The Gut Microbiome and Immunity. Podcast with Dr. Lucy Mailing

Within our gut resides a vast ecosystem that guides countless facets of health and performance.

Now, the most obvious function of the gut is breaking down food and extracting nutrients, which of course is super important. But its influence appears to extend far beyond that. Emerging research shows that your gut microbiota may impact many different and seemingly unrelated aspects of health and bodily function, including appetite and body weight regulation, lifespan, mood, cognition, and even athletic performance.

We also know that the gut plays a role in the immune system. In fact, it is thought that over 70% of the body’s immune cells reside in the gut. This might sound kind of weird at first, but it actually shouldn’t be too surprising. Think about it: The gastrointestinal system is the primary route of contact with all the gnarly things that surround us in the external environment. Every day, it is bombarded with loads of stimuli from the outside world. Some of these are very useful, like food and beneficial flora, but others are potentially dangerous, like pathogens or toxins. In that context, it makes sense that the immune system and the gastrointestinal system would develop a close mutualistic relationship.

Throughout life, gut microbes shape and regulate the immune system, and the immune system in turn guides the composition of the flora in the gut. When this ecosystem is healthy, it provides ongoing resistance against invasion by pathogens. This is why people who take antibiotics that wipe out a broad spectrum of microbes sometimes (ironically) become more vulnerable to certain opportunistic infections that are normally kept in check by friendly residents of the gut.

So how do they do this? We think gut microbes work a lot of their magic by generating crucial metabolites. For instance, you probably know that gut microbes can ferment dietary fiber into short-chain fatty acids. These metabolites feed the cells that form the gut barrier, and stimulate secretion of a protective layer of mucus that helps keep microbes a safe distance from our gut epithelium.

These metabolites may also help modulate the immune system response to invading viruses. For example, one remarkable study from a couple years ago found feeding mice a high-fiber diet increased survival when the rodents were infected with influenza by elevating production of SCFAs. This rise in SCFAs seemed to help curb damaging inflammatory responses in the lungs from the innate immune system, while at the same time boosting antiviral immunity by activating T cells. Studies like this suggest that we may be able to influence our immune system, at least indirectly, through our diet.

So, does this mean that eating lots of fiber can help protect us from getting sick? What about taking antibiotics? Or other pharmaceutical drugs? And how does aging figure into this puzzle – could maintaining a healthy gut microbiome help protect older adults, who are generally at greater risk of infection?

On this episode of humanOS Radio, Dan speaks with Lucy Mailing. Lucy has a Phd in Nutritional Sciences from the University of Illinois. Her research focused on the effects of diet and exercise on the gut microbiome and gut barrier function in states of health and disease. She is now involved with research determining the effects of an autoimmune protocol diet on the gut microbiome and intestinal barrier function in eczema and psoriasis, and to examine the effects of exercise on the gut microbiome in the context of inflammatory bowel disease.

She recently wrote a broad overview on what we know – and what we don’t know – about the role of the gut in the immune system and some ideas of what we can do to support the gut-immune axis. This obviously is relevant not just to COVID-19, but to your health and risk of disease in general, so we knew we had to have her on to discuss it.

To learn more about how gut health affects resistance to infections, check out the interview below!

01:00 – Intro by Dan.

03:15 – Intro by Lucy and how she got into the field.

04:12 – What is the gut barrier? Definition and function.

05:20 – Relationship nexus between gut barrier and immune system.

07:28 – What does a healthy gut microbiome entail?

10:00 – Parallel with microbiome and phytochemicals from plants.

11:00 – Inflammation and dietary effects of eating gas-inducing foods.

11:52 – Butyrate supplements – Dr. Lucy Mailing’s take on it.

14:19 – Impact of antibiotics on the gut barrier and systemic immunity.

16:59 – Personal anecdotes about antibiotic use by Dan and Lucy.

18:04 – Role and use of probiotics in general and after antibiotics.

21:14 – Deep dive on PPAR-gamma and gut dysbiosis.

27:34 – Aging and the gut.

28:52 – Precursors to butyrate production.

31:42 – “Rewilding” the gut microbiome – a cautionary tale.

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Lucy Mailing - 00:00: Microbiome research as a whole has spent the last two decades trying to define what is a healthy microbiota? And it's tricky because as individuals, we only share about a third of our gut microbes from one person to the next, and the other two thirds is determined by all kinds of different environmental factors, geography, even just random chance of which microbes we get exposed to when we're younger, potentially. So, there's so many different things that are going in there. What we do know is that if there is this core healthy microbiome, it's not at the level of specific microbes. It's actually at the level of microbial functions. So, you might have a different microbe in your gut than I do, but they fulfill the same function in each of our guts. So, there's a lot of, basically, this metabolic redundancy between different microbes being able to fulfill the same functions in the gut.

Kendall Kendrick - 00:50: humanOS. Learn. Master. Achieve.

Dan Pardi - 00:56: The gut, including the flora living inside the gastro intestinal tract affect many different aspects of health and performance for their hosts. Research in this field has shown us that gut health may impact many different and seemingly unrelated aspects of health, including appetite and body weight regulation, lifespan, mood, cognition, and even athletic performance. We also know that the gut plays a role in the immune system. In fact, over 70% of the body's immune cells reside in the gut. Throughout life gut microbes shape and regulate the immune system. When this ecosystem is healthy, it can provide resistance against invasion of pathogens. They may also help modulate the immune system's response to invading viruses.

01:42: For example, a study from a couple years ago found feeding mice a high fiber diet increases survival when they are infected with influenza, by elevating production of short chain fatty acids. This rise in short chain fatty acids seems to help curb damaging inflammatory responses in the lungs from the innate immune system, while at the same time boosting antiviral immunity by activating immune system T cells. Research into beta-glucans from mushrooms has shown similar results. So, does this mean that eating lots of fiber can help protect us from getting sick? What about taking antibiotics or other pharmaceutical drugs? And what about aging, could maintaining a healthy gut microbiome help protect older adults who are generally at greater risk of infection?

02:23: In today's episode of humanOS, I am speaking with Dr. Lucy Mailing. Lucy has a PhD in nutritional sciences from the University of Illinois. Her research focused on the effects of diet and exercise on the gut microbiome and gut barrier function in states of health and disease. She recently wrote a broad review of what we know and what we don't know about the role of the gut in the immune system and how gut health influences our resistance to infections and some ideas on what we can do to support the gut immune access. This obviously is relevant not only to COVID-19 but to your health, including your risk for disease in general. So, we knew we had to have her on the show to discuss this. Lucy, welcome to Human OS Radio.

Lucy Mailing - 03:05: Thank you so much. I'm excited to be here.

Dan Pardi - 03:08: How did you get into this field in the first place?

Lucy Mailing - 03:11: So, I had a long struggle with chronic eczema and pretty much tried everything down the conventional route, dermatologists, allergists, and never really had any success with that. I was just given steroid creams and told hopefully I'll grow out of it, but if not, I'm going to be stuck with this for the rest of my life. And I think it was on 2014 my sister put me onto some information about the paleo world and the potential for our diet impacting skin health. And I just went down the rabbit hole, really, and it kept building from there and I decided to turn my career around and focus on the gut microbiome and how that mediates the effects of our diet and lifestyle factors on our overall health.

Dan Pardi - 03:53: Once you are exposed to this field of ancestral medicine, it's really eye opening and world changing and exciting.

Lucy Mailing - 04:00: Definitely.

Dan Pardi - 04:01: So, the gut barrier is considered, I guess, our first line of defense since we're talking about immunity because, obviously, one key way for things to get from outside of the body into the body is for us to adjust them in the forms of food and liquids and things like that. Give us a primer on gut barrier function and also how this relates to our immune system.

Lucy Mailing - 04:18: In a lot of ways we can think of the interior of the gut as being actually outside of our body.

Dan Pardi - 04:24: Weird idea.

Lucy Mailing - 04:24: Yeah, it is a weird idea, but just like our skin is a barrier towards things that land on it, our gut is a barrier towards things that we ingest. So, the gut is really just this hollow tube and all the things that pass through your gut are outside the body. The gut barrier is really this single layer of specialized cells that are about the width of a human hair and they have to form a really tight barrier to prevent things from entering the body. A lot of things can mess with that gut barrier function, but essentially it's connected to the immune system because that gut barrier is the separation between the things that are in our gut, like dietary proteins, our microbes and the immune system, which kind of lies below that gut barrier.

Dan Pardi - 05:06: This interaction between the gut barrier and the immune system is really fascinating to me. Things like Peyer patches, that seem to be detecting the food that you're consuming and then responding to whatever it's detecting in an intelligent way and then the bi-directional relationship between immune aspects of the gut and the food that's coming in. Talk a little bit more about that relationship and how that works.

Lucy Mailing - 05:28: It's really quite amazing how our immune system can distinguish between things that are normal and harmless and things that are pathogenic, so it has a really important job of keeping those two things straight. And when that goes awry, then we have things like autoimmune disease, inflammatory bowel disease, food intolerances, other things going on, but that distinction should normally be there between things that are harmless and things that aren't and the gut immune system is basically constantly sampling the gut environment and seeing is this harmless, is this not? And launching an appropriate immune response to either dampen inflammation, if it's something that's not really going to be harmful to the body, or ramping up inflammation and launching an appropriate immune response over pathogens to prevent their invasion into the body.

Dan Pardi - 06:15: As I was looking more into Peyer patches for the show with Jeff Chilton, on mushrooms, I had the thought that the reactions of the immune system to different things that come in is almost similar to exercise. It almost seems like a stressor, which amplifies the immune response, but ultimately it's good for the host.

Lucy Mailing - 06:32: That's a really interesting analogy there. I think there's been several studies that have shown that germ-free mice, which are essentially mice that are raised in a sterile bubble and don't have any microbial exposure, they have a really underdeveloped gut immune system and systemic immunity as well. So, definitely need some of that exposure from our commensal, our harmless microbes, and even potentially pathogenic microbes to have that immune and gut homeostasis.

Dan Pardi - 06:58: This relationship is symbiotic, but it has to maintain its balance in order for it to continue to support us in the way that it would like. So, what does the healthy gut look like and how should things be functioning when it's all working as it should?

Lucy Mailing - 07:10: Yeah, that's the big question, right? And I think it's the trickiest question for researchers to try and elucidate. Microbiome research as a whole has spent the last two decades trying to define what is a healthy microbiota? And it's tricky because, as individuals, we only share about a third of our gut microbes from one person to the next, and the other two thirds is determined by all kinds of different environmental factors, geography, even just random chance of which microbes we get exposed to when we're younger, potentially. So, there's so many different things that are going in there. What we do know is that if there is this core healthy microbiome, it's not at the level of specific microbes. It's actually at the level of microbial functions. So, you might have a different microbe in your gut than I do, but they fulfill the same function in each of our guts. So, there's a lot of, basically, this metabolic redundancy between different microbes being able to fulfill the same functions in the gut. We do know that there seem to be a few key characteristics of a healthy microbiome.

08:12: One, is that it tends to have a high number of microbes that produce butyrate. So, butyrate is a short chain fatty acid produced from the fermentation of dietary fiber in the colon. And Butyrate's really key because it's providing 70% of the energy for our gut epithelial cells that form that gut barrier. So, without butyrate, our gut barrier suffers and so does the gut immune system as well because butyrate has a lot of anti-inflammatory properties, in terms of regulating the gut immune system. So, that's one thing, having enough butyrate producers and one of the ways that we can make sure we support those, is with dietary fiber.

08:48: And the other thing that seems to be characteristic across the board of healthy gut microbiota is that it excludes microbes that thrive in the presence of oxygen. The scientific term for it is facultative anaerobes. Basically the healthy colon is supposed to be pretty much devoid of oxygen, the mucosal and the interior of the gut. It's supposed to be really low in oxygen, an anaerobic environment and that selects for the beneficial microbes and selects against a lot of the opportunistic pathogens like E.coli, Salmonella. All of these are facultative anaerobes that can grow in the presence of oxygen and tend to be more inflammatory. So, we do see that if there is a core microbiome, it tends to have higher butyrate producers in healthy individuals and lower abundance of those microbes that can survive with oxygen.

Dan Pardi - 09:36: Another parallel that just came to mind is the endocrinological system and nature of phytochemicals. It's been really hard for us to say that this one phytochemical is essential, but then if you stand back and you look at how all the different phytochemicals in nature play an important role on things like metabolism, brain health, et cetera, you have a clear parallel between that type of system, where the effects are distributed, and the effects of the microbiome and how it can look very different but still have an outcome that is propitious.

Lucy Mailing - 10:04: Yeah, definitely and I think that really speaks to how we evolved in terms of there were changes in our environment. If we lost one microbe from our guts, we didn't want that to be the end of us, right? So, the idea that there is this redundancy in dietary exposures, in microbes, in so many other things that we really are resilient across a wide range of things. That being said, our modern environment is not exactly within that spectrum, often, that we are prepared to be able to deal with.

Dan Pardi - 10:32: If you are eating a diet that let's say produces a lot of gas in the stomach, could that be then shifted creating an opportunity for pathogens that you don't want there to get a foothold and grow?

Lucy Mailing (10:43): Definitely. To be fair, it hasn't been shown mechanistically, at least in the small intestine. The small intestine is a little bit trickier to study, a lot of unknowns like irritable bowel syndrome and those types of symptoms, but it is clear that inflammation can definitely cause a shift in the gut towards oxygen leakage into the mucosa and an expansion of those facultative anaerobes, and a reduction in the butyrate producers. So, if you have inflammation going on, it's likely going to be shifting you in that direction and it is a vicious cycle, right? Because dysbiosis in itself can cause inflammation in the first place and then you have inflammation that's then keeping those microbes around, that you don't necessarily want in there.

Dan Pardi - 11:22: Right. Going back to butyrate for a moment, you can also ingest it directly now, you can buy supplemental products and consume butyrate. Do you recommend that?

Lucy Mailing - 11:31: I do in some cases, particularly if you know you're not producing enough butyrate. The amount that you can safely supplement with, that is targeted to the colon, is pretty low compared to what a healthy person would produce from dietary fiber over the course of a day. But if you're not producing enough, if you've got some gut inflammation going on, perhaps you have inflammatory bowel disease or something else where you've got this low abundance of butyrate producers, low butyrate production, then yeah, definitely supplementing with butyrate could be one potential strategy to support the health of your gut barrier, and also break that vicious cycle. Because when you support the gut barrier, the gut barrier actually supports a healthy consortium of microbes.

Dan Pardi - 12:13: How would you know if you're a low butyrate producer?

Lucy Mailing - 12:15: The best way would be to get a comprehensive stool test and you can, from that, look at the abundance of different butyrate producers in the gut and you can also measure fecal butyrate levels directly. There are some issues with that depending on the methodology used, so it's not always a perfect measure. It's often better to look at whether you have the capacity to produce butyrate and also the fecal butyrate levels and try and make sense from there.

Dan Pardi - 12:39: Is there a less sophisticated way to know? So, instead of getting the test done, can you know with any sort of challenge, like I took some supplemental butyrate and I noticed my energy improved or I felt better right away? Is there anything that you can do to test a more experiential outcome versus more of an objective one from a stool test?

Lucy Mailing - 12:59: Certainly, yeah. There's really not any reason not to try empiric treatment. Just try some supplemental butyrate. I don't recommend the high doses of calcium and magnesium butyrate that some people are taking or recommending, just because they don't necessarily get to the colon where it should be produced and where it's needed and they're kind of providing mega doses in the hopes that some of it gets to the colon. So, I recommend smaller doses. There's a couple of different products, that I have no association with, but that are more targeted to the colon. ProButyrate is one and then Butycaps is another, which is a triglyceride form. Both of those have been shown to be more targeted to the colon and could potentially be useful to do an empiric trial with that. I do know people who have no gut symptoms, who have had neurological benefits from supplemental butyrate as well.

Dan Pardi - 13:42: Interesting.

Lucy Mailing - 13:42: So, there's a lot of dynamics we don't fully understand and I do hope we see more clinical trials with butyrate supplementation.

Dan Pardi - 13:48: Me too. Let's talk about antibiotics because this is another area that, of course, impacts the gut. They provide something that is of great value in some ways, but there's also a lot of thinking that we're overdoing it with antibiotics. So, give me your thoughts about how they actually ultimately affect the immune system and what your take is on whether or not you should take them or not, if you have a choice?

Lucy Mailing - 14:12: Great question. So, antibiotics definitely impact a lot, they're not selective for our beneficial bacteria. Most that you're taking most of the time will be broad spectrum, so they're not discriminating between the healthy and pathogenic bacteria and really wiping out everything. They're also stressing the gut barrier as well and making it inflamed, which can essentially start the cycle of dysbiosis. There's a number of studies that have shown that our guts mostly bounce back after antibiotics but not completely. So, often there is a slight reduction in diversity or there's a slight loss in certain microbial species that are important.

14:47: It's not always a complete recovery and that has major for our risk of chronic disease, our risk of respiratory infection, all kinds of things. So, certainly while you're taking antibiotics, that's when you're most susceptible. Particularly, when you take antibiotics you're wiping out everything in the gut and there's a concept called colonization resistance, and that basically means when your gut is chock full of microbes, it's basically all of those metabolic functions are being filled by all of your microbes and it's hard for any one pathogenic microbe to come in and knock out those existing microbes to gain a spot in your gut and take hold and cause infection.

15:26: But when you take antibiotics you're basically knocking out all those bacteria out of their normal niches in the gut, and you're opening up the chance for a new pathogen to come in. One that people might be familiar with is C. difficile, that's really common after antibiotics, especially if you're in a hospital environment where you might be easy to be colonized by that particular microbe and it's really quite serious. And interestingly, one of the best ways to treat it is to put in a whole consortium of microbes with a fecal transplant to try to bring back the entire ecosystem such that it can resist that C. difficile. But this certainly is not only applicable to gut infections. When I did this deep dive of the research on how the gut microbiota impacts systemic immunity, there were several studies that suggest that antibiotics can reduce our immune response to respiratory virus infection and this is potentially through a number of mechanisms, but one is potentially it's knocking out all of those butyrate producers and it's reducing butyrate, which is critical to, both to gut barrier function, but also to systemic immunity as well.

Dan Pardi - 16:30: I'm wincing because when I was a teenager to combat acne, I was on antibiotics like erythromycin for years. Then I got sick a lot more frequently from that point forward. Do you know of anything that suggests that even if you had a pretty significant exposure earlier in life, that there are some things that you can do later once you gain more awareness of, this connection can have a negative effect and that there are things you can do to make things better?

Lucy Mailing - 16:56: I'm in the same boat as you, Dan. I had countless antibiotics growing up, funnily enough for upper respiratory infections, which were probably viral, but I also got sick really frequently, so I would say we do have the potential to bounce back from that. The fact that you and I are both pretty healthy today I think is a testament to that. If you do all these lifestyle improvements, you start eating a better diet. All of these things can really help our microbiome to bounce back. If you have to take antibiotics, and there are some cases where it's necessary. There are some things that you can do to help.

17:26: One thing that I've been really outspoken against recently is the ubiquitous use of probiotics after antibiotics. This is an area we definitely need more research, but there was a few studies published, one specific very comprehensive study published in 2018 that showed that probiotics after antibiotics might actually delay the return of the native microbiome. It does seem to be conferring some protection against C. diff, against other pathogens, but it's delaying the return of the butyrate producers, which are really key in restoring full gut health. One strategy that might be more beneficial is to consume a lot of prebiotic foods, so you're supporting the return of those butyrate producers. And also, when you're taking antibiotics and your butyrate producers are wiped out to supplement with butyrate to basically support your gut barrier during that time where it's not getting butyrate from your normal microbes. So, I'm really looking forward to seeing more research in that area, but I think some preliminary data we have from animal studies suggest that that butyrate approach might be really helpful.

Dan Pardi - 18:28: Tell me about probiotics. Do you feel that they have a place in just the regularly healthy person, who isn't dealing with any sort of specific gut issues? You see information on probiotics and prebiotics on a daily basis, this one associated with improvements in mental performance or decreases in mood disturbances, or improvements in muscle mass gain, or making somebody more lean. I mean, the diversity of topics that you see a connection to is remarkable, but how do you know what to do yourself? What are your thoughts on probiotics in general for a healthy person?

Lucy Mailing - 19:00: One thing that's really key is that the effects of probiotics are strain specific and disease specific. If you've got a gut condition, it's really important that you're using specific probiotic strains that have been studied in that condition and I think we have enough data to do that. 50 years ago we might've had to do some trial and error with different probiotic strains to see which had an effect, but now I think we have the clinical data to be able to choose probiotic strains appropriately.

19:25: In a healthy person it's certainly not going to be nearly as significant as all of the diet and lifestyle factors. Sleeping well, consuming fiber, exercising, all of those things are going to have much more effect than just taking a probiotic supplement every day. That being said, if you're going for a specific thing and there's been some clinical studies about a specific strain that you're interested in, there's not a lot of harm in trying clinically studied strains. It's important to emphasize that because there are a lot of probiotics out there that have never been studied for safety. Some of the soil based probiotics that haven't been studied for safety, people are taking and they may never be able to get them out of their guts because they're spore forming. Those can be potentially detrimental if you don't select the right strains because they have the potential to stay in the gut.

20:08: And other types of probiotics, typically, if you have an adverse event, you stop taking them, it hasn't colonized your gut. There's not going to be any long-term effects from that. So, I don't think there's a lot of harm in trying probiotics for healthy people, especially those that have been well studied. At the same time it's not going to be the end all be all for health. We need to temper our excitement about new strains that come out, especially when it's only one or two studies.

Dan Pardi - 20:30: Let's talk about PPAR-gamma agonists and their influence in this equation. What are they and what do we know about them in terms of their ability to influence infection?

Lucy Mailing - 20:40: This is a specific pathway that I've written about extensively because it actually mediates that switch in oxygen leakage into the gut. So, within the gut barrier, you've got those epithelial cells, each of those epithelial cells, normally they're taking in butyrate and they're using that for their metabolism. That metabolism of butyrate uses up oxygen that they're getting from the bloodstream. And so, when they use that oxygen, the epithelial cell has plenty of oxygen in it, but the gut mucosa where the microbes are, that remains very low in oxygen. Butyrate is activating that PPAR-gamma pathway, which is basically this positive feedback loop. Increasing the metabolism of butyrate, increasing the utilization of oxygen, and when we are missing that butyrate or when something goes awry, when we have inflammation, when we take antibiotics, that PPAR-gamma pathway gets shut off or it certainly goes down a significant degree, the gut is then starving for fuel.

21:40: It can't metabolize butyrate, so what it does is it pulls glucose from the bloodstream and our gut epithelial cells really aren't meant to do this, it's a backup to their metabolism. And so, they're pulling glucose from the bloodstream. The glucose gets fermented into lactate and that produces some energy for the gut cell. It's not as efficient as the butyrate metabolism, but it's providing it some energy to survive. But in doing this, that type of glucose to lactate fermentation does not use oxygen, so oxygen is still diffusing in from the blood to the epithelial cell, but it's not getting used up for metabolism. Instead, it leaks out of the cell into the gut lumen. That's where all the microbes are. And so, we have this low PPAR-gamma activity, we have this increased lactate fermentation, so now we have oxygen, we also get lactates spilling out into the gut as well.

22:31: And these are what facilitate the expansion of those facultative anaerobes, those more inflammatory microbes, E. coli, salmonella, a lot of the microbes in the proteobacteria phylum, that tend to be more inflammatory. It appears that this PPAR-gamma is the center control switch of the metabolism. If we don't have any butyrate and we're in a situation of oxygen leakage and we can stimulate PPR-gamma with a drug, it can actually swap the metabolism back and help to prevent that oxygen leakage, restore hypoxia in the gut and help to prevent that gut dysbiosis. If we can do things that switch back, we could potentially get out of this vicious cycle of inflammation, oxygen leakage and gut dysbiosis. There's a number of interesting ways that we can do that, some of them are diet and lifestyle factors, for sure. Butyrate is one of the key stimulators of that PPAR-gamma pathway, so getting enough fiber in our diets and potentially supplementing with butyrate can support that PPAR-gamma pathway.

23:34: Fasting has been shown to increase it. Exercise increases PPAR-gamma activity in the gut, so all of those things that we know are really good for our health are also supporting this gut metabolism to promote a healthy gut microbiota. So, that was kind of a long winded background on PPR-gamma. But what's also really interesting is that some of these drugs that are shown to be specific activators of this pathway have actually been shown to reduce the mortality of mice when they're infected with pathogenic strains of the flu. The drugs that they're using are active systemically, so we don't know whether gut PPAR-gamma is especially important there. Certainly this is very protective in models of gut infection and I think it'll be really interesting to see more research in this area, about how we can potentially use this knowledge to develop treatments to shift things back to a better state in the gut and overall.

Dan Pardi - 24:27: I've looked into PPAR-gamma before for brown fat activation, and you see actually a lot of natural compounds and things in like capsaicin, curcumin, cinnamon, green tea, fucoxanthin from seaweed. There's lots of different foods, so not only fasting and exercise, high butyrate producing diet, but also then the phytonutrients can directly stimulate PPAR-gamma. Are there any well-designed interventions that include phytochemicals known to activate PPAR-gamma, in an attempt to ameliorate a situation, when there is a higher oxygen state in the gut?

Lucy Mailing - 24:59: That's a great question. I'd love to see more research. There are plenty of compounds, like you mentioned, that activate PPAR-gamma, plenty of natural compounds. There are very few studies that have used those. There's one herbal compound, it's called DBZ that has been studied in China. It's a Chinese medicinal formula that's been shown to activate PPAR-gamma in the gut and potentially prevent gut dysbiosis, but it's not really widely available to source. There's a number of others that you mentioned, curcumin, sulphoraphane's another one. All of these we know they activate PPAR-gamma in the gut. I haven't seen any studies that have actually shown how that impacts gut dysbiosis or infection, but I think it's always going to be harder to fund studies like that.

25:41: But sometimes it can be crazy to be getting down into the weeds of all these nitty-gritty pathways, but we need solutions for gut dysbiosis, right? So, I did a deep-dive and pulled out all these things that, rationally, why can't we combine these? All of these phytonutrients are safe to take, why not combine them into rational integrative therapies and try them? Maybe if we get enough anecdotal support, someone will eventually be able to do a study in that regard. Certainly mesalamine, mesalamine's actually a drug treatment that's used for ... It's the first line treatment for inflammatory bowel disease, that's been shown to activate PPAR-gamma and prevent a lot of this dysbiosis.

26:17: I'm generally not a fan of pharmaceuticals. I think people probably got that from the beginning of our talk today, but I do think mesalamine is one of those where it's actually potentially treating the root cause of disease and there's a lot of potential there. And then butyrate's another one that has been demonstrated in studies.

Dan Pardi - 26:34: One area that I'm interested in is aging and the gut. Dealing with COVID-19 right now, older people are most susceptible to succumbing to this infection. How does the gut microbiome change over time and what do we know then about this relationship between the gut, the immune system and aging? How do those three interact?

Lucy Mailing - 26:54: So, aging has often been associated with a decrease in microbial diversity and also a shift towards a more inflammatory microbiota. Having more of those facultative anaerobes, having less butyrate producers. So, that's been shown in a number of studies, but this may not necessarily have to happen. And I think this is the distinction between typical aging and the possible way to age well. And that several studies have shown that when they look at groups of healthy, long lived individuals, they actually have a microbiome that looks just as, or even more diverse, than young individuals. We think there's this characteristic effect on the microbiota that occurs with aging, but maybe it doesn't have to happen if we can take care of ourselves and avoid a lot of the chronic diseases that are associated with aging.

Dan Pardi - 27:44: That's fascinating. Since we've been talking so much about butyrate, what do we know about precursors to butyrate production?

Lucy Mailing - 27:50: So, there's a number of different fibers that are fermented to butyrate. Fiber is the primary precursor to butyrate production. So, it's actually really interesting in that there've been a lot of attempts to find prebiotics that will work in everybody to increase butyrate. But this doesn't really seem to pan out across everyone because everyone has slightly different gut microbiotas. So, even though we have, even across healthy individuals, we have similar microbial functions, it seems that the response to adding a prebiotic fiber is not always the same.

28:24: So, some people you add a prebiotic fiber, a specific prebiotic fiber, let's say inulin or resistant starch and their butyrate does increase significantly. Other people, no change and some people even go down at butyrate. So, we don't exactly know why that's happening, but I've definitely gotten away from trying to do nutritionism to try and get down to the nitty gritty of what types of fiber we need and just say, "We don't exactly know which types of fiber are going to be best for your gut. So, it's best to eat a wide range of different plant foods, different fibrous foods, and you're probably going to get what your microbes need."

Dan Pardi - 29:03: Imagine the scenario, you have low butyrate producing microbes currently, you're taking in fiber and you're not producing a lot of butyrate. You then take butyrate, over time, directly, and because you're providing that fuel source, the butyrate producing microbes start to flourish and become more abundant within the ecosystem. And then you go back to the fibers that you were taking previously, where you didn't actually produce much butyrate from them and you're having a different effect from taking them. That's an interesting idea, actually, that you could potentially improve the system by exogenously supplementing with butyrate for a little while. I'm putting that out there as a hypothetical.

Lucy Mailing - 29:38: I've seen at least one published study that suggests that supplementing with butyrate can actually start a positive feedback cycle and increase the amount of butyrate producers. And it's not a long-term solution because, like I said, supplementing with butyrate is likely never going to reach the amount of butyrate you should be producing. And butyrate producers, they are fulfilling an important function, not just in the butyrate that they're producing, they have a lot of other activity in the gut. They're potentially producing other compounds that are shaping the gut ecosystem.

30:09: It's a complex system and we like simple solutions and linear thinking. We do X, Y is going to happen, but I always have a healthy dose of taking some of these findings with a grain of salt and realizing that, wow, this is a complex system. We don't always know exactly what's going to happen, especially when we put in something that is not naturally going to be found there.

Dan Pardi - 30:30: And thinking about the health of a microbiome, we've talked about rewilding, Tell us what that term actually means and some evidence for that and infectious disease. And then, I'd love to talk to you about what that strategy could look like in humans. What does rewilding mean?

Lucy Mailing - 30:44: This article that I wrote recently was the first time I've ever used this term, but essentially this study that I came across when I was researching the connection between gut and immunity, they basically looked at the effects of bringing back some of the natural diversity to the guts of lab mice. Much like modern day humans, lab mice live in a very sanitized, restricted environment. They don't really have any natural microbial exposures, so they've lost a lot of the microbes that they've co-evolved with, much like we have. And so, what was really interesting was that they took the microbiota of a wild mouse and they re-instituted it into lab mice over several generations. And then they tested the immune response of the rewilded mice, the mice that now have this wild microbiome, to influenza and also to a carcinogen. Compared to the regular lab mice, the mice that were reconstituted with this wild microbiome had reduced inflammation and increased survival after the flu infection.

31:43: With the carcinogen they also had improved resistance to developing colon cancer, so that was amazing to me and it was the first study to suggest that some of our soil exposure, things like this, could potentially be really important for supporting our healthy gut microbiota and optimizing our immunities. There's a lot of people who talk about rewilding the microbiota. This was the first study I'd come across that actually supports that with evidence since suggests maybe there is something to the exposures that we get in natural environments.

Dan Pardi - 32:12: That's an aspirational idea because how do we do that in modern living humans? We don't really have the ability to tolerate potential downsides. We only have one generation to affect, ourselves, so if you care about your gut microbiome, you want to exercise, you want to sleep well, you want to eat a nutrient rich and diverse diet, good circadian alignment. What might you add, more specifically, to somebody who is looking to take care of their gut directly?

Lucy Mailing - 32:40: I'll be honest that most of my recommendations here would be speculative, since we don't have any evidence for rewilding the gut in humans, we don't know exactly what that would look like. I certainly would caution against anyone trying to consume soil or things like this because we've spent so much time in a sanitized environment, we are potentially not able to resist pathogens quite as well and you don't know what's going to be in that soil. That said, gardening, spending time in nature, there's potential to breathe in microbes that could potentially impact our gut, so consuming organic vegetables that are potentially less sprayed, have more of their natural microbes on it. That is certainly a way that we would have naturally acquired microbes over the course of our lives, naturally. Beyond that, I'm not sure. I'm definitely open to ideas about how we can do this, but also think it's important that we consider the safety of any of these things, especially given that the modern human typically has a more hypersensitive gut to parasites and these kinds of things.

Dan Pardi - 33:42: The cautionary tale is zero drop shoes, we were compelled by the idea of walking around more in bare feet and what that can do to the structural alignment of our musculoskeletal system and all the good things that can come from it. And people that would then rapidly adopt that having been wearing running shoes for a long time, their bodies were acclimated to that other device on their foot. A lot of people, we tried to make that transition too quickly and suffered consequences because of it, and you could easily draw a parallel here. So, I like the cautionary approach. Stick with the things that we know are good for us. We can monitor this subject, but in terms of acting directly, wait until we see what more definitive and certainly safe.

Lucy Mailing - 34:25: Yep.

Dan Pardi - 34:25: Dr. Lucy Mailing, thank you so much for coming onto humanOS Radio. You are a wealth of knowledge. I love your approach. It's great to hear your take on this during this disturbing and crucial time where everybody's focusing in on their immune system. So, thank you so much.

Lucy Mailing - 34:40: Thank you, Dan, and I really enjoyed this conversation. So, I'm looking forward to seeing all the future of your work as well.

Dan Pardi - 34:45: Thank you. Now, where can people go to find more about what you're doing?

Lucy Mailing - 34:49: Yeah. I'm at lucymailing.com or on social media @LucyMailingPhD.

Dan Pardi - 34:57: All right, everybody, go follow her. Lots of good stuff that she puts up all the time that's useful to read and insightful, and will help you have as cutting edge understanding of this subject as there is to have. So, thanks again.

Kendall Kendrick - 35:10: Thanks for listening and come visit us soon at humanOS.me.