeing, again, this is clinical. So this isn’t randomized controlled data, this is case studies. But what we’re seeing is it can take… It depends on the diagnosis. But for the average person, it’s three to seven months that they take a postbiotics and then they don’t need to take it anymore. And it’s not immediate, which I was talking to a friend of mine who’s a microbiome researcher at Harvard. And she said, “Well, good, it shouldn’t be immediate.” If it’s immediate, then you should be suspect. Because then people’s guts are going to disintegrate again. It does take a little while but it’s not permanent. It, I mean, you’re not on a supplement permanently. You’re on it for three to seven months, and then what we’re seeing is most people after seven months can come off. And we’re seeing that for autoimmunity, for some neurological diagnoses, for mental health diagnoses. The mental health thing I think is really interesting. But you also have to remember, serotonin, dopamine, GABA, all of those are metabolites made by microbes.

So they’re in a postbiotics. So you’re actually taking some serotonin and you’re taking some dopamine and you’re taking some GABA. And so we’re seeing people who are suffering from depression or anxiety, it’s three doses and they’re like, “Well, I feel way better. I feel better.”

Dr. Kara Fitzgerald: So you might see turnaround in circumstances pretty quickly.

Dr. Heather Zwickey: Oh yeah. I’ve got some case studies from some physicians where it’s pretty amazing how fast people who have anxiety and depression turnaround.

Dr. Kara Fitzgerald: Yeah, yeah.

Dr. Heather Zwickey: It’s usually a week at least.

Dr. Kara Fitzgerald: I mean, the reality is, with all due respect to your Harvard colleague. In clinical practice, we know some people are just incredibly sensitive and that information will impact quickly. I think the real transformation is like, I always think of it as a changing of the guards, and this is probably what she was referring to, the real rebuilding and redesigning the microbiome. That’s the longer journey. But I think people can experience pretty profound effects relatively immediately as you’re describing, or very immediate quickly.

Dr. Heather Zwickey: I agree. I think the other thing is that she sees folks who have been in the hospital and who have picked up some drug resistant strains of microbes in the hospital. And it takes a while for those things to get out of your system.

Dr. Kara Fitzgerald: Oh man, yeah.

Dr. Heather Zwickey: But shifting our microbiome can happen really quickly. I was reviewing a paper with a student this morning. And four hours after eating a high fiber meal, you see a complete shift in microbes. Four hours.

Dr. Kara Fitzgerald: Yeah. That’s incredible. Yeah. I remember learning in school, actually. Nigel Plumber delivered a lecture. And, what did he say? A whole new genus or species, in 20 minutes or something. Just because of the gene exchange that you mentioned earlier. You can change things up pretty darn quickly. Well, so this is a very exciting time, and I know people listening to this are going to be really jazzed up that we’re really moving away from the era of Lactobacillus and Bifido. Although, well, they’re important players in our guts so they’re going to be, I think, part of our probiotic world as they should be. But what you’re-

Dr. Heather Zwickey: Here’s a couple of things I think about Lactobacillus and Bifidobacteria. First is, if we start thinking about all of the insults that we get to our system. So our exposure to pesticides, and maybe you try to eat all organic but the moment you eat out, you’re probably being exposed to a pesticide here or there. They are highly sensitive to pesticides, and we know that glyphosate kills those guys off. So if you get Lactobacillus and Bifidobacteria for a day, it might just be enough for what you need for what you were exposed to the day before. Right? So we know people feel better when they take a probiotic. I’m not saying that probiotics are ineffective. Not at all. I’m just saying that for people who are really sick, we might have an addition that might be eaten better.

Dr. Kara Fitzgerald: Right, yeah. And I think that that’s an important point to make. Because there are good products out there. Any clinician-

Dr. Heather Zwickey: Oh, for sure.

Dr. Kara Fitzgerald: … we’ve used them forever. And of course, the addition of fermented foods too, and a whole foods diet. But yeah, this new door that’s being opened is, this whole postbiotics world is very exciting.

Dr. Heather Zwickey: So, I think the other piece that’s really exciting is prebiotics. So we-

Dr. Kara Fitzgerald: Let me just ask you one more thing, because the train will leave the station. Three to seven months for a real therapeutic transformation. I mean, are you taking a postbiotics daily, is just part of your regular health regimen? I mean, is this something recommended? I mean, I have to admit that I’m using them and we’ll bring them into clinical practice. And what about long-term use? Is it a waste of money? Is it smart? Is it just unnecessary?

Dr. Heather Zwickey: Oh, I don’t think it’s unnecessary. I think that the average person could probably benefit from taking a postbiotic daily. They are still at a stage where they’re relatively expensive, so you might pay $200 for a month. Which in the supplement world, that’s a little higher than the average supplement. But if you think about all of the work that goes into creating one, it’s why they’re a little bit more expensive.

Dr. Kara Fitzgerald: Yeah, sure.

Dr. Heather Zwickey: But yeah, I think for folks who can afford it, and especially if you’re thinking about longevity, we do know it’s reducing inflammation. It’s helping people sleep. It’s helping with a lot of the things that we know shorten our lifespan so it probably will increase longevity.

Dr. Kara Fitzgerald: And wasn’t there some longevity, some early research looking at C. elegans in-

Dr. Heather Zwickey: Oh yeah, yeah.

Dr. Kara Fitzgerald: … postbiotic.

Dr. Heather Zwickey: Yeah. And it makes the C. elegans much more vigorous. So yeah, people get a lot of energy or worms get a lot of energy.

Dr. Kara Fitzgerald: Worms. That’s cool. Okay. So then it’s good to… So we can use it long term, there’s no contraindication maybe if people want to, given that it is a little bit more expensive, you could probably take it less frequently-

Dr. Heather Zwickey: Oh sure.

Dr. Kara Fitzgerald: Maybe every other day or every few days. Okay.

Dr. Heather Zwickey: I mean, I recommend that for a lot of supplements. We did some research with Oregon Health and Science University, gosh, now a decade ago, showing that we actually… And this was an animal study, but we actually got a stronger effect if we administered an alpha-lipoic acid supplement every other day or every third day than we did if we gave it every day.

Dr. Kara Fitzgerald: And why do you think that is? Yeah.

Dr. Heather Zwickey: I think that has to do with receptor recycling. So if you’re administering something that requires a receptor for uptake, you have to remember that once you give it then the receptor binds to the substrate and it gets internalized. And then you don’t have the receptor for 24 hours. So there’s no receptor the next day you might as well just wait and give it the day after when the receptor’s back.

Dr. Kara Fitzgerald: God, that’s fascinating. That’s a whole other conversation of what that might apply to.

Dr. Heather Zwickey: Exactly.

Dr. Kara Fitzgerald: Like vitamin D. Although there’s evidence that keeping vitamin D up, taking it at least weekly and maybe even more frequent, has shown consistent D levels in serum which was actually associated with better outcome.

Dr. Heather Zwickey: Yeah. And then the other thing you have to remember with vitamin D is vitamin D receptor has different homologous. And some people can have the highest levels of vitamin D, and if their vitamin D receptor has mutation in it, they just never get enough vitamin D. So, I think we always forget about the receptors.

Dr. Kara Fitzgerald: Yeah, we do. Yeah, I know. Yeah. I mean, it’s interesting bringing it top of mind. You’re right. Yeah, absolutely. Okay. So you were going to talk about prebiotics and you were going to go into something interesting.

Dr. Heather Zwickey: Oh yeah. So I think that the field of prebiotics is another topic that is hugely expanding. So one of the things that we saw about four years ago now is there was a great study showing that certain spices are acting as prebiotics and that they’re manipulating our microbiome. And then they started showing that different polyphenols had an effect on the microbiome. And now we’re seeing that one of the reasons that a lot of medicinal herbs are working the way they are is they’re affecting the microbiome. So it totally shifts how we think about herbal medicine, in my opinion. We have these groups and that react differently in different people. Well, one of the reasons that they’re reacting differently in different people has to do with the starting microbiome of the person. So you may give somebody an herbal medicine, and it works great for them because their microbiome immediately digests that herbal medicine and produces the substrates that it needs. And in the next person, they have a different microbiome and they don’t get the same result.

And I think, again, as we look at things that historically we’ve struggled to explain in natural medicine, like adaptogens. How come when cortisol’s high, it does one thing and when cortisol’s low, it does a different thing. Well, because when cortisol is high, your microbiome looks one way and when cortisol is low, your microbiome looks a different way. So different microbes are processing it into different substrates depending on where the cortisol level is. So we’re starting to understand now why we see different results with herbal medicines than we see with pharmaceuticals.

Dr. Kara Fitzgerald: That’s fascinating. It’s like the host influence on the microbiome that dictates the microbiomes activity and the production of postbiotics. It makes me think about genistein. I mean, going back to my research and thinking about epigenetics and polyphenols are what we’re calling… We’ve been calling them methylation adaptogens but they’re epinutrients extraordinaire. They do extraordinary… There’s all sorts of interesting stuff on influencing the enzymes involved in epigenetic expression like DNA methyltransferase and the 10; 11 translocation enzymes. But a lot of them do that because they’re transformed by the microbiome first. Maybe all of them, but certainly a lot of them. And it makes me think about genistein and equol. And genistein is just this extraordinary isoflavone, it’s an extraordinary epinutrient. If we can transform it, if we have the gut microbiome to transform it into equol and then we have something that I think really is one of our most, is an important player systemically even though some people are anxious about soy which is our main source of genistein. Any thoughts on that?

Dr. Heather Zwickey: Well, I think that if you just look at the structure of soy estrogens versus human estrogens, you see that it’s totally different. And so the nervousness about soy is people who have a misconception. So yeah. No, I absolutely agree that when we started thinking about plant medicine, we started looking at it like they were pharmaceuticals. And so we’re looking for just one active ingredient or two active ingredients, or maybe five. But what we have to remember is in this complete product of 300 things, there are going to be things that are shifting microbiomes, things that are binding to different aspects of the DNA. There’s so many different mechanisms. We’re even finding nanoparticles in a lot of herbal medicines now. And remember that nanoparticles can, in different environments make different shapes and bind to different receptors. So, there’s so many things that are going on.

I think that we have to rethink how we think about herbal medicine. And I also think then that is going to influence as we think about prebiotics, we may choose a different prebiotic for one patient than we choose for another patient.

Dr. Kara Fitzgerald: Yes.

Dr. Heather Zwickey: Because their microbiome is different. I have a postdoc right now who’s working on people with rheumatoid arthritis, and can they even process green tea extract? Because if their microbes are missing, then they might not have the appropriate microbes for processing green tea. Whereas you want to give them green tea to reduce their inflammation, does it work in people who are missing certain microbes?

Dr. Kara Fitzgerald: What do you mean process it? Like at liberating the catechins, or what do you mean?

Dr. Heather Zwickey: Exactly.

Dr. Kara Fitzgerald: Okay.

Dr. Heather Zwickey: Yeah. Processing into the… So I think the easiest one to think about in terms of a pathway that is metabolite, secondary metabolite is think tryptophan, microbes turn it into serotonin and then serotonin is further metabolized in the melatonin, right?

Dr. Kara Fitzgerald: Yes.

Dr. Heather Zwickey: So you can’t make melatonin unless you first make serotonin. So if that is the case, if you’re missing the microbe to catalyze the reaction as serotonin then you’re not going to sleep at night because you’re also not going to make melatonin.

Dr. Kara Fitzgerald: Right.

Dr. Heather Zwickey: Right?

Dr. Kara Fitzgerald: Yeah.

Dr. Heather Zwickey: So that’s the sort of thing we’re thinking about. I think the other thing that’s really interesting in the prebiotic literature is starting to look at human milk oligosaccharides.

Dr. Kara Fitzgerald: Yes.

Dr. Heather Zwickey: So there are products out that have human milk oligosaccharides in them. And now when we’re thinking about repairing dysbiotic gut, so you give somebody a postbiotics and then you want them to eat all these plant-based foods to try to get their microbes going again. But we might need to back up a little bit. If we’re thinking about folks who were born cesarean section and never breastfed, we need to start with some human milk oligosaccharides to start feeding those microbes that never got the opportunity to fill their niche. So I love this idea of as we rebuild the gut, taking an approach that actually was physiological, that historically we were breastfed so let’s give them some human milk oligosaccharide.

Dr. Kara Fitzgerald: Hundred percent.

Dr. Heather Zwickey: Yeah. And then we start adding some of the more plant-based foods and some of the spices, and we gradually work our way up.

Dr. Kara Fitzgerald: That’s absolutely amazing. Yeah, that makes complete sense that we would have human milk oligosaccharides in a prebiotic product for the many, many adults who weren’t able to be breastfed. I actually sourced breast milk for my adopted daughter. Just was something that I was just in aggressively committed to doing. Understanding its importance. And, I think that there are other times many of us were not able to have access to it. Yeah. So it makes total sense that you would have the package. Breast milk to fecal microbiome transplants. the whole line of the alimentary. Yeah.

Dr. Heather Zwickey: Yeah.

Dr. Kara Fitzgerald: What else? Just in our closing, I don’t know if you mentioned it here but before we got on you talked about seeing some changes with the postbiotics in Parkinson, which immediately made me take a note as I thought about somebody who I want to prescribe it to. You’re looking at autoimmunity and seeing some amazing work there. I think in allergies also there’s some really amazing evidence in the clinical setting. Thinking just about the massive rise in allergic disease with the use of antibiotics, especially early in life. So just in thinking as we wrap up, maybe some of your final thoughts on, I just threw out like 87 things but…

Dr. Heather Zwickey: Well, that’s okay. So I think one of the things we have to remember, just to put it in context. We are at the beginning of 2023 and we’ve just come through a pandemic. And we know that pandemics trigger autoimmunity. And I expect we’re going to see a large increase in autoimmunity because we know infectious disease and molecular mimicry are both big triggers, right? And so the coronavirus, we know there’s molecular mimicry there. We know that likely we’re going to see incidents of diabetes, MS and inflammatory bowel diseases increase. The only peripheral mechanism that we know to stop autoimmunity is to increase T regulatory cells. And how do we increase T regulatory cells? We do it with our gut microbiome. We do it with vitamin A and vitamin D and nutrition, and that’s it. Like that’s what we’ve got. So the more that we are paying attention to the microbiome right now, the more we might be able to curve the upcoming autoimmune crescendo, if you will.

Dr. Kara Fitzgerald: Yes. Yeah.

Dr. Heather Zwickey: It’s coming. It’ll take-

Dr. Kara Fitzgerald: Just a huge point. I did a podcast with Mymee not too long ago. What are they? I mean, they crunch a lot of data, but they… Anyway, go check the podcast out. We’ll put it in the show notes, I can’t even describe it. But what they said to me is that ANA is so prevalent now, to your point, they’re doing this collaboration with Mount Sinai Hospital. And post COVID ANA levels are so high that the hospitals actually stopped testing them. They’ve basically decided there’s no reason because everybody’s positive and reflexing to actually see what type, and all of this is something they’ve decided isn’t worth their focus. But there is this tsunami of autoimmunity that is already showing up early because we can see ANA, we tend to see it rise early.

Dr. Heather Zwickey: Yeah. And the unfortunate thing is that in our current system, autoimmunity does this and we catch it when it’s up here somewhere-

Dr. Kara Fitzgerald: Yes. Yeah. We don’t think about a little..

Dr. Heather Zwickey: … and when it gets down here, then we can actually push it off. We can extend this length of time, maybe even prevent it. We know that clinicians are seeing lots and lots of diabetes come in the door, and they don’t know if it was undiagnosed pre-diabetes, pre-COVID or if COVID is triggering diabetes. We do know that there is a shared epitope with a couple of diabetes antigens so it’s entirely possible that it’s triggering

Dr. Kara Fitzgerald: One? You’re talking Type I?

Dr. Heather Zwickey: That is for Type I, yes. That being said, it’s because it’s happening in adults they’re calling it type 1.5, right? LDA, late diabetes onset. Anyway, I just think that we have to remember we do have a backup in our system. Our backup is our T regulatory population. And if we have a good T regulatory population, we should be able to calm down any aberrant T-cells. That’s actually what my research at Yale was showing was that when we did cancer vaccines on people, it triggered autoimmunity. But the T regulatory populations then shut it down within a few weeks. So if we can do that with what we’re seeing now by increasing T regs, it’s a no-brainer. The problem is it’s diet, right? How to get our good T regulatory population, the number one way is omega-3 fatty acids. Well, where’s our omega-3 fatty acid consumption in the United States? It’s way low.

Dr. Kara Fitzgerald: Way down. Yeah.

Dr. Heather Zwickey: Yeah. So we really have to think about how we’re counseling people to eat, and if they’re not eating fish then make sure they’re taking omega-3’s. Because we know that this is coming. And if you have a family history where you have a genetic background that you’re prone to a particular type of autoimmunity, now is your time, take those omega-3’s.

Dr. Kara Fitzgerald: Awesome. Omega-3’s number one. A and D you mentioned, and also potentially the postbiotics. Have you looked at T reg production with Postbiotics?

Dr. Heather Zwickey: Yeah, absolutely. Yep.

Dr. Kara Fitzgerald: And I’m assuming it was good?

Dr. Heather Zwickey: And with the oligosoccahrides, yeah. I mean, it’s the short-chain fatty acid production really that’s leading there. And the number one metabolite in the postbiotics is short-chain fatty acids. So yeah, it will also help with prevention.

Dr. Kara Fitzgerald: Well, Dr. Zwickey, it was awesome to get to spend a little bit of time with you today and just listen to your brilliance. It makes me miss our days at NUNM.

Dr. Heather Zwickey: Well, we used to sit around and just geek out about science all the time.

Dr. Kara Fitzgerald: Yes, yes, yes. I envy your postdocs. But hopefully our paths will cross more and more now that we’re getting back out into the world. Thank you so much for joining me today on New Frontiers.

Dr. Heather Zwickey: Thanks for having me. It’s a lot of fun to talk with you.

Dr. Kara Fitzgerald:  As always, thank you for listening to New Frontiers in Functional Medicine, where our sponsors help bring the very best minds in functional medicine, and today is no exception. Not everyone can be a sponsor on my platform, and I so appreciate the good work, relentless research, and generous support from my friends at Rupa Health, Biotics and Integrative Therapeutics. These are brands I know and trust in my own clinic and can confidently recommend to you. Visit them at RupaHealth.com, BioticsResearch.com and IntregrativePro.com, and please, tell them you learned about them on New Frontiers.

If it’s not too much to ask, I would appreciate a thumbs up and a kind review wherever you listen to New Frontiers. Thanks.

Heather Zwickey is an inspiring researcher and educator who breaks down complex science into stories that everyone can understand. Dr. Zwickey bridges integrative medicine and western science, describing mechanisms that underlie many natural medicines. Heather Zwickey earned a Ph.D. in Immunology and Microbiology from the University of Colorado Health Sciences Center with a focus on infectious disease and vaccine development. Dr. Zwickey went on to complete a postdoctoral fellowship and teach at Yale University School of Medicine where she worked on immunotherapy for cancer. She launched the Helfgott Research Institute and served as its director for 17 years. Dr. Zwickey established the School of Graduate Studies at NUNM, developing programs in integrative medicine research, nutrition, and global health among others. Dr. Zwickey currently co-leads an NIH funded clinical research training program focused on training the next generation of integrative medicine researchers. She teaches at many universities and speaks at conferences world-wide.

www.heatherzwickey.com

www.thaena.com

www.nunm.edu

2019 paper, Interplay between the human gut microbiome and host metabolism

Studies re spices as prebiotics: here and here.

New Frontiers Mymee podcast: What to do when autoimmune patients fail standard elimination diets

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