About the guest: June Round, PhD is a microbiologist whose lab at the University of Utah studies microbiome-host interactions, gut microbiota, immunity, metabolism, obesity, and other disorders.
Episode summary: Nick and Dr. Round discuss: how the immune system and gut microbiome interact; dietary fiber & short-chain fatty acid production by gut microbes; nutrient absorption; obesity & metabolic syndrome; type I diabetes; cleanliness, development & the “hygiene hypothesis”; and more.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Nick Jikomes 0:25
Whether food, drugs or ideas, what you consume, influences, who you become. On the mind and matter podcast, we learn together from the best scientists and thinkers alive today about how your mind body reacts to what you feed it before starting mind and matter, I spent 10 years in academia doing scientific research. I got a PhD in neuroscience, where I focused on neuroendocrinology and the neurobiology of behavior, and before that, I specialized in molecular developmental and evolutionary genetics. I use my scientific background to help parse and translate the information that guests share on the podcast. In addition to the podcast, I write long form written content inspired by the show, where I integrate what I've learned across episodes. I also have a free weekly newsletter where I provide you with upcoming guests, share links and provide commentary on scientific studies and research that I'm reading and more, visit mindandmatter.substack.com to find all of my content. This episode is ad free, and I rely on my audience to support my efforts. If you're getting value from this content, please consider becoming a paid subscriber to the minded matter substack for just $5 a month, you'll get early access to episodes and other content, full episode transcripts, and I'll prioritize answering your questions in emails and the comments sections. You can also support me by checking out the links in the episode description to my affiliate partners who make various health and wellness products that I use and enjoy myself, you'll receive a discount and help support the podcast that way. And if you want the benefits of a paid subscription, but it's not in your budget, simply sign up for my free weekly newsletter. Send me an email, and I'll give you a complimentary paid subscription. Word of mouth is the best way to help the podcast grow. So if you like what I'm doing, please share your favorite episodes with family and friends. The purpose of the podcast is to provide you with information obtained largely from primary sources, the people doing the research and producing new knowledge. This content is never meant to serve as medical advice. And with that, enjoy the episode. Thanks
June Round 2:22
for watching. Appreciate it. Can you start
Nick Jikomes 2:24
off by just telling everyone a little bit about who you are and what your lab studies?
June Round 2:29
Sure. So I'm at the University of Utah. I'm in the Division of Microbiology and Immunology in the department of pathology, and my lab is interested in the interaction between the commensal microbes that live on your body and the immune system, and we're really interested in how these organisms promote health. So I think a lot of people, when they think about microbes, they think about disease. They think about pathogenesis. Of course, they equate microbes to the pandemic. They're always just thinking about getting rid of microbes. But we think about microbes in a very different way. We think that there's a lot of microbes that are present on a healthy body, and our real interest is identifying those microbes and how we might be able to utilize them to prevent diseases.
Nick Jikomes 3:24
And most people, you know, when you start talking about the microbiome, people talk about good versus bad bacteria. It's intuitive as to why they're doing that, right? Bad bacteria would be, you know, a pathogen, something that could make you sick or even kill you, potentially a good bacteria, you know, I guess, what's implied there is that it's contributing something to your health or to the functioning of the organism, potentially even something that's necessary. Do you think it makes sense to talk about good versus bad bacteria? And if so, what does good mean to you? Exactly,
June Round 3:55
it's such a good question. Nick, I guess I can't help but think of good versus bad, because a lot of our studies have identified bacteria that are beneficial, but I think in reality, it's definitely more of a spectrum. Good bugs can go bad, for sure. There can be organisms in your body that might be providing you a benefit, and then, if they're provided an opportunity, let's say they get out of the gut and into the systemic part of your body, they could cause a problem. So I think, or I think what you're hinting at is absolutely right, and that's not, there's not always good bugs and always bad bugs.
Nick Jikomes 4:37
So some of the good ones can become bad. And you know, my understanding is that this often means, you know, they have to sort of be in the right place. They have to be contained in the right area. And if they get out of where they're supposed to be, quote, unquote, then, as you said, they can become bad.
June Round 4:54
That's right, yeah, definitely. They need to be contained. Most of our microbiome lives in the intestine. In. So certainly, if those microbes get out, let's say they get in your liver or in your blood, they're, they're going to cause problems. Although, you know, most of them are highly anaerobic, so they, you know, can't survive in highly oxygenated areas. So most of them will, will rapidly die. But yes, if they get out of the out of the compartment, they can do some bad things. Yeah,
Nick Jikomes 5:23
and, you know, I've had, I've had microbiome people on before, and we've talked about various aspects of it. So my understanding is basically, right, we've got our immune system. You've got microbes in your gut and elsewhere, and the immune system is sort of, there's sort of a delicate balance there. On the one hand, you don't want to destroy some of these microbes, but the other hand, you want to contain them, keep them at bay, prevent them from going where they're not supposed to be. Can you give us just a general, basic sense for some of the communication that happens between the immune system and the microbiome? Sure,
June Round 5:55
definitely. I'll focus, I guess, on the things that my lab studies, because I know that stuff best. So we're really interested in antibodies. So most people are familiar with what antibodies are, but they're molecules that B cells produce, and you make a ton of them in your gut. You, the average human makes about two grams a day of an antibody called IgA, and these antibodies are one of the primary ways in which we contain our microbiome. So these antibodies are very specific for microbes. You know, there's lots of different parts of your immune system. Some of your immune system is very general and just recognizes, you know, cell wall, components of bacteria. But there's another part of your immune system which is very specific, and this is the part that antibodies are part of. So these antibodies are highly specific for the microbes in your gut, and they help to control them. And they don't just they do keep them contained in their area like we were just talking about, but they also control the types of molecules that they let those bacteria Express. Bacteria or fungi are viruses. I should, I should point out so they don't let, they don't let organisms Express molecules that are harmful to the host. So if there is a harmful toxin or adhesion or something that makes that organism, you know, invasive to the host. Antibodies will target it, and that bacteria will down regulate expression of it. So it's not about always getting rid of the bacteria. It's kind of about controlling their function, their behavior,
Nick Jikomes 7:38
I see. So, so it sounds like we IgA, this antibody we produce. We produce quite a lot of it. And if I'm hearing you correctly, you know, normally, when I sort of naively think about antibodies, you sort of mass produce them when you get sick, and they sort of just cover the entire outside portion of a bug, and then that's sort of a step towards destroying that bug. But it sounds like these IGA antibodies. They can actually be used not to sort of destroy or completely suffocate these microbes, but they actually just control, sort of, there's sort of a molecular communication there, and it controls what the pathogens are actually making molecularly. Yeah,
June Round 8:16
that's a great interpretation of it. And most people think like you Nick where they think about the mass production of antibodies, and they're in our blood, and their whole function is to tag a microbe for destruction, and IGA does do that in the gut. It just IGA is different in the sense from other antibodies in the blood, because it doesn't mount. There's no inflammatory response associated with IgA, its sole purpose is to target those organisms, and it does get rid of, you know, basically it groups the organisms that it wants to get rid of together, and then you will essentially poop it out. So there is some eradication that happens. But ultimately those bacteria, because of that response, will down regulate those those molecules. And,
Nick Jikomes 9:05
you know, before we get into some of the specifics around some of the work that you've done, some of your recent studies, so when we say that there's good bacteria, and you know, with the caveat that good bacteria could become bad, and things are a spectrum like, what are some of the major things that we know good bacteria generally do. Is it that they are providing key nutrients that we can't really produce otherwise or absorb otherwise? Is it they're sort of merely taking up space to box out pathogens like, what are some of the good things that tend to come from these gut microbes? Well,
June Round 9:37
I think you named, you know, some of the top two that people think about is, first of all, they take up a ton of space that kind of excludes any pathogenic bacteria. This is actually like a really important function of the microbiota, because they have evolved to live with us peacefully, whereas pathogens haven't. But by them taking up the space. Yes, that prevents us from getting sick, and C difficile is probably one of the best examples. So if you undergo antibiotic treatment, you kill a lot of those commensal microbes, and then C Diff has an opportunity to bloom, and this causes a lot of people problems. Another major benefit of bacteria is indeed, metabolism. So they do, you know, we can't process a lot of the fibers that we eat, like cellulose in plants. Our microbes help us extract energy and things that we might not normally extract. They can also, they also produce molecules that help absorption of certain things like lipids and sugars, they can also prevent absorption of things that perhaps are not good for us. So we still don't understand fully their metabolic capabilities, but we know that they're really important for metabolism. And then, of course, one of the major things, and that's what we study in my lab, is that they're really important in teaching your immune system about what to fight off and how to fight it off. So we in our lab, we use germ free mice, which maybe you've had previous guests talk about, but these are mice that have no microbiome of their own. And if you infect these animals with any sort of pathogen, they basically just die because, and it's largely because their immune system hasn't been taught how to fight off that pathogen. So, so it's like really important for our immune system maturation,
Nick Jikomes 11:39
yes, and the immune system has to be trained across development in order to function properly and effectively at getting rid of pathogens. You're saying, if you create animals that don't have a microbiome, basically there's no bacteria living inside of them, or other microbes, their immune systems just don't learn how to how to function
June Round 11:58
properly. That's right, yeah. So if you compare their immune system to that of a normal animal with a normal microbiota, they're missing a lot of immune cell populations, or the immune system populations that are there are very naive, or they're, you know, reduced in number. So that's it's a really important thing our microbiota does is to teach our immune system. And
Nick Jikomes 12:21
when you say germ free animals, how are you making these? Is this like a genetic thing? Or do you have to give them lifelong, you know, antibiotic treatment for birth,
June Round 12:30
so the way the original so we don't antibiotic treat these germ free animals. They basically live in these little bubbles. And you have to be very careful about the food you feed them. And we just have to keep them in the bubbles and only give them, you know, sterile food. The way the original germ free animal was created was that you had to do a C section of a pregnant mouse mother, and then those babies, they're like beads on a string. So you basically plump them in, like a plop them in a little sterile solution, and then you place them in this bubble, and then you take them out of their sack, and someone had to hand feed the first germ free mice ever made, because there was no mothers in the Oh, wow.
Nick Jikomes 13:20
So, so a couple of things here, like this is just sort of a lineage that's been going forever like this, since you made it, since people made it.
June Round 13:28
Yes. So now there are facilities around the country that maintain these animals germ free. And anytime you want to read or you can re derive any animal germ free, and you just have to take it through this process, but now they're now you can use the germ free moms that are currently in the bubbles as surrogate mothers. Yeah,
Nick Jikomes 13:47
yeah. And, you know, I don't necessarily know if this is your area, and I don't think we'll go into this too much, but, but I want to ask, because it's interesting. So you said, you know, when these mice were created, a C section is done. The little developing mice were taken out. One thing that's kind of implied there is that the microbiome they would have had would have come from the birth process. It would have been seeded by the mother, to a large extent. Can you talk a little bit about that? Is that basically how our microbiome of most animals get started? Yeah.
June Round 14:19
So at least in mammals, that is the case you acquire. You're fairly sterile when you were born. There's like, you know, contention as to whether there's microbes in the placenta and things like that. But you're basically sterile when you're born and you acquire your your first seating is really through the birthing process. So through the mom's vaginal canal is where you're really seated with your microbiome. Now, if C section babies often have a very different microbiome than a baby that's born via a vaginal birth, and then as you grow up, you acquire microbes, again, from your mother. Yeah, you'll get some from your, you know, father and siblings and then your environment, but really, that first seating is from that then initial birthing process.
Nick Jikomes 15:08
And do we know how, I mean, sounds like there's quite a big difference between babies born naturally passing through the vaginal canal versus those born by a C section. I was, I was a C section. Baby myself, Do we know anything about humans? How those two populations differ?
June Round 15:26
Yeah, there's, there's a lot of epidemiological studies done on this. Babies that are born via C section tend to develop more autoimmune disease. Later,
Nick Jikomes 15:39
interesting. I have an autoimmune condition.
June Round 15:43
I'm sorry to hear that. It's minor, and maybe later we can talk about some of the stuff we're doing with early life development, but that is one of the major things that is different with babies that are born via C section and yeah, vaginal birth is that they develop things like IBD, yeah, another disease that the tendency is, is that if you're born via C section, you have a higher chance of developing that later. So,
Nick Jikomes 16:13
and I guess if we, if we sort of put that together with what you said about the germ free mice, if germ free mice don't develop a very effective immune system because they completely are largely lack of microbiome. I think, you know, if you compare the C section babies to the natural birth babies, it would imply, at the very least, that their immune systems get trained up in a different way. And perhaps this is related, why you see these things with autoimmunity?
June Round 16:40
Yeah, that's right. I think, you know I said, I said, those microbes are really important in training your immune system to fend off a pathogen. But the microbes are also equally important in teaching your immune system when to not respond to things, including, like your own tissues, yeah, like, remember what autoimmune disease is, is when your immune system is inappropriately recognizing your own tissues. Yeah, so important in that,
Nick Jikomes 17:09
yeah. If I had to guess, I would guess that a natural birth results in a microbiome that's probably more dense and diverse in composition.
June Round 17:19
Yes and no. I don't know if the studies are clear on that. I think it's that the microbes are very different. So, yeah, when you're born via you know, a vaginal birth, there's a lot of lactobacillus that you're introduced to. There's a lot of, you know, Candida that you're introduced to. Whereas, if you're born via a cesarean birth, then you tend to have more of skin microbes. So I think you're not supposed to be exposed to those moment yet. Yeah,
Nick Jikomes 17:50
I've even heard, I've even heard that babies born by a C section tend to have microbiomes that start to resemble the skin microbiome of the doctor, whoever delivers the baby, that's
June Round 18:02
interesting. I've actually never heard that, but that's funny. That surprised me. I
Nick Jikomes 18:07
have not verified that, but I think I read that somewhere. Okay, so like, the composition of the microbiome, obviously, is very important for how the immune system gets trained up. It's natural to think how that would be related to things like autoimmune disorders or just your general ability to fight off pathogens. So the other thing I want to ask you for some background here is, you know, one of the things that seems like it's a fairly rock solid part of the literature that I hear over and over again is, you know, when we talk about nutrients that are good for your microbiome or that promote a healthy and diverse microbiome, the one that comes up the most is fiber. And you mentioned that fiber, things like cellulose, we don't digest them, but as people often say, they're food for the microbiome. What I want to I want to unpack that a little bit more. What do these microbes do with the fiber, and what are they producing that then turns out to be good for us, sure.
June Round 18:56
Um, so the mic, this is not, you know, I will disclose that this is not my area of great expertise. We don't study this a ton. But of course, it's one of the bigger things in the microbiome literature, is is diet. So the the fiber that there's lots of different types of fiber. So first, I'll say that not all fiber is created equally, and not all fiber is going to be metabolized by the microbes equally, and not all fiber is going to have a benefit. So there's, you know, there's been a couple studies that I've seen where the fiber inulin, which is one of the ones that a lot of people will take, actually is really bad for certain diseases. It's good for some but bad for others. Based off of you know, how the microbes metabolize it and how it influences your immune system. But I think you know, one of the best metabolites that studied because of fiber production, is short chain fatty acids. Yeah, you've heard of these before, but this, I mean, I. Everyone studies short chain fatty acids, and these just seem to be globally good for you, in that they induce an anti inflammatory response. They can also act as fuel for your intestinal epithelial cells, so your intestine is lined with these epithelium that's kind of one of the major cell types that creates a barrier between the microbiome and the host. And the short chain fatty acids are solely made by the microbiome, and they can be fuel for those intestinal epithelial cells and keep them, you know, keep that barrier tight. Yeah,
Nick Jikomes 20:36
yeah. Well, that's interesting. So, so these short chain fatty acids, maybe we'll talk about chain length later. But shorter, sort of smaller fatty acids. They can be used directly as fuel, sounds like. So if you've got microbiome, if you got microbes in the intestine, they can take that fiber, make these short chain fatty acids. It seems like it's a really good, efficient way to locally have energy for those cells. They probably don't need to spend as much of their, you know, their their time and energy making fuel, if you can have these microbes producing it locally, right there,
June Round 21:07
that's right, yeah,
Nick Jikomes 21:11
and so, and so. So what would be the difference between, you know, just at a high level? So when we talk about a short chain fatty acid being used for energy, as opposed to something like glucose, is there anything worth mentioning? There is like one of them better or preferred by our cells as a fuel source?
June Round 21:29
You know, glucose always seems to be the preferred fuel source for everybody, our cells and the microbes. So, you know, I don't think that I can intelligently comment on whether or not short chain fatty acids or glucose are preferred. I think it, you know, it all involves the environment, what the cell is doing, what the cell needs.
Nick Jikomes 21:54
And I guess one last question I have here is, so they produce the some of these microbes produce these short chain fatty acids, which can be used by cells for energy and perhaps for other things, is, are there other ways to get short chain fatty acids, or is this the only way
June Round 22:10
so our body doesn't produce them? It's, you know, the fermentation byproduct of fiber that produces them. The other way to get them is people do synthesize these, like chemical companies synthesize them. So for instance, in the lab, we can buy, because there's lots of different short chain fatty acids, there's butyrate, there's proprionate, and you can purchase these, and you can orally take them, and a lot of people will do that in their mouse studies to show that, oh, this short chain fatty acid is sufficient to have this effect. But,
Nick Jikomes 22:49
but other than that, other than these products, is this not a com Is this not really a component of natural sort of whole food diet?
June Round 22:57
Not that I'm aware of? No. So
Nick Jikomes 23:00
I know that there's, you know, the microbiome has been connected to, you know, all sorts of stuff. And we'll talk about some of that. Obviously, it's connected to, you know, gut issues that we can talk about, inflammatory bowel disease and things like this. But it's also been connected to obesity. And, you know, we're going to talk about one of your papers that that, that you shared with me that's really, really interesting here, but before we get to that in particular, what's sort of known, what's out there in the literature right now in terms of the connection between the gut microbiome and obesity.
June Round 23:31
So what is currently known is that a I guess, very on a very basic level, that the microbiome, when it is less diverse, if you will, is associated with increased obesity. So what does diversity mean? You know, we have these. We have these kind of like arguments in the lab about this, I think just on a very superficial level, if you are missing certain microbes, and we are still uncovering what these specific microbes are and what they do, you seem to be more prone to gaining weight. So your microbiome composition seems to be very important in how you gain or lose weight,
Nick Jikomes 24:19
and in in principle, like, what would be the ways we imagine that could happen? So off the top of my head, I could, I could imagine, well, maybe certain microbes are making certain key nutrients or producing metabolites that have to do with energy expenditure in our bodies, maybe regulating how much of the calories we're actually absorbing from the food that we put into our mouse, what's sort of the space of possibility there?
June Round 24:42
Yeah, so I think one of the first mechanisms ever discovered was really from Jeff Gordon's group, and this was when they basically took a microbiome from a obese mouse and transplanted it into a lean mouse, and that animal gained weight and. What they showed is that that microbiome was really good at extracting energy, so it was able to extract more energy from the food, and then it gave more energy to the host.
Nick Jikomes 25:11
I see, did those mice actually eat more? Was all that accounted for just by absorbing more
June Round 25:18
in the transplant? The animals did not eat more. It was more about, you know, them just having more nutrients and and extracting more energy. The obese animal used for the microbiome transplant, it was a leptin deficient animal, so it just constantly eats, you know, there's, there's no doubt, there's a component of, you know, diet in influencing the composition of your mic,
Nick Jikomes 25:43
but just just that microbiome change was accounting for a lot here. That's right, yeah, interesting. So tell us a little bit about this paper that you shared with me. Can you set that up for us in terms of what kind of questions you guys were asking, what the basic setup is sure
June Round 26:01
so during my so this was one of the first studies I embarked on when I started my own lab. So during my postdoc, I had been studying a bacteria that we had discovered was able to prevent inflammatory bowel disease in mice, and the mechanism by which it was doing that was inducing a T regulatory population, which is an anti inflammatory cell, and that's how it was able to suppress inflammatory bowel disease. And we identified a pathway within the cell that it was able to induce this T reg population. So it was basically inducing it by making a polysaccharide that bound to a toll like receptor on a T cell. So it and a toll like receptor is one of these receptors in innate immune cells that's able to recognize many components of bacteria. So they're somewhat skews. So
Nick Jikomes 26:59
these, yeah, so these are receptors are for, therefore, sort of recognizing what is and is not a pathogen or a human cell.
June Round 27:07
They are but they're very they're broad in scope, so they recognize pieces of bacterial cell walls or bacterial DNA, and they can do that whether it's a commensal or a pathogen. So they don't, they're not really great at differentiating between the two.
Nick Jikomes 27:24
I see, I see, they can just sort of see, like, this is our cell. This is human cell or not?
June Round 27:29
Yeah? Basically, yeah. So people are still trying to understand how these cells help distinguish between commensal and pathogen, but it made us really interested in that pathway with respect to because it seemed like this pathway was really important in inducing a healthy homeostatic intestine. So we made an animal. So I should preface this like I I did not get start my lab thinking I was going to study obesity. I would I thought we were gonna, you know, find a pathway that was involved in IBD. But, you know, you just follow the science. So we made this animal where we got rid of a signaling molecule that's downstream of toll like receptors. It's called Myd 88 and basically this is a signaling molecule downstream of most of toll like receptors. By getting rid of it, you're you're essentially disrupting the ability of whatever cell type we were looking at, a T cell at the time, but you're disrupting the ability of that T cell to signal through any of those toll like
Nick Jikomes 28:33
receptors. So does that mean basically, the immune system can recognize when it meets a non human cell through this toll like receptor, but it can't act on that because you're sort of blocking the information
June Round 28:44
flow. That's right, exactly. And I should say that we only knocked it out in the T cell, so the rest of the cells in the mouse's body were able to make that recognition. So they were still active. So one when we made that mouse, one of the major phenotypes of that mouse is that it had a significant reduction in the amount of IGA it produced in the gut. And you said we produced normally, a lot of it, a ton of it, right? But this mouse, when we knocked out this pathway, was not making as much. Then, if you let those animals grow up to old age. Most people do not let mice sit around in their in their facilities beyond eight weeks, because it's very expensive to keep mice. For some reason, my graduate student decided she was going to not cull any mice, and she was going to let them grow up to be like, over a year old. And these animals developed this spontaneous obesity. They were like, really fat. They were like, she always called them like, little
Nick Jikomes 29:45
pancakes. But late in life, did it develop this? Late in life?
June Round 29:49
Late in life, yes, it was not immediately. We didn't observe it in like, an eight week old
Nick Jikomes 29:56
animal I see so as the mice are growing up and going through adolescence. And things and becoming young adults, they basically they looked normal, macroscopically to the eye. That is
June Round 30:04
correct? Yes. So they did have this IGA deficiency at that early stage. But it wasn't until later in life that they developed the obesity. If you did put the animals on high fat diet, they were they developed the obesity quicker so you could start to observe it. But yeah, it seemed to be a spontaneous phenotype, which is very rare to see in animals. Actually, normally you have to push the obesity by giving them a lot of fat or eating their diet in some way. So this, this was a really striking phenotype to us, because we had knocked out this immune pathway, we thought it was going to be involved in gut homeostasis, but these animals were getting fat, so it made us think about the microbiota. I'm a microbiota lab, so of course, we thought about that. So we did transplant studies, where we took the microbiota that formed in these obese mice and we transplanted them into germ free wild type mice that did not have this knockout, and those animals got fatter
Nick Jikomes 31:10
same timing with the same developmental timing. No,
June Round 31:13
they actually gained weight faster than these other animals. Okay, so what I will say is, when you take that microbiota from the knockout animal and put it into a wild type animal over time, the immune system and that wild type animal will will kind of reshape that microbiota to be more of a healthy microbiota, if that makes sense.
Nick Jikomes 31:36
Yeah, yeah. And so in the genetically engineered mice that develop obesity in late age. Did you characterize, sort of how that's developing in terms of, are they expending less energy? Are they eating more? Or does it appear to be one of these things where they're just absorbing more from what they do eat?
June Round 31:56
Yeah, so we did all of that characterization, and the animals didn't eat more. So they were eating the same as the wild type animals. They were not expending more or less energy than wild type animals. The major difference seemed to be that they were not absorbing lipids as well. So there were more not absorbing them as well, not absorbing them as well, yes, so there was more left in the stool that would be excreted. Well, I'm sorry, the knockouts were absorbing more the wild. Okay, I
Nick Jikomes 32:28
was gonna say, I said that backwards, so that was so, yeah. So basically, they're pulling more fat out of the food and absorbing it to the body. Yes, yes, yes. Okay, and is that? So a couple questions here. So one, is it a specific type of fat? Are they? Are they absorbing saturated fatty acids, or is it just sort of everything?
June Round 32:51
So the ones that we really noticed a difference in were these long chain fatty acids. I mean, these are just like basic like once you once your lipases break down the fats that you eat, you get these long chain fatty acids. They bind to specific receptors on intestinal epithelial cells, and then they're taken up into the intestinal epithelium and then basically packaged into these chylomicrons and sent throughout the rest of the body for use. So those were the long chain fatty acids. Were the ones that we were noting were really different in our animal and is there,
Nick Jikomes 33:30
I'm asking from a place of ignorance here. So chain length is important for a variety of things when we start thinking about the different fats that animals consume and what they can be used for. So you're talking about long chain fatty acids here. These are the ones that are being absorbed more by these genetically altered mice earlier, when we were talking about fiber in the gut microbiome, that they were making short chain fatty acids. Is there any differences we should talk about here in terms of the short versus the long chain fatty acids that you think are relevant?
June Round 33:58
You know, other than their chain length, I mean one the long chain fatty acids I'm talking about are ones that come from the diet that have been acted on by the lipases that are excreted from your pancreas. So those, these are more dietary fats, and then our host enzymes make them into these long chain fatty acids. The other ones you know that we were talking about before, are products of the microbes, yeah? But at the end of the day, molecularly, it's, it's a difference in chain length. So I don't know that there's any anything to speak of beyond that, yeah,
Nick Jikomes 34:34
but I guess you know one of the questions so, so it's, I don't know this for a fact, but this is, this would be what I guess. So the short chain fatty acids are more readily burned as fuel. That kind of makes sense to me, that the shorter ones would be used as fuel more and then the longer ones are, they just more apt to be used for energy storage. And then maybe this is, yeah,
June Round 34:55
I see where you're going with this. Yeah. So short chain fatty acids can be absorbed. Charged more readily by an intestinal epithelial cell and used right then and there. Yeah, long chain fatty acids tend to be bind to receptors on the surface of the intestinal epithelial cell and then taken up and then delivered to the rest of the body. So I guess what you could say is short chain fatty acids are maybe used more locally, even though they delivered throughout the body as well, whereas the long chain fatty acids are packaged up and then sent to the rest of the body. So
Nick Jikomes 35:30
these long chain fatty acids, they're not just a repository for energy that can act as signaling molecules it sounds like and it just sounds and they just need to sort of be processed more before they can be used. Yes, you're That is correct. Okay, so, okay. So what comes next? You've got these genetically engineered mice. They get fat in late age. They've got this interesting immune phenotype that you've engineered into them. What comes next here?
June Round 36:01
So the next question to us is, well, there, I guess there's two, but you know, here we know it's a microbiota driven obesity. So one of our initial questions was, what microbes are driving this obese phenotype? So I think normally when you do these experiments, you're asked, you're looking at the obese mouse, and you're and you're asking questions about, well, what microbe is there that's making them obese? Because that's generally like, what pathogenesis people think about, like what microbes they're causing a disease. And we did do those study. We looked and there was nothing that really jumped out at us too much. The one thing we really noticed was different when we knock between the knockout and the wild type animal is that the knockout animal seemed to be missing a group of organisms within the clostridia. That was the biggest difference in them and the microbiota that we noted is really microbes missing in the knockout I
Nick Jikomes 37:02
see. So these animals don't have certain clostridia bacteria, that's correct. And what do we know about those bacteria? Like, what's our baseline knowledge? There? Are they doing something in particular that's important? So
June Round 37:15
at that point, we knew that some members of clostridia could induce Tregs that had been shown in the literature. But beyond that, we didn't know a ton. Because I should say this is like a huge class of microbes, okay, okay, and they're highly uncharacterized, I
Nick Jikomes 37:32
see. So there's all sorts of different species that are in this general group.
June Round 37:36
That's right. And when we had discovered it was this group, one was at 2019, we published that paper. So much more has been done regarding sequency and taxonomy of this group. A lot a lot of things have changed. But what's unique about these bacteria is that most of them are spore forming. So a spore a bacteria that can undergo sporulation, it's a way of protecting itself. So if, if it undergoes environmental stress, it can basically go into its spore form, and it can resist things like antibiotics. It can resist desiccation, which was, it was a nice way for us to be able to isolate these organisms, because we were able to take a healthy microbiota and extract all the spore forming organisms, which were mostly clostridia, and we could give them back to those obese mice, and we can make them lean again. So that was kind of the proof of principle experiment that we did to show like these are the organisms that are making these mice lean, helping them to stay lean, I see.
Nick Jikomes 38:41
So you've got this genetically engineered mouse. It's missing this key component in T cells of the immune system, and they get fat in late age, and they seem to be missing certain bacteria. But then you can give them the bacteria, and it reverses the obesity phenotype.
June Round 38:58
That's correct, yeah.
Nick Jikomes 39:00
How do you how do you give them, how do you give them the bacteria, and how is it a full reversal? How quickly does this happen? How dramatic is that reversal?
June Round 39:09
That's a good question. So we give the we give the bacteria via an oral gavage. So it would be the equivalent of a person like just taking a pill, yeah, yeah. It's like taking probiotics, that's right, yes, and we give it. We give it to the mice every other day. So it's not, you know, it's not a ton the reverse. The reversal is pretty dramatic. And actually, I shouldn't say the reversal. It is the prevention, because we, we basically start giving these clostridia to these animals before they develop, okay, because we knew, we knew that they would develop obesity later in life, yeah, so gave them the organism early in life. So we were asking if we could prevent the onset of obesity if we provided these organisms. So that's what we did. We still have to do that, the reversal experiments. We haven't done
Nick Jikomes 39:57
those. Yeah, yeah. Interesting. Okay, so. Genetically engineered mice. They're defective in their immune system this particular way. They don't have certain microbes that they would otherwise have. They develop obesity late in life, unless you give them these bacteria earlier in life, and then they don't develop obesity.
June Round 40:16
That's right, you're really good at this Nick
Nick Jikomes 40:18
Thank you. I'm just trying to make sure we're following so, so how do you interpret that so far? Is it just, and I may have missed this, were you giving them back just one species, or is it sort of like a bunch of different species in this family of bacteria? Yeah,
June Round 40:34
it was a it was a big group. It was probably 40 to 50 different types of organisms, all of them being spore formers, but all of them being part of clostridia.
Nick Jikomes 40:44
And then that, I assume, you characterize, sort of what was going on under the hood, the lipid absorb. The lipid absorption probably then just looks normal in these mice.
June Round 40:53
That's right, yeah, when you put in those clostridia, you resolve that increased absorption of those lipids. And
Nick Jikomes 41:00
so how do you so, you know, one thing people might think about here that I think immediately comes to mind is, you know, so many people have had experiences, or know of people who've had experiences where you know, even sometimes within the same family, or you know your friends, or whatever you know, you seem to be eating more or less the same diet. It's not obvious that one person's, like, completely gorging, you know, more than the other person, or even people that are, you know, really trying to lose weight, and they're cutting back, and they fail to do so, you know, one person's lean, one person's not lean or obese, but they seem to be eating comparable diets. This, you know, starts to kind of sound like that, where you could eat the you know, it's possible this. I mean, I think what this shows it's possible for two animals to eat the exact same diet and have dramatically different results in terms of body fat deposition, because the microbiome is regulating how much is being absorbed. That's
June Round 41:50
right. That is exactly right. And I think it's still not a very popular thing to say, because most people think it's, you know, energy out what you eat. If you expend the energy, you're going to be thinner. But what you just said is, right, we just showed two animals had the exact they ate the exact same they did the same movement, but one got obese and one didn't, and it was all based on the types of microbes they have. So to me, this, this is a really important finding, because this says the types of microbes you have are going to dictate your body composition, and this is going to dictate, you know, health.
Nick Jikomes 42:32
And you know, one thing that's interesting, unfortunate, you might say a little tricky, is these mice don't develop obesity till late in life. So it's not like, you know, you could see something happening earlier on. How do you start to think about like, you know, what that might mean for humans, and sort of detecting, you know, it's sort of like they go through their entire life and something you know is different about them under the hood, but they don't develop this phenotype till later in life. How do you start to think about that from from more of a human perspective? Sure.
June Round 43:05
So I think there's probably two things to say there. The first being is that we were able to induce these animals to become obese earlier in life, if we pushed it with a high fat diet,
Nick Jikomes 43:21
I see, so they more readily develop obesity is you most might say that's the phenotype, and it just, if you don't push it with a high fat diet, it takes a long time to set it longer I see, I see, so
June Round 43:31
diet was a really important component here, and we can talk more about why. Mechanistically, I think that is the case. The second thing to say, I just forgot, so maybe it'll come to me in a
Nick Jikomes 43:47
minute. Yeah, we'll come back to it. I wanted to ask you, so when you look under the hood and you compare the mice you guys made, the genetically engineered mice that are predisposed to obesity, basically, what else, if anything, is sort of wrong with them? Do they have fatty liver disease or the insulin resistant? What is sort of the physiological or metabolic health profile look like?
June Round 44:11
Great question. So it's not just obesity. These animals develop fatty liver they don't clear glucose as well. So they they they're starting to look like they're getting diabetes. So it's basically metabolic syndrome. It really is a metabolic syndrome. And I think we keep that terminology in our in our paper a lot, and this is, you know, something that's becoming a huge problem in western civilization.
Nick Jikomes 44:35
And the other thing that was interesting is, I think you have a result here where you took these genetically engineered mice that develop obesity, and as you said, you know, they're missing certain populations bacteria in the gut, they're developing metabolic syndrome, and then you just put them, you co housed them with other mice. What happened there?
June Round 44:59
Um. So those are interesting experiments. So this is very similar to a transfer, a microbiota transfer, so when you put mice into the same cage, they're coprophagic, so they essentially eat each other's poop. So that's, you know, essentially that's what a microbiota transfer is, is you are feeding mice. So by
Nick Jikomes 45:20
their nature, mice will automatically do a microbiome transfer. That's right.
June Round 45:25
So generally, if you put mice into the same cage, their microbiome starts to converge and look more like one another. It's not always the case, but for the most part, that's that happens. So when you put knockout and wild type mice together, what we saw was actually those, the animals, the knockout animals that were co housed with wild types. Those animals got, oh my gosh, they got fatter, so they took on the phenotype of whoever they were. Those mice that they were caged with. Those experiments are really nice, because you can start to follow what microbes are moving to what animal. And that was really one of the key experiments that helped us identify this clostridia population.
Nick Jikomes 46:14
And so when you give these animals high fat diets, can you say a little bit? So what does high fat mean exactly in terms of total fat, and is it important at all what the specific sort of fatty acid composition or the other composition of the food is?
June Round 46:30
So our high fat diet is a 45% high fat diet, which is actually low for what other people do in the field, a lot of people get 60% high fat diet. Most of the fat is coming from a palmitate in these diets, although not exclusively, and I think the source probably does, does matter, but that's just the diet that we
Nick Jikomes 46:53
is that a saturated fatty acid or unsaturated? Um,
June Round 46:58
I don't know. I think it's saturated. Okay?
Nick Jikomes 47:00
I'm with you, like, 80% sure it is okay. So, okay, so it's 45% fat. I don't know the numbers off the top of my head, but I believe, like, what would be a typical, average American, or someone eating the so called Western diet, I think it's, you know, roughly 50, 60% carbs and maybe 35 40% fat. So, you know, I guess, kind of generally in the this ballpark. Yeah.
June Round 47:23
I think that's one of the reasons we use the 45% high fat diet, because we felt like it was, it was more akin to what a human might consume, as opposed to 60% which just seemed outrageous. Yeah, no, I guess if you're eating McDonald's all the time, you might hit that
Nick Jikomes 47:40
and so you co house these mice, you've got the obese one and the non obese mice, the lean mice become obese. So do their phenotypes converge? Do the obese mice come a little bit more lean and the lean ones become a little bit more obese? Or do the lean mice really just take on the obese phenotype?
June Round 47:59
The lean mice take on the obese phenotype. It was not a convergence, which I thought it would be, yes, yeah. So,
Nick Jikomes 48:13
yeah. What do you have any thoughts on, like, why that might be, or is that mysterious at this point? Yeah.
June Round 48:22
So I think what was happening. And again, what I said before is that these, these experiments, were one of the critical ones to tell us that, like I help us identify who the important microbes were. So, um, because what you do is you sequence prior to the cohousing experiment, and then you sequence after the cohousing experiment. And what this does is it really helps you to because the microbiome is incredibly complex. So we're always asking questions about, you know, who, who is it? So when you do these sequencing experiments, then you can, then you can identify the key microbes. So what we did is we could find the microbes before and after transplants, and you could see the clostridia. You could see those Clostridium moving around and wherever the clostridia were, the mice were lean, and wherever they were missing, the mice were fat. So that's what really highlighted who was important here? Yeah,
Nick Jikomes 49:23
and it's also, it's kind of a convenient, or like, optimistic, type of result, in the sense that, okay, you're showing that you can basically prevent a phenotype by just introducing the right bacteria. You can do this orally. Obviously, you know, people, not just in the scientific world, but but, you know, out in the the rest of the world. You know, probiotics are a big thing. Now there's lots of marketing around these things, but the implication is that something like this could work in principle, if you, if you take an oral, an oral pill that contains the spores of the right bacteria, at least early enough in life, that. Can, at least, in these mice, be sufficient to prevent the onset of something like obesity, that's
June Round 50:04
right. And so we've had, we have a study that's in review right now, because I told you that these clostridia were like, 40 to 50 different organisms. That's really hard to grow that up, put it in a pill, yeah. So we've been really interested in identifying, like, who is the member of this consortia, or members who are really driving the Lean phenotype, because just as you said, it seems like a really great way to just stay lean is to just make sure that you have the right bacteria. And we've identified one, one particular species in that group that's driving most of the lean phenotype, and we can purify that organism out and give it to mice and make them lean. So this is really exciting to me, because now we can also go and look at this, the microbiomes of humans, because there's a ton of studies that characterize the microbiomes in humans, and if you look at humans who are obese or have type two diabetes, this particular species is missing, I see, so it really makes us feel like, you know what we're finding in mice might be applicable to humans. I
Nick Jikomes 51:10
see he has, I was actually going to ask that next, I think, is, how much does the micro gut microbiome of mice match match match humans? But it sounds like at least for this species like this is a we both have this in our microbiome. We can both be missing it. And there's at least a correlation between not having it being obese in humans. That's correct, right? And so is that like coming up next, or is someone going to test this in in humans?
June Round 51:38
We are trying. Yes. It's a little bit trickier to do these types of things in humans, because you have grow up the bacteria to a certain like cleanliness level,
Nick Jikomes 51:45
right, right, right. And I think one of the tricky things here is, well, so a if we go back to the question of reversing the phenotype versus preventing the phenotype from developing, you were able to prevent it from developing by giving mice the right bacteria, you know, throughout their life. The question is, can you, you know, if it, if you do the experiments where you reverse it in adulthood, that would imply that maybe something like that could work in humans, if that didn't work in the mice, then you've got, you've got a greater challenge, because you've got to somehow detect the people are deficient in these, in these bacteria early enough in life, and then supplement them with it before they ever develop obesity. How are you sort of thinking about all that? Yeah,
June Round 52:27
and this goes to the thing that I forgot to say earlier, because you asked me, like, how do you parse out people who might be more prone to developing obesity or not? Yeah, I think if we can identify the specific bacteria that are really driving the phenotype, kind of like what we're doing now, it's really easy to detect these bacteria various molecular methods, PCR, for instance, in people's stool. And one could imagine, you eventually will get to the place where people are sequencing their microbiomes. Let's say, you know, when they're younger, and asking like, are we missing? Am I missing this microbe that will make me lean? And if so, then you could say I'm going to supplement myself so that I can prevent late onset obesity. Yeah. So I do think that as we progress on in this field, that you'll be able to make these types of predictions by looking at the microbiome early in life to see what you have.
Nick Jikomes 53:24
And so I guess technologically, it's now feasible that you know at some point if humans organize themselves, you know our healthcare system in the right way. You know you go in for your yearly checkup, maybe you get some blood work done to look at your lipids and things like this. This tells you you know about your cardiovascular disease risk and other things. Or maybe you also get your microbiome checked, and we can see, okay, the six year old actually is, is missing the clostridia, or whatever species that that we think should be there. And then you can supplement accordingly, accordingly. Yes,
June Round 53:56
I think that this is like one of the futures in in clinical practice is that we're gonna, you know, a lot of people are sequencing their genome to see what genes might predispose them to different diseases. I think eventually we're gonna be doing the same with our microbiome. We're just still at the stage of trying to figure out what bugs doing what
Nick Jikomes 54:15
Yeah, and so in your experiments, obviously you've got these, all of these tools and these experimental conditions that you guys can engineer in mice. And this allows you to, you know, start figuring out mechanisms and doing all the work we just talked about. When you think about sort of naturalistic obesity, let's call it in humans. You know, we're not engineering humans to miss, you know, a component of toll receptor signaling. We're not doing like things like that. And yet, obesity is what it is, it's, it's, it's spreading like wildfire, basically. What are you know, and let's just suppose that, like in certain mice, you know, at least some of this, and some people have to do with microbiome deficiencies. What are the plots? Plausible sources of those deficiencies in humans? Is it the way that humans are born? You know, a lot of people born from C section versus vaginal birth. Is it the use of antibiotics in early age? How do you start to think about what could be disrupting what's plausibly disrupting the microbiome in humans?
June Round 55:19
I think the two easiest answers to that question are going to be diet and then antibiotic use early in life. So some of Marty blazer's work has shown that if you treat animals with antibiotics early in life, you can even remove those antibiotics and let them grow up. The animals that saw antibiotics more readily got obese.
Nick Jikomes 55:45
So merely giving animals, mice, in this case, antibiotics early in life, taking it away, everything else is normal. They're more prone to obesity.
June Round 55:54
That's right, and that could be because you're you know, what that suggests is because you're deleting some specific bacteria. Diet is also another major one. We don't I don't think we fully understand how diet regulates the composition of our microbiota. But going back to this bacteria that we're studying that prevents obesity, we have found that if, if you give the animals a high fat diet, this particular microbe actually cannot colonize the gut anymore, and then try to grow it up. If you take it into the lab and grow it up in a high fat diet media, that animal, or I'm sorry, that microbe can no longer grow. I think microbes are some can be the fats can be toxic to some microbes I
Nick Jikomes 56:41
see, yeah, and that makes sense in principle, like, you know, the as we mentioned, these fatty acids, you know, fatty acids aren't just a source of potential energy. They're signaling molecules. They have information they can stimulate in cells. So basically, what you're saying is the idea here would be, if you happen to, you know, obliterate the microbiome or lose a species through antibiotic use or whatever. If you then, if that person, if you sort of let that person, let that animal develop, if they have, say, a high fat diet that could actually prevent the colonization or the bacteria that you want. But if, if you don't have a high fat diet, perhaps that wouldn't And so basically, the dietary context can dictate whether or not, you know a certain bacteria species can grow back, and then that's going to have implications for things like obesity in this case.
June Round 57:27
Yes, that's right. It's very complex all of it, yeah,
Nick Jikomes 57:31
and you know, it's, uh, you know, it's like one of those chicken and egg things when we think about, like, what's what's happening in the naturalistic case. So obviously, changing your diet can change your microbiome. Your microbiome can change how your diet is used by your body. So, like, how readily? Like, do you think it's feasible? Or do we know, for example, that you know, let's say, let's say someone is eating a high fat diet, and they have for most of their lives, if you change the diet, you know, in a fairly dramatic way. Is that a reliable way to change the microbiome? Or can the microbiome sort of get locked in in a way that's really hard to change?
June Round 58:10
Well, I certainly think that if you're on a particular diet for a long time and you're not allowing colonization of those organisms, they're not going to magically come back. So I think you would have to do something along the lines of changing your diet and then reintroducing the microbes that you've lost. You would have to do both, for sure, because I do think, as you said, the microbiome can get locked in, so to speak, because when you
Nick Jikomes 58:42
think about like, when I start to think about different strategies for doing this, I start to think about things like, okay, so, so when you say, introduce new bacteria, there's a question of, do you know if we're talking about humans, it's like, do you take the probiotic pill that has been Made to have these bacteria. Or do you say, go on a fasting regimen and then eat a diet that will be conducive to that bacteria blooming? Is that? How do you think about that? Are there? Do you think a healthy microbiome can often come as a natural consequence of eating a healthy diet, whatever exactly that means. Or are we going to need to really like, put bacteria spores in a pill and do it that way.
June Round 59:26
I guess I envision that you can get to the place where you're just missing certain microbes, and then unless you reintroduce them to the system via a pill or a fecal microbiota transplant, just eating a fiber rich diet is not going to get you back to the place you need to be, because those organisms are gone, and once they're gone, yeah, unless you reintroduce them to the system, yeah,
Nick Jikomes 59:54
yeah. If the origin, I guess, if the origin of these clostridia bacteria, in this case. Is not dietary, right? Like, let's say, like, I don't know. Do they come from, like, the vaginal microbiome? And you know, after you're born, you're only born once, so you don't get, you don't get a second chance to seed your microbiome. So maybe you need to introduce them explicitly. Do we actually know what the origin of these bacteria were that you were studying?
June Round 1:00:17
So these organisms aren't necessarily from the vaginal tract of mom. These probably get seeded later. I mean, again, this is this field is still in flux. We're still learning where you get all these organisms, but you really only find them in the intestine of of humans. So it's not something that's getting introduced by food. It's got to be getting introduced via your interactions with your family or humans, but yeah, you don't find them. It's they're not being introduced during the birthing process. Yeah,
Nick Jikomes 1:00:50
yeah. So, you know, obviously we talked about germ free mice and giving mice antibiotics early in life that can predispose them towards obesity. How do you just as as a human, not necessarily as a scientist, you know, I'm sure at some point you're gonna have to take antibiotics. I'm sure, if you've got kids, they either have taken antibiotics when they got really sick, if they really needed it, or they might have to in the future, if and when those things happen in your life. How do you think about managing your life subsequent to the antibiotic use, given everything you know about the microbiome? Yeah,
June Round 1:01:24
it's a question I get quite a bit. You know right now, most of, if not all of the probiotics that are available for people to purchase are a very narrow spectrum of our microbiome. They are lactobacillus and Bifidobacteria. These are, like the organisms you get in your yogurt. It's kind of shocking, really, that the probiotic industry hasn't expanded beyond those organisms, but those organisms and adult and an adult gut are very minimal type of microbe in your gut.
Nick Jikomes 1:02:00
So they're probably just easy to make and manufacture, right?
June Round 1:02:04
They are and they, you know, they can withstand oxygen, some of these other microbes, you're going to have to grow them up in a very strict anaerobic environment. And I think they're just going to be harder to manufacture, which is probably why we don't see them on the market yet. So I don't think right now if we have the right tools to restore our microbiome the way that I would like to restore the microbiome after, let's say, an antibiotic exposure. But with that said, for instance, you know one thing that they're doing is kids who are born via cesarean section, they're now swabbing the mom's vaginal tract and colonizing the baby with that. That's not something that was done, you know, when I was born, probably when you were born. This is something that's fairly new. So people are starting to think about more natural ways of replacing the microbiota. If we have to to do some of these things, like, you know, babies, some babies just have to be born via cesarean section, right? Right? Yeah, yeah. High fiber diets, right? This is, this is, I eat a lot of fruits and vegetables to ensure that I'm feeding my microbiome correctly.
Nick Jikomes 1:03:17
And I'm not sure if this is your area, but I do want to go back to some things you said at the beginning. So you mentioned, you know, we talked about fiber as food for the microbiome, and the microbiome producing short chain fatty acids, two things I want to cover. So one is on the input side there, what fiber you're eating. You mentioned, there's different types of fiber. Can you give us a little bit more of a sense for the different types and which ones are, are the fuel for short chain fatty acid production? Yeah,
June Round 1:03:45
I don't think I'm going to do that question very good justice,
Nick Jikomes 1:03:49
okay, only
June Round 1:03:51
because that's not my area of expertise. If you ever want to talk about that, you should invite Eric Martins onto your podcast. Okay,
Nick Jikomes 1:03:57
that's, that's a good tip. I'll look them up, but I guess sort of high level, there's different types of fiber, not all fibers created
June Round 1:04:04
equal. That is correct. Yes, because, I
Nick Jikomes 1:04:06
think just because, just because something says fiber on the nutrition fact doesn't mean it's going to be the one you might think it
June Round 1:04:11
is absolutely that is absolutely true. Yes, like I said, inulin is one that's well studied in the field. It's one that a lot of people can buy off the shelf, but there have been several studies, at least in mice, that if you give it to mice, those animals will be more inflammatory in their gut under circumstance, certain circumstances. So I think this field just needs, you know, certainly more more research.
Nick Jikomes 1:04:38
So what are some of the other types of experiments that you guys have been working on in the lab. Is it mostly focused on microbiome and obesity or or do you do other stuff as well? It sort of sounded like you this was kind of a serendipitous direction you went
June Round 1:04:52
in. Yeah, we work in a lot of areas, because people at the University of Utah are just incredibly collaborative. So we have projects. In cancer. We have projects in pancreatic development. We have projects in autism. One thing that might be of interest in pertaining to our conversation is the pancreatic development stuff, and this is because it involves an early life perturbation to the microbiota. So I can talk about that one, because I think it might be of interest to you. Yeah, yeah. So I had a really wonderful postdoc in the lab. Her name is Jennifer Hill. She's now started her her own lab, and she was interested in understanding how the microbiome could influence beta cell development. So beta cells are a cell type in your pancreas that make all the insulin in your body. Obviously, very important cell type, and it's also the cell type that gets destroyed in type one diabetes. So the immune system attacks these beta cells. What's interesting about beta cells is they don't replenish. Basically, they develop when you're very young. So within their first year of life, they undergo this very large proliferative event that sets the number of beta cells you'll have the rest of your life. Also, as we've talked about, the microbiome during early life, that's when you're kind of the compositions in flux. Basically, after three years old, your composition pretty much looks like the composition you'll have for the rest of your life. So she was really interested in this early life event and beta cell development. So what she did is she set up this experiment where she perturbed the microbiota during 10 day intervals of the mice during their first 21 days of life. So she pulsed with antibiotics for the first 10 days, took them off, let them grow up to adulthood. She then did it for, you know, the another 10 day interval, and then another 1010, day interval, let took them off, antibiotics, let them grow up. What she found was amazing to me, and it was a little bit scary, is that if she pulsed with antibiotics between postnatal day 12 and postnatal day 21 but not before and not after. Those animals had significantly fewer beta cells when they were adults. Also could produce less insulin and could not their glucose as well. So it's like that, that small window, yes, yeah, basically ruined how their beta cells developed for the rest of their life.
Nick Jikomes 1:07:27
And so I guess the natural way to begin thinking about this, at least, is okay, you give antibiotics at some window early in development. That's obviously going to wipe out a lot of the bacteria, because the microbiome is is involved in training up the immune system. That's going to affect how the immune system gets trained, and because something like type one diabetes is the immune system inappropriately killing these beta cells. You know, it's very natural to think that there's, there's a pretty straight line to connect here.
June Round 1:07:57
Perhaps, yes, we were, we were solely focused on beta cell development and not necessarily looking at the immune system effects, but we did identify that macrophages, which is an innate immune cell, which seeds the pancreas early in life, the microbiota during this early window was important for instructing those cells to go to the pancreas and and enhance beta cell development. So the implications and type one diabetes, we're still figuring out. We think that we've identified the specific microbe that positively influences this process, and if we put it into an animal prone to developing type one diabetes, you can get reduction in type one diabetes. But what we don't know is how this microbe is preventing that immune destruction. That's something that we're still trying to figure out, but we think this could be used in enhancing beta cell expansion later on in life. And people who do have type one diabetes, because, you know, again, their beta cells have been destroyed. How are we going to replace them? We think microbe might do
Nick Jikomes 1:09:13
that. Yeah. But I mean, it sort of seems like a general pattern or theme with this, and, you know, considering lots of other stuff that you know, if you if you perturb the you know, there's multiple ways to say this or think about this, if you perturb the immune system at different phases of early development, especially either directly by, you know, creating genetically engineered mice or something like this, or indirectly via alterations to the microbiome. There are many different ways that things can be disrupted, whether that's beta cell function in the pancreas, you know, or any number of other things we might talk propensity to obesity, presumably, even, you know, development of the nervous system or the cardiovascular system or what have you
June Round 1:09:53
That's right. Yes, you're getting it. You're right.
Nick Jikomes 1:09:58
Yeah. What do you think you. Know, as as a scientist in this area, and you know, as as did you say you have kids? I do so, yeah, and as a mother and stuff, how do you think about, you know, just a big, vague question, but you know, we do lots of things in our lives, especially in our early lives and in the newborn's lives that are definitely disrupting or nudging the immune system in different ways that we probably don't fully understand. Do you think that maybe we don't think carefully enough about that as a society? I'll just say it that way.
June Round 1:10:36
Yeah, I think we're at a point where so my oldest child is 19, my youngest child is three. I when I had my first child, I very much was in the mindset of, I've got to keep this baby so clean, like, if her pacifier fell on the ground, I was cleaning it. I didn't want her to crawl around on the ground. You know, anytime she had a remotest ear ache, I was taking her to doctor, giving her antibiotics. But as I started investigating this area, because I had her very early in my career, I wasn't even thinking about the microbiome when I had her, but my three year old, I treated her very differently. If her pacifier fell on the ground, I actually just gave it right back to her. I didn't wash it off. I made sure that she was eating, like, foods high in fiber. She was eating broccoli and grapes, not you know, I was really thinking about, like, I've got to feed her microbes, and if she did have an earache, I would let her struggle with it for a little because a lot of kids can just fight it off. You don't have to give them antibiotics to clear it off. So I think the way I raised my first child is more in line with how our society thinks about microbes, like you got to get rid of them, but I think we need to let our kids get a little bit dirtier. So as I hope that answered your question,
Nick Jikomes 1:12:04
yeah, yeah, no. I mean, this ties into, you know, something I've talked about with others before, which is, I think they called the hygiene hypothesis, the, I guess the broad idea here would be that it's actually our clean, our cleanliness, our taking of antibiotics, our hyper cleaning of pacifiers, and constantly, always washing our hands and always, you know, being clean, getting rid of the microbes. This is actually causing us certain problems, at least some of the time, because, you know, it's affecting how our body's interacting with the microbiome and with these pathogens. It's affecting how the immune system develops. Is the hygiene hypothesis, something that is plausible or that sort of ties into any of this?
June Round 1:12:46
I personally do think that at least a lot of the studies in mice and the epidemiological studies in humans, because, again, you can't do causal stuff in humans, they support this idea that not having enough microbes can predispose you to certain diseases. And you said this before, it's certain diseases. Obviously there are bad, micro, infectious microbes out there, and we don't want to have our kids exposed to those. We don't want to be exposed to those. But I absolutely think that the hygiene hypothesis is plausible, and many people are called many people refer to as the microbiota hypothesis. So maybe it's not just about because a hygiene hypothesis is more about not seeing infectious microbes, and that the whole process of fighting off an infectious microbe and clearing it helps to train your immune system. But some people refer to it as the microbiota hypothesis, because thinking more about the commensal microbes and how they're training your immune system. But yeah, I buy into it,
Nick Jikomes 1:13:49
yeah. And so in obviously sharing the universal disclaimer with everyone that none of this is ever medical advice, and we are not physicians. How do you I want to go back to go back to something you said that I was interesting about, you know, raising, raising your children and, you know, letting them, you know, fight off the infection, if they can, at least for some time. How do you, like, make those determinations around, like, when to use antibiotics? So the default for a lot of people, as you mentioned, was, you know, even for me, growing up, was okay, the child is sick, give antibiotics immediately, even if it's a viral infection. How do you make the assessment of like when it's appropriate to use antibiotics, and not at least for yourself?
June Round 1:14:30
So we definitely talk to our physician, and we always go in with a disclaimer that, you know, we don't want to use antibiotics when they're not necessary. And I think more and more clinicians are not prescribing antibiotics as much as they used to like for instance, when I was young, I drank. I remember that pink bubble gum tasting ampicillin. I think they still give it to kids. Now, I had that so much when I was a child, and when you're baby sick, you just want to make it better. Some. Parents go in and they beg their doctors to give them an antibiotic, even when it's a viral infection. But the we make the decision based off of a conversation with our physician, and then watching, of course, our daughter, you know, we monitor her fever and her pain levels, and so it's, an interaction with our doctor and then us, us basically seeing how much that child can tolerate before we'll use antibiotics. Obviously, you want to catch it before it gets too, too bad,
Nick Jikomes 1:15:32
yeah, but you know, you just use, I guess probably a lot of intuitive feedback, like, you know, a mild fever is going to be less of a concern than a crazy fever. Sure.
June Round 1:15:43
Yes, you're right. Monitoring those numbers, we definitely look at that. You never want to get it
Nick Jikomes 1:15:49
too high. So what is sort of on the horizon for your lab, just in general, but especially related to this obesity phenotype that we talked about today.
June Round 1:16:00
Yeah, so related to the obesity phenotype. Identification of that of the specific organism has been really monumental, because now we can start to really tease apart the molecular mechanisms by which this bacteria keeps the animal lean. We've identified one molecule that this microbe makes, which just so happens to be a lipid. So it's, it's making some sort of lipid that then makes the host lean. Do you know, what is it? You know, it's a it's like a unique bacterial lipid. It's uncharacterized. So we're trying to figure out exactly what it is, we think that it blocks ceramide synthesis in the gut, which is having a lot of ceramides in the gut, is associated with obesity. So we think that it's making a lipid that blocks this obesity pathway.
Nick Jikomes 1:16:58
What are ceramides? Exactly? So ceramides
June Round 1:17:00
are just, they're sphingolipids. It's kind of a different type of fat. Sphingolipids are really important, for instance, in cell membranes. So they're really important and good for you lipids. But if you get too much, too many of these types of sphingolipids, it can change the energy balance in your gut. So they have been associated with obesity cardiovascular disease, because if you get too much of them, you can disrupt cell membranes and cells start dying. Yes, so the future of our research, then is to really identify these microbial molecules, because, of course, we want to understand the basic mechanisms, but also, you know, a big part of me wants to be able to utilize these therapeutically. So another direction of my lab is trying to test this particular organism and the molecules that it makes in humans. So we're moving in that direction which is slow,
Nick Jikomes 1:18:06
interesting. This has been fascinating. Dr round, anything that you want to reiterate from our conversation or final thoughts you want to leave people with related to microbiome, diet and obesity related stuff?
June Round 1:18:20
Yeah, I think the thing I always end with, and I've probably already said this a million times as we've been conversing, is I really encourage, especially the research in this field, the researchers, to start focusing on the microbes that are present during health, identifying those beneficial microbes. I mean, we still have this mindset of finding microbes that are associated with the disease state and always studying kind of the infectious bad organisms. But I think we can really learn a lot by just kind of reversing that thinking.
Nick Jikomes 1:18:56
All right. Professor June round, thank you for your time. This was this was great.
June Round 1:19:01
Thank you, Nick for having me appreciate it. It's been fun.
Nick Jikomes 1:19:13
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Microbiome & Gut-Immune Interactions in Obesity & Metabolic Health | June Round | #178