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Nick Jikomes
What did you eat for breakfast?
Carolina Tropini 5:46
I ate cereal.
Nick Jikomes 5:48
What kind of cereal?
Carolina Tropini 5:50
Oh, I. So this is a it's kind of a loaded question because this is a strong area of negotiation with my family about which cereals are going to be allowed. So we do one scoop of cereal that has a little bit of sugar and one scoop of cereal that doesn't have sugar. But some some kids in my family cheat and get more sugar than they're supposed to. I
Nick Jikomes 6:12
see And is that how much of that is intentional given what you study?
Carolina Tropini 6:17
Well, to have cereals with high fiber is very intentional. So we tried to we tried to load up our diet with as much fiber as we can. But it turns out that the recommended amount by FDA regulations and other sources of advice is actually really low compared to what humans have evolved with. So you normally see 35 grams recommended amount. But if you look at what our ancestors did, and they of course had different health issues, and we have now but from the perspective of the microbiota, they seem to be doing better. They used to eat maybe 100 250 grams of fiber per day, which is an incredible amount and definitely not something that is easy to reach, no matter how diverse your cereals may be.
Nick Jikomes 7:06
And so when you say ancestors, are you talking about hunter gatherers living before agricultural society developed?
Carolina Tropini 7:12
Yeah, do you know them? It's interesting, where we draw that line of and substance industrialization seems to be a major issue for microbiota related diseases. And so we normally think about most of the problems raising maybe in the last 100 150 years in terms of how how much processed food that we're able to get has become. So
Nick Jikomes 7:35
are you saying people, people living like 100 150 years ago, we're getting 100 plus fiber, grams of fiber per day, not
Carolina Tropini 7:43
quite, they do really go to 150 grams, like you need to go into much more ancestral societies and even traditional societies right now that the do rely on 100 gathering have are able to to get that type of fiber from roots and vegetables at the source from for the environment.
Nick Jikomes 8:02
Interesting. And so you study the gut microbiome, we're going to like one of the things we're going to talk about today, I want to go through the different parts of the digestive system from from one end to the other, and talk about the differences in the microbiome and each of these. But before we do that, I just want to give people like a bird's eye view of some certain certain things. So you hear about the microbiome a lot these days, you hear that there are I don't know, what is it trillions of bacterial cells in our body, you know, on the order of the same number of cells in your body that are human cells are microbial cells. And the microbiome is got some diversity to it, that diversity varies between individuals, it varies within an individual across their lifespan, et cetera, et cetera. But I want to get a sense for like how, like what the overall bird's eye level of diversity of the gut microbiome is. So in terms of the dominant phyla, or types of bacteria in the human gut? What does that heterogeneity look like? Are there certain species or certain phyla that predominate heavily? Is it you know, very spread out? What does that diversity actually looks like? Yeah,
Carolina Tropini 9:13
that's a very good question. I like to think about our gut microbiota is a bit of the diversity that you might find in a forest. So there's, there's probably hundreds of different species that are lying around and characterizing them at the phylum level, I think is there's there's maybe five top types of phyla. But that doesn't tell you very much about how diverse that then may be that the diversity of the bacteria that are within our gut is pretty incredible. You know, if you think about what it means to be a different family, you know, family within the world that we live in, we think about primates and felines and so these are pretty different animals. And in the world of the microbiota, maybe we're looking at 20 different families. And so that gives us to think a little bit More of the sense of what the real diversity means there are very specialized microbes that are very good at breaking down fiber, and they're just not good at all at dealing with a disruption that may be due to an over the counter drug that we take, there are going to be microbes that are very good at dealing with our immune system, and then can hide places that are microbes that can't tolerate the fact that in some parts of the gut, there's actually no oxygen. And so they, they don't do very well there. And vice versa, microbes that really like places that are not oxygenated. And so that I think in thinking about it is a bit of a more of a forest ecosystem, as opposed to just this catalog of microbes. That gives you a better appreciation of what the ecosystem really is and what it can do.
Nick Jikomes 10:44
And so, we're going to talk about like eating and how the microbiome changes in response to diet and things like that, in adults. But a question I have is, how does how does the microbiome and a human being like originally get set up? Presumably, there's microbiome even in utero, in the developing fetus and the developing baby. So where did the initial seeds of that microbiome actually come from?
Carolina Tropini 11:10
Yes, this is a very controversial topic. So it's really unclear whether there are microbes in utero. There, there was some research that indicated there might be but then there were some complaints that it might have been due to contamination. And so I think the jury's still a little bit out on how, how much it spreads in utero. But the way that if it, even if it is there, it's probably not in very large amounts, because they're not easily detectable. And so the the main exposure to microbes that that a baby has, when it comes to out in the world is really bond exposure in the in the vaginal tract when in the birthing canal. So that's, you know, before even the baby takes its first breath of air, the first thing is exposed to is this coding of microbes that, that come from the vagina that come from stool, they really kind of gets all mixed in together, the the birthing process is messy. And the once that initially inoculation gets set up, then these are often microbes that will really help the baby be able to consume maternal milk. And it's really beautiful, in my opinion, and how tidally connected this process is to the baby's health. If you think about breastfeeding, about a quarter of the maternal milk by dry weights is actually components that the baby cannot consume. They're just sugars that are broken down by the microbiota, and helps it get started in a way that is healthy. So this component is so important that even mothers that are not nourished, still habit, you know, they will not have sailed the fat compounds that are important for the baby, but it's they still have these sugars that are just for the microbiota. So
Nick Jikomes 12:52
it's you said one quarter of the weight of breast milk or sugar. Okay, the dry weight sugars that only the microbes can break down? That is correct. So I mean, another question there is the the composition of the microbiome in the birth canal, that's going to seed the baby's microbiome, you just said it's so it's very important, because that's what's going to help the baby break down a lot of what is actually in the breast milk, which is going to be the predominant food source for some time, I would imagine that the diet of the mother and other factors in her life can affect things going into her body. So diet, pharmaceuticals, what have you could affect the composition of the microbiome that she's gonna see the baby with. But I would also imagine how the baby is born. It could be relevant here, since not all babies are born by the traditional passage to the birth canal.
Carolina Tropini 13:51
Yes, absolutely. So from the perspective of the mother, we know that having both a healthy diet as well as a healthy microbiota during pregnancy is very important, because those are the nutrients that the babies exposed to while in the womb. And on the other side, what do you get exposed to if a baby's born by C section say, we found that babies tend to have a microbiota, sometimes it's even more similar to the surgeon's skin microbiota than the mother. And so there are now a lot of effort into trying to understand can we actually do maternal seating for babies that have to be born by C section, so that you can take a swab from from the mother you ahead of time if it's a scheduled C section, and then try to get this first process to happen a little bit more naturally. But maybe just do add one more thing about the importance of the mother's microbiota even before the birthing process. The reason why the microbiota is so important ultimately to our health is the fact that whatever microbes produced can ultimately affect any component in our body. So that The same way that you might take a pill by mouth to affect your headache, even though you're taking it through your digestive tract. The same way that microbes, whatever they make in the secrete can make it through your entire blood system and affect any cell in your body. And so you can imagine that we have evolved with these microbes over millions of years. And we've come to expect in terms of our developments, certain compounds that these microbes gave us. And so changes in microbiota can potentially make an effect for a lot of different types of development. So we're just starting to learn about some of these delicate connections that overall, they're quite robust, because they have come from millions of years of evolution. But we have stepped in heavily and heavy handed in the last 100 and 150 years.
Nick Jikomes 15:52
And I don't want to get too off track here. But I mean, I was blown away when you said, one quarter of the dry weight of breast milk are things like sugars that the human baby itself cannot digest, unless it's got the right microbes inside to do that, that for them. What about like, you know, we make so many like modern alternative foods today, when I think about something like baby formula doesn't have those types of sugars in it.
Carolina Tropini 16:20
It doesn't yet there, this is a big race for a lot of the formula producers to try to have more of this diversity. But the problem is that this diversity of sugars is very hard to obtain and synthesizing these sugars is not easy at all. So it's, it's also something that you cannot get from other animals, for example, milk from cows doesn't have quite the same diversity of these sugars. Milk from primates is still different, it seems to be something that is very, very specific to the the human host that to that we have this.
Nick Jikomes 16:53
Yeah, I mean, the other thing that that you said was very important, I think, is even a malnourished mother will still produce those sugars, so they must be very important for something. What are the metabolic consequences of the sugars as opposed to something like glucose? Or the ordinary sugars? We normally think about? Are they processed differently? Are they having different physiological effects for the baby?
Carolina Tropini 17:14
Yeah, absolutely. So you know, if you think about sugars, and even even sugars that we think are not coloring for us, because we can't break them down, those are sugars, that usually the microbiota will break them down. So stevia, all these different alternative sugars are things that the microbiota, because of the incredible capacity of breaking down different compounds had it has, it will likely be able to draw some energy from it. And so from the perspective of these special sugars that go in maternal milk, these are very, very special things that we have evolved to produce in order to keep our microbiota together. And on the other side, if you have something like pure glucose, pure glucose gets absorbed and goes into your bloodstream, immediately, sugars that cannot be broken down by us. But we're basically the host of this microbiota, that's kind of how we determined in the in the field, these triggers will make it very far down the digestive tract. And by making it that far down, it means that they're not released into the bloodstream really quickly, which means that it's basically it's a longer term process of, of consumption, which is different than if you have if you if you drink an orange juice versus if you eat the orange, where the sugars are be liberators in a very different place. And so this this liberation of sugars, when it happens via the microbiota in distal parts of the gut, those tend to be just what we have evolved with. And so in some sense, like they're healthy just by default, because that's what our whole system is expecting to see. It's not expecting to see pure sugar within your mouth, say, I see.
Nick Jikomes 18:51
So the baby's probably getting a more a slower drip, a more consistent intake of sugar for energy throughout the day, simply in virtue of the fact that it's got these sugars that are slower to absorb.
Carolina Tropini 19:06
And also these sugars don't get to turn into glucose for the baby. They microbiota will consume them, and it turns them over into other compounds. So these compounds are called the short chain fatty acids. They're some of the major amounts that are produced by the microbiota. And they're so important for our gut that if you if you give choice to Kelowna sites, so these are some of the cells that are part of the colony, if you give a choice for to these cells between eating pure sugar and eating these compounds that ultimately are turned into sugar for energy by the cells, they will actually choose to use the microbiota produce compounds, the searching fatty acids, and the searching fatty acids have a lot of importance also for reducing inflammation. They are important because they're their signal molecules for the brain. They have a lot of more complex interaction. Since with the our immune system and with the function of our bodies, then then sugar can have, you know, sugar is like this, this this cheap coin that you know kind of gets exchanged for energy very, very rapidly. But this more complex compounds have really indicated a relationship with the, our body function across the entire body, I
Nick Jikomes 20:21
see so many cells of the colon, or at least certain cells of the colon, give them the choice between using short chain fatty acids, or straight glucose, they will prefer the short chain fatty acids. And presumably the way to think about this would be that we've just we've evolved for so long in the presence of enough fiber and other things to feed this microbiome. And those short chain fatty acids are produced by that microbiome, you know, in the colon. And so those cells are just adapted metabolically to be able to most efficiently extract or use the short chain fatty acids for energy, even even more effectively than than glucose.
Carolina Tropini 21:00
Yeah, that's, that's really well said. And you know, another way in which we see this really tight connection is in the fact that our our body creates this layer of separation within microbiota. And so this is the mucous layer, get the screen and in fact, on most surfaces, but very much so in the digestive tract. And this surface not only provides a mechanical barrier that prevents the microbiota from invading us. But it's also a source of a lot of these sugar types that are part of this mesh have this mucus component. And so when we don't eat our fiber, we're still able to feed our microbiota based on these compounds. The problem is, is that if the microbiota doesn't have any fiber, then it will make this layer much smaller and thinner, which then creates problems with pathogens. But in some mammals, this layer is so important, because you can imagine what might happen during hibernation for some animals, some animals are not eating anything during this time, but they still want to keep their microbiota. And these animals that Hibernate have thicker mucus layers prior to hibernation, that allows their microbiota to survive, and actually produce nitrogen even during times when they're not being fed. And so again, like they're just really beautiful and complex interactions that we just have evolved with. And that's that's kind of how our, our old mammalian function is expected to have this microbial component.
Nick Jikomes 22:27
I see. So before we get to the oral microbiome, the gut microbiome in the colon, we've we've been involving, in concert with these microbes for a very long time. And that microbiota down at that end of the digestive system is expecting a lot of fiber. And the fiber is then turned into short chain fatty acids by those microbes. And the cells of our colon. Really like those short chain fatty acids, they're really used to them, they're adapted to using them for energy. So what your I don't want to tell people, there's no such thing as too much fiber. But it sounds like the dietary guidelines, you said the fiber recommendations are much lower than what humans would have been consuming for most of human history. And so they're probably well under what our cells are expecting, so to speak.
Carolina Tropini 23:18
Yes, but here's the trick, though. The problem is it. When we haven't eaten this type of food over generations, we've actually lost some of the microbes that were able to break down these fiber. So it's not that today you are and I could go out and say like, I'm gonna eat 150 grams of fiber and be okay, we probably would have really bad tummy aches. And in fact, it's patients that have inflammatory bowel disease, they find eating fiber really problematic, even though it's ideally that's, we would really like them to have more of these anti inflammatory compounds via the microbiota. This is very much an ecosystem issue, because you you not only need to have the nutrient sources for the microbiota, you also need to have the right microbes to be there, to break it down. And to make the right compounds to do this,
Nick Jikomes 24:08
obviously, so over time, as humans started eating less than less fiber and their their diet started to change, certain lineages of bacteria in the microbiome started dying off, and they're not with us anymore. And so if you were to just go back to eating, you know, if you were like one of the Paleo Diet people and you really wanted to literally eat like a, like a hunter gatherer did, that would actually be problematic, because you don't actually have the microbiome composition that our ancestors did.
Carolina Tropini 24:36
Exactly.
Nick Jikomes 24:39
Interesting. Okay, so, let's, let's now just imagine a normal human adult. And we can unpack that as much as you think is necessary, but think about adults. Now. Let's maybe walk people through how the microbiome looks and works differently in different parts of the digestive system. Starting starting with the oral microbiome, so So what are the microbes like in our mouth? How are they different from microbes, you know, further down in that adjustive tract? And what are they doing for us? They're are they involved in things like pre digestion of food? Are they doing other things? What does the oral microbiome look
Carolina Tropini 25:16
like? Yeah, the oral microbiome is, is very diverse, it's very tolerant of oxygen, because of course, it's in a in an oxygen environment. It's, it gets constantly washed down to their digestive tract. So in some sense, it can seed the rest of the gut by being there. And it's thought to break down a lot of sugars that that come in from, from our diet. So you know, during mastication, that's when we start breaking down the food. And these bacteria take advantage of this. And so the fact that the mouth microbiota is probably one of the first parts of the microbiota that was identified in an ad lib and live in hook. And I guess, in maybe early 1700s, as I was looking at his dental plaque and looking at how this animal kills that he called them, but it actually ended up being a bacteria, how they were moving around. And so these, these microbes have long been known to be there, and we try to get rid of them by brushing our teeth. But in practice, they just like any living organism, they just try to take advantage of the food resources that are available to them. They can create these strong biofilms. And so that's what dental plaque ends up being. They're these strong constructs of different species of bacteria that formed these had the strongest, sometimes quite hard to layers, which are hard to get rid of, in the part of the problem. And part of the interactions that of course, we have with these microbes is what happens in that time. So when we get to caries and different dental diseases, when there's trigger that gets leftover, these bacteria can ferment the sugar, they produce acids, they make holes into our teeth. And so through these holes, they can start building up larger colonies and more sugar gets in and then you kind of get this tooth decay process that takes place. And again, this is something that our ancestors didn't have to deal with, because they just didn't have access to sugar. And so that's not something that we're ready to deal with, evolutionarily speaking.
Nick Jikomes 27:28
So normally, when we think about dental hygiene, and cavities, we think about we think about the the practices that we have, like brushing our teeth and using mouthwash. So if someone is getting cavities, it means you're not brushing your teeth and or flossing enough, you're not cleaning your mouth enough. How much of the development of say cavities or something and just general dental hygiene, how much of it has to do with us engaging in those practices, versus having a diet that's conducive to cavity causing bacteria. So I guess another way to put this is, if you took a hunter gatherer, an ancestral human, and you just fed them their normal diet, and they're in that context, and you took a modern human and you fed them, say, the standard American diet, and neither one of them brush their teeth with toothpaste we did whatever hunter gatherers did with their teeth. Or you took that hunter gatherer and you just gave them the modern diet. Will, would they develop more cavities, because they're getting more sugars? Yes,
Carolina Tropini 28:33
simple sugars that get stuck between the teeth are a major cause for cavities. And so the departed, the point is that the the only types of sugars that hunter gatherers were really exposed to, and we see this in current traditional populations, as well as it's maybe honey, berries and fruits. But in those cases, to the sugar tends to be sequestered within fibrous structure. So even if you get some fiber stuck in your teeth, they probably just bugging you, and you take it off. And so, you know, the old way of brushing teeth is, you know, chewing on a stick. And so this type of things worked just fine. If people were we're not really having a, as far as we know, anyway, we're not really having the same dental problems that occurred when sugar was discovered and how tasty it is kind of clear. I see. So
Nick Jikomes 29:30
in the absence of food, where the sugar is readily available to the microbes in your tea in your mouth. The old way, the traditional way that hunter gatherers would take care of their teeth was basically just physically remove obvious pieces of food, because any piece that was there wouldn't have nearly as much sugar exposed and available to the microbes as much of our food does today.
Carolina Tropini 29:55
Right and you know, it can kind of see it also with with pets as well, you know, we're now having to brush our pets teeth, which is not something that pets in the wild. And really do, you know, the way that dogs keep their teeth clean is because they chew on bones. And that helps them keep things clean. And but the introduction of also sugar and you know, who can resist a puppy asking for a piece of your, your candy, right. But yeah, this ends up being the same problem for other animals as well.
Nick Jikomes 30:28
Interesting. So, as you go from the oral microbiome, through the esophagus into the stomach, how does how does the how does the size and the diversity change? How does what the microbes are doing change? You know, one obvious thing that comes to mind is when you get down in the stomach, it's obviously very acidic environment, the same microbes won't be able to survive down there. But what does it microbiome look like in the stomach? And what are those microbes doing in that organ?
Carolina Tropini 30:57
So in the stomach, the low pH is really this barrier for a lot of pathogens to get through. And so one of the things that he said, for example, interesting, is it for people that take antacids, this tends to be a risk factor for developing certain types of intestinal infections. And so that, again, like this is it the core, a big function of the stomach is to to limit the infection from potential pathogens that may be coming through. But one of the things that's interesting about the stomach is it while in the, in the main part in the bulk is very acidic, close to the stomach epithelium, you actually have very neutral pH. And so there's there's still a mucus layer, and there are microbes, notably, Helicobacter pylori, which was discovered and its connection with the with stomach cancer, you can recite there. And so, over time, there's been this discovery and this appreciation that even microbes that have longed for long time thought to be really problematic, such as, like, go back to actually have a positive effect on our immune system. So why don't one of the ways that now the the understanding around helicobacter has changed is that it actually, the best situation that maybe wouldn't be possible is if you were exposed to helicobacter when you were a child, but you get rid of it before adulthood, that may be the best way of setting yourself up for health, because eligo better later on in life, it's correlated with cancer. But lack of helicobacter seems to not stimulate the immune system in a way that that is positive enough. And so this type of think, interesting interactions with the bacteria that can survive in places that are very inhospitable, such as the stomach kind of gives a bit of a vignette into how complicated some of these interactions are, you know, there's, there's not going to be a microbe that it's just good or just bad. Usually, there's this whole spectrum of positive and negative aspects to it.
Nick Jikomes 33:02
And so, the stomach is this huge barrier to pathogens, because it's acidic, it opens up in the small intestine, and that's where a lot of our nutrient absorption is going to be happening. I would imagine the microbiome is probably bigger and more diverse. When you get into the small intestine, you start moving forward. So is that true. And you know, just in general, how, how's the microbiome composition changing as you go through the small intestine, the
Carolina Tropini 33:28
small intestine is still very aerobic, so it has microbes that are able to tolerate this level of oxygen. But it's also, as you said, the site where most of the nutrient absorption comes in. And so they're the immune system goes down hard on the microbiota and prevents large scale proliferation. So you actually have low diversity at low overall levels in an effort to try to have most of the nutrients actually being absorbed by us. And it's not until the later parts of the digestive tract that then the levels of the microbiota become incredibly high and incredibly dense.
Nick Jikomes 34:06
I see. So because this is a site of stuff coming into the body nutrients, but you also don't want bad things like pathogens to get into the body from the cavity or the lumen of the intestine. I imagine this is why so when you say the immune system is active, I imagine that includes just a lot of immune cells that are surveilling the area, tight junctions that, you know, physically prevent stuff from getting in all that stuff.
Carolina Tropini 34:30
Yeah, no, no. So antimicrobial peptides, there's just a lot of activity in the small intestine to ensure that the microbial levels are really low. When that doesn't happen, then there's there's specific diseases that have overgrowth of bacteria in the small intestine. And
Nick Jikomes 34:46
so what will be examples of those diseases and what what are some of the general symptoms? Yeah,
Carolina Tropini 34:52
so one of the probably most notable one is SIBO. So this is a small intestinal overgrowth of bacteria And in those cases, there's there, there's some diseases that that, unfortunately are not very highly controlled. And one of the challenges is that the our usual way in by our I mean, like as a, as a human community and human society of trying to combat bacteria, when their overgrowing is using antibiotics. But one of the issues with using antibiotics, as we found is that you have this very nonspecific way of affecting the growth of many, many different bacteria, both the good ones and the bad ones. And so the the fact that bacteria can become resistant to this antibiotics has basically taken away a lot of the tools that we had initially to combat some of these diseases. And so the right now the use of antibiotics around a lot of these diseases of overgrowth is changing, because they're not as effective as they once were.
Nick Jikomes 36:01
Interesting, can you say more about these antimicrobial peptides? Just briefly explained for people who don't know, what exactly is a peptide? And, you know, where, where are they produced in the intestine, and I mean, I would have met sounds like there's a lot of them produced. So they're, they're very important here.
Carolina Tropini 36:19
Yeah, so antimicrobial peptides are this innate way of the animal body to regulate which more how much of microbes may be around. So a peptide is a is a small component, a small part of a protein. And they're, they're components that they're very small, and they're usually charged, they're charged in a way that they can interact with other molecules that are have the opposite charge dinnerly, bacteria have a negatively charged membrane, and a lot of these peptides tend to be positive. And so by attaching them to the membranes, it can disrupt them, then and then have this very, very blanket way of, of keeping numbers down. And the immune system has a way of producing these, that basically is like kind of a first response to changes that is not adaptive. So you know, when we're talking about infections, there's there's two types of response that immune system has. The first one is the innate response, which is the first blanket response of say, you know, you can imagine like in a city that is being attacked to you shut down, enclosed and all the doors and so like this is, it's not a nonspecific way of trying to keep out the problematic parts. So the these, these peptides are a way in which the immune system responds very, very rapidly in a nonspecific way to the deceptive insults. And the other one is the the adaptive response, which is the one that is then more sophisticated, but takes longer to actually come up.
Nick Jikomes 37:55
I see. So so as a, as opposed to generating antibodies, which tend to be very specific for particular proteins from particular bugs, these anti micro peptides are just sort of like sticky little mini proteins that just sort of stick to the outer surface of any bacteria that might go
Carolina Tropini 38:11
through there. Yeah, in a very high level, that's, that's kind of the principle.
Nick Jikomes 38:16
Okay. So you get through the small intestine, much of our nutrient absorption will have happened. Now, you get to the large intestine, and it sounds like in the large intestine, you're going to have a larger microbiome, more microbes, and presumably, the composition or the types of species living there is also very different.
Carolina Tropini 38:35
That's right. So by the time that you get to the large intestine, all the stasis stuff that we wanted to take out from the diet, we've done that it's out there, what's left is things that we really cannot digest. And so a lot of the fiber and now that we have diets that are very high in, in protein, and in nitrogen reduction tends to be more nitrogen that comes through in that part of the garden. It's also one of the factors that is just changing the way the microbiota can function. And because now we can use the these more precious nutrients. But it but that point, because the ideally, the fiber is quite diverse, there's a lot of different linkages that are connecting this complex sugars. And so you need a lot of different types of microbes that will have a lot of different types of enzymes. And so to give you a sense of the metabolic capability that the microbiota in our large intestine has, the the estimates are about 150 times the number of genes than us humans have. And so like that's an immense metabolic capability that we don't, we don't want to store within us. We're basically just offloading all of this complex biochemistry to microbes that naturally have a much smaller genomes, but there's many of them in many different species that can break down these fibers. So
Nick Jikomes 39:54
this fiber gets down to large intestine because we can't digest it. It can be broken down by all of these microbes, we've evolved with them down there for so long that our bodies expect that fiber to feed those microbes, they generate other things like the short chain fatty acids we were talking about. There's more to unpack there. But can you explain to people what is fiber? And why can't we digest it?
Carolina Tropini 40:18
Oh, yeah, that's an excellent question. So fiber is, is a bit of a casual and very fuzzy phrase. And in fact, in the, in the microbiota field that we've been trying to, to come up with them with a with a better terminology around it. So we often talk about microbiota accessible fiber, which is basically compounds that are not broken down by us, that are made mostly of sugar residues that are connected together with different glycosylated linked linkages. And so like, these are our different connections that in order to be broken down to get to the simpler sugars, you need very specific enzymes that will allow these businesses thematic processes to take place. And we can break down some type of fiber, right that if you think about starches, we have some ability of breaking them down. So we do have some inherent ability for simple sugars to break them down. But for sugars that are more complex, and they're very highly branched, we just don't have the enzymes to do this. And so that's when we really rely on the microbiota to do this.
Nick Jikomes 41:28
And so like, other than the short chain fatty acids, is there anything else that gets produced by the microbiome in the large intestine, that we are absorbing other types of nutrients or other types of molecules that are relevant physiologically, yes,
Carolina Tropini 41:44
an incredible amount, we'd still very much dark matter, we do not know how many, we just know that the incredible proportion of the molecules that we have in our blood are not molecules that we produce, they come from our diet, and they come from metabolites that our microbiota produces. And we're just starting to look at the tip of the iceberg because it's really incredible the diversity of compounds that get made. And a lot of the compounds are very small molecules that will make it to the brain, they will make it to every distal side of our body. And in trying to understand how different molecules will affect our health is a very complex question, particularly if you're to study it in humans, because every human has a different microbiota, a different diet, a different lifestyle. And so making these connections really requires careful experimentation.
Nick Jikomes 42:41
Yeah, I was struck by what you said earlier to that, as the human diet has changed over time. directionally, we've been eating less and less fiber, we've actually seen a die off of certain bacterial lineages that we used to have inside of us that enabled us to deal with that volume of fiber. So obviously, the microbiome is going to change in response to our diet. I'm interested in sort of the, the sensitivity or stability of the microbiome. So for example, obviously, obviously, the microbiome is going to change in response to what we put in our bodies food wise. But is it? Is it super sensitive? If you change your diet at all? Is it definitely going to change it? Or can certain populations kind of become entrenched and sort of impervious to certain changes in the diet?
Carolina Tropini 43:29
Yeah, then, you know, it's, it's both very malleable, but it's also very unique. And so there's been studies showing that you can tell who's been in a room just based on the microbial signature that they leave behind. And so this is something that is pretty stable over the long term, as long as you don't do really extreme changes. And at the same time, when we look at the abundance of different species, those can change and fluctuate a lot. Because one day you ate strawberries, and, you know, that caused a bloom in a specific type of bacteria that really likes to break down the strawberry fiber. And so the there's on one side, I think that it's very, very exciting how malleable the microbiota is, because you can change it really drastically based on their diet. On the other side, we know that it's hard to have new species and trench. And so particularly when you're when you're an adult and your immune system is, is now pretty set on who's going to be allowing to come in and out.
Nick Jikomes 44:38
And so, you know, we talked about the interplay between the immune system and the microbiome earlier, we talked about antibiotics, I would imagine that one major way that the microbiome can have big shifts that stabilize such that someone, you know, starts out with a microbiome, you know, microbiome, a, and they end up with microbiome B which is just very, very Different. I imagine one way that that can be triggered is through the heavy use of antibiotics. So if someone say, gets an infection, and they're taking one or more antibiotics for an extended period of time, let's imagine a situation like that the person goes on antibiotics, they get rid of their infection, they come off antibiotics, let's assume their diet is constant. Is the microbiome likely going to go back to the way it was? Or is it likely going to be different in some important way?
Carolina Tropini 45:29
This isn't, I think it's really important topic and really important question of kind of this recovery, there's been some studies that basically have shown that the use of antibiotics usually changes the microbiota, and particularly the fixed species that are at low abundance, just because they're the fluctuations that end up maybe causing them to disappear, then if you don't get them back, they're just gone from your own ecosystem. And we live in a society that is very different from our ancestral ways, which prevents us from getting certain types of infections, but also prevents us from being recalculated by microbes that we might want to keep around. So if someone is taking antibiotics, it really depends on how long the antibiotic courses, it also depends on on the practical re exposure that they might have to some of these microbes. In some of the studies, they also looked at is the microbiota that we get back the same? And are there ways in which we can help it so one of the things that people often think about when you think about the microbiota is thinking about probiotics may be beneficial. And actually the in those studies, it looked like exposure to probiotics actually got to to a different microbiota than what you started with. And the best way to get to the same microbiota that you had before, was basically keeping a stock of the microbiota head before antibiotics and then taking it back after, which of course, are they're still very experimental ways of doing microbiota restoration. But in the same light in which how we're doing ecosystem restoration, that's a little bit how we think of microbiota therapies. Yeah,
Nick Jikomes 47:12
I mean, so it makes sense that the ideal way to replenish the microbiome you had would be to keep a sample somehow of the one that you started with, let's force ourselves to be brutally practical here, especially for the people listening that are concerned about microbiome health. So you said you have kids at home, you probably have young kids at home, it sounds like. So at some point, if it hasn't happened already, some of them are going to get sick, and they're probably going to require or be recommended to take some antibiotics. So given your background as a microbiome, ologists and your role as a mother who's had to deal or will have to deal at some point, presumably with the use of antibiotics and your children, what are the major things you're thinking about in terms of how you're going to respond during and after those antibiotics are used in terms of how you manage their their lifestyle?
Carolina Tropini 48:01
Yeah. So first off, I should say that I'm not that kind of doctor. So I should really not be giving any clinical advice.
Nick Jikomes 48:09
No. Yeah, no, I'm saying. So your kids go to the physician. Yeah.
Carolina Tropini 48:13
So, you know, I think one of the one I think that's really challenging about the microbiota, and how we can use it in health is it humans are very, very good at dealing with acute problems. Humans are really, really bad at accusing, dealing with chronic problems. And the microbiota demonstrates itself into chronic problems now, not in the acute problems. So if you have, say, a microbiota that is not very diverse, you may be at higher risk of developing inflammatory diseases, you may be at higher risk of developing obesity. But these are all things that don't play out overnight. And you can think of, of the decision that a physician has to do when there's a risk of sepsis and the risk of sepsis is maybe one in 10,000. How do you weigh that against a risk of even one in 500 of developing obesity in 20 years? Those are the type of questions that when people are trying to use antibiotics and decide whether to use them or not sometimes are faced with, and in general, people will tend to try to not get sepsis right now. And downplay the effect, even though it might be higher probability over the longer term. And so from the perspective of taking antibiotics, what it can tell you about, you know, what, what I tried to do personally is try to resist the impulse of treating something immediately. Clinicians are also becoming more and more aware of the negative effects of antibiotics, not just because of the the effects of the microbiota, but also because of how we're, we're raising antimicrobial resistance that then we will not be able to fight by the overuse of this antibiotics. And so I think that overall the the level of antibiotics are being prescribed is much, much lower than it was even five to 10 years ago. But in practice, what I think that means is that if someone is sick before getting antibiotics to give it a chance to know whether it's maybe a viral infection, and then the antibiotics actually would really not be helpful. And it's also a matter of, of changing our perspective, also as patients to, to know that some of the time, the best way to beat an infection might just be to wait for our own immune system to take over and do what, what it knows how to do. But again, you know, when you're a mother, and you're exhausted, your kid is crying and has a fever, you want to do something about it. So they're not easy decisions.
Nick Jikomes 50:44
And so let's just say for whatever reason, a mother has consulted with a physician or child is sick with some kind of bacterial infection, it's decided that antibiotics are appropriate for that infection, and they are used. If you were in that situation, thinking about the microbiome in the recovery phase, would you be inclined just to make sure the diet was what you thought it should be? Would you be inclined to use something like probiotics? How would you think about it in that particular situation?
Carolina Tropini 51:17
Yeah. So you know, I can tell you what, what I do is kind of an individual. I've had to take antibiotics, you know, there have been times diabetics are, of course, incredibly important to combat infections. And so in terms of the recovery from, from from probiotics, we're not at the stage yet where you can save your microbiota and then read oxalate yourself. And so what I tried to do is to basically have a natural recovery of my microbiota by having different types of fiber. The problem with probiotics in pills is that you're inoculating a billion of one species. And so try to imagine what that looks like in in, say, us, MIT has had a massive wildfire, and now you throw in a billion rabbits, is that good? Is that bad? Will the rabbits even survive, right. And so in trying to think about the microbiota is a little bit like your own ecosystem. That's also the same principles that we should apply here. If you want to do ecosystem restoration, you're probably not going to be doing very much good by adding a billion rabbits. But maybe you want to try to get rid of over growing species that may be invasive. And so you can do that, with respect to your gut by, you know, starting with actually foods that are not super high fiber if you've had a tummy ache. And so like, you know, step in and introduce it more slowly. So you're really trying to rebuild your ecosystem, and allowing it to recover in kind of its entirety. There's also different types of probiotics, you know, probiotics that come in a pill form, those tend to have just one or a couple of species that, in some cases, may have been proven to have some positive effects, sometimes not a lot of the ones that you find over the counter are, are not really proven, you don't really know whether they're dark species or not. But there's also ways of, for example, eating fermented foods, which have a naturally occurring bacteria, and those tend to be very positive for stimulating the immune system. And so unless certain things have have really been shown to have like a positive effect, I, my family and I tend to stick with things like well try to have some more fermented food and try to rebuild the natural environment. And the the other part of it, I think that is a kind of a an approach in lifestyle, that to try to ensure that you're not blocking yourself off from any microbial exposure. That is not how we evolved when, obviously, you don't want to go out and try to catch all the infections. But there's also no need to be scared of exposing yourself to dirt we see this in. This is a data that has been really clearly shown and how, for example, kids that have dogs, kids that have older siblings, kids that have some way of bringing some underwater dirt in the house or live on a farm have a much lower incidence of asthma and allergies, compared to kids that live in very, very clean environments. And so there is some amount of exposure to these microbes that is just important for your immune system. And so every time that you disrupt your microbiota, that's something to think about that they didn't exposing yourself with microbes that are are healthy for you, is a good way to try to keep these ecosystem working as it should.
Nick Jikomes 54:40
That might be counterintuitive for some people. You know, if you grew up on a farm, you have a lower rate of asthma, but like aren't you around more animals and more things that could trigger you know, asthma like symptoms? So is this are you getting Is this the the hygiene hypothesis, and can you just kind of unpack that a little bit more for people? Yeah,
Carolina Tropini 54:57
absolutely. So this was something that was found or pretty early on in, in settlements of in city settlements that, that people tend to have this hay fever when they would go visit their relatives in farms. And so this this correlation of these hay fevers will then then turn out to be allergies. And the fact that they were more prevalent in in seedy settlements, as opposed to more pastoral and countryside, the type of communities started then asking the question of is the cleansiness. Part of the reason why a lot of these, this type of inflammatory and allergic diseases were were becoming more prevalent. And so since then, there's now been a lot of studies that have really shown that our immune system, particularly in childhood, needs to have the right types of triggers in order to work properly. And if it doesn't have exposure to some types of triggering in these are often bacterial or dirt triggers, then it starts acting against compounds such as pollen and other types of allergens, that otherwise would have not been a problem.
Nick Jikomes 56:11
Interesting. Wow. So the gut microbiome, I think about the gut microbiome, you know, we think about, obviously, the gut, stuff that has to do directly with the gut, the absorption of nutrients, diseases of the gut, things like that. But the influence of the microbiome, as you know, and I think many people know, at this point, extends beyond the gut. And it can affect you know, that what our microbiome in our gut is doing can affect things, you know, elsewhere in the body. One of the areas here that I thought was really interesting that you wrote a paper on has to do with microbial endocrinology. So can you explain what that little subfield is? And start to talk about the microbiome in that context? Yeah,
Carolina Tropini 56:55
absolutely. So I think this is a super exciting field, because it's a, it connects the endocrine and so that the hormonal changes in our body, also to our microbes, and, and I think it really underscores how tightly connected all of the processes in our body are, we tend to think about hormones as a way that is very, very human that affects puberty, if a high affects a estar cycles, it affects a lot of parts that we think that are interesting, intrinsically human. But what it turns out is that the hormones that we produce can be modified by the microbes in our gut, and they can change either by activating or deactivating them. So to give you a very high level, summary about this, in either the testes or in the uterus, there's hormones that are produced. And so for females, we mostly think about estrogens. And for males, we mostly think about testosterone. But these are produced both by males and females. And when they're produced in, they're given out into the blood, and they're usually come associated with the specific proteins that would prevent them from actually becoming active. And there's also some modifications that happen in the liver, that inactivate these hormones, so the body is constantly turning off these hormones and the way that they act. So while normally, when we go, say get a blood blood drawn, and we look at these hormones we normally took, take a look at the overall levels. But it's not always that you'd be looking at the active levels, which ultimately are what make a difference. And so while the liver continuously inactivate these hormones, and shuttles them in a way that will make them more likely to go out in urine, a lot of gut microbes actually do the opposite, they will take away this inactivating molecules and will activate them again. So you have this balance in which your microbes can activate them, some microbes can even degraded hormones like testosterone. And you have this balance in which now your your body's responding both to cues that come from, you know, our own cells and cues that come from the microbiota in order to to change these processes.
Nick Jikomes 59:14
I see so the microbes can directly its sounds like you know, they can directly modify things, things like sex hormones. Exactly. Is there? Are there any things? Are there metabolites they produce that have estrogenic or androgenic effects? So for example, are there certain components in food that are eaten up by the bacteria and causing him to spit out something that has a hormone like effect in us? Yeah, so
Carolina Tropini 59:47
this can happen in a number of different ways. Like there are service products that can be metabolized into compounds that look like estrogens and so like these can get to cross react with sto Didn't receptors and give some of the same effect with the with estrogen?
Nick Jikomes 1:00:03
So you said soy rich products? Yes. Okay.
Carolina Tropini 1:00:07
The other thing that can happen is it there are some microbes that can produce their own hormones, particularly in the case of testosterone. Or they can do this starting from cholesterol in a very similar way to how humans we use cholesterol to get down to hormone creation.
Nick Jikomes 1:00:22
Do we know? Do we know the net effects of any of that? So for example, you know, soy like soybean oils, things like that very common, they've become much more common in recent years than they have in the past. Is that having like a net estrogenic, or anti estrogenic effect through some kind of competition between these estrogenic metabolites and our endogenous hormones? Yeah,
Carolina Tropini 1:00:48
that's a very good question. And I think a very complex one I'm not aware of, I guess I have a full agreement about this, that there are human populations that have consumed soy for millennia, and, you know, in as part of their normal diet and their normal cycle. So I don't think that a blanket statement would be appropriate. But in it really very much depends on how different microbiota are balanced. It also depends on how the diet may be balanced with that or compounds in but there's definitely some of the data that I think is very strong. And in showing the the impact of the microbiota and modifying these hormones, is it when we look at animal models that do not have a microbiota? So these are, we were talking about that with in humans, in mammals anyway, in the uterus, there's not thought to be a microbiota. So there's animal models that can be derived by C section, and do not have microbes anymore. And so these are, can be a way in which we can test like what is the effect of not having a microbiota. And so in these animal models that don't have a microbiota, but have an otherwise normal function in normal diet, we see that they have very strong changes in in their puberty in their sexual function. And so this underscores the importance of the microbiota in, in having some of these changes to Hormonal Health that did our normal.
Nick Jikomes 1:02:13
I see. So it sounds like most of the details around all that have yet to be worked out. But we at least know that if you take away the microbiome entirely, you see hormonal and other effects that are strong enough to change things like when puberty happens. So so pretty major developmental changes.
Carolina Tropini 1:02:32
Yeah, and you know, some of the the other studies that have been done have been, for example, around prostate cancer. And this is a disease that often there's imbalances and maybe too high levels of testosterone. And one of the things that sometimes it's done in patients that have prostate cancer in a way that where there's too much production of testosterone is that there's a castration that takes place to try to reduce the testosterone and limit the impact of a genetic given impact of the testosterone. But there have been some patients that were found to be at basically insensitive to the castration, they were still producing very high levels of hormones. In those cases, that microbiota was implicated in this high production of, of testosterone. So they're the the mechanisms are still being worked out. But there's, there's now starting to be a lot of data that implicates the microbiota, both in positive but also negative ways in this changes in the hormonal and active or hormonal levels.
Nick Jikomes 1:03:31
Are there any connections between the microbiome and gut hormones that regulate the hunger itself? So another way of saying that maybe is, Can changes in our diet are changes that we need to make to our diet? For for natural reasons, like, you know, I could imagine, you know, if a woman gets pregnant, for example, her caloric and nutrient needs are going to change, are there any changes there that seem to be mediated by the microbiome?
Carolina Tropini 1:03:56
Very much so. So this is a an area that I'm tendentially informed about. So I'm gonna be pretty general about it. But there, there's definitely evidence that the microbiota can influence hunger, they can influence how the feeling of society and so the, the the microbiota is so tightly related with us that it is influenced by our circadian rhythms. So circadian rhythms mean when the expectation that our body has of daytime and nighttime and of cycles of feeding and things like that. And so what are the things that anyone that has ever traveled and gotten jetlag knows is that there's definitely discomfort and changes to your digestive health and the way that you to adjust things and that's partly due to the microbiota and not knowing anymore what was going on expecting food at times that that it's not coming so there's there's definitely changes that they you can kind of experience in your day to day life that have to do with the microbiota and then too reaction that it has a with. Yeah with with their expectation or when food should be coming or how hungry we are.
Nick Jikomes 1:05:10
So obviously we've we've talked a fair amount about how what we put on our body changes the microbiome, we focused largely on dietary inputs. We talked about antibiotics as well. What about things like pharmaceutical medications? What do we know about, you know, anything from, you know, psychiatric medications, to say, you know, hormonal medications like birth control, do all of I would guess that probably anywhere you look, there's going to be some effect. But what are some of the most salient things that we've learned or that we already have some handle on in terms of other medications, besides antibiotics, that we put into our bodies fairly frequently, that are having major changes in the microbiome.
Carolina Tropini 1:05:56
This is, I think, in very important in a growing area of research, so anything that makes it through our gut, obviously, can be modified or even broken down by the microbiota. But even things that don't start out in our gut can make it there. We talked about hormones and how they can be modified in the gut. Anything that makes it through a blood system can potentially be modified in the gut because of the high interaction between the portal blood system and in the gut and the exchanges that can happen there. So there's definitely a lot of effort in trying to understand how different microbes can either enhance the effect of certain drugs or prevent them. So to give you an example, there are some drugs that can be broken down by the microbiota, and so they don't have an effect anymore. There are drugs that we we deem safe and but they will have a negative effect on the microbiota over longer timescales. So to give you a sense, a lot of the over the counter drugs that we take, we talked a little bit about antacids, like this is true of laxatives, they will just change the microbiota because they set up an environment that is not the same anymore. So laxatives often work by creating in a somatic imbalance with the guide, which throws out water and increases the motility, while it also draws water from the bacteria at some bacteria can tolerate this, and so they will go away after a long term exposure to laxatives. And the problem though, is it? It doesn't, at least to me, it doesn't make sense to say like, well, we shouldn't be using any drugs. Like that's obviously not, not the point. But I think it's important to know that just like with any ecosystem, if you apply a change, there will be a response from the ecosystem and knowing what's good, what's bad, what's neutral. Those are very loaded words for ecosystems. Because if you think about a forest, you can probably distinguish a forest that is healthy for one that is unhealthy. But it's hard to know whether a forest is healthier than another one. If they both look less Yeah.
Nick Jikomes 1:08:03
And even if you can easily identify healthy versus unhealthy when they're clearly different. That's very different from saying, so you can't just look at a healthy forest and be like, Oh, it's got XY and Z. So if we put those things in the unhealthy one, it will become healthy. It's it's so complex, in like literally the the math sense that you just can't predict system level outcomes from individual changes and individual variables.
Carolina Tropini 1:08:31
Absolutely. And so you know, in thinking about microbiota changes, say that you want to take it you said, you know, if microbe X is good in you, you may not be good in me because I don't have the rest of its friends that would keep it happy. Right. And so the the way that this this kind of applies is I think they will we'll have to play out on a much more ecosystem level type of health approaches.
Nick Jikomes 1:08:58
What are some of the major projects and questions you're working on in your lab right now?
Carolina Tropini 1:09:06
We're very excited about thinking about the microbiota at different scales. So from a more clinical perspective, we study a lot to the impact of the microbiota on inflammatory type of diseases, for example, IBD. So corns in colitis are some of the diseases that we're looking at. And we were connected with clinicians to try to understand how changes in the microbiota and how specific types of bacteria that can cause inflammation, how those change the environment, and then lead to our microbiota. This less resilient than scaling this down to specific applications. We're interested in how certain types of drugs may affect people that have different types of microbiota. So to give you an example, what happens when people undergo bowel preparation, that, of course, reduces very strongly the microbes that you have there. What happens if you lose some of the microbes? They're important. And so we're we're focusing in on specific microbes that we know that are being lost in industrialized human populations and trying to understand, do we want them back? If we do want them back? Can we get them back? How do they change their immune system? How did they change the interaction between different microbes? And so, you know, in kind of scaling from a clinical questions, we kind of go down to the individual cell level and trying to understand how are these microbes producing what they produce? How are they interacting with other microbes? And how can we strengthen some of the relationships in a way that as we proceed towards microbiome therapies, that we have something that you're not talking about ecosystem restoration that we actually can, can make useful for the human population as a whole.
Nick Jikomes 1:10:49
So one of the things tied to the microbiome that I've heard about that, where you see very dramatic results, types of results, where they write about in the newspapers and stuff has to do with fecal transplants. So you perform a fecal transplant in animal models, for example, and I believe that they've seen results like you know, if you do the transplantation, from the skinny mouse to the obese mouse, the obese mouse become skinny, you get dramatic results to do with diseases of different kinds. So why do fecal transplants seem to produce results that dramatic? And what are maybe one or two of the most well known or well worked out examples there?
Carolina Tropini 1:11:33
Yeah, so the fecal microbiota transplants have been demonstrated, particularly in animal models, but they've also been shown to be incredibly helpful in combating C Diff infection. So C difficile, is this pathogens that that often comes up after antibiotic treatment, and then they cannot be eradicated because it's a, it's very resistant. And in fact, it thrives when the rest of the microbiota is depleted by antibiotics. So it really takes advantage of the reduced diversity of the microbiota. And so in in early experiment was was trying to in cases in which patients were really, really struggling, and it was kind of deemed to be as a last step, and at last try was to take up microbiota from a healthy donor, and then transplant it. And in those cases, the efficacy of this treatment was incredible over 90%, which is something that is very rarely seen in any type of therapy that we would normally deal with. And so this led to this very strong excitement of how we could restore these disrupted ecosystems by transplanting this this healthy microbes. And, and one of the challenges with this is it in as we talked about, these are a complex ecosystems, which are very, very diverse and very, very messy. And so one of the the ethical questions around it is a what constitutes a healthy microbiota that we would put into a patient that has a specific type of disease, also, with the understanding that say, you may have a very healthy tropical forest, and you're trying to transplant it into a desert? Well, it probably will not take hold there, because you just don't have enough water to support it. And so in more complex diseases, where this has been tried, the the efficacy is much lower, and we find that a lot of the microbes are not actually able to survive when they're implanted. And so the this is, I think, something that we need to go much more towards precision medicine for these type of approaches, because right now, it's a very blunt tool of just saying like, well, we'll take this ecosystem that seems to be healthy in this one person, put it in a completely different person and and hope that it provides the same the same types of health. So the, you know, probably the, the CDF example is probably one of the largest examples in animal models. There's a lot of has been uncovered, both from the perspective of what is transferable. So there's definitely, as you mentioned, the, you know, the obesity that can even be transferred, because sometimes there's also the opposite experiment was done in which in obese microbiota was transplanted into a skinny microbiota, and the skinny mouse became obese. And it turned out that the reason why that happened is because the microbes from the obese mouse were very, very good at capturing the energy. And so they were releasing a lot more energy for the same amount of food to their host than the microbes coming from the skinny microbiota. And so there's, there's going to be a lot of things that are transferable in some things that maybe are not and so you know, this this question about transferring obesity, it was one of the things that a lot of patients worry about and want to know about their donor, whether this may be the case, but in terms of the the human data, so things that are really very much being worked out.
Nick Jikomes 1:14:54
So yeah, the microbiome has captured a popular consciousness to some extent to Pretty large extent at this point. I think one of the reflections of that is that it's very common to see today, people taking probiotics. And I don't mean like someone has a specific deficit, like they had antibiotics and like they know for a fact their microbiome has been depleted. I don't even mean people that have like actual gut issues that have been diagnosed, but just normal people walking around that are just sort of concerned with their health at a normal level. You know, they've heard of microbiome, they've heard of gut health, they see probiotics of all kinds marketed out there on store shelves. I know a lot of people in my life that just take a probiotic, when they take, you know, a vitamin C pill, or vitamin D pill, or whatever, that's part of their daily supplement routine. And as far as I can tell, most of the time, they don't even know maybe what the species are that are in there, they don't really know what's known about them, taking a sort of a bird's eye view. But thinking about the average consumer out there the average person, what are your thoughts on the probiotic products that are out there? Do you take any, how should people think about that? Do we know enough that it even makes sense that people are buying these things? What's What's your take on the probiotic supplement industry?
Carolina Tropini 1:16:12
I think we're very much in the early days, and it's an industry that is very much been exploited because of the excitement that, that people will have around diet and around supplements. And so we've tested this several in the lab, and we found that sometimes it's they're not alive. Often, they're not the species that they say they are. So that the ones that are not regulated tend to tend to often not be what they're marketed to be. That said, they're unlikely to do harm. Because they they did they do tend to be bacteria that are easy to to be grown. And they also tend to be not the type of bacteria that adults would have, which is one of the parts that I think that is most bizarre about the use of probiotics is that they tend to be bacteria like lactobacillus Bifidobacterium, all of these bacteria that are found to be mostly are, they're found mostly in babies, not in adults. And so there's a little bit of a disconnect about how relevant they would even be with an adult taking the supplement, which is usually the case when that happens. There are probiotics that have been that have shown efficacy in human studies for very specific indications. But in those cases, I think it's it is important to try to see what they're being used for and how they're being used. One of the the challenge with microbiota therapy is that oftentimes, even when we want to make a microbe to stick around, and we provide it in the probiotic form, it will actually just transit through and so that's part of the, you know, the idea would say that, for the most part, they will cause no harm. But one of the challenges that even if you do find that microbe that you really, really want, it's maybe not something that you're able to have and stick around. And then conversely there there are microbes that for as I was saying for specific indications have been shown to be very important, you know, an example of this is E coli nissle. And so this was a was a microbe that had been found in 1917. During World War One, when there was like this outbreak of salmonella, and there was like this one soldier that had had shown that it was resistant to this. And it turned out that it had this microbe that basically was providing colonization, colonization and resistance from this pathogen, just based on the fact that it had a similar similar way of nutrient requirements in the salmonella did and so basically displace it based on this. So there are some microbes that have been very well worked out for how they work and how they could protect from specific things. But we're not there for most of the ones that you would see in in stores.
Nick Jikomes 1:19:14
It sounds like a fair summary of your perspective for the average consumer is that a majority of the time a healthy majority of the time, you know, the casual consumer, someone who's just concerned about gut health but but doesn't have a super specific thing with a super specific diagnosis where a particular species of bacteria is known to be the solution. The average consumer, probably not worth it to stress about taking a daily probiotic.
Carolina Tropini 1:19:43
Again, with with the caveat of not giving medical advice, it it probably doesn't make that big of a difference but but I think that for all things that have to do with with health and diet. We're not there yet at the law level of looking at one person and being able to say these are the bacteria that you need. This is the dye that he should have with these bacteria. We're getting there, we're not there yet. I think that there's an important space for, for people to try different things and see what works with for them. Because sometimes there are things that are unexpected, you know that this is happened a lot with, for example, with IBD patients that they have found that certain types of food that normally would be counter indicated in general, for patients with inflammatory diseases actually have found that that helped them. And so I think that there, there also needs to be some openness from both the scientific and clinical perspective, that there are a lot of things that we don't know, and even sometimes the traditional medicines that we've discounted, because in some types of trials have not worked. They may work for individuals. And so there's there's so much diversity, not only from the microbial side, also from the human side, that there will be things that are not standard that work for some people. And and I think it's important to be open to those as well.
Nick Jikomes 1:21:04
Can you actually, you know, just give us the basics on what IBD is, and how common it is, one gets the I get the impression just sort of walking around and hearing about it from people that seems to be becoming more prevalent. So is that true? And what exactly is IBD?
Carolina Tropini 1:21:22
Yeah, inflammatory bowel disease is a, it's an inflammatory disease. That is the name says it involves a digestive tract. And one of the things that that I think is most critical about inflammatory bowel disease is the level of pain and effect on daily life that it has on patients that habit, it's an extremely challenging disease, that it's invisible, because it's, it's not something that will be overt. And so people that suffer from this disease there are often feeling unseen. And there, it's also because of a affecting the bowel is something that that is hard to deal with and explain when sometimes like you might have to go to the bathroom really quickly. And the prevalence is quite high. It's almost at 1% in North America, and it's by 2050 is expected to be at at 1% of the population, which is it's an incredible fraction of the population. It's also being diagnosed earlier and earlier in, there's a lot more pediatric patients than there used to be. And one of the things that I think is really interesting about inflammatory bowel disease is that while it has a genetic component that is being still being sorted out, and this is a pro inflammatory response that to the immune system has, and effects on the on the intestine, specifically, the genes that are involved with this are actually genes that have been known to be around human communities, at least since until the Black Plague. So there was recently a study that showed how some of the genes that helped protect us against the plague in the medieval times were actually selected upon and those are genes that are known to be positively correlated. So they seem to be at least enriched in people that have IBD. And one of the things that for a long time, scientists wondered about is it well, if this genes have been around for so long, why are we only seeing IBD. Now, why is this a modern disease?
Nick Jikomes 1:23:28
So just to make sure I'm following, you're saying that there's genetic evidence that people who survived the Black Plague because they had a genome that enabled them to survive the black plague, their descendants are now more abundant than the descendants of people who didn't live through that plague and pass on their genes. And those same genes seem to be connected to IBD.
Carolina Tropini 1:23:52
Exactly, yeah. So those genes tend to be when and enriched they tend to correlate with the development of the disease. The thing that's interesting, too, about IBD is that while those genes have been present since at least medieval times, they the first diagnosis of IBD, did not happen until the 1800s. And also it only happened in industrialized countries. So when we look at, for example, in certain countries in Asia, the first diagnosis of IBD has happened much more recently, and really strongly correlates with the industrialization. So it correlates with the changes that have to do with increased use of drugs, increased the use of foods that are highly processed, and the changes in lifestyle that we can associate with with industrialization itself. And that's really where the microbiota plays in a role because while our genome has stayed relatively stable over this time, one of the things that has changed very much it has been our microbes. And what we see in the in patients with inflammatory bowel disease They tend to have much lower diversity of the microbiota. And they tend to have a microbiota, it's more inflammatory. So instead of having these microbes that produce this anti inflammatory compounds that we were talking about earlier destruction fatty acids, we've actually seen that they produces a compounds that tend to be pro inflammatory, and tends to have species that can cause inflammation throughout the body.
Nick Jikomes 1:25:25
Interesting. So when you talk about fostering a healthy microbe, giving the microbiome what it needs to to thrive, and be a healthy microbiome, relatively speaking, the thing that you talked about most there, in terms of dietary components is fiber. So we've talked about that. High, high fiber, a sufficiently high fiber content in your diet is important for the microbiome, because it's a primary food source for the microbes that are living in your large intestine. Are there any you talked about fermented foods as well? So fiber, fermented foods? Those are the ones I hear about the most? Are there any other big ones in terms of nutrients in our diet that are good for the microbiome? And then the flip side of that, are there any things in the diet any particular components that tend to be good for a not so healthy microbiome?
Carolina Tropini 1:26:18
Yeah, so I don't think that I think that, in general, having a diet that is diverse, and has enough of the nutrients that you think about being healthy for the human tend to be also healthy for the microbiota. The the fiber part is definitely one of the major sources of nutrients from the microbiota. But the microbiota also requires a lot of the same nutrients that we otherwise would think about, you know, whether it's making sure that there's nitrogen, one of the things, for example, in the guide is that there's a, there's a very high shortage of, of Iran, and the body does this on purpose not to have overgrowth. So you know, anyone that has tried to taking a lot of iron supplements, like me suffer from constipation, through the microbiota, being able to overgrowth. So there's, there's a lot of other nutrients that we usually don't think about that will affect the microbiota through this. On the other side, the nutrients that may have a negative impact on the microbiota as it relates to our own health or, or things like emulsifiers, those will, they can negative impacts of microbiota, because for example, when you're taking emulsifiers, so these are compounds that often are used in in foods to hold them together, instead of having them separate between the oil parts, I can think about it salad dressings, and things like that have a lot of emulsifiers. And those are things that work a little bit like soaps, and so when you take them, they will also wash things off in your intestines. Now, for example, the mucus layer that we were talking about that creates this healthy barrier between us and the microbiota. It also can disrupt the membranes of the microbiota. We talked a little bit about alternative sugars and how those ones can be cheap sugars for the microbiota, they will still give us energy, even though they're technically not taken up by our own cells directly. And so there's, there's a lot of different compounds that can have these effects that are indirect, and they can negatively affect our health.
Nick Jikomes 1:28:23
I see so so emulsifiers are one because they literally wash away some of the microbes in our gut,
Carolina Tropini 1:28:29
they will disrupt surfaces that have have some fats and associated with them. So again, these are kind of indirect effects, but they can change the membranes of these microbes and take off some of our mucous protective layer,
Nick Jikomes 1:28:47
RC, so it's altering the gut environment in a way that's then going to naturally lead to different populations thriving or dying. Exactly. Interesting. Any other any other major ones that you can think of, or that have been clearly demonstrated,
Carolina Tropini 1:29:02
you know, the, in practice, anything that we take by mouth, water, change the microbiota, and knowing whether it's good, bad or neutral, as we were saying is going to be challenging. You know, one of the things I think that it's interesting in thinking about more obvious things like no taking antibiotics, is it the microbiota itself produces antibiotics all the time. And in fact, a lot of the antibiotics that we have are produced by their microbiota. The problem is not the compound problem is the amount and the location. When microbes produce antibiotics. They do it to have very short chain range interactions with microbes around them and keep those at bay. But when we take antibiotics, we take them when we flood the entire system with super high concentrations of them, which are then not natural, you know things like Micromax and have been in the repertoire of antibiotics of our Earth for millions of years. And you know, within 30 years, we were able to wring it out And then make it become not successful anymore because now there's resistance, you know, and despite this millions of years of use of this antibiotic by the microbiota, it was able to microbiota use it. So luckily, that didn't, did not give rise to resistance. And so that's, that's going to be happening similarly to other compounds, too. One of the issues that we have with the, with the way that we take compliance by mouth is that we, we tend to flush our system with very high levels of things like even contraceptives and other compounds in medicine that we take by mouth, if only we had a way to have them more localized, they could have a very more limited impact and, and have different effects and impact our the rest of our ecosystem in a way that is less major. Yeah,
Nick Jikomes 1:30:52
that makes that makes sense. If we are taking medications and other things, systemically, oftentimes, the benefit, or the thing that we want to happen is a more local, is a more local thing. It's happening, you know, in particular cells or particular parts of the body. So if you had a local delivery mechanism, you would naturally decrease the side effects that are going to come from that thing going elsewhere and just doing other stuff. Yeah.
Carolina Tropini 1:31:13
And I think that actually, that is also one of the reasons why they microbiota is so exciting, as a therapeutic. And this something that my lab also works on illustrated to see, can we leverage the microbiota as a way to have a very specific delivery system. So when I can think about these microbes, they sense their environment, they're able to tell when say, there's changes due to inflammation, there's changes, because maybe cells are growing faster, and so the temperature is higher, because there's a cancer there, those cells can detect these changes in the ecosystem. And if the detection of those changes was tied to the delivery of specific drugs, then now you have drugs that are carried by these microbes that can be delivered only at the site where they need to be delivered. So like this delivery of drugs through the microbiota is is one of the frontiers that they were thinking a lot about in the next stage of
Nick Jikomes 1:32:06
therapeutics. What's one good example of a major unanswered question to do with the microbiome that you think we will likely have solid answers to in the near future? Meaning, you know, let's call it two or three years.
Carolina Tropini 1:32:23
And really major question that I think we will have answered is how the microbiota can insert itself. So you know, we were talking about from the perspective of the probiotics like it can be really important. If we want to restore species, can we get them back? And so this question of when are we able to get them back, I think is going to be a major one that will be answered. You know, on one side, we may be able to do fecal microbiota transplants of our own microbiota to restore it, but what if we wanted to take microbes that we have never been exposed to? You know, do we need to do this in the infancy? Or can we do this later? I think this is going to it's a very important question. And I think it's one that we'll be able to answer in the next few years.
Nick Jikomes 1:33:06
I have not looked into these in detail, but there are no companies out there selling products, where you take a sample from your mouth or from the other side of your body. And they you send it in, and they analyze it and they can give you a fingerprint of your microbiome, and apparently give you you know, diet recommendations and things like that, based based on those results. Do you think those are legitimate? Is that is that is that tech there? Is our ability to do that accurately in place? And are those things that couldn't be worth looking into for those interested?
Carolina Tropini 1:33:43
there's starting to be some studies, particularly out of Israel, that are correlating the breakdown of specific fibers and sugars with specific microbiota makeups. But But I think we're still in pretty, pretty early days. So right now, if you were to phenotype, your microbiota, you basically will get a list of species. And so think about what that would mean. If you were looking at this species in, in a park, right, like, there's 50, lions and 73 Godzilla and right, it's, it's not that informative. It doesn't really tell you about are the lions healthy, are there enough gazelles and so we're still at this stage of by looking at these lists of microbes? There's only so much information that that you can have like you can know that maybe there's no elephants there. And actually, I think that for your environment, you really should have elephants, but we're not there yet. At the level of, of having this, this phenotyping be useful enough, except in extreme cases, right? Like if you have a lot of invasive species, then it becomes obvious that something needs to happen. But again, like if you have something that looks relatively healthy, we still need more data to know you should be eating more Broccoli and have more bacteroides in you. We're not there yet.
Nick Jikomes 1:35:07
Well, I mean, we've gone over a lot based on anything to do with the microbiome, anything that we went over that you want to reiterate or any final thoughts you want to leave people with, given the topics that we touched on today?
Carolina Tropini 1:35:20
Yeah, so I think that the main thing is that it's a really exciting time for the microbiome. I think that there's this risk renaissance and appreciation of the importance that is a hazard I think it's it's a little bit like it was in the early 2000s for the the human genome right of the the thing that promised that it hasn't for revolutionising medicine. And one of the challenges with the thing with the human genome is that the people got so excited about it, that then they got a little bit burnt out, because then some of the impacts we're not seeing right away, you know, gene therapies, we're starting to see it now. 20 plus years later. So I think that we're a little bit in the same phase for the microbiome is that there's, there's sometimes a bit too much hype, in that it does affect things throughout the body. But in terms of seeing solutions for how to get ourselves be better, we'll need a lot more than saying, Here's your pill, and you'll be fixed. So in thinking about these, I think that the main thing that is important is to think about them as big ecosystems that we carry around that we should take care of, and try to make sure to, to re establish and feed and keep diverse. But their burdens are not things that are likely going to be fixed by one pill at any point. Because just like with the with gardens and wood forests, there needs to be a good amount of attention and care for them throughout the diversity of species and interactions that they have with us.
Nick Jikomes 1:36:52
Alright, well, I think that's a great place to end it. Thank you very much again for joining me. This was interesting. We covered I've covered the microbiome before, but we got to stuff today that was very different than anything I've talked about with other people. So so thank you.
Carolina Tropini 1:37:03
Yeah, thank you so much for you for the interview. This is fun, too.