Today, you can find claims about how to improve your gut health with foods in grocery stores, to the supplement aisle at your local pharmacy. But, do those claims hold true? The science about what constitutes a "healthy gut" is still uncertain, but what scientists do know is that our gut microbiome holds the keys to a lot about our overall health. Our gut microbiome can impact our brain, mental health, digestion...and even our likelihood of developing food allergies or catching common colds.
On this episode, Profs. Cathy Nagler and Eric Pamer of the University of Chicago discuss the science of our gut microbiome and the questions their labs are investigating about the function of our gut. Nagler is an immunologist and the Bunning Family Professor in the Biological Sciences Division and the Pritzker School of Molecular Engineering; Eric Pamer is professor in the Department of Medicine, Microbiology, and Pathology, and director of the Duchossois Family Institute.
(Episode published March 16, 2023)
- How sleep affects human health, explained—UChicago News
- Polymers help protect mice from anaphylactic reaction to peanuts, UChicago research finds—UChicago News
- Food allergies can be reversed in mice by targeting the microbiome—Science Daily
- A compilation of fecal microbiome shotgun metagenomics from hematopoietic cell transplantation patients—Nature.com
Paul Rand: Some epidemics happen in a sudden and obvious rush. Others kind of slowly creep up on us.
Tape: Nearly six million children in the U.S. now suffer from food allergies. That’s equal to two students in every classroom, with a dangerous condition that can easily turn deadly.
Paul Rand: Growing up, I remember only one or two kids in my school who had peanut allergies, but today, you can find a kid with an allergy in nearly every classroom. Food allergies have exploded.
Tape: It really is almost an epidemic. We don’t know exactly why they’re-
Tape Are we better at catching this-
Tape: ... or is it this is really... These are kids who are so much more allergic.
Tape: This is real.
Paul Rand: These days, it’s not just hundreds of thousands of people with food allergies, or millions, but tens of millions.
Tape: It’s a rise that is an epidemic by definition. For some countries, it’s doubling every 10 years.
Paul Rand: The question is, why?
Cathryn Nagler: It’s changed so fast. It’s changed in a generation that people don’t believe that this is a real change in that they think that people with food allergies are just complaining. It’s a really serious problem.
Paul Rand: That’s Dr. Cathy Nagler.
Cathryn Nagler: I’m an immunologist and a professor in the Pritzker School of Molecular Engineering, and in the biological sciences division.
Paul Rand: Nagler’s Lab has been at the forefront of food allergy research. They wanted to understand what’s causing this uptick in food allergies. They found answers in a place that’s gotten a lot of attention over the last few years, our gut microbiome.
Tape: Several companies now offer at home gut microbiome testing.
Tape: There’s a new organ in our bodies, a newly discovered organ that we call the microbiome.
Tape: The microbiome.
Tape: The gut microbiome.
Tape: The gut microbiome.
Paul Rand: We all know the phrase, trust your gut, or go with your gut feeling. Well, it turns out there may be more truth to that saying than you think.
Cathryn Nagler: The function of the gut microbiome, what is clear is that it extends way beyond the gut.
Paul Rand: In fact, it may even affect our brains.
Cathryn Nagler: Yes, yes.
Paul Rand: It can even cause us to feel anxious or sad.
Cathryn Nagler: That’s through this gut-brain axis that’s just starting to be elucidated.
Paul Rand: Our gut is responsible for all sorts of things you would never expect.
Cathryn Nagler: Unhealthy gut is reflected in all of these, what’s called chronic non-communicable diseases. Food allergy, obesity, IBD, autism, all of these diseases that have been increasing in parallel over the last 30 or 40 years, many scientists believe are a consequence of a loss of diversity, of bacteria and other microbes in our guts.
Eric Pamer: It’s probably at this point hard to find a disease that isn’t impacted by the microbiome.
Paul Rand: That’s Dr. Eric Pamer, Professor in the Department of Medicine, microbiology and pathology, at the University of Chicago, where he directs the Duchossois Family Institute.
Eric Pamer: As an infectious disease physician, my interest has been on how these bacterial populations provide resistance against infectious diseases.
Cathryn Nagler: There’s a lot of potential for our understanding of the microbiome and for our ability to take that into understanding and to develop new drugs, to treat disease.
Paul Rand: If you’re saying to yourself, “Well, I take my probiotics. I can skip this episode.” Well, you should know it’s not that simple.
Cathryn Nagler: Some of what you hear, especially as it relates to probiotics, some of it is not entirely based in science. There’s no really good evidence that they have efficacy in preventing or treating disease, even though you can buy them at any whole foods.
Paul Rand: Welcome to Big Brains. On our show, we translate the biggest ideas and complex discoveries into digestible brain food. Big Brains, Little Bites, from the University of Chicago Podcast Network. I’m your host, Paul Rand. On today’s episode, the importance of our gut microbiome.
You may not realize it, but all day, wherever you go, you carry millions of tiny living hitchhikers with you. They’re called microorganisms and they’re all over your skin, in your nose and in your gut. We share these microbes with everything we touch, from subway rails, to dishes, to the computers on our desks.
Cathryn Nagler: First, let’s define the microbiome.
Eric Pamer: The microbiome, in general, is understood as being the collection of microbes that either live on our surfaces or within our body cavities that are accessible to the outside world.
Cathryn Nagler: We’re going to talk mostly about bacteria, but there are other microbes, including viruses, fungi. They all live together in a complex interactive community.
Paul Rand: If you had to think about how this actually works in humans, specifically, how does a microbiome work in humans?
Eric Pamer: I’m going to focus predominantly on the microbiome that resides in the intestine. That collection of organisms is different depending on where in the intestine you are.
Cathryn Nagler: The gut relevant to this discussion is going to be the last part of the small intestine and the large intestine. That’s where these bacteria live because they have to live in the absence of oxygen. It’s trillions of bacteria, not even talking about the other microbes that are living there, talking to each other, talking to the other microbes, talking to our bodies.
Paul Rand: The bacteria in our gut have many important functions, but the one you’re probably most familiar with is breaking down the food that we eat.
Eric Pamer: For example, when we eat an apple.
Cathryn Nagler: We can’t digest dietary fiber without our microbes. They ferment the fiber into important products for our health. There are certain vitamins that our bodies can’t make. The microbes make it for us.
Eric Pamer: One of the best known is Vitamin K, which is essential for us to have good blood clotting. We depend upon these bacteria to help us break down these foods. In their absence, although we can survive, we don’t survive as well.
Paul Rand: For our gut microbiome to do its job well, it needs a diverse range of microbes. But over the last several decades, the diversity we need has been slowly dwindling.
Cathryn Nagler: The biggest culprit is the overuse of antibiotics.
Eric Pamer: My interest in the microbiome developed when I was working as the chief of infectious disease at Memorial Sloan Kettering Cancer Center. I had a close relationship with the bone marrow transplant team at that institution because infectious diseases represented one of the major complications of bone marrow transplantation. What we learned quite early on was that the microbiomes of bone marrow transplant patients are profoundly impacted by the antibiotics that are administered to patients.
The trigger for using antibiotics and bone marrow transplant patients is very easy to pull because these patients are profoundly immunocompromised. We know that the immune system provides critical defenses against these dense populations of bacteria that live within our gut, because every once in a while, one or two of them slip past the barriers. Our immune system is sitting there and waiting and protects us.
Paul Rand: In fact, 70% of our immune system is located right in our gut. The two are intimately linked with one another.
Eric Pamer: Our immune system is really essential for our survival, in part, because it protects us from the dissemination of these bacteria from the gut. But it’s a two-way street. It turns out that our immune systems are also triggered by some of the products of these bacteria that live in our gut. In order for us to have normal immune defenses, these microbes need to be there in order to drive the immune system’s development.
Paul Rand: You can think of the gut like a encyclopedia. It gains more and more knowledge from the bacteria and microbes it interacts with, becoming smarter and stronger over time. But antibiotics can reverse some of that progress.
Eric Pamer: Not all antibiotics are the same, but there are certain antibiotics that can wipe out almost all of the normal residents of the gut. I’ve heard many times that it takes people months to recover from a course of antibiotics and before their bowels move normally and before they feel well again. I sometimes refer to as a wound in the patient. It’s the collateral damage to the microbiome.
Paul Rand: Got it.
Eric Pamer: We are not providing them with an effective way of reconstituting their microbiome. I’ve lived with this, in this field now for close to 15 years as a physician who now has probably a deeper knowledge of the microbiome and its health impacts than most physicians. What I preach is, think about the antibiotic choices you make. If you can treat with an antibiotic that doesn’t kill anaerobic bacteria in the gut, then choose that one.
Paul Rand: Okay.
Cathryn Nagler: One approach we can make towards the use of antibiotics is to improve diagnostics. When a child comes into a clinic with an ear infection we should be able to have a diagnostic that can determine whether that infection is bacterial or viral in a couple of hours, instead of just jumping for the antibiotics. We have the technology to do that. We’re just not doing it. Not to say that people should disregard their doctor’s advice, but have a conversation about whether that antibiotic, whether there’s evidence that an antibiotic is necessary, or whether we could stop and test for the presence of a bacterial or viral infection.
Paul Rand: But of course, antibiotics aren’t the only enemy of our microbiome that we need to be aware of. There’s another factor that has played a big role in our gut health.
Cathryn Nagler: The other big factor is diet. Our microbes have co-evolved with us. We’ve changed the diet. They eat what we eat. We’ve changed their diet and they’ve had to adjust to this new environment that we’ve put them in.
Tape: What happens when hot and cool combine? Hot eats, cool treats. With a taste that’s going to drive you fruity.
It’s a part of this complete breakfast.
Cathryn Nagler: We are consuming a fast food diet that’s poor in Whole Foods.
Tape: This nine layer gastronomic indulgence is known as a Big Mac.
It’s a real American phenomenon. Those big name restaurants we know we can rely on from city to city across the country.
Cathryn Nagler: All of those factors together have led us to have a 21st century microbiome that’s out of sync with the aspects of our health that it was previously controlling very well.
Paul Rand: A lot of your research is focused in on food allergies, is that right?
Cathryn Nagler: Yes. It’s a big problem. In the United States, 33 million Americans currently suffer from food allergies, some of which are life-threatening.
Paul Rand: Tell me if this stat is right, but I think I saw something that almost 400%, 377% increase in the prevalence of food allergies between 2007, 2016.
Cathryn Nagler: That’s correct.
Paul Rand: Does it affect children more than adults, or any age group more than adults? What characteristics do you point to?
Cathryn Nagler: Historically, it’s often appeared first in children, but we’re seeing more and more adult onset food allergies. You can become allergic to any food at any point in time, but there are nine foods that are the biggest defenders.
Paul Rand: Okay. I hate to ask you, but can you tell me what the top nine are?
Cathryn Nagler: Sure. Peanuts, tree nuts, shellfish, fish, milk, eggs, wheat, soy and sesame.
Paul Rand: Is it likely that people will outgrow some of these allergies?
Cathryn Nagler: When I was a child, I had an egg allergy, which I outgrew in a few years. That was common 40 years ago. Now, we’re seeing some children outgrow their allergies, but many more continue them into adulthood. As I mentioned, and as you mentioned, we now have adults that are exhibiting food allergies for the first time.
Paul Rand: It’s remarkably we talk about this, and I would say probably 10 or 15 years ago, my wife, who had always enjoyed shellfish, ended up eating and getting violently ill. She tried it a second time to make sure and realized it was the shellfish that really got her. It seemed to the point that you’re saying. It came out of nowhere.
Cathryn Nagler: Yes. That that’s a common finding.
Paul Rand: My goodness. Okay. My understanding is that your lab was actually the first to identify a link between the microbiomes in the gut and food allergies. Is that right?
Cathryn Nagler: Yes. What we found is that there was a particular subset of commensal bacteria that regulates the function of the epithelial barrier by secreting products that control the access of allergens into the blood. If these bacteria are depleted, that function is lost, the allergens get into the blood where they can stimulate cells of the immune system called mass cells. Mass cells release the mediators of an allergic response. One of these is histamine, which everybody knows because we take antihistamines when we have an allergic response.
Paul Rand: How did you end up finding this link?
Cathryn Nagler: We showed it by treating mice with a cocktail of broad spectrum antibiotics to deplete some of the bacteria in the gut. When we did that, we showed that those antibiotic treated mice had an allergic response that wasn’t seen in the non-treated mice. We went on to isolate different types of bacteria and finally identified the particular bacterial class that’s involved in the protection against allergy.
It didn’t kill all of the bacteria in their gut. It killed some of them. But then we were also able to use germ free mice, which have no bacteria, and confirm what we saw in the antibiotic treated mice.
When protective members are depleted because of our lifestyle factors, we have some barrier dysfunction. We don’t protect the epithelial barrier in the way that we had been doing. That’s what’s allowing allergens to gain access to the systemic circulation, to the bloodstream, and elicit an allergic response.
Paul Rand: Out of all of this, that you have a startup company that’s going to start addressing some of these things?
Cathryn Nagler: Yes. Our goal is to restore this barrier dysfunction to prevent the initiation of an allergic response, or tone down an existing allergic response by blocking the allergen from continuing to interact with with the immune system.
My startup company, ClostraBio, was co-founded with Jeff Hubbell, a bioengineer and a guest of your podcast. Jeff created chemical polymers that can deliver microbial metabolites to the lower part of the gut where most of these bacteria live. The metabolite we’ve started with is butyrate. There’s already a large body of evidence in support of butyrate’s ability to regulate both the intestinal barrier and the immune system. We can show in animal models that after only two weeks of treatment, our drug can prevent allergic mice from responding with an anaphylactic response to challenge with the allergen. We can also treat mouse models of colitis. We call our polymer system a drug delivery platform because we can use it to conjugate other discovery polymers as they become of interest. I would guess that there are hundreds of, if not thousands, of microbial metabolites waiting to be discovered. We can use our polymer backbone to create lots of different formulations on the same backbone.
Paul Rand: Give me five years out. If everything goes right with what you’re doing, or maybe it’s 10 years out, what do you see happening?
Cathryn Nagler: We hope to be in clinical trials in one year. We’ve already met with the FDA. We’re finishing all the studies for an investigation on new drug application. I’m very hopeful that our drugs will be effective in treating food allergies and to emphasize that the increase in food allergies is very real and life threatening and needs interventions. I hope we can provide one.
Paul Rand: As we’ve learned, our microbiome rules, so many aspects are of a physiology, from digestion to our ability to fight common colds and viruses, to how likely we are to develop food allergies. It’s not surprising that gut health has become a hot topic these days, but what does a healthy gut look like? Can you really optimize your gut health? We’ll find out after the break.
If you’re getting a lot out of the important research shared on Big Brains, there’s another University of Chicago podcast network show you should check out. It’s called Entitled. It’s about human rights, co-hosted by lawyers and new Chicago law school professors, Claudia Flores and Tom Ginsburg. Entitled explores the stories around why rights matter and what’s the matter with rights.
Recently, scientists have learned more about what influences our microbiome and how our microbiome influences us, but they’re still figuring out what a healthy gut microbiome looks like and how it varies from person to person.
Cathryn Nagler: We can’t exactly define a healthy gut microbiome because it’s going to be different for someone living in Chicago and someone living in Africa, for example. It’s going to be different based on geography and environmental exposures. We don’t really know all the components of a healthy microbiome.
Eric Pamer: Every human, except for identical twins, has a distinct genome. The genome influences our relationship with the bacteria that reside within us. A bacterium that is completely innocuous in one individual may trigger an inflammatory response in another one. The only way to really know if you have a diverse microbiome is to provide a fecal sample and have it sequenced. I’m not recommending that because it also has a possibility of raising concern that may be unwarranted. There are certain bacteria that in certain circumstances have been associated with adverse outcomes that are probably very limited and shouldn’t alarm anybody. There are associations between certain bacteria and autism, for example, that are not well substantiated.
Paul Rand: COVID-19 actually became a turning point for our understanding of a healthy microbiome. One of the big mysteries early in the pandemic was why some healthy patients were able to recover from the virus while others weren’t so fortunate. That question intrigued nurses at U Chicago Medicine and they had a novel idea. Maybe the answer could be found in the patient’s microbiome.
Eric Pamer: Yes. This is an important study that the pulmonary critical care group here with JP [inaudible 00:21:59] put together. We collected samples from patients who ended up being hospitalized in the medical intensive care unit because of respiratory compromise. These were people at the more severe end of the Covid spectrum. What [inaudible 00:22:18] group was able to do was to identify microbiome characteristics of these patients near the time when they came into the medical intensive care unit, and then correlate that with the subsequent outcomes. Out of the 71 patients that they examined, about 30 of them had progressive respiratory failure and died, and 40 of them improved and did better. They were able to show that the composition of the microbiota, at the time of the initial entry into the medical intensive care unit, could predict the course that they were going to subsequently follow. That suggests that the composition of the microbes in the gut may influence the progression of inflammation in the lung during the course of Covid.
Paul Rand: What did those microbiomes look like in people that were able to recover versus those who couldn’t?
Eric Pamer: The patients who didn’t recover, there were more of a specific type of bacterium that belongs to a family, referred to as enterobacteriaceae. More importantly, what the Patel group was able to do was to demonstrate that the metabolites that these bacteria produce were very different between the two groups. There were certain small chemicals that the bacteria in the gut produced that were present at much higher concentrations in patients who recovered and were essentially missing in the patients who had progressive failure. Now, some of these metabolites have been demonstrated in animal models to enhance immune defenses to support healing of epithelia, including in the lung, and to reduce inflammation. It’s a real balance of optimizing defenses, preventing the defenses from going overboard and damaging the lung, for example, and then contributing to the reestablishment of normal tissue barriers.
Paul Rand: There’s also been other studies about the relationship with the gut microbiome and even other diseases, whether it’s Parkinson’s, or hypertension, or others. Is there some correlation between what you described and what you’re seeing as the correlations between some other diseases?
Eric Pamer: Yes. We have papers coming out now showing the really remarkable impact of the microbiome on outcomes of liver transplantation, heart transplantation, and on patients with severe liver disease, as well as patients undergoing cancer therapy here. We’re really just at the beginning. An important point though is that the microbiome isn’t the only explanation for these diseases. It’s a contributing factor. It can influence the severity of inflammatory response, but it is generally not the only driver of that response.
Paul Rand: I guess the question is, if you have a response, the strength of your gut microbiome could be a really contributing factor in how well you either fend it off or how quickly you could recover from it.
Eric Pamer: Exactly. I think that’s a very good way of putting it.
Paul Rand: This begs the question then, and of course, everybody listening to this is saying, “Oh my gosh, what do I do about it and how do I strengthen my gut?” You’re sitting around with a bunch of your colleagues and somebody says, “Let me tell you what I’m doing for my gut health.” Y’all start comparing notes. What are you saying and what are your colleagues saying?
Eric Pamer: It comes back to fiber and upping our fruits and vegetables and reducing our processed foods.
Paul Rand: It’s not a very lively conversation, is it?
Eric Pamer: No, it’s not.
Paul Rand: If somebody wanted to say, I guess the question would be, we all kind of know that basic advice, but of course, everybody is not going to sit down. They know that they’ve heard it. They’re looking to say, “Well, got it, but give me a hack.”
Cathryn Nagler: We are doing an interventional study, for example, with potato starch. That’s been shown in scientific studies to be a dietary fiber that’s effective in expanding populations of butyrate producing clostridia.
Paul Rand: Okay. If I’m listening to this podcast, I’m going to go run out to the store and try to buy a bag of Bob’s potato starch. Is that something that I should be doing?
Cathryn Nagler: Yes. At one point, Jeff Hubbell was adding it to his coffee.
Paul Rand: My goodness.
Cathryn Nagler: It doesn’t taste good, but you can add it on to your cereal or something like that.
Eric Pamer: I think there’s a big push now to find ways to get people to increase their fiber. We evolved originally eating lots of vegetables and ingesting a lot of fiber, but our diets now in Western society are often quite fiber poor, which is not providing the lower intestinal tract with the nutrients that they need.
Cathryn Nagler: Another example from Justin Sonnenburg’s lab at Stanford, showed clearly that fermented foods, like kombucha, for example, can increase microbial diversity and reduce markers of immune inflammation. He’s actually done a clinical study on that. There is some truth to what the popular media is saying about gut health, but so much of it is not science-based that it’s hard to pick out the truth from the fads.
Paul Rand: What is the distinction between what is real there and what is fad there?
Cathryn Nagler: Unfortunately, a lot of it is fads.
Eric Pamer: Any CVS or Walgreens has shelf upon shelf of probiotics.
Paul Rand: They do.
Eric Pamer: These are sold over the counter. They are loosely regulated, largely because they don’t make very clear health claims, because the moment you start to make a health claim, the FDA is going to regulate you much more stringently. Those probiotics have been studied extensively. The benefits of them are probably very limited.
Cathryn Nagler: So far, the biggest success with transferring live bacteria has come from fecal transfer, meaning transferring whole feces from one individual to another. That is not really desirable, for obvious reasons-
Paul Rand: You’re right.
Cathryn Nagler: ... but it’s effective in treating C. difficile colitis, which can be, is a life-threatening form of colitis. When you transfer fecal material from another individual, a healthy individual into those patients, it cures the disease.
Paul Rand: My gosh. I may be sorry I’m asking this, but how do you transfer fecal material?
Cathryn Nagler: You can put it into capsules tubes. There’s a lot of different approaches. All of them, basically, unappealing, I think.
Eric Pamer: What we have now learned is that the bacteria that live within us are difficult to culture. They can’t survive in the presence of oxygen. They don’t smell good and they don’t taste good. They’re not likely to make their way into yogurt or other processed foods, but they are the ones that are probably going to be the probiotics of the future.
The big goal of the Duchossois Family Institute here, among many other goals, but this is my goal, is to find a way of reconstituting people’s microbiomes with useful commensal organisms, our next generation probiotics, so that when we complete a course of antibiotics, we in infectious disease say, “Okay, now what we have to do is we have to sew up this wound.” We do it by giving capsules that contain these that will reestablish some of the normal metabolite profiles that we like to see.
Paul Rand: Gotcha.
Eric Pamer: I think that is something that needs to become part of medical practice. In fact, we at the University of Chicago, are coming close to completing a manufacturing facility referred to as a GMP facility to be able to manufacture some of these obligate anaerobic organisms so that we can give them back to patients after they get treated with very broad spectrum antibiotics.
Paul Rand: GMP means what?
Eric Pamer: It means good manufacturing practices.
Paul Rand: Okay.
Eric Pamer: It’s a clunky name for something that is absolutely critical for the conduct of clinical trials where we produce something that we’re going to put into human beings. That needs to be FDA approved. We have to apply for an investigational new drug approval to do these trials. In order to do that, you have to have a facility that guarantees purity of one’s product, the cleanliness of it. That was a multi-multimillion dollar investment on the part of the University of Chicago for us to be able to grow these bacteria in a form that we don’t just put them into mice. We are actually going to reintroduce them into people. And we are going to be the only academic institution with a GMP facility that can produce anaerobic bacteria in capsules forms for clinical trials.
Paul Rand: We’ll have to check back in with Dr. Pamer and Nagler as they continue to design the probiotics and microbiome drugs of the future. In the meantime, be kind to your gut.
Matt Hodapp: Big Brains is a production of the University of Chicago Podcast Network. If you like what you heard, please leave us a rating and a review. The show is hosted by Paul M Rand and produced by me, Matt Hodapp and Leah Ceasrine. Thanks for listening.
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