Microbiome Insights is proud to be the sponsor of season 3 of Ruairi Robertson's Biomes Podcast.
In this second episode, Ruairi talks with Dr. Jotham Suez about his groundbreaking research on artificial sweeteners and their impact on the gut microbiome. Dr. Suez, from Johns Hopkins University's School of Public Health, shares insights into how these sweeteners affect glucose homeostasis, the implications for public health, and the future of food processing in the age of the microbiome.
The Impact of Artificial Sweeteners on Gut Health: Insights from Dr. Jotham Suez's Research
Dr. Jotham, Suez, a prominent researcher at Johns Hopkins University's School of Public Health, has been making waves in the field of microbiome science. His journey began in high school and led him to the Weizmann Institute in Israel, where he earned his PhD. Today, he runs a microbiome-focused lab at Johns Hopkins, exploring the complex interactions between diet, microbiome, and health.
Understanding the Gut Microbiome and Sugar
When we think about the gut microbiome, we usually focus on the large intestine, where most gut bacteria reside. Simple sugars we consume are absorbed early in the digestive tract, leaving little to none for the colon bacteria. However, in individuals with conditions like diabetes or obesity, simple sugars might reach the large intestine, influencing the microbiome. Dr. Suez suggests that high sugar diets can alter the microbiome, potentially leading to metabolic diseases such as diabetes and obesity. This alteration might be a combination of diet components and the interaction of sugars with bacteria throughout the gastrointestinal tract.
Artificial Sweeteners: A Closer Look
Artificial sweeteners like saccharin, sucralose, aspartame, and stevia are used to replace sugar in many foods and beverages. While they are designed to provide sweetness without calories, their effects on health are complex. Dr. Suez's research has shown that these sweeteners can change the gut microbiome, both in mice and humans.
Key Findings from Dr. Suez's Research
- Impact on Glucose Homeostasis in Mice: Dr. Suez’s initial experiments involved giving mice common artificial sweeteners. The results showed a disruption in glucose tolerance, suggesting that these sweeteners might affect blood sugar regulation through changes in the microbiome.
- Human Studies and Personalized Responses: In a small human study, participants consumed saccharin, which led to increased blood glucose levels in some individuals but not in others. This response was linked to differences in their microbiomes. A larger follow-up study confirmed that saccharin and sucralose could raise blood glucose levels, and this effect was again dependent on the individual's microbiome.
- Oral Microbiome Changes: Dr. Suez's research also found that artificial sweeteners could alter the oral microbiome, which could have implications for oral health. However, the specific impacts on conditions like cavities or periodontitis require further study.
Implications for Public Health and Future Research
Artificial sweeteners, along with other food additives, are widely used and have been approved based on traditional safety assessments. However, the understanding of their impact on the microbiome is still evolving. Dr. Suez emphasizes the need for larger, more personalized studies to determine how these substances affect individual health through changes in the microbiome.
The Role of Fiber and Probiotics
Preliminary evidence suggests that a diet sufficient in fiber might mitigate some of the negative impacts of artificial sweeteners on the microbiome and glucose regulation. Probiotics, though promising, require more research to identify which bacterial strains might be beneficial.
Conclusion
Dr. Jotham Suez's work highlights the intricate relationship between diet, microbiome, and health. As we learn more about how artificial sweeteners and other additives affect our gut bacteria, we can make more informed decisions about their use. Future research will continue to unravel these connections, guiding public health recommendations and dietary choices.
Listen
Links to Apple, Spotify, and Podbean
Full Transcript
Host (Ruairi Robertson): Okay, great. So thank you very much, Dr. Jotham Suez, for agreeing to have a chat about your really exciting research that you've been involved with for a number of years now, and I suppose are continuing to do. So maybe if you can just tell us about your background in science and how you got into microbiome science to where you are today.
Dr. Jotham Suez: Sure, yeah. So I work at Johns Hopkins University and specifically the School of Public Health. The department I'm in is called Molecular Microbiology and Immunology, and I guess that's telling I've been a microbiologist pretty much ever since I became interested in biology all the way back in high school. So before coming to Johns Hopkins, I did my PhD at the Weizmann Institute in Israel. I was very fortunate to win an award by the NIH called the Early Independence Award, so I transitioned pretty much directly from my PhD to this independent position. So I now run a microbiome-focused lab at Johns Hopkins for slightly over three years.
Host: Great. I suppose what you're known for or your research, mainly, I suppose it must have been during your PhD and probably what you're continuing to do, has been highly impactful, but I think it's probably fair to say highly controversial at the same time, not because there's any doubts about the science, but because it's a topical field or it's a very kind of topical. Maybe you can, we're going to speak a little bit about what you've looked at and it's about the effect of sweeteners and additives such as that on the gut microbiome and their downstream metabolic effects. Before we get to that, maybe we can talk a little bit about how the gut microbiome handles sugars as we know it, because we have to think about sweeteners in the context of what they're replacing usually and that is sugar. Maybe you can talk about what we know already before this about how the gut microbiome handles sugar.
Dr. Suez: Absolutely. So I should say that when we think about the gut microbiome, we usually think about the population of microbes in the large intestine, in the colon. There are microbes who are other gastrointestinal tract all the way from the oral cavity and all the way down to the colon. So for example, yeah, there are bacteria in your stomach, there are bacteria in the water and other parts of the upper GI, much less than in the colon. So the gut microbiota we usually figure out in the context of bacteria, even bacteria that are healthy are the ones in the colon. And these ones don't really see simple sugars. So the simple sugars that we consume in our diet are mostly absorbed very proximally in the gastrointestinal tract, or mostly the duodenum very early in kind of like the transit of food through the gastrointestinal tract. In healthy individuals, there is very little to maybe even none of those simple sugars that reaches all the way in the large intestine.
Host: But is there like a threshold, you know, for, because with our Western diets, I'm assuming that there might be a kind of overspill. Because we do see from the data that there are associations, at least between sugar intake and a certain microbiome profile in the large intestine. So is that due to other parts of the diet that kind of come along with sugar? Or is there an overspill that some of these free sugars do make their way down into the large intestine and interact with the larger community of organisms there?
Dr. Suez: Yeah, absolutely. I would have to guess that it's probably a combination of multiple factors. As you have said, there might be a threshold. There have been more recent works, particularly looking at individuals with diabetes, individuals with obesity. I cannot say these are necessarily very strongly established at this point, but there are very interesting observations. that they do see these simple sugars all the way down in the large intestine. So potentially, as you said, maybe there's a threshold that beyond it, that spillover of these simple sugars into the colon, but it's certainly not the normal classical scenario of how we think about nutrition and its absorption. It is very true that both in preclinical models in mice or definitely also in humans, consuming a diet that is very rich in sugar, we see a very strong impact on the microbiome. We do know that these are very clearly associated to have some involvement in the pathogenesis of diabetes or obesity. It's definitely possible that sugar is just kind of a marker for other components that are also enriched in the diet. Usually it would go hand in hand, for example, with an ultra-processed diet that has a lot of additives that we will probably talk about today. So yeah, so there might be some spillover, but also probably other factors in that kind of unhealthy diet that are impacting the microbiome.
Host: So you think it is these other components of the diet that are causing these changes in the microbiome that we see in these kind of diets rather than sugar itself?
Dr. Suez: So, a third, and I guess I forgot to mention it, a third factor, and I guess that probably all three are true and there might be more. is that as we said, there are microbes throughout the gastrointestinal tract, including where most simple sugars are absorbed, the duodenum. We do know that, for example, fructose, which is very common in those high sugar diets, especially if there's a high fructose component to the diet, can interact with bacteria in the duodenum. This has been shown to underlie, at least in preclinical models, several components of metabolic syndrome, like hypertension. So probably the interaction with the bacteria in those more proximal regions of the gut also plays a role.
Host: Right. And what do we know about kind of indirect effects that the sugar might have? So say it isn't directly making its way to the large intestine where it has direct interaction with the bacteria, is there some sort of, or do we know anything about these indirect metabolic or inflammatory effects that a kind of high sugar diet would have on the microbiome? So... Could there be, I don't know, some sort of systemic downstream signaling that happens when you consume lots of sugar, which changes the environment, you know, at the intestinal barrier in the colon, which changes the bacteria that like to live there, or what do we know about that?
Dr. Suez: Yes, so something that we know very clearly from mostly preclinical models, but there are evidence to support that in humans. is that those diets that are rich in sugar are associated with reduction in insulin tolerance. This goes usually hand in hand with, we wouldn't necessarily call it inflammation. Per se, but it's a low grade inflammation. So signals coming from the microbiome that can trigger the immune response find their way into our metabolic tissues like the liver, like the fat tissue, where they don't trigger a robust full inflammatory response. It's not a sepsis, but they do trigger a low grade inflammation. which goes hand in hand with the disruption of insulin tolerance, also hand in hand with that goes disruption of the gut barrier. So something about those diets changes the microbiome to a configuration that then degrades the intercell barrier, allowing those signals to come out of the gut into the circulation, into those systemic sites. Whether it's sugar itself or other compounds and that's a great question. A lot of times these diets are also poor in fiber. So that... would definitely have an impact on the microbes because that's their primary source of good. They're also often high in fat, and specifically saturated fat, that also can impact the microbiome. So it's not easy to isolate, especially in humans, the impact of just the simple sugars. It's really a combination.
Host: And so, I mean, I know we're discussing simple sugars and you've kind of alluded nicely to these other components of the diet or other things that could change the microbes. So there are other types of sugars, more kind of complex ones, which can make their way down to the gut and cause some changes as well. So one example of these are this group of FODMAPs. which are fermented oligo disaccharides and monosaccharides and polyols, I think is the long name. And so in general, they're good for the microbiome because they're fermented and if you're healthy, but isn't it correct to say that in people who have IBS or people who have a dysbiotic, if you wanna use that word, or a disrupted microbiome in some way, don't tolerate these well because they get fermented. What can you tell us about these kind of more complex sugars, if you want to call them that, or complex carbohydrates and how they may contribute to conditions in the gut through this fermentation?
Dr. Suez: Yeah, absolutely. So our gas bacteria can definitely ferment pretty much anything that adds its way to the large intestine. That includes some of those polyols that are not metabolized by our own. body definitely not in those proximal regions of the gut. Not everyone would necessarily have the bacteria that can perform these functions. And maybe this is why some people are not as sensitive to their impacts as others. So this works pretty much the same as we think about prebiotics. So these kind of like fibers that you would consume to enrich the microbiome for beneficial purposes. But if we don't have the microbes that would respond to them then maybe you would not experience those benefits. So. kind of the opposite picture. If you're consuming those polyols, it might have a negative impact. Only if you have the bacteria that can prevent them, you would experience that impact. The literature about whether a surgery to a low FODBAP diet is not super conclusive, potentially because of that heterogeneity, but it does seem to, a low FODBAP diet does seem to change the microbiome in ways that this in some studies can improve symptoms of IBS. So... Yeah, that fermentation of polyols by the microbiome can definitely contribute to some of the symptoms that we're seeing in these individuals.
Host: And do we know about, we know this fermentation predominantly occurs in the large intestine, as you've mentioned, because it's this site of absorption and fermentation, I guess. Is there anything known about not fermentation, but direct interaction between some of these sugars or some of these things in the small intestine? I know things are passing through much more quickly, but do we know as much about the small intestine and the direct interaction between some of these nutrients and the microbes that are there at that barrier? Or is it not known or is there not much interaction?
Dr. Suez: Yeah, I mean, we usually tend to think about the fermentation because that's probably the most, number one thing we expect the bacteria to do. There's a food source, they try to eat it. But like we said, not necessarily every microbe has the capacity of degrading or utilizing those nutrients, well, not nutrients, I guess we can call them foreign nutrients. But it doesn't mean that they can't have any impact on the microbiome in other ways. Potentially, they can disrupt the microbiome in other ways, because that would be toxic to some bacteria. And we do see... in more basic in vitro studies that when you culture various bacteria, including gut bacteria in their presence, some gut bacteria just die in their presence, which people have been using, for example, in toothpaste to kind of like get rid of bacteria in the oral cavity, but maybe the same effects also happen to bacteria in the gut. So yeah, there can be more impacts other than just being a source of energy for the bacteria.
Host: Right. Okay, so I mean, I guess we're, leading on to is a lot of the research that you've done is into the effect of artificial sweeteners on the microbiome. So I guess from a public health perspective, that's an interesting question because more and more food, the sugar and foods are being replaced by these non-nutritive sweeteners. So maybe you can give us a little bit of insight first into what these artificial sweeteners are to give people kind of an explanation and, you know, if there's any history around them and maybe talking about their safety record because they have been used for a long time, isn't that correct?
Dr. Suez: Yeah, absolutely. So artificial sweeteners are part of a group, as you mentioned, of non-nutritive sweeteners or sometimes also called non-caloric sweeteners, precisely for the reason they contain very little to no calories whatsoever. Within that broader group we would consider. account both the natural non-nurture sweeteners like stevia, for example, monk fruit extract, but also the ones that are completely synthetic manmade like saccharin, sucralose, ASK, aspartame and neotame. These are the most common ones and also the top ones that are approved both in Europe and in the US. So yeah, they have been around for quite a while. Saccharin was discovered actually behind me here at Johns Hopkins. in the late 19th century. Kind of serendipitously, they were working on synthesizing benzene derivatives, and the postdoc that was working on that went to have his very late lunch in the evening, and he held his sandwich and it was sweet, he was drinking his water, they were sweet, and the postdoc realized that he had trace amount of that component on his gloves. Well, not on his hands, on his hands that were not gloved. And that component or that compound was saccharin that they synthesized in the lab. So the PI, he went on to become the president of Hopkins, but the postdocs went on to become rich because they have commercialized saccharin.
Host: That's great. So saccharin really has been around for a while and pretty much ever since it was introduced, there were already some concerns about saccharin safety. US president at the time Teddy Roosevelt is famous for saying that anyone who thinks saccharin is injurious to health is an idiot. So you can see that already, you know, more than a century ago, people have already been having doubts about saccharin safety. The other studios that you're using are much more recent. So we've been using things like Aspartame and ASK only maybe from the 80s and sucralose, which is very popular now. It's really already been around since the 90s. Of course, some of the other non-rejective sugars like stevia or monk fruit have been used but for centuries now, but they've only really been commercialized very recently. So in terms of their impact of sugars on cardiometabolic health, which is what we, the primary reason that we use them is to help prevent or treat conditions related to cardiometabolic health. Really these concerns have been around, I would say, for, you know, with some true backing evidence. It's been around for several decades now. So there have been some concerns about saccharin and cancer more than a few decades ago, which have mostly been discovered to not be applicable to humans. So those concerns were valid in the animal model where they were discovered. Probably it is not that mechanism does not apply in humans, but. The concern that maybe sweeteners are actually contributing to weight gain, contributing to disruption of glucose homeostasis. This has been around for, I would say, maybe since really strong debates since the nineties. And the challenge is that what type of evidence you're using to base that concern on. So there would be now, at this point, we have tons of associative data that shows that people that consume... products with no-nutrients tend to be heavier, are at greater risk for developing diabetes when you're already with diabetes. And this is really from at this point from hundreds of thousands of individuals across various studies from different parts of the world. But the challenge with interpreting those associative data is that we don't know what comes first. So it's sometimes hard to know if these people already had some risk for weight gain or for diabetes, maybe some family history. And this is why they're consuming these sweeteners more often than people that don't consume them. Or maybe the other way around, that the sweeteners are indeed causing weight gain, are causing destruction because of homeostasis. So really to disentangle the cause and effect, one needs to perform intervention studies with the gold standard being the randomized controlled trials. where we would randomize some people to consume a sweetener and some people to either consume nothing or a regular caloric sugar. This is where the evidence becomes really confusing because you do see evidence that are supporting those associations. So you do see some studies where people that start consuming these sweeteners gain weight or their blood glucose levels go up, but you see studies that are showing the exact opposite, that these are actually beneficial for cardiopulmonary polychaeth. And also studies are just in between. The sweeteners are not doing anything. So this is really kind of the landscape of where we started to perform our research at very conflicting literature.
Host: Right. But the kind of, the main mechanism of that, if you want to call it that, is because, theoretically, if someone replaces a lot of their sugar with non-caloric sweeteners like this, they're just not getting all those calories that they might. I mean, there's people who drink tons and tons of Coke every day, and if instead... the example being if they took diet coke instead or some sort of Coke Zero or whatever it is, so that it's been sweetened instead, they're not getting all those calories from sugar. And so yeah, you're correct, that there does seem to be kind of conflicting evidence. There does, I think, seem to be some good randomized trials that show that because of this, there is a reduction at least in calorie intake, but maybe, I don't know, do people then try and replace those? those calories with something else? Could that be one of the reasons that some of these trials show a negative effect?
Dr. Suez: Yeah, that's a really interesting question. So you are correct. So definitely just the mere replacement of a caloric sugar with a non-caloric sugar would, unless there's an immediate compensation in other ways, would at least in the short term would cause a reduction in total caloric intake, which would probably at least in the short term lead to weight loss. And that has been seen in multiple trials. So very recently the World Health Organization have performed their own meta-analysis about the impacts of sweeteners and specifically on cardio metabolic health. And within those randomized controlled trials, they say that there are evidence they're not of very strong quality, but there are evidence that in the short term, replacing caloric sugars with non-caloric sugars do lead to weight loss, but this is only true in the short term and the effect is very small. So definitely something happens here that kind of like negates those benefits in the longer term. And one of them could definitely be what you suggested. So this is maybe more of a behavioral question, which is I can speak to, but it's not the main thing that I researched, but there are evidence that people did compensate, but by, you know, they're reducing the calories in one place, they kind of like allow themselves to consume more calories from other sources. And there are also other mechanisms somewhat related to behavior where there is an hypothesis that maybe the intake of the sweet taste without coupling that with calories disrupts our natural responses to an actual meal that has both a sweet taste and calories. So our body knows how to interpret the signal coming from sweet taste as something that's going to provide energy. And therefore the secretion of hormones like insulin, for example, would be adjusted to the amount of sweetness that we're going to experience, but if we're only providing sweetness without calories, then maybe we're disrupting the normal response to carbohydrates. So that's also another mechanism, not microbiome related, that can maybe explain why in the longer term those benefits are kind of like gone.
Host: So you're saying that there is some evidence that maybe counter-intuitively we think that, or people thought that the sweeteners would reduce your blood sugar. You're not getting the sugar anymore to create that, but there might be some sort of direct effect of these sweeteners that signal to our cells in some way. Is that at the gut barrier or at the liver where it is to, is it produce more insulin or produce less insulin or prevent the absorption of sugar or what do we know about that, those direct effects?
Dr. Suez: Yeah, so this is where it becomes complicated. What we do know is that, and this is pretty well established, very few evidence to the contrary, but for the most part, our evidence is that if you just consume a pure sweetener on its own, there's no what we call a post-prenatal specific response. You drink pure sucralose, blood glucose stays flat, it doesn't go up. But we do see that in the longer term, if we feed mice or humans with let's say sucralose, we do see elevation of blood glucose. So something happens not in the acute sense, but maybe over time. And Definitely one of these mechanisms could be what I just described, we call it the uncoupling theory, where we're uncoupling calories from the sweet taste. But of course, there can be impacts that is not directly on our own cells, but really on our body through the gut microbiome, which is what we study. And so people have been studying multiple different mechanisms. I would guess it's probably more than one mechanism is occurring. Yeah.
Host: Well, you've kind of led in nicely to what we're going to talk about mainly then, and that's your research on you maybe trying to find the missing link in that pathway through which possibly these sweeteners actually have a detrimental effect on glycemia and metabolic health. So you published a few years ago now some evidence in mice. I think we'll start there before we go on to the humans. Maybe you can tell us what you found in that original paper where, I mean, I'm just going to give the summary where you essentially showed there was a detrimental effect, let's say, of some of these sweeteners on glycemic health and this was dependent on the microbiome. Maybe you can give us some detail on what exactly you found.
Dr. Suez: Sure. So there are several reasons that we thought the microbiome might be relevant in this discussion about the health impacts of sweeteners. One is likely to discuss that there isn't much known or there isn't much good evidence that they have any direct impact on our own body cells. And we do know that they don't contain calories. They don't. impact black glucose directly or in an acute sense. So if they're not impacting our body, how can they impact cardiometabolic health? Maybe through a mediator to microbiome. This is one reason why we thought the microbiome might be interesting. And our main reason for us to be interested in the microbiome is that we know that in humans, people have different microbiomes. So my microbiome is different than yours. And we can actually use it to predict who is it coming from. And we do know that the heterogeneity in the configuration of the microbiome mediates personalized responses to various diets, to various therapeutics. So we're really wondering if it's possible that the microbiome can mediate personalized responses to sweeteners, because if that's true, that might explain that very conflicting literature. Maybe some studies have more of those people that are susceptible to the impact of sweeteners. Some studies have less of these individuals. But of course we needed some information about the basic impacts of sweeteners on the microbiome, which is indeed why we started. with lab animals. So the first experiment we've ever done was a very fun one. They just went to the supermarket. I purchased these sachets of sweeteners and people add to their coffee. And we added that to the drinking water of mice, regular healthy adult mice. And we just let them drink these sweeteners, not really do anything else. We're eating the regular diet. And a few weeks later, we measured their glucose tolerance. So we used a very standardized glucose tolerance test where you give the mice a bolus of glucose. You just see how high blood glucose goes and how much time it takes for glucose to go back to normal, reflecting the ability of the body to take glucose from the blood into the target cells. And we saw that mice that we gave them both saccharin or sucralose or asthmatase, so three very popular artificial sweeteners, indeed had disruptions in their glucose homeostasis. So they had a disrupted glucose. And we've done that experiment then in different types of mice, different doses of the sweeteners. We use the regular mouse diet, we use the Adobe Sugetix diet for the bias. In every single way that we studied that, we saw that the sweeter scaly did disrupt glucose steroids in these mice. So that to an extent have been shown even before the work that we've done, maybe not as systematically, but it has been shown before. What we were really curious is whether there's any link to the So what we've done is really profiled the microbiome of these mice working in the sweaters. And indeed we saw that the sweaters were able to change the microbiome. And what we've done in that study for the first time is to show that the two things were connected. So we were working with germ-free mice. This is our, sorry about that. We're working with germ-free mice. This is our gold standard for establishing causality for a microbiome of interest. So these mice are... They don't have any microbiome. They live in these isolated bubbles, can transplant the microbiome just into them and see if this causes a development of any symptom. So we took the microbiome from animals that were drinking sweeteners. We transplanted that into germ-free mice. The germ-free mice don't receive any sweeteners, so they only receive the microbiome altered by sweeteners. And we saw that was sufficient to disrupt glucose homeostasis in the recipient germ-free mice. We were able to show...
for the first time that disruption of the microbiome by streeters is sufficient to disrupt glucose homeostasis.
Host: And maybe I can stop you there before you go. What were those changes? What were the bugs that were responsible for those changes?
Dr. Suez: Yeah. So we saw actually changes in the abundance of dozens of bugs and it wasn't in just one direction. So we saw a lot of bugs that have decreased in their abundance, but we also saw others increasing in their abundance, which could be due to multiple reasons that I can hypothesize about. There doesn't seem to be necessarily a consistent signature of which bacteria are changing with different sweeteners, which might be expected since they're very diverse chemically. We've also, two years ago, we tried to kind of perform a literature review of all the changes that people have reported after our study in the impact of sweeteners on the gut microbiome. And there might be some trends that are persistent across trials, but it's really hard to... nail down which microbes are always responding to sweeteners, that's certainly something that we're actively working on now.
Host: Right, great. And so that study was fascinating. And then some people were criticizing it as well for a few different reasons. Some people suggested that the doses of sweeteners were too high maybe in the mice that were provided. Other people cited this evidence that we've spoken about before showing from clinical data there are randomized trials showing that replacing sugar with sweeteners is beneficial in the law, well, in certain terms for reducing weight, for example. And so the kind of question is whether this is clinically relevant and whether the use of these mice that you've spoken about, germ-free mice, are really truly representative for humans. So in a general context, not just in sweetener studies, What are your thoughts on the relevance of using germ-free mice for microbiome trials? Because there are limitations, but there's also huge strengths.
Dr. Suez: Yeah, I mean, well, first of all, I would say for any preclinical model, whether it's a regular mouse or germ-free mouse, we definitely don't want to establish public health policy exclusively based on studies in preclinical models. Of course, we always want to use that for discovery. And this is where I think the germ-free mouse is very powerful as a tool for discovery can help. identify pathways, it can help identify mechanism that we can, we can, and we should test in humans. And this is where then we should make decisions based on the studies in humans. But sometimes we don't even know what to look for in humans. And there are things that we cannot study in humans. So we perform these studies in quick-neutral models, then we have some insights that we can then test in humans. So yeah, the geography mouse model, the most powerful thing about it, of course, between the microbiome and any health readout that you're interested in. They are of course not a very natural model so we don't have the germ-free humans and we do know that there are some differences in how they develop in compared to an animal that was born colonized with microbes. Some of these are amenable. You can tweak their diet in a way to make them more similar to a keep them in a way that the fact that they might be to an extent somewhat immunocompromised, you can protect them from various exposures. But yeah, they're not a natural model. A colonized mouse maybe is a bit more natural. It's still a mouse and not a human. So I definitely think these models are good for discovery. We shouldn't just base our clinical decisions just on animal models.
Host: Yeah, but then you kind of tried to address that more recently. And... address some of these concerns that people had. And I suppose just followed on the kind of natural progression of your research anyway to say, well, we found these nice findings in mice. Is this applicable to humans? Maybe you can tell us about then the clinical trial that you conducted more recently where you fed these different non-nutritive sweeteners in relevant doses and did very detailed microbiome profiling. to see what the effects were. So what did you find in that study?
Dr. Suez: Yeah, so actually one thing that led to that study that we haven't discussed is that in the original publication we had back in 2014, there was a human component. There were two human components actually, but one of them was a tiny human side. Today I barely talk about it because we have the larger one, but we had a study with just seven individuals that they definitely don't think we should make public health decisions based on studying seven individuals. But what we've done in that study is to give healthy people, so people without diabetes or people without obesity, we gave them saccharin, 12 sachets a day. And this is, I think, where the comment is made about the dose might be high came from, because in the mass we definitely went to very low doses. But yeah, that's a very tiny human study that the previous old one, they were drinking 12 sachets a day, which is still within the acceptable daily intake, but it is pretty high. And we followed up on both their microbiome. and the glucose tolerance. And we saw that I like in the mice, which was very clear signal, mouse jinx, saccharin, the mouse becomes glucose intolerant. In humans, we saw two subsets. So some people, four out of the seven, responded to saccharin. We didn't get all already after a few days of saccharin consumption, they had elevated blood glucose versus three out of the seven that had no impact. And we could also link that to the microbiome. And this is really where we wanted to. perform a much larger study because that was very intriguing. It was sort of a proof of concept, but what we saw in mice can potentially be applicable to humans, but of course not strong enough to make any decisions in humans. So yeah, the new study, we wanted to control for several things. So we wanted to try more sweeteners. The previous one that we've done was only with saccharin. So the new study was saccharin, but also sucralose, aspartame, and stevia. We reduced the dose for each of the sweeteners to six sachets a day, which to some people that might sound still high, but if you consider the various routes for which we're exposed to sweeteners, which is not just sachets in our coffee and not just diet coke, that's actually quite close to what people can get. And for some of these sweeteners, it's very much below their acceptable daily intake. So more sweeteners, lower dose, we also extended the exposure period from one week to two weeks We've included also two control groups in that new study. So the sachets that people consume, a lot of people don't pay attention to that, but most of the mass in the sachet is actually bulk in glucose. So it's not enough glucose to spike your blood glucose, it's just there as a filler. Therefore we had a control group that was consuming the same amount of glucose that's in the sachet, but without the artificial sweetener. And another control group that was just performing the protocol without taking any supplement. So we followed upon these people before, during, and after supplementing their diet with sweeteners for two weeks. We profiled their microbiome both in stool samples and in the oral cavity, pretty much every day throughout a period of four weeks. And they also were wearing a continuous glucose monitor. So we had data on their blood because throughout a period of one month, they were performing those standardized glucose tolerance tests multiple times throughout the study. And we also collect a bunch of other data to try to understand how the microbiome can impact cardiometabolic health in this field.
Host: Great. And well, what did you find?
Dr. Suez: So first thing that we found is that all four stages that we studied, so saccharid, circular, aspartame, and cvac can change the human microbiome, both in stool samples, it's kind of a maybe proxy for the gut and also in the oral cavity. The reason why I'm starting with that is that hadn't been shown before in humans. So there was a question of whether what we saw in mice even translates to human in the sense that can these swimmers even change the human microbiome? So our study says that yes, it can change human microbiome. There's also some complicated evidence there. There are now a few more studies where some support our data, others do not, we can talk about it later. But yeah, so we showed that these swimmers are definitely not inert because they can change our microbiome in both two sides of the body. They can also change the level of various metabolites that we can measure in the blood of these participants. So first thing that we found, these swimmers are not inert. The second thing that we found is that in two groups of sweeteners, the people that were consuming saccharin and the people that were consuming sucrose, as early as one week after they started drinking the sweeteners, continuing to the second week of exposure, blood glucose levels did indeed go up, especially in that standardized glucose tolerance test. And once they stopped drinking the saccharin or the sucrose, blood glucose levels really started going down. And we did not see these impacts in the two control groups. So we can really say that... in our study, saccharine and sucralose caused a disruption of glucose homeostasis. Another component that was really interesting for us is that although saccharine and sucralose had these impacts as a group, if you consider what happened to every individual in that group, there's actually quite an interesting heterogeneity. So some individuals really had a much stronger response to the sweetener as opposed to others. And that was even true also in aspart
ame and stevia. as a group, if you just consider the average increase in blood glucose, they were not significantly different from our controls. But within those groups, there were some individuals who were definitely strongly impacted and others that were very not impacted. And when you consider if there's any connection between the impact that we saw on the microbiome and the impact that we saw on blood glucose, the answer was yes. So you could really tell apart who might be a responder and who might be a non-respondent based on the microbiome that they had before we exposed them to the sweeteners. And then we've done those same experiments with the germ-free mice. We took the microbiomes of the responders and the non-responders, we put that into germ-free mice. And we saw that the germ-free mice that received the microbiome from the responders had indeed an elevated blood glucose response as opposed to mice receiving the non-responder microbiome. So we were able to say, yes, there is a heterogeneity in response to sweeteners in humans. And it is at least in part explained by the microbiome.
Host: And I'm intrigued by the oral microbiome results. Well, you found that changed. And what I suppose are the implications of that is before we talk about the gut and all those kinds of things, could that potentially contribute to cavities or poor oral health or what do we know about that?
Dr. Suez: Yeah, that's a really interesting question. So each of the four sweeteners that we studied had an impact on the oral microbiome and the impacts were different between those four sweeteners. To some extent, you can say that maybe this is a good thing. So people have been suspecting that dark-fuselage swinephrodias can be toxic to some bacteria that might be pathogenic in the oral cavity, might be really do very, for example, cavities of periodontitis. So in that sense, maybe it's good that swindlers can alter the oral microbiome. We did see, and that was, I think, mostly, yeah, with saccharin. We saw actually expansion of several members of the genus Streptococcus, that some members are pathogenic, some are beneficial. The ones that we saw are definitely not considered classically beneficial. Some of them are potentially pathogenic. We haven't really followed up on the oral microbiome just yet, but there is a potential there for both a benefit and a harm.
Host: Wow. And so, I guess one of the interesting findings, as you've talked a lot about, is this personalization, where some people seemed to do worse with these sweeteners and some people didn't. So, I know there were small numbers, but do we know what were the kind of protective features? Like what did, was it that someone with a more diverse microbiome didn't respond as badly to the sweetener or what did you find of that? Or what do we know of it?
Dr. Suez: Yeah, we definitely tried to explore that. So, you know, if they were very... clear signatures, we were powered to detect this. For example, if it was just something like a very diverse microbiome versus a low diversity microbiome, this is something we were able to detect, but this is not what we found, unfortunately. So, it doesn't seem to be as simple. We looked at also a lot of non-microbiome covariates. We looked at habitual diet, are vegans more protected or less protected? Does biological sex play a role? Smoking, physical activity? And none of this really... explain why someone will age, none of these really explain why someone will be a responder or not. In terms of the microbiome, we were hoping that we would be able to predict response based on the microbiome. Previous works that we've done in this field of microbiome-based nutrition really taught us that we need very large numbers to produce these predictive algorithms. So, it's definitely something we're working on now. We have some insights that we haven't published yet about. what might lead someone to respond more to swedeos or not. And I can say that it does depend on whether we talked earlier about direct impacts of swedeos on the microbiome. It is probably to an extent related to whether swedeos can exert a direct impact on the microbiome or not.
Host: Okay, yeah, that was going to be my next question, whether you can say or not what those mechanisms are. How does a change in the microbiome lead to I'm sorry, a non-nutritive sweetener induced change in the microbiome lead to more sugar being present in the blood. Is it about more absorption or less absorption? Is it about some sort of signaling to the pancreatic cells that don't respond and produce insulin or what do we know about that?
Dr. Suez: So yeah, people have been definitely trying to explore that. We've also tried to explore that. We are seeing several metabolites that have known to be associated with type 2 diabetes that are becoming more dominant in these individuals. So potentially the sweeteners alter the microbiome to a configuration that can impact the pathogenesis of type 2 diabetes through known mechanisms, because we do see that the same metabolites that we've seen before in other contexts, not related to sweeteners, we do see them also in this context. So that's something that we saw in 2022 publication, others have seen the same. One of the mechanisms for which the gut microbiome has been known to contribute to type diabetes is what some people call metabolic endotoxemia. So that's something that we've already touched a bit about before. So there's the structure of the gut barrier and then micro antigens like the LPS or the flagellin that is on the surface of some bacteria can then get from the gut. into the circulation where it's not supposed to be, and then it can trigger an inflammatory response. So if it was, you know, an LPS kind of pathogen, it might trigger a very strong immune response. But the LPS kind of gut bacteria only triggers a low-grade immune response, but it's just enough to disrupt insulin signaling and eventually lead to insulin resistance. So there are evidence that swindlers can contribute to that mechanism, but unfortunately there are studies that don't find support to that mechanism. And I'm Accordingly, if I had to guess, I would say there's probably multiple mechanisms that are occurring, but we still don't have conclusive evidence for even one, unfortunately, but we're definitely, we and others are working on that.
Host: So you're working on, great. So I suppose non-nutrient sweeteners are only kind of one category of all these different additives that we consume and that could theoretically have an impact on the microbiome. And I mean, what else do we know about other additives? Do they act in similar ways? Are there safe food additives, if you want to put it that way, that don't seem to interact with the microbiome? What do you know or what do we know about, yeah, these other additives?
Dr. Suez: Yeah, I would say, maybe I'll start with your last question. Are there safe food additives? I don't want to say that all food additives are necessarily detrimental to our health, but I think what we are learning, from our work and what I will mention in a second about other food additives is that in the past we have not really considered their impact on the microbiome. I mean it might be important for our health. Now that we are aware that these impacts exist, we definitely should put some attention into what these impacts might be before we can say for sure that an additive is safe or not. So yeah, definitely sweeteners are only one additive that we add to our diet. If we think about ultra processed diets that have definitely been associated with a high risk for multiple diseases including of course, cardiometabolic diseases. These contain a whole bunch of additives pretty much around the same time that we published our work on artificial sweeteners. There was a study that also has then been followed up quite extensively about the impact of dietary emulsifiers on the microbiome where they have found that emulsifiers can alter the microbiome. In their study, it was more clear that these changes were sufficient to disrupt the gut barrier, which was then also on one hand associated with components of the metabolic syndrome, like weight gain and disrupted glucose of theostasis, but also a contribution at least that they started with a preclinical model contribution to an animal model of inflammatory bowel disease, which, you know, might be sensible if you think about disruption of the gut barrier. So most of the phyros, dietary most of the phyros have definitely been studied from pretty much around the same time when we publish our studies on our future sweeteners, also in the context of how they impact the microbiome and then downstream the host's health. Food colorants, some of them have definitely been investigated recently in the context of how they impact the microbiome. Some food colorants can indeed change our microbe cell configuration if it's sufficient. to contribute again in preclinical models to models of IBD. Food preservatives, so sodium propionate has received some attention as a food preservative that can also disrupt the microbiome, also leading to disruptions in gut barrier, and then to, again, animal models of metabolic syndrome. So there seem to be quite a lot of things that we add to our diet that can change our microbiome. And this is maybe I'm going to say that not necessarily everything that changes your microbiome is bad for you. It's also not always good for you to change your microbiome. But the fact that it changes your microbiome is not necessarily important. What we do see in our work and all of these works, but the other food additives, that they are also able to associate that with detrimental impacts on our health. And this is where, yeah, I would say this is important.
Host: Yeah, that was going to be my next question. I mean, it's important to state that all of these additives, as you mentioned, have been approved, they've been used for years, and they've gone through all these safety checks, and clinical trials for years before we had this knowledge about the microbiome. So it's more of, I suppose, a philosophical question. How do we make public health decisions based on the microbiome now, or do we? How much evidence do we need from your kind of work and other people's work that maybe an additive go under tighter regulations or be used less due to its changes in the microbiome? How do we quantify that?
Dr. Suez: Yeah, I would say, you know, some things that you might want to consider in terms of how these substances are regulated or tested. Some of the changes that you might want to do are not necessarily directly related to the microbiome. I think, you know, if you consider literature on artificial sweeteners and how, for example, the healthy doses were determined, there's actually pretty small cohorts. maybe not large enough to capture those kind of heterogeneity between individuals in response to the sweeteners. And, you know, even if you, so, you know, I would just, I read a bit, I found a study back in, I think in the eighties about, maybe it was early nineties about sucralose and how the absorption versus excretion of sucralose. And I think it was a study of eight individuals. And even in that study, there was quite heterogeneity. There's a, how much sucralose was found in the gut versus excreted. So maybe there was already some evidence, but people have only looked at the averages and not really considered that heterogeneity. So, I would say generally, I think we need to pay more attention to those precision or personalized impacts and for that we need to have larger studies when we do these testings. But in terms of the microbiome, I do think that profiling the microbiome as part of a safety process is relevant. But yeah, if... there's only an effect on the microbiome without any other impact of health, and it's not necessarily as important. This is where I think our basic science should inform those follow ups because we can say, you should search for let's say the abundance of that molecule that you know is produced by the microbiome and can be detrimental to health. This is something maybe you would want to test for in those participants in those safety trials.
Host: So finally, what do you think is the future of food processing now in the age of the microbiome? Because the way that industrialized populations live, we are naturally going to eat more processed foods. But they're by default, they're probably going to have more impact on the microbiome for good or bad. So what is the future, I suppose, both for scientific research and both for public health? when we're trying to create foods that are processed, but hopefully don't detrimentally impact our health?
Dr. Suez: Yeah, you know, this is a very important, I would say maybe health equity or health policy question, because we do actually want people to hopefully eat, not to say less processed, but less ultra processed diets. We do know that there's a very strong association to a detrimental impact on health, whether it's because of the additives or something else about those diets. So, we would actually want people to eat less processed diets, definitely more fruits and vegetables. And of course, this is more easy in higher income countries than lower income countries or higher income populations. And I agree that we're probably going to see just more industrialization, more processing of our foods rather than the opposite, but. What we and others are trying to understand is whether it's possible to kind of like offset some of these impacts with also, let's say you are eating a diet that is relatively rich in all three process foods. So maybe if you also have a sufficient intake of fiber, maybe that's enough to offset those impacts. There's definitely been strong literature to support it. At least a sufficient fiber diet, not necessarily a high fiber diet, at least a sufficient fiber diet, which is something that most of us don't have, can offset some of the... negative impacts of other things in our diet on the microbiome and consequently on diseases related to the microbiome.
Host: And do we know that? Sorry to interrupt for the sweeteners at all. Have you done any of those experiments to say if you add fiber in plus the sweetener or if you add some sort of probiotic species, let's say, can that improve these detrimental effects?
Dr. Suez: Well, probably I think I can talk for another full hour.
Host: Okay, we'll have you back another time. But is there any sort of like thing you can do at the same time or something to prevent these glucose changes that occur?
Dr. Suez: Yeah, so we have very, very limited evidence to suggest that in a fiber-sufficient environment, the changes would not be as detrimental, the changes to the microbiome consequently glucose steroids, would not be as detrimental as in a low fiber setting. This is all animals, this is not the humans. But potentially translating to humans. So yeah, I would say fiber, that's probably a study that we and others should continue to look at. In terms of probiotics, because we don't really know, can't say for sure which bacteria are the ones that are missing, that are mediating those important impacts on our health, it's hard to know which ones we should reintroduce in the context of sweeteners. And like I said, there are a lot of challenges with probiotics. Next time.
Host: Yeah, that's for another episode, I think. But that was brilliant. Thank you very, very much, Jotham. I think we got through a lot there. And maybe we will discuss the next time about, well, more about this or onto Probiotics the next time. So, thank you very much for discussing today.
Dr. Suez: Thanks.