Is A Ketogenic Diet Bad For Your Gut, Should You Eat Resistant Starch, How Exercise Changes Your Gut Bacteria & Much More With Lucy Mailing.

On this episode of the Ben Greenfield Fitness Podcast.

There's a lot of great general gut health information out there, but very few people who have a deep understanding of the science and are really taking a comprehensive approach which specific interventions might help certain types of people. This suggested to us that exercise, yes, has independent effects on the gut microbiome, which are then largely erased when you return to a sedentary lifestyle. I've seen a lot of people who have really stubborn diet dysbiosis where rationally combining some of these integrative treatments can really start to move the needle back in the right direction.

Health, performance, nutrition, longevity, ancestral living, biohacking and much more. My name is Ben Greenfield. Welcome to the show. All right folks, my podcast guest today is a wealth of knowledge on all things gut related. I've been incredibly impressed with her since she was recommended to me. She is very smart, as you're about to find out, and we talk about everything, probiotics, prebiotics, sibo, constipation, diarrhea, all that fun stuff. So her name is Lucy Mailing. You're going to love today's show. Well folks, the lady who I am about to interview is someone who was brought to my attention by a previous podcast guest, Dr. Tommy Wood, who I have the pleasure of knowing because he's actually a pretty smart doc himself and is always kind of finding some, some different information, some diamonds in the rough, always thinking outside the box. And so whenever he recommends that I look into someone, I do. And he actually introduced me to Lucy, Lucy Maling, who's a PhD in microbiome researcher and a scholar of all things integrative and evidence based gut health. So I began to look into Lucy and I read as I always do leading up to interviews. I kind of try to immerse myself in what somebody is doing and I read just about every article that is on her website, which is fantastic because she's doing some really, really good blog posts over at lucymailing.com lucy l u c y mailing.com and I'm also going to put that link in the show notes if you just go to BenGreenfieldFitness.com Lucy Mailing she has multiple peer reviewed journal articles out there and she presents at a lot of national and international conferences, particularly in the realm of again, evidence based approaches to the gut microbiome and to nutrition science and specifically its impact on the gut. There were some things that I was reading up on as I was preparing to interview her, such as whether or not a high fat or Ketogenic diet actually is bad for your gut. An interesting link between oxygen and gut dysbiosis. And then also some really fascinating research on how exercise impacts the biome and what we can learn from kind of like an athletic microbiome and how exercise impacts the microbiome. So plenty that we are going to get into today. And Lucy, welcome to the show.

Thanks so much for having me on, Ben. I'm really excited to be here.

Yeah, I'm stoked to have you on. And I didn't tell you that I was going to ask you this, but when you, whenever I'm talking to somebody about the gut, I kind of like to know what they've eaten that day leading into the interview. And so I'm curious, since we're recording this in the morning, did you have breakfast and if so, what'd you have for breakfast this morning?

I did not have breakfast, but I'm on eastern time so it's about 1:45 now. We had bacon, potatoes, some kraut and veggies for lunch.

So do you, do you fast until lunch pretty regularly?

Pretty regularly, yeah. I feel most productive in the mornings if I don't eat.

Yeah. You know, Rhonda Patrick, another researcher in the realm of some areas, nutrition science, she has in the past recommended that women don't really intermittent fast longer than about 10 to 12 hours due to the potential for some endocrine disruption or I believe she was potentially concerned about some leptin issues, et cetera, or this idea that women especially like active premenopausal women don't seem to respond as well to longer intermittent fasts compared to men. Have you, have you heard that, have you looked into that at all?

Yeah, I've definitely heard that and there is some data around that. But personally, just through a lot of experimentation I really became interested in gut health and the whole nutrition area through my own journey with chronic eczema. And one of the only things that really helped my eczema was fasting. And when I was at my worst, I even did 24 hour fast. Typically I was just eating one meal a day that was extremely helpful for me and then even did some as long as a seven day water fast and it really helped my eczema. So, you know, maybe it's definitely possible that there was some hormone changes that I wasn't aware of at the time that happened with that. But I had this very visible sign that I could see whether something was working for me and at least for my eczema. Fasting was really Beneficial.

Yeah. And this is all really anecdotal for me, but what I've found with all of a lot of the female clients who I've worked with is that those who are very active, those who are athletes, especially like triathletes or marathoners, or those who just really have a thing for CrossFit, whether or not CrossFit is even a thing now going forward with all the, all the politics right now around, around Greg Glassman and CrossFit. But either way, those women do not seem to respond very well at all from an endocrine standpoint to, and you know, I'm talking about, you know, thyroid progesterone, et cetera, to frequent bouts of longer term intermittent fasting. Whereas women who seem to be like, doing a lot more, you know, whatever, gardening, walking, eating hefty amounts of, you know, kind of like a western, a priceless approach of very nutrient dense, often, you know, fat rich foods in between those fasts seem to do pretty well. So sometimes I think it comes down to physical activity and arguably even body type. You know, like a lean ectomorphic female kind of similar to a lean ectomorphic male, actually. They just don't seem to respond as well to like these frequent bouts of intermittent fasting, nor actually, you know, oddly enough even need them for the reason that many of them are doing this, which is to stay lean, for example.

Yeah, I definitely think there's a lot of, lot of variability and I do know a lot of women who don't do well with intermittent fasting, especially those who are doing more high intensity exercise. So.

Yeah, interesting. Well, we could talk about not eating the whole time, which is absolutely not fun. I'd rather talk about eating and what it does to the gut and just the gut in general. So how did you get interested in the gut and kind of your unique approach when it comes to the way you analyze or tackle all things gut?

Yes, I just mentioned I kind of got interested in the gut through my own journey with eczema. And I'd gone the whole pharmaceutical route without much improvement and was basically told, hopefully you'll grow out of it. But then towards the end of high school and beginning of college, it really only started to get worse. And fortunately, around 2014, my sister came across the Paleo movement. And that was when I really first became aware of the connection between our diet, gut health and skin health. And in those early days I was just reading a lot of blogs. Chris Kresser, Mark Sisson, Sarah Ballantyne. Some of your work Ben and I had a lot of initial success with dietary experimentation with autoimmune protocol, low histamine, intermittent fasting, as I mentioned, and some targeted supplementation, which all really made me a firm believer that there was a root cause underlying my skin issues and that my gut was very likely involved. So then in 2015 I started a PhD program at the University of Illinois studying the gut microbiome. And I also began working part time as a research assistant for Chris Kresser. That's when I really started to dig into the primary scientific literature as well. And I think this is where my approach has really come to be quite unique. There's a lot of great general gut health information out there. You know, eat bone broth, consume fiber, take your probiotics. But very few people who have a deep understanding of the science and are really taking a comprehensive evidence based and integrative approach and bringing a bit more to the table as to which specific interventions might help certain types of people.

Yeah, it's really interesting by the way, because you know, my wife used to have really bad acne and eczema and when we were first married, she brought back home a book. It wasn't even really a book, it was like a bound, you know, stitched together eight and a half by 11, you know, set of pages written by this guy named Loren Cordain called the Dietary Cure for Acne. And it was more of an insulinogenic approach to, to eczema and acne. Although, you know, because the paleo esque approach that was proposed in that book obviously eliminated a lot of common immune system triggers and may have affected the biome as well. But you know, a, that was how I actually first became exposed to just this idea of eating ancestrally or just even the word paleo was when I saw her skin completely clear up what seemed like overnight. And at that point I was like, oh, there must be something too. Perhaps not, you know, drinking whey protein shakes and eating chicken and broccoli and rice for breakfast, lunch and dinner. I should look into this whole like ancestral nutrition paleo diet. And that's what first got me interested in was, was my wife working on clearing up her skin issues. But again, I was always under the impression that skin issues were on my understanding from that book, a little bit more kind of like insulin based and possibly a little bit more autoimmune based. And you know, it wasn't until recently, you know, in the past few years that I really became very familiar with this idea of the skin microbiome and the role of diversity of the gut microbiome when it comes to acne and atopic dermatitis and, you know, psoriasis and eczema and all these issues that seem to be related to literally like a brain gut skin axis, which. That was something that was proposed in a paper way back in the 30s, but it doesn't seem like it's gained a lot of attention, this idea of affecting the gut to improve skin health. Until recently.

Yeah. It's starting to get interest in the literature and we're starting to see more dermatologists kind of wake up to the idea that there is a gut skin axis and it's playing a major role. But, yeah, that's really fascinating about your wife. I actually did not have quite a rapid improvement. And it took a lot of dietary experimentation, tweaking of various things that would modulate my gut health, would try and improve nutrient status. And because of that, actually, I went down the rabbit hole much further than I probably would have if I'd gotten a quick fix with the first diet I tried. So it's interesting that my longer journey actually led to a lot more learning, which I've been able to use to help other people now.

Yeah. And so for you, it all started with the skin, and then you just started to take a deeper and deeper dive from there.

Yeah, and actually shortly after, I was starting to fix my skin troubles. Actually, when I went Paleo, my skin started to improve, but my gut actually got worse. So I developed some ibs, I think, because I've been eating processed foods, nothing but processed foods for the first 19 years of my life, and then was trying to transition to incorporating these foods that I knew I needed in my diet. So I had a few years of trying to figure out my IBS as well, which also led to a lot of learning and a lot of interesting gems, you know, in the literature. There's so many things out there that are not being used clinically that are really amazing in terms of the insight they can give us in gut treatment.

Interesting. Like what would be one example?

Yeah. So, I mean, maybe we can get into the oxygen gut dysbiosis connection if you want to.

Yeah, let's start there. I mean, I know that you've done some writing about particularly colonic health and how that's related to a low oxygen environment that's rich in microbes, Meaning that there's a possibility that maintaining some amount of hypoxia in the colon could be beneficial. Get into that.

This is a topic I've been really interested in over the last year, ever since I met Dr. Sebastian Winter and Dr. Andreas Boimler, who were involved in a lot of the initial studies on this. And maybe we'll start by talking about butyrate, which I'm guessing many of your listeners are familiar with. So, butyrate is a short chain fat acid metabolite that's produced from the bacterial fermentation of dietary fiber. So when you eat fiber, your microbes are producing butyrate. And under normal conditions, Butyrate provides about 70% of the cellular energy for the cells that line our gut and form the gut barrier, which we know is really important for maintaining that tight barrier between our microbes and our immune system and our bloodstream. Our gut epithelial cells, they take butyrate up, they metabolize it, and they use it to generate cellular energy through a process called fatty acid oxidation. This metabolism of butyrate uses oxygen in the mitochondria, which is constantly being diffused into the gut epithelium from the bloodstream. So oxygen is coming in from the bloodstream, and our gut epithelial cells are using it to metabolize butyrate. What a group found at UC Denver that they published in 2015 was that butyrate is actually required for maintaining the hypoxic state of the colon. So when they wiped out butyrate with broad spectrum antibiotics, the gut epithelium stopped utilizing oxygen. It had to rely on glucose metabolism instead of butyrate. And the oxygen, which isn't used for glucose metabolism, built up in the epithelial cells and then ended up spilling out into the gut lumen, which is where all the microbes are. This is a real problem if oxygen starts spilling into the gut. And studies in Dr. Boimler's lab at UC Davis have really elegantly demonstrated that this switch in epithelial cell metabolism from metabolizing butyrate to. To metabolizing glucose and the subsequent oxygen leakage into the gut is actually a primary driver of gut dysbiosis. And this is because the normal microbes in our gut do not do well in the presence of oxygen. So all of our really important butyrate producing bacteria and other beneficial microbes tend to do really poorly when oxygen starts diffusing into the gut. And instead, we see an expansion of microbes that do tolerate oxygen, which happen to be much more pro inflammatory, like proteobacteria species in the phylum Proteobacteria, like Salmonella, E. Coli, Pseudomonas. A lot of these microbes we Think of as like opportunistic pathogens.

Okay, so, you know, butyrate is interesting, and I don't know if my podcast with Joel Green will have come out by the time that I release this interview with you, but we do discuss butyrate quite a bit in that show. And he gets into how clinical studies have shown that, you know, like people with advanced colon cancer all have diminished levels of butyrate and that butyrate can basically in a way neutralize these cancer promoting micrornas that are packaged in exosomes and then also do a lot of interesting things like it activates genes that promote brain health, which is super interesting. The link between butyrate concentration, Alzheimer's and Parkinson's and stroke and autism. It seems to have some kind of an exercise memetic effect in terms of mitochondrial proliferation. It seems toyou've alluded to literally activate pathways that seem to directly kill cancer cells. And part of that is lowering the colonic ph and perhaps allowing for the state of hypoxia in the colon. And based on all this, I'm curious what your thoughts are, because what Joel had discussed is that high intake of butyrate, particularly via butyrate supplementation, may actually wind up potentially feeding cancer cells or resulting in some gut dysbiosis. So it's not as though more is better and that the way in which butyrate is introduced into the gut, either A via supplementation, which he's actually not a fan of, versus B, kind of like this luminal nutrition type of approach of introducing, for example, one of the more common ways to increase butyrate, high amounts of fiber would be a more beneficial approach would be like dietary fermentable fibers. When you step back and look at things, if you were to look at butyrate supplementation versus intake of dietary fermentable fibers to increase butyrate levels via that method, versus the final approach, which would be like more of a ketotic diet, which appears to be able to simulate a lot of what butyrate does. But doing so with beta hydroxybutyrate instead of high fiber consumption, what do you think is the best way to increase butyrate concentrations?

I'm definitely only a fan of butyrate supplementation. If you're not producing enough butyrate from the fermentation of fiber, or you're not eating a ketogenic diet that is producing sufficient ketones to provide energy for your gut epithelium. So I really see the supplementation as kind of an alternative if there are a lot of people who are suffering from gut dysbiosis and they really can't tolerate fermentable fiber.

Yeah, especially people with sibo. Like, if people with sibo consume one of these, like acacia fiber or inulin based supplements or prebiotic fiber blends, or even like do the green banana or the cooked and cooled potato or rice type of trick, they can sometimes literally be painting the back of the toilet seat and have a balloon baby in their stomach. And for those people trying to improve butyrate concentration via the intake of fermentable fibers is just like total bad news bears. So for those folks, what would you say? Supplement with butyrate or just shift to a ketogenic diet to allow for doing what butyrate would do, but instead doing it with ketone bodies like acetoacetate and beta hydroxybutyrate?

I think there are a subset of people who wouldn't tolerate fiber and could shift to a ketogenic diet and have benefits. But there's a number of reasons, whether related to gut health or not, that someone might not be able to tolerate a ketogenic diet. And we can talk about the gut health reasons in a second. Essentially, if I recommend butyrate supplementation, I definitely don't recommend megadoses. I think it's really important that we're providing a dose that is more like what would be produced in the gut and also providing in a way that it's released in the colon. And there's only a few supplements out there that I'm aware of that actually are more targeted to the colon and are providing this more like slow release, low concentration butyrate. And those are the ones that I, with my clients have seen greater benefits from. And I don't have concern with that given the low dose. I really don't have a lot of concern with that in regards to the adverse effects, especially with people where I've seen their stool profile and I know they're not producing butyrate.

Right. And you talk about those in one of the articles that you wrote. I think it was probutyrate. And then one called butycaps Tributerin. Right. Those are the two that you actually like that seem to do a good job populating the colon with butyrate.

Yep. And I have no affiliation with those. Just independently have found those to be beneficial and they've got the science behind them to show that it does track to the colon.

Now, if someone wanted to actually test, which you briefly alluded to a few moments ago, to see what their actual butyrate status was in the gut, or test whether or not they had any of these pre existing conditions that might risk them having some type of hypoxic condition in the gut that would allow for bacterial overgrowth or increased risk of colon cancer. What kind of tests would you actually get to look at you butyrate and your hypoxic status, so to speak?

We can test for example for butyrate, we can test fecal butyrate, but that's not always the greatest measure because it's a combination of how much butyrate you produce and how much is absorbed. So it's hard to determine, you know, if you have a lot of fecal butyrate, maybe you're just inflamed and not absorbing much of it. But it generally tracks with butyrate producing microbes, which is typically what I look for first. So I usually do a stool profile and I actually look at, do they even have the microbes that are producing butyrate?

And when you, when you say stool profile, are you talking about like one of these like biome, ubiome, longevity type of panels? Are you talking about more like a Genova diagnostics stool panel? That's more looking at, you know, yeast parasites, fungus, et cetera?

Yeah, I use, I use both longevity and GI effects depending on the particular client, depending on whether I want those clinical markers.

You're doing a one, two combo. You're looking at the biome via something like longevity and then you're looking at the rest of the gut via something like Genova diagnostics.

Correct. So you can actually, it's mostly the GI effects gives the clinical markers and it's also doing parasitology via microscopy. So it's kind of another look for parasites as well. So I'm kind of pairing those up because I don't have one test that can, I feel I can provide it all. So it does depend on who I'm working with, what tests they've had in the past. But typically those two kind of I find are covering the bases. But basically from either the longevity profile or somewhat from the GI effects, you can kind of look at the known butyrate producers in the gut and how abundant they are.

Okay, got it. And then if someone were found to be low in butyrate, that's when you're stepping back and saying, okay, this person's either a candidate for increasing the amount of fiber or, or if they have SIBO or something like that, instead supplementing with some kind of butyrate supplement and, or shifting to a ketogenic diet. So that instead of using the fiber to do what butyrate is doing, you're instead just getting acetoacetate and beta hydroxybutyrate.

To do that, right? Definitely. In the short term, I mean, obviously we want to address whatever's causing that bloating and distention that's going to prevent them from being able to reintroduce fiber. So the more we can bring down inflammation, the more they might be able to then reintroduce fiber. And also, inflammation itself actually inhibits the growth of butyrate producing microbes. So it's kind of this multifactorial approach in someone who's got that inability to tolerate fiber. But yeah, that's definitely the basic thinking about butyrate in terms of how can we get them the butyrate they need, and if necessary, that might be supplementation in the short term.

So overall here, the big picture thus far is that we know that there's this issue with gut dysbiosis and colonic inflammation that is present in a lot of people that often reflects low butyrate concentrations. And that's brought on, or is it brought on by hypoxia in the colon or does it cause hypoxia in the colon?

So actually, hypoxia is what we want. We want at least we want mucosal hypoxia. So we want our epithelial cells to be getting oxygen, and it's a problem if they're not. That's typically not what we're talking about. We're talking about mucosal hypoxia, which is basically how much oxygen is actually leaking into the gut lumen, where the microbes are.

That's right. Because when we're talking about the anaerobe that would be without oxygen. So butyrate is an anaerobe. So that means that you would want a low oxygen environment for butyrate concentrations to rise. So low gut oxygen levels.

Correct? Yes. Butyrate producing bacteria are all anaerobes. So we want a hypoxic environment to promote the growth of those beneficial anaerobes and inhibit the growth of the oxygen tolerant E. Coli, salmonella, those guys that like oxygen more.

Okay, got it. And so in addition to something like fiber intake, if that's appropriate, or a ketogenic approach, if that's appropriate, or butyrate supplementation using something like the, the, the, the, the probuterate or the butycaps that you mentioned, is there anything else from a Dietary or a supplementation standpoint that you think does a good job in terms of supporting gut hypoxia or supporting this PPAR gamma activation, which. And you can get in a little bit more. You briefly mentioned the PPAR Gamma, but you can get a little bit more into that and how that fits into this picture as well as kind of part of your reply to that question.

So what's really interesting is there seems to be this gene, ppar gamma or ppar gamma, which acts as the control switch of epithelial metabolism. So I mentioned that butyrate metabolism is kind of the default, and that's what we want. And when the gut becomes inflamed or there's no butyrate present, we switch to that glucose metabolism, and that's what leads to that oxygen leakage into the gut and the loss of hypoxia. So that PPAR Gamma we can kind of think of as the control switch of metabolism.

Okay.

What's really interesting is that activating this gene in colon epithelial cells can actually switch metabolism back in the direction we want to. Metabolizing those fatty acids like butyrate and using oxygen, which should in turn also shift the balance of bacteria back to a healthier state, since we're restoring that hypoxia.

Okay, got it. So stimulating the PPI or gamma pathway could prevent or revert or reverse gut dysbiosis. And that would be something that you'd want to try to do along with increasing butyrate levels. Now, if you increase butyrate levels, is that something that in and of itself is going to help with PPAR gamma expression?

Yes, exactly. So butyrate is an activator itself of PPAR gamma. So it's kind of like a positive feedback loop, essentially. And then there's other things. Exercise has been shown to activate gut PPAR Gamma. Fasting ketones is another one, since it's kind of playing the role of butyrate. And we can talk about that a little bit more if you want. Certain phytochemicals like curcumin, sulforaphane have been shown to activate PPAR Gamma and even certain pharmaceuticals for really severe cases, like mesalamine is the first line drug therapy for inflammatory bowel disease. And I'm typically not a fan of pharmaceuticals, which you may have gotten from my introduction earlier, but I actually feel like this is one of the only drugs that is actually treating the root cause of disease. And I've seen a lot of people who have really stubborn dysbiosis where rationally combining some of these integrative treatments in collaboration with their gastroenterologists can really start to move the needle back in the right direction.

I certainly would agree that in some cases pharmaceuticals can have a pretty significant impact. Especially, you know, for example, Mark Pimentel is a pretty smart guy when it comes to sibo, you know, which I've talked about a lot before on the show. And you know, even like a low dose, like a quarter of the dose that would normally be used for constipation of a really good prokinetic pharmaceutical like procalopride I think is the one that it goes by in the US but basically a motility agents along with in some cases like low dose rifaximin or some type of antifungal. Those are all pharmaceuticals, but short term doses of those, especially in lower amounts, seems to, along with lower fiber intake for a short period of time in terms of anything that could potentially feed the bacteria in the small intestine just seems to absolutely be an amazing combination for people with sibo that doesn't seem to be going away. And that's another perfect example where pharmaceuticals in more severe cases can actually be really helpful.

I've seen a subset of people who do seem to benefit from that approach. And I don't know if you want to get into this because it's a whole rabbit hole, but I really think our paradigm around SIBO has been misguided. And much of this is because a lot of the early research was based on culture based tests which really skew the abundance and the types of bacteria that you'll find. A lot of the microbes that live in the small intestine don't grow in culture, and others grow really well in cultures. And there was a really interesting paper that came out last year by Dr. Perna Kashyap's group that showed that people who have symptoms of functional GI disorders most often have small intestinal dysbiosis, not actually overgrowth. So it's not that we have too many microbes in the small intestine, it's that we have the wrong balance of microbes, much like we do with colonic dysbiosis.

So what would be an example of the type of microbes that would be imbalanced with something like sibo? Are you talking like Akkermansia and like one of the Lactobacillus or what exactly are you talking about?

It really depends on the person. As far as I saw with that paper, they weren't really able to identify specific types of Bacteria that tend to be overgrown across the board in everyone. I've seen other papers that have suggested that proteobacteria might be overgrowing in the small intestine. Akkermansia, we typically think of as more prevalent in the large intestine. But I also think there's a lot of, you know, sometimes people might think they have small intestinal symptoms, and it's actually something in the large intestines. A lot of people are stuck in this paradigm of we have overgrowth, we need to kill the overgrowth, and they end up overdoing it with the antibiotics or with really potent antimicrobials. And I think they're just doing more harm. They're wiping out diversity potentially. They're stressing the gut epithelium. So they're. They're really potentially feeding this cycle if they're not careful. And I think that's why we see so much of sibo. You know, you treat it and it comes back. You treat it and it comes back. And I think it's because we're not addressing that root cause underlying the sibo, and we have this paradigm that it's overgrowth instead of trying to modulate the ecosystem back to a healthier state.

Interesting. Now, one other thing that I wanted to ask you about related to maintaining a state of hypoxia in the colon was in one of your articles, you commented that if, like, basic diet and lifestyle interventions weren't enough, then targeting PPAR gamma, which you just kind of went into some of the ways that we could do that. Some of the herbs, the butyrate, exercise, et cetera. But then also colonic energy starvation could help to break the cycle and reverse gut dysbiosis. What's colonic energy starvation? And how would one do that?

Sorry, that was actually probably a confusing writing on my part. We're actually targeting colonic energy starvation is what I mean by replenishing colonic energy.

Okay, that confused me, too. Okay.

Yeah. The state we're in that we don't want to be in is colonic energy starvation, where we're relying on glucose for the metabolism. We don't have enough butyrate. So it's targeting PPAR gamma is going to essentially help to replenish colonic energy so that that gut barrier can heal.

Okay, got it. And I'm going to link to this article in the show notes@bengreenfieldfitness.com lucymailing just like it sounds like mailing a postcard. And then, Lucy, because you have kind of like this list from butyrate to ketones to fasting calorie restriction exercise, sulforaphane, curcumin, some fatty acids and a few different herbals that pull that off that help to feed the colon. So I'll put a link in the show notes to that article if any of you want to kind of go through that list that Lucy has created for ensuring that colonic energy is not starved off. And then just one other thing to put a nice pretty loop on this discussion of hypoxia and colonic energy before I actually have a few more questions about ketones in the gut and that is that as you note in the article, if you have to take antibiotics, it appears that one of the best things you could do is actually to take butyrate because antibiotics just completely wipe out butyrate producers.

Right, right. And I really hope we see more studies in this regard. But some initial animal studies have suggested that taking butyrate during antibiotics does prevent the expansion of those pro inflammatory oxygen tolerant microbes. So if we can, it's essentially helping to maintain the hypoxia while you're taking antibiotics and in the weeks after.

Yeah, the data I've seen on probiotic supplementation to take care of some of the issues created by antibiotics has been pretty weak. But I think that butyrate's smart. In the past I've always recommended glutamine and colostrum and bone broth to help to kind of heal the lining of the gut. And there's like an ayurvedic tea I often recommend called decoction tea, which is made from like licorice root and marshmallow. It's very nourishing and helpful for the gut as well. But based on what I've learned from your article, I'm probably going to throw butyrate or butyrate producers in there as another thing that would be smart if one has been on an antibiotic regimen because it does make pretty good sense. So we talked a little bit. We didn't really describe it too much, this idea that for example, even in the absence of fiber that ketone bodies like beta hydroxybutyrate or acetoacetate may do for the gut a lot of what something like a higher fiber or a higher fermented fiber or resistant starch intake might do. But when it comes to a ketogenic diet, it seems like some of the chatter goes back and forth on whether a ketogenic diet, particularly a high fat ketogenic diet, is good or bad. For the gut. So what are your thoughts on whether a keto diet is good or bad for the gut?

I think there's a lot of misconceptions there that a ketogenic diet is necessarily going to have a negative impact on the gut. And this is something I've been pretty outspoken about for a while, partly because a ketogenic diet was helpful for healing my own gut. And that didn't make sense to me. So I dove into this more and more. One of the most important things to point out initially, even before we get into kind of a deeper discussion, is that we don't really know what constitutes a healthy microbiome. We do have some ideas as researchers, but there is such a high degree of variability between healthy people in terms of their microbial composition that it's not always easy to say whether one microbial composition is healthier than another. Of course, there's also a right way and a wrong way to do a ketogenic diet. You can do it with processed meat and refined seed oils, and in that case you probably will do harm to your gut. But you can also do it with pastured meats, healthy fats and plenty of non starchy vegetables, berries. And I don't think there's any reason to believe that that would lead to gut dysbiosis.

What about the potential for, because I've even said this in the past, that high saturated fat intake, it appears in the absence of appreciable amounts of polyphenols and flavanols and even arguably fiber may actually present a little bit of an inflammatory state with the gut. Which is why I've always recommend people who are doing especially like a high saturated fat ketogenic diet also include a high amount of antioxidants and plant based nutrients and fiber. What are your thoughts on that or do you have any?

It's definitely possible that we need some degree of antioxidants or things to counteract the effects of saturated fat. Most of the saturated fat data I've seen is in mouse models and they have slightly different fat metabolism. So I'm not sure how comfortable I feel extrapolating those to animal models. And also just all of our, you know, when you see high fat diet in the literature, it's almost always an animal model and it's, you know, their high fat diet is also really high in refined sugar.

Well, yeah, high fat diet and animal models, that's like soybean oil and lard and sugar with almost no fiber like that. That's how they're Actually studying high fat diets and animal models, I don't think a lot of people are aware of that.

Right. So I do think there's a subset of people though, that might not do well with a high saturated fat diet or ketogenic diet. And in particular, I think people who tend towards hydrogen sulfide overgrowth might have a particularly bad time with keto or with a higher fat diet. And that's because the two primary sulfate reducing bacteria that produce hydrogen sulfide are desulfovibrio and Bilophila wadsworthia. And these two microbes tend to really thrive on animal protein and animal fat. So those people might actually do better on a more plant based, Mediterranean type diet, at least until they've kind of figured that out and address that issue.

Yeah. If someone does have hydrogen sulfide producing organisms, which would basically be a situation in which high amounts of butyrate could actually cause some gut dysbiosis. I know that one of the ways to know that is basically just you have very sulfurous smelling stool or very sulfur smelling gas. But is there a test for hydrogen sulfide producing organisms?

You can typically see them on a stool test like longevity, I believe GI effects also test for desulfovibripisure. Not sure if they have bilafila on there, but a simple stool test, you can look at your abundance of those microbes. And typically that tends to correlate with symptoms, which for hydrogen sulfide overgrowth, typically we see more like diarrhea, gut hypersensitivity, sharp abdominal pain, sometimes lower blood pressure or like racing heart. So those are some of the indications that you might have a hydrogen sulfide overgrowth. I wouldn't go on symptoms alone, but with a stool test you can kind of identify whether that might be an issue for you. And also if you tend to feel worse, you know, if you get a lot of gut issues from going on a ketogenic diet, that would be a red flag as well.

Right. A lot of rotten egg smells in the bathroom sometimes. People often don't do well with like high amounts of cruciferous vegetables or even things like eggs and glutathione. Pretty much anything very sulfurous seems to be an issue. And people who have these type of hydrogen sulfide problems, have you found any good fixes for that? Any good fixes for people with a high amount of hydrogen sulfide or hydrogen sulfide imbalances?

Yeah, I'm actually working on a course on this right now, so hopefully that'll be released maybe even before this podcast airs. But Typically shifting in the short term to a more plant based Mediterranean type diet with more carbohydrates and less animal products for a period of time. Molybdenum supplementation seems particularly important because it actually inhibits the hydrogen sulfide production by the sulfate reducing bacteria. And then butyrate can be beneficial for kind of because these are proteobacteria so they like the oxygen. So the more we can kind of target that ppar Gamma pathway, all of those interventions are also going to help in regards to hydrogen sulfide as well.

And don't eat anything that smells like farts, like eggs or like beans, broccoli, cauliflower, cabbage, like any of these sulfurous foods. And again, like even glutathione for example.

Yeah, a lot of sulfur containing foods and supplements do tend to be triggers for some people. Interestingly, usually it's not every sulfur containing food or supplement though. It's very, sometimes very variable depending on the person. So some people can tolerate those, but they can't do any animal like any animal protein or fat. So so it is a little bit individual, but initially it might be a good idea to go on a plant based very low sulfur diet and then slowly reintroduce to figure out which sulfurous things are giving you issues.

Now another concern about high fat diets are these so called lipopolysaccharides and that's the molecule that you're going to find in the cell walls of gram native bacteria. It's associated with low grade systemic inflammation. It's particularly an issue if one eats a very high carbohydrate and high fat meal such as a big fatty steak with fries or a giant bowl of ice cream. But there are even concerns in the absence of the high amount of carbs that a high fat diet would increase LPS absorption. So are you concerned at all about fat enriched meals causing this increase of lps?

Not as much. I think the real issue with LPS in the bloodstream is coming from a leaky gut. When you have intestinal permeability, that's when you're going to be getting the bulk of your of LPS getting into the bloodstream and causing endotoxemia and inflammation. So yes, you know, you do have some LPs basically hitching a ride on these chylomicrons with the absorption of fat, but that actually may be effectively detoxifying that lps. So there's actually things that neutralize the LPS as part of the chylomicron that may actually reduce the inflammatory potential and I actually saw one, one study that I think was brought to my attention by Chris Kelly recently that postprandial inflammation doesn't seem to be connected to high fat kind of micron transport.

So. So what you're saying is don't eat a high fat diet in a stress state before you go, exercise in hot weather and take ibuprofen afterwards. All of all things hot weather, exercise, non sort of anti inflammatory drugs and eating in a stressed state are all things that can increase gut permeability. Like those would be all big no no's, especially if you're going to have a high fat meal.

Right. And you know, and make it a healthy high fat meal, not you know, refined seed oils and, and processed foods. Yeah.

Okay, interesting. All right, cool. So we know that the ketogenic diet with some of those clarifications that you've just raised is probably not going to be that big of an issue for the gut. So we focus on high quality fats and we avoid processed and refined oils like canola and corn and soybean oil. And then make sure that ideally you get vegetables and if you have high amounts of hydrogen sulfide, maybe not, maybe less of the sulfur producing ones. I believe you also mentioned, and this is something I talked about when I wrote my article about the high amounts of coconut oil for example, being potentially inflammatory and some of the things that may fight against that. And I recommend some of these same things that you recommend in your article is like berries and coffee and cocoa and some of these polyphenol and flavanol rich foods. Those seem to be a good idea also. And then the last thing I would be like pay a lot of attention to gut permeability and make sure that's not present if you are gonna, you know, be eating a high fat ketogenic diet.

Right, okay.

Yep, got it. Cool. All right. So next thing that I wanted to ask you about was this paper that you did, I work on, I think in your graduate research about exercise and the gut microbiome and how exercise actually impacts the microbiome. I think most people, just because it seems to be kind of like out there in the literature now and even in popular magazines like Outside magazine, I think did an article on this about how the biome of pro athletes was significantly different in terms of bacterial composition compared to the average person. And so I think a lot of people are kind of mildly aware of this. But can you explain some of the more interesting things that you found in terms of the impact of exercise in the gut? Microbiome and in particular, the practical takeaways, what we can actually learn from a practical standpoint when it comes to performance or exercise in the biome.

Yeah. So this was my primary focus of my graduate work in Dr. Jeff Wood's lab at the University of Illinois. And since 2008, there have been a number of controlled studies in animal models, both in our lab and others, showing that exercise tends to increase microbial diversity and also increase butyrate concentrations. So it increases the capacity of microbes to produce butyrate and also an increase in individual microbes that we believe to be beneficial. Lactobacillus bifidobacterium. We also had a number of cross sectional human studies that followed that, where research essentially compared athletes to sedentary individuals and found that the athletes tend to have higher microbial diversity, greater short chain fatty acid production, greater butyrate production. But of course, we also know that athletes tend to eat very, very differently than non athletes. And diet has a major impact on the gut microbiome. So when you account for the dietary changes, especially the increased protein that athletes are eating, a lot of those differences fell away. So the jury was really still out as to whether exercise had independent effects in humans. In 2017, our lab performed the first longitudinal study of exercise training on the gut microbiome in humans. To basically try and fill this gap in our knowledge, my colleague Jacob Allen and I recruited 32 previously sedentary human subjects, male and female. We had a lean and an obese group, but they were otherwise healthy. And we put them through a six week aerobic exercise training program. So it was three days a week, progressive in duration and intensity, done on a bike and or treadmill.

How long are they exercising for? 3 days a week.

We started them out at 30 minutes at 60% intensity, 60% heart rate reserve, and then we ramped them up to 60 minutes at 75% heart rate reserve by the six week time point.

Got it. So basically they were doing a total of like three hours a week on a bike for split into three separate sessions by the time the study was over.

Yep. Okay. Um, and it was, it was fairly intense for them, given that they were all quite sedentary beforehand. So what we found is that exercise training increased fecal butyrate levels and the abundance of butyrate producers, particularly in the lean folks, which was interesting to us. Not exactly sure why we didn't see the same in the obese group, but maybe diets having a stronger pull on the microbiome there. When a subset of Those participants returned to their sedentary lifestyle for a six week washout period. We saw a reversion of the changes in the microbiome. So this suggested to us that exercise, yes, has independent effects on the gut microbiome, which are then largely erased when you return to a sedentary lifestyle.

So, and by the way, have they looked at this at all in like trained individuals who are already doing an exercise program and change that, or trained individuals who detrain, for example, and whether or not that impacts the biome?

Yeah, so I have seen, I think I saw a poster at a conference a year or two actually where they, I believe it was elite swimmers and they were looking at them at their post season taper where they were reducing their training load. And there definitely were changes in the gut microbiome in those elite swimmers. So I think there, there definitely do seem to be changes in elite athletes too, with differences in the training load. I don't think they would be quite as significant as, you know, what we're seeing here with sedentary individuals suddenly starting a fairly intense exercise program. But definitely some benefits to be had even for the athletes.

Okay, so obviously, I mean, the big obvious takeaway is if you exercise, you're probably going to see things like a decreased risk of colorectal cancer, better gut microbiota composition, assuming that you're not over training or overdoing high intensity exercise in the heat, for example, and largely a positive benefit when it comes to overall gut health and microbiota composition. But then like, aside from that, are there other things that we can take away from this? Like, like for example, could you take a specific probiotic strain that would simulate in your gut what exercise might be doing to your gut? If we know the type of strains that are being changed when you exercise, then this kind of relates to like, I think what some magazines picked up on when this research first started was like, could you like, whatever, analyze LeBron James poop and then supplement with the same bacterial strains that you find in that and see some kind of like a change in your own athletic capacity or performance potential or ability to be able to slam dunk a basketball?

Yeah, I'm not sure it's going to give you any slam dunk capabilities, but it's certainly an interesting idea as to whether we could improve performance by transplanting microbes from elite athletes. There was actually an interesting paper published in Nature Medicine last year that seemed to suggest that this might be possible with a single microbe, Viennella atypica. But reading that there were A number of limitations that makes me question whether that result will translate to humans. So in that study, they looked at marathon runners before and after their marathon basically, and looked at which, which microbes increased during the marathon. And they found that in about half of marathon runners they had this increase in vionella. And when they then transplanted vionella into mice, they found that only slightly more than half the mice ran longer in the exhaustive exercise experiment when they were supplemented with vionella versus when they were supplemented with lactobacillus as a control. So there was a lot of hype around that study, but I remain skeptical that that's going to translate to humans.

Yeah, well, like the New York Post, they had one article about, it was about how poop transplants are the final frontier in athletic doping. And they talk about this semi, this semi pro cyclist who had, I think she had cetophyseal or equal coli or salmonella or some type of gram negative pathogen or something like that. And she got a fecal transplant, but it was from like a, a fellow competitive cyclist. And right after she got the transplant, like her performance went through the roof and she moved from amateur up to pro racing. And you know, again, the, the big elephant in the room there, the big stinky, poopy elephant in the room is that, you know, she probably had a, a pretty good response in terms of the way that her gut felt while training. And maybe it was just that she was able to train without bloating and, and flatulence and gas and GI upset and not the actual bacteria, the magical bacteria she was getting from the pro athlete that she got the transfer from. But regardless, something seems to be happening.

Yeah, that's really interesting. I think it will be more really fascinating to see how a full FMT from exercised animals into other animals or humans could impact aerobic exercise capacity or fitness biomarkers. And I actually think my old lab may be doing some experiments in that regard that may hopefully come out in the next year or so. But we actually did a cool study using germ free mice during my PhD, which basically we took a group of mice that exercised for six weeks and a group that remained sedentary. And when we transplanted the exercise microbiome into germ free mice, they actually had higher body weight, which we wish we'd been able to do body composition. So we don't know whether that was muscle mass or fat mass or what exactly. But interestingly, those mice were actually protected against colitis when they received the exercised microbiome instead of the sedentary microbiome, regardless of the fact that the recipient mice didn't actually exercise.

You know, it's just one of those things that I want to be careful about, because, especially, like in the biohacking sector, we always hear about these studies that may produce small changes or anecdotal changes, and then, you know, all of a sudden somebody's saying, whatever, shine red light on your balls and you're gonna go break Olympic records. And, you know, I in no way want to endorse something like fecal transplants or taking probiotics to see big athletic performance breakthroughs. Like, at the end of the day, 99.99% of the results you're going to get as an athlete come down to sweating your ass off and putting in the hard work and recovering smart. But I do think some of this stuff's just interesting, at least in terms of the way that the body actually responds to an exercise protocol or even some kind of a. A transplant or possibly even probiotic supplementation. But again, I'm one of those guys who's like, yeah, it's interesting. Maybe it's gonna put a little bit of icing on the cake, but, dude, you gotta go out and do the hard work still. So right now, there is one other thing that I want to ask you about, because I did find your thoughts on this fascinating, and it is something that I think a lot of people are curious about. And this actually isn't the very last question I want to ask you, because I want to get into anything else that's going to be super exciting in the frontier of gut health. But resistant starch. Resistant starch is obviously something that's getting a lot of attention right now. A lot of people are taking it for everything from better lucid dreaming to gut health. And so what are your thoughts on resistant starch, and if possible, because I think some people don't even know there's three different kinds, or really four different kinds of resistant starch. What the different kinds are and what your overall thoughts are based on what you've seen when it comes to resistant starch.

Yeah, I get a lot of questions about that one. And I think this is one of those areas where broad brush recommendations for gut health can really do more harm than good. So for those who aren't familiar, resistant starch is a form of starch that is resistant to digestion by us, the host. So it passes through our GI tract to the colon, where it can then be fermented by specific bacteria into short chain Fatty acids like butyrate. So there's four primary types of resistant starch. Type 1 is primarily found in whole or partially intact grains, seeds and legumes. Type 2 is found in raw potatoes, green bananas, raw plantains. This is the most common supplemental form of resistant starch and is commonly available as potato starch or raw potato starch.

These are given names like Rs1, Rs2, Rs3, et cetera.

Right? Yep, exactly. So type 3 or Rs3 is retrograde resistant starch. So that's formed when starchy foods like potatoes, rice, legumes are cooked and then crops cooled. And then type 4 is synthetic man made resistant starch, like high maize, corn starch.

Got it. So, so you got your four different times. Rs1 Rs, Rs1 and Rs2 are typically like a little less modified in terms of like Rs1 just being like grains and seeds and legumes. Then Rs2 in mostly some of these raw bananas or unripe bananas and, and some raw nuts and raw potatoes. And then like the RS3, that's when you cook and cool. And then RS4 is just a straight up synthetic man made resistant starch produced by chemical modification. And that might. I like one example I could think of for that would be like one I used to use when I was racing in triathlon. It was called you can superstarch. And I think there's another one called Vitargo that's kind of similar. And I remember take that stuff and just be like super bloated after because it was designed for glycogen storage disease to allow for kind of like a slow bleed of glucose into the bloodstream. But man, it would just sit in your gut and ferment. Holy cow. So anyways, so we got these four different kinds of resistant starch. Do you think they're actually beneficial? Because it just seems to me like from an ancestral standpoint that not many folks would like grab a green banana off a tree and eat it and you know, or you know, even it seems like a little bit molecular gastronomy to just like cook a food and and then cool it and then reheat it for a high amount of resistant starch. Even though I think a lot of people are just getting resistant starch by accidentally doing that. But what are your thoughts on the actual benefits or non benefits or cautions behind resistant starch?

There are a number of studies showing the potential benefits of resistant starch mainly in regards to like blood sugar regulation, laxation, satiety, cholesterol levels, A lot of the general benefits we think of as from soluble fiber as well. And resistant starch also tends to increase the production of butyrate, though this is quite variable between individuals. So there's been studies that basically show when they feed 20 people, resistant starch, some people increase their butyrate production, but other people actually decrease theirs. And I think it's really important that we distinguish between these types of resistant starch, because they really are quite different. And there's at least a few studies that suggest that resistant starch type 2Rs2, which is the type found in raw tubers, raw potato starch, can potentially increase gut inflammation. It can increase microbial cell damage, which is similar to the effects that antibiotics have, and also increase biomarkers of colon cancer risk. And I think, honestly, if we think about it, you know, like you said, it makes sense that, you know, evolutionarily, our microbes are evolutionarily adapted to cook tubers. You know, the advent of cooking significantly increased the digestibility and consumption of starches. So RS3, which is the retrograde resistant starch formed when starchy foods are cooked and then cooled a little bit, that's much more evolutionary familiar. And this is the resistant starch from those whole cooked and cooled plant foods. And if you're eating a wide variety of those, I generally don't really see any need to supplement with isolated resistant starch.

Yeah, I mean, there are some cases where I think some of, some of the starches are engineered. And I never called all of Vitargo is classified as resistant starch. But a lot of bodybuilders will use that while training for really fast release of glucose into the bloodstream for glycogen replenishment or like that. You can superstarch. Some people who don't have it ferment on them find it to be a really stable source of energy during exercise. But in terms of the actual benefits on the gut, it appears that there may not be many there. And in fact, in a lot of people, it seems to result in a lot of fermentation and bloating, especially like the. The synthetic resistant starches.

Definitely.

Okay, so overall, the big takeaway with resistant starch is it has been shown as a prebiotic fiber to allow for things like greater satiety or improved insulin sensitivity or reduced blood glucose response. But those responses are kind of highly individualized. And this Rs2, like raw potato starch and green banana flour, etc. That's probably one that may exacerbate, exacerbate dysbiosis or cause mucosal inflammation. And if you were going to get more resistant starch, just try to get it from like whole cooked plant foods that you could then cool and take back out and reheat.

Yeah, absolutely. I think, you know, I'd like to see more studies with RS2, but currently I don't feel comfortable with high dose supplementation of that and could potentially lead to what you were saying, the gut inflammation and gut dysbiosis.

Got it. Okay, cool. So you also obviously are kind of like living at the cutting edge of all things gut and gut microbiota research. And I know like you recently were attending the Gut Microbiota for Health world summit that took place and you're constantly pouring through the literature on this stuff. So what are you excited about when it comes to what's emerging right now in the field of gut research or gut microbiota research?

Yeah, that's such a tough question for me. I just feel like there's so many interesting areas of development and I did attend that summit. I actually also hosted summit myself in May where we had more than 20 of the top microbiome researchers present, many of whom shared unpublished data. So the recordings from that are still available if anyone's interested in listening to those. It was called the virtual Microbiome Summit.

Okay.

But I think one of the most exciting developments that was presented by Dr. Erica Sonnenberg is around understanding the industrialization of the microbiota and how we might try to bring back some of that lost ancestral diversity or essentially reintroduce some of those missing microbes. So there are a number of talks around that and I think I'm hoping that we really learn more about that because we really have lost over 50% of our ancestral diversity.

I honestly personally think part of that is just gardening and hunting. Yeah, that's my takes. Get outside, get dirty, go field, trust some dead animals and you're probably going to get a ton of ancestral bacteria just from that alone.

It's possible. I'd love to see some studies around that, like the rewilding the gut microbiome.

Okay, so that's interesting.

Yeah. And then there's also a lot of amazing work being done in regard to using microbiome data to predict clinical outcomes or particular interventions using machine learning. And I think we're going to see a lot more of that in the next decade. And then relative to the ketogenic diets, I forgot to mention it earlier, but Dr. Peter Turnbaugh's lab just published a study on ketogenic diets and how they impact the gut. And they found that it decreases bifidobacteria, which most people would think would be a bad thing. But that actually was associated with a reduction in Th17 cells, which tend to be elevated or overactive in many different types of autoimmune disease. So it was actually beta hydroxybutyrate levels in the gut was actually inhibiting the growth of Bifidobacterium, but that effectively reduced autoimmunity.

That's interesting. I know a big part of gut microbiota health is related to bifidobacteria and Akkermansia balances. Did it do anything to Akkermansia?

I'd have to go back and look at the study. Ketogenic diets typically do tend to increase akkermansia, at least in humans. I'm not sure if they saw that in their study. They were primarily focused on the bifidobacterium story.

Super interesting, huh? Well, your blog is really great. And again, I'm hoping that those of you who are listening who are interested in the gut, tune into Lucy's writings because they're really good and this gave me all sorts of interesting things to think about. I'm actually, do you know Naveen Jain, the guy who runs viome, that microbiome testing company? Okay. I'm having dinner with him tonight, so maybe this gave me a bunch of fodder of things to talk about when I'm chatting with him. Because he likes to talk about the gut.

Yeah. Great.

So this is great. This is perfect timing. And then I'm actually going to interview him tomorrow, so maybe I'll be able to use some of this as fodder for that because I just, I love to geek out on this stuff. And again, for those of you listening in, I'm going to link to all the studies and everything that we talked about. If you just go to BenGreenfieldFitness.com Lucymailing that's BenGreenfulFitness.com Lucas Lucy L U C Y Mailing M A I L I N G and Lucy, thank you so much for your time. Thanks for coming on and sharing all this stuff with us. It's just super fascinating.

Thanks so much, Ben. I really, really enjoyed this.

Awesome. All right, folks. Well, I'm Ben Greenfield, along with lucy mailing of lucymailing.com signing out from BenGreenfieldFitness.com have an amazing week. Well, thanks for listening to today's show. You can grab all the show notes, the resources, pretty much everything that I mentioned over@BenGreenfieldFitness.com along with plenty of other goodies from me, including the highly helpful Ben Recommends page, which is a list of pretty much everything that I've ever recommended for hormones, sleep digestion, fat loss, performance, and plenty more. Please also know that all the links, all the promo codes that I mentioned during this and every episode help to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. So when you listen in, be sure to use the links in the show notes. Use the promo codes that I generate because that helps to float this thing and keep it coming to you each and every week.

RA.