On today’s episode of the Gutbliss Podcast, I’m going to be talking about probiotics. And with me in the studio today, I have somebody who is very well qualified to talk about probiotics. It’s Marc Tewey, who is the CEO of a company called ExeGi that makes a probiotic, Visbiome. Marc, welcome to the Gutbliss Studio.
Thank you, Dr. Chutkan. I really appreciate you having us.
Thanks so much for being here, and full transparency: ExeGi is a sponsor of the Gutbliss Podcast. I’m going to start with a quick definition for anybody out there listening who is not as familiar with the difference between a pre-, a pro- and a postbiotic. Prebiotics refer to the actual substrate, the food that the bacteria – the microbes eat. A probiotic refers to a living organism that, when ingested is supposed to confer a benefit, and postbiotics refer to the products that the microbes make, so things like short-chain fatty acids, etc. Marc, how do you make a probiotic?
Well, probiotics are living organisms. To make them, you ferment them, sort of like you do with yogurt. So what we do to make a probiotic for a therapeutic application is you have a big bank of cells, it’s called a master cell bank, with a bunch of vials, hundreds of them. They’re sitting in liquid nitrogen, and you pull one out and you ferment it in a liter or so of culture media. The media could vary depending on the type of product. And then you incrementally step that up into a larger and larger vat of material. And these production facilities, they’re very cool. They have these huge tanks that are two, three stories tall, and they’re filled with this culture media, they’re stainless steel, and there’s lots of stainless pipes around. It’s a pretty cool operation. And then you ferment them for a period of time. They’ll actually produce acid when they ferment, and they become a form of liquid yogurt. And then what you do is you’ll separate the bacteria itself from the culture media, the leftover stuff. And you do that by centrifuging the bacteria, sending it through a machine that separates it from the culture media. You’ll rinse them. So it’ll go through a process where you are actually rinsing them with water and then centrifuging them again. And then they’re going to go into a process where you’re lyophilizing them. This just means you are freeze-drying them and putting them into a state of suspended animation. So they’re hibernating in that lyophilized state. And then with that lyophilized product, you have a stable probiotic. It can go into a sachet, a little packet. It can go into a capsule. You know, there’s gummies and various different forms of probiotics out there. And then when I consume the probiotic, assuming it’s a well-made probiotic, hopefully it will come out of that hibernation state and now begin to ferment again, but now in your GI tract. And this is where it’s going to do its good stuff. This is where it’s going to hopefully confer some of those therapeutic benefits that you mentioned.
And you actually have some great qualifications for being in the probiotic business because you were a brewer, is that right? Shortly after college you started a brewery.
Yeah, I had a small microbrewery in Baltimore called Brimstone Brewery. I was a home brewer and very interested in fermentation and making beer and this was long before there were a million breweries everywhere, so it was very early in the days of microbrewery. But yeah, we had a small microbrewery in Baltimore, and we fermented beer – ales of various shapes and sizes. And, we had a fun time with that.
In case you’re wondering, though, beer does not confer a probiotic effect in the gut. I do not recommend beer as a living probiotic to take, unfortunately. Okay, so this is how you make a probiotic. It’s a pretty complicated process. And then there is the issue of, once you’ve made it, how do you make sure that these bacteria, as you said, these are living organisms, how do you make sure that they’re alive while you’re getting it to the customer? Tell us a little bit about that process.
So, it’s a really important part of the process, and I think it’s something a lot of companies short step, mostly because you have to keep them cold. Most probiotics are of a specific genre, so specific types of bacteria, and most of these types of bacteria that have therapeutic benefits will die if they’re exposed to very elevated temperatures, like 100 plus, in a lyophilized state. When they’re in your body, they’re going to now become activated, and they use that heat to help become activated. But in that lyophilized state in a pill, without nutrients, they’ll die off. So what we do is we refrigerate the probiotics from the manufacturing plant all the way through the supply chain to the consumer. We even ship the product with a little temperature monitor to make sure that it gets to the consumer alive. And it does make for a more complicated supply chain, but it’s really, really important. The challenge with probiotics is many probiotics are “shelf stable” in that they’re okay at 75 degrees Fahrenheit, so a refrigerated store temperature or room temperature. The problem is you don’t know how it got to the CVS or how it got to your house. Probably in a truck, probably a UPS truck or a FedEx truck or who knows what kind of truck. And those trucks could very easily become exposed to elevated temperatures, but you would never know. The product doesn’t change color. There’s nothing about the probiotic that changes. It’s not like if the milk that you’re drinking got exposed to heat before it got to the grocery store, you’re probably going to figure that out because it’s going to smell bad, right? You just don’t have that with probiotics. So there’s a chance that the probiotic that you’re eating that’s shelf-stable was exposed to elevated temperatures along the way, and you could be eating placebo and never know it, and you’re kind of wasting your money then. So without that supply chain assurity, it’s really hard to know if the product is alive or not. Now, there are some types of probiotics, like yeast probiotics, like Saccharomyces boulardii, which are sort of naturally resistant to elevated temperatures, but most of the lactic acid-producing lactobacillus, bifidobacterium-type strains of probiotics will die if exposed to elevated temperatures.
And that’s one of the things when people have looked at probiotics, particularly the shelf-stable ones, and tested them, they found that the actual number of viable bacteria in them is typically well below what that CFU number is, that colony forming unit. It might be a big number on there, like, you know, 5 billion, 10 billion, 50 billion, but when they check, they find that the viable bacteria are a lot less.
Yeah, and that’s something to watch also as you look at different products is you want to look for products that have a minimum. When they say, okay, I have 10 billion bacteria or 100 billion bacteria, they’re saying that that’s the live cell count before the end of the shelf life. So we actually include more bacteria than that. So if you took our product the day that it was manufactured, it would have more than what our label says. Because what we’re doing is we’re buffering that CFU count to make sure, because there’s going to be some natural die off, even at a refrigerated temperature over the course of a two-year shelf life. So you do want to make sure that you have enough of a buffer in there. But some products will say, well no, it’s a billion at shelf life, right? There’s a national probiotic that’s one of the biggest in the world, from one of the biggest companies in the world, and it says a billion bacteria at shelf life, but it might be as low as 10 million. It says a billion on the front of the box, but then if you look at the back in the fine print, it says it’s one times 10 to the ninth at manufacturing date but could be one times 10 to the seventh by the end of shelf life when you consume it. So it’s much lower – 10 million.
If I am doing the math, there’s a big difference between 10 million and 1,000 million, which is a billion. That is a huge difference.
Yes, it’s like a 90 plus percentage drop in the live culture count.
So tell us a little bit about some of the studies, because I’ve been using this product for a long time, from when I was full-time faculty member at Georgetown, seeing a lot of patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. And that was when I was really first introduced to the product, well over a decade ago, particularly in patients with ulcerative colitis who had had their colon removed and had inflammation in the remaining segment, that last bit that’s left in place, called a pouch, the ileal pouch, for something called pouchitis. So that’s a fairly technical indication, but you have some indications for some other conditions that affect lots of people, so tell us a little bit about those.
So Visbiome is a medical food product, so all the intended uses are intended for its application as a medical food in the dietary management of certain conditions. So our intended uses are IBS, irritable bowel syndrome, ulcerative colitis, as you mentioned, pouchitis, and then we also have some data in antibiotic-associated diarrhea, which is really good. We have a number of additional studies outside of those fields, but we don’t include that as part of our core communication to medical doctors. And most of our communication is to medical doctors about the product itself.
I’m glad you mentioned antibiotic-associated diarrhea because when people ask me about that, I give a really annoying answer. I say: “well, you shouldn’t have taken the antibiotic in the first place”. And they’re like: “you’re really annoying. That is not helpful to me!”. So I still want to point out that the number one question you need to be asking your doctor if you are prescribed an antibiotic is: “is this antibiotic absolutely necessary?” That is the most important question. There are a bunch of other questions you can ask too, I’ve talked about them in some of the podcast episodes, they’re in my book, The Microbiome Solution, but if it is established that yes, an antibiotic is absolutely indicated and you have to take it, there are things that you can do afterwards. I mean, you’re not necessarily going to completely reverse the effects of the antibiotic, but there are things that you can do to mitigate the effects. And taking a probiotic is one of them. I usually tell people, take the probiotic sort of in between when you have to take the antibiotic. So if you’re taking an antibiotic at 8 a.m. and 8 p.m., try and take it right in the middle. Any other tips for people?
No, that’s the same recommendations that we would make. So the probiotic is going to be impacted by the antibiotic, depending on the antibiotic and depending on the probiotic. So there’s going to be some effect there. So you just want to space it apart as far as possible. Yeah, so if it’s twice a day, try and separate it by four hours or so, more or less.
And how long do you usually recommend for people to take the probiotic after they’ve finished the antibiotic?
About 10 days after the antibiotic is what we recommend. So we recommend consuming a certain amount during the course of antibiotics and then for a period after.
And can you tell us a little bit about how Visbiome came up with this particular unique combination of eight different strains of bacteria?
So, the formulation itself, as you mentioned, it’s an eight-strain probiotic blend, and it’s a very high-potency probiotic. So, our lowest dosages are 100 billion bacteria, and then we go up to about 900 billion bacteria. It was invented by a man named Claudio De Simone, Professor Claudio De Simone, who’s a medical doctor based in Rome, Italy. And he had this concept back in the late 1990s that probiotics could be therapeutic. Probiotics have been around for arguably thousands of years. People have been using various forms of cultured yogurt and things for therapeutic benefits for a long time. But if you go back to the literature in the 1990s, there weren’t a lot of studies on very serious GI disorders. It was mostly like traveler’s diarrhea and things like this, and most of the products at that time were very low potency relative to the Visbiome product. So he had a concept that he could take this multi-strain blend, and he had a rationale for each of the individual strains in the product, and delivered in a very, very high dose. And the first studies that they did were in this condition called pouchitis, which is, as you mentioned before, it’s basically a condition that happens in people that have a pouch anastomosis. So if I have ulcerative colitis and I have to have a piece of my colon removed, I have this thing called a J pouch. And the microbiome of the J pouch gets very dysregulated. So he felt like he could change this microbiome with these therapeutic benefits. And those studies were very positive. They were published in very top-tier medical journals like Gastroenterology. And that was one of the first times that a probiotic was shown to be therapeutically beneficial in a really serious GI condition like this. And it was massive doses. So at the time there was about an 1,800 billion per day dose that they were giving in those studies.
And I just want to point out that this is completely antithetical to how pouchitis was being treated and still is treated by a lot of people, which is to give antibiotics. So to actually disrupt the microbiome even more.
Yeah, they use that for the inflammation part, and then you use probiotics to hopefully keep the patient in a remission state. So that’s how he came up with the De Simone formulation. And then that spurred more and more research. So he is a researcher, and he loves to work with other researchers and study the product. So the way that he got this out into the community is he would partner with other academicians around the world. So we now have about a hundred human clinical studies going back to the early 1990s, and almost all of those are partnerships that he formed where he provided the product to the investigator and then just let them have at it. And he didn’t direct the research, he maybe gave some insight, but basically he just let it go and saw what happened. And most of those studies were successful – not all 100 studies, but the majority of them have been successful in important clinical arenas.
I’ve had the pleasure of meeting him on a few occasions and chatting with him and he is definitely passionate. And a lot of the literature we have about probiotics actually comes out of Italy, so they have a very robust tradition. When we come back, we’re going to talk about some of the newer indications for probiotics, including viral illnesses and psychiatric conditions.
We are back with our guest Marc Tewey talking about probiotics. I mentioned right before the break that one of the new areas with probiotics is this idea of viral illness. So viruses are not bacteria, obviously, and they are not susceptible to antibiotics. You can’t treat a viral infection with an antibiotic. So when we see somebody with a viral illness treated by an antibiotic, it’s usually to prevent or treat a secondary infection. So, for example, during COVID, we saw people had pneumonia from COVID, but sometimes developed a secondary bacterial pneumonia and were treated with antibiotics. But the tricky thing here is that we know that antibiotic treatment can sometimes make a viral illness worse. And one of the examples of that is rotavirus. Rotavirus is a diarrheal illness that kills about half a million children a year. And the studies show that there’s a five times higher rate of rotavirus and more severe infection in children who have recently been treated with antibiotics. And that’s simply because you are sort of eroding that microbial army that part of their job is to fight the viral illness. So we’re seeing a shift, I think, also with this idea that with viral illnesses, instead of giving antibiotics – which not only don’t treat the virus, but can potentially make the person more susceptible and have a worse outcome like we see with rotavirus – how about using a probiotic? So can you tell us a little bit about some of the studies you’re doing in that area?
Rotavirus is very interesting, and there’s been some work done, I think Bill and Melinda Gates Foundation was doing some work trying to develop some probiotics potentially for rotavirus, which affects a lot of developing nations and so there’s some complexities there. Like how do I get it – remember all that cold chain stuff – like how do I deal with that in certain countries? So that’s a little complicated. But that’s an interesting arena. The area that we’re focused on is with HIV. We performed some studies out of Rome several years ago where they looked at administering probiotics to patients that were long-term HIV patients that had HPV, human papillomavirus, in their body, particularly in the anal cavity. So what happens for some HIV patients is the HPV starts to grow. The immune system of the HIV patient is advanced in that they have antiretrovirals now, so the medicines that we have available to treat HIV are very good, but the immune system is still not up to the same level as an otherwise healthy person. So what happens is they have a lot of this HPV virus, and then the HPV virus causes cancer in the anal cavity. And it can happen in the vaginal cavity as well. So obviously HPV ultimately causes various vaginal cancers, and that’s why we have HPV screenings. The same issue happens in people that have had HIV for very long periods of time. We have a study that shows that we can reduce this viral load in HIV patients that have HPV. So the next question is, okay, can we, over long periods of time, prevent these anal cancers from taking place? There’s a group based at University of California, San Francisco, that put together a clinical trial and we’re working with them on studying this issue in detail with a large group. It’s called the CAMPO group. It’s based in several centers around the United States, Mexico, and Puerto Rico. And this is a significant unmet need in the HIV community; secondary cancers that are really ultimately a result of the long-term HIV are a major issue. There’s not a lot of options at this point. So the hope is that we could reduce that HPV load and then ultimately reduce the cancers long-term. We’re very early in this. We have a very small study that was done in Italy, which pointed to some favorable outcomes, but we’re still a long ways away from actually having a solid product that’s indicated for that application.
It’s an interesting area because we are seeing more and more that a lot of these cancers are virally induced. You think about hepatocellular carcinoma, liver cancer that kills millions of people worldwide, and that often occurs in people who are infected with hepatitis. You think about throat cancers from HPV, etc. So the idea that cancer is a result of an infection – a viral infection, and we can actually treat it with bacteria, is really fascinating and sort of comes full circle. And not to suggest that chemo doesn’t have a place, but again, instead of suppressing somebody’s immune system to treat cancer, which can often lead to secondary cancers and more widespread disease, that you’re actually bolstering their natural immune defenses with bacteria.
And the concept in HPV is pretty simple. There’s a lot of antiviral components that are created when the bacteria ferment in the GI tract, but also it’s this basic concept of overpowering and overpopulating the gut with these healthy microbes, these healthy bacteria that help to prevent the HPV virus from growing. It’s sort of like the healthy lawn – doesn’t have a lot of weeds because there’s just no space for them. All the nutrients are being absorbed by the healthy lawn. So it’s the same basic concept.
Marc, you’re basically describing the thesis for my last book, The Anti-Viral Gut, and this idea that it’s less about the potency of the pathogen and more about the health of the host, and specifically the microbial health. When we think about all the different ways that bacteria are able to fight viruses, one of the really simple ones is just competing for binding spots. So we think about SARS-CoV-2, the virus that causes COVID, and the ACE-2 receptors that it binds to. Bacteria sort of jump ahead and bind, take up all those binding sites, and so the SARS-CoV-2 can’t bind, and it can’t create that infectious and inflammatory cascade. It’s like musical chairs, right? And it takes up all the chairs, so SARS-CoV-2 has nowhere to sit down, and of course there are lots of other things too. Some of the things you talked about, some of these postbiotic products that are being created and cytokines and all the different things. But the idea of using bacteria that are naturally in our gut to fight viruses is completely up my alley. I spend a lot of time talking to people about antibiotics and the damage they do, notwithstanding that they’re still probably the greatest invention, certainly in the last century in the medical world, but they do a lot of damage to the gut. So it’s exciting to think about how something like this, a probiotic that can essentially battle viruses, could have broad use.
In that case, the product itself is, it’s actually intended for use as a drug. So this is a new arena for probiotics, they are actually called “live biotherapeutics”. So this is a product that’s made to the standards of drug products, which is sort of an elevated manufacturing standard, and then it goes through the full FDA process. And it’s a much higher potency product than anything that’s commercially available as a non-drug medical food or dietary supplement. So in this case, the dosing administration for that clinical protocol is about 3,000 billion live bacteria per day. So it’s a huge amount of probiotics.
And this would be, I would anticipate, a prescription product, correct?
That would be the goal. Long-term you’re trying to make this a prescription product and go through the whole FDA approval process. So that’s a big, long process, but yeah, that’s something that we’re working on.
Do you think that this could have efficacy in non-immunocompromised patients down the road?
Good question. I don’t know. That’s something we could explore, but I’m not sure.
We are back talking about probiotics, past, present, and future. And one of the future areas that I’m really excited about is this idea of “psychobiotics”. And I think it’s a natural progression from nutritional psychiatry, which is also a really interesting area. People like Dr. Drew Ramsey and Dr. Uma Naidoo, I think, are pioneers in that field, which basically is just saying that what you eat affects your mental health the way it does affect the rest of your health, your gut health, immune health, etc. And although it sounds so obvious and intuitive, it’s amazing that it is sort of revolutionary in the psychiatry world that you can actually influence disorders like anxiety and depression and even more severe disorders like schizophrenia through what we’re eating and through food. And so, psychobiotics, I think, are just sort of an additional progression of that. So you also have some studies to talk about.
Yeah, this is a really exciting new field. This is, you know, the gut-brain axis, as they call it. Obviously, there’s a direct connection, direct neurological connection between the gut and the brain. I think there were even studies years ago where you could cut those nerve endings and affect depression in ways. So we have one study that was done in Zurich, Switzerland, using our formulation in patients that were depressed and actually hospitalized. And it was used as an adjunct along with other therapies. There was some effect, for sure, not dramatic. I think we’re still early days in this concept in this research. We have a second study that we’re looking to start later this year at University of California also looking at depression. So I think there’s certainly something here. I don’t think that anyone is really ready today to make a recommendation that this should be a core part of management of mental health disorders. But this is how science works. You get these early indications, and you go, well, maybe it doesn’t work in this particular type of depression or this particular type of anxiety, but maybe it works in this other type. Maybe there’s other treatments that go along with it that help. So it takes many, many years to really source this out and figure out, is it really working in patients?
And I think there’s also the issue of the augmentation with diet. So, for example, if we look at something like FMT, fecal microbiota transplant – a poo transplant for want of a more delicate term – there’ve been a lot of studies in neurological diseases like Parkinson’s and autism spectrum disorder, and what the data show is that if you just give a stool transplant and you don’t do anything differently, you don’t see much effect. But if you get that person to change their diet, now you really start to see some changes. So are you looking in any of these studies at diet plus probiotics, and are you looking at live biotherapeutic doses or more standard doses?
So I think for any of these applications, you’re going to need pretty serious doses. So it’s not something we’re looking at for our live biotherapeutic product – the drug version of the product – yet, but it is something that we’ve considered for sure. The first step for us has been these smaller studies to see if it’s safe. It seems to be safe. There doesn’t seem to be any issues with consuming probiotics if you’re on SSRIs or other things. But the next step would be more research and really identifying therapeutic areas that make more sense for us.
And I just want to emphasize, again, this idea of food versus probiotics. It’s really both! And it’s true for anything. If you think about it, if you have reflux and a doctor prescribes a proton pump inhibitor (and lots of reasons why you might want to reconsider before taking that unless you absolutely have to), but in a situation like that, if you also cut down on your caffeine and stop eating late at night and eat smaller portions and do all those other things, you’re going to have a better result from that proton pump inhibitor than if you just took the drug alone. So it’s true for virtually everything. If you have heart disease and you change your diet, if you have rheumatologic disease and you change your diet, and so we would anticipate the same thing here with probiotics, right? And particularly because you are trying to create an environment in your gut that is favorable to the growth of these organisms. It’s a big new concept and field that’s just getting started, really. But it’s pretty cool and it’s going to be interesting to see where it goes over the next 10 years. So one of the things in terms of future probiotics that I’m also excited about is this idea of a more sophisticated fecal microbiota transplant. Nobody’s super excited about the idea of having somebody else’s poo introduced into their body, whether that’s rectally through a colonoscope or with an enema or orally with capsules or a scope. So this idea that you would take your innate microbes, and you would amplify them out of the body and reintroduce them. So sort of like a super probiotic but derived from your own stool. Although you could argue, well, just take a probiotic, right? That might be a better way to do it. Can you think of any major differences between those two things?
So it’s a really interesting idea. Just knowing how probiotics are made, it would be super, super complicated. That would be a drug for sure. So you would have to get FDA approval for each individual product. Even if it’s your own stool, there’s so many different regulatory complexities involved with doing that. And then you’d have to figure out, it’s so hard to ferment the individual strains by themselves, right, in a soup. And you’re dealing with, in this case, probably a thousand different species of bacteria, and all have different needs to grow. And so, you’d have to selectively figure out how to grow this pool of strains over here, but maybe not this pool over here. And then maybe it’s different person to person, you know, it would be cool, but super complicated.
So right now we should probably just think about getting a stool transplant from a really healthy plant eater who doesn’t eat McDonald’s?!
For C. difficile colitis, which I’m sure you’ve talked about, this is like standard of care now, and there’s two drugs that are approved, which are fecal transplant products, and they work pretty well. So we may be heading in that direction.
Marc, thank you so much for joining us today on the Gutbliss Podcast. It’s been great hearing about all the different studies, particularly in areas like cancer in immunocompromised patients, viral illnesses, and mental disorders. This is really exciting stuff. Thanks so much.
I want to leave you with three takeaways about probiotics and their potential uses.
1. If you are taking a probiotic, make sure that it has the appropriate research behind it. For example, does it have a medical food designation, which means it has been tested and found to be effective for the dietary management of a specific disease or condition, or are those just marketing claims on the packaging.
2. Avoid products that give the amount of bacteria (CFU) “at time of manufacture” because that doesn’t account for the rapid decline of bacteria that occurs between when the probiotic is made and when you consume it, so you want to make sure the labeling is referring to the amount of viable bacteria present when it actually reaches your GI tract.
3. Current indications for probiotics include conditions like IBS, UC, traveler’s diarrhea, etc. Future indications may include viral illnesses, mental health disorders and even cancer. But remember, the efficacy of whatever you’re taking – whether it’s a high grade live biotherapeutic, a prescription medication, an over the counter probiotic, or a supplement – all are going to be more effective when combined with dietary change: more plant fiber, less ultra-processed food.
So that’s it for this edition of the Gutbliss Podcast on the future of probiotics. If you’re looking for more detailed information on probiotics check out my second book The Microbiome Solution. Coming up next week on the Gutbliss Podcast, one of the most misunderstood GI disorders: SIBO, small intestinal bacterial overgrowth.
