Episode 44: You are what you eat or, more precisely, what your MICROBIOME eats.
How much influence does the gut microbiome have on developing eczema or allergies? Turns out, quite a lot. Join this special excerpt from our research symposium to learn how antibiotics in pregnancy and early childhood increases eczema risk and how adding "biotics" might prevent it in the first place. Our speakers are Dr. David Margolis (University of Pennsylvania) and Dr. Nikole Kimes (Siolta Therapeutics). If you like our podcast, please consider supporting it with a tax deductible donation. Read the transcript.
-
Lynita: Welcome to the podcast. This episode showcases two of the speakers from the 2024 GPER Research Symposium focused on the connection between the gut microbiome and eczema. Enjoy.
Angela: Welcome to the Symposium on the new science of gut health and its implications for childhood eczema. How exciting, right? I'm Angela Tiru, professor of Psychology, eczema parent and board member with Global Parents for Eczema Research, a global non profit founded by parents. Focused on improving the future for children with moderate to severe eczema through breakthroughs in research and family support. And today our speakers will share their research into how we can both avoid exposures that damage our gut and its barrier, and potentially how we can repair the health of our gut with innovative solutions that could reverse or even prevent eczema in the future. I will now pass the mic to the amazing think tank, Korey Capozza, GPER’s Executive Director. She will introduce today's topic and our first speaker.
Korey: Good morning. Today, we're going to talk about the connection between the gut and the skin. Our gut is home to trillions of microorganisms, the microbiome, and this microbiome plays a key role in training our immune system, especially in early life. It helps to maintain a balance in our immune system and teaches it to work properly. When the gut microbiome is imbalanced, it can lead to a leaky gut and that damaged barrier then allows in toxins, allergens and bacteria, which enter the body and trigger the immune system to respond. When the immune system is wrapped up and responding to these invaders. We get systemic inflammation, which we see in eczema. How and why the gut barrier is becoming so disrupted is likely related to diet and environmental causes. And you're going to hear more about that today.
I'm really delighted to introduce David Margolis, He is Gerald S. Lazarus, Professor of Dermatology and Professor of Epidemiology at the University of Pennsylvania, Perelman School of Medicine. Today, he's going to be talking about his work on oral antibiotic use in early life, especially in pregnancy and early childhood, and how that might impact the topic of dermatitis for eczema risk.
Dr. Margolis: Thank you very much for the invitation to speak. So I'll be talking about today's antibiotic exposure and the risk of a topic dermatitis in childhood. I'm an epidemiologist, so we're going to talk about large data sets and what we can gain from knowledge of those large data sets.
So there seems to be a march where people develop things like atopic dermatitis or food allergies early on, and then often develop things like asthma and rhinitis.
And there's many who now believe that, actually, the skin breakdown then leads to the food allergies as well. Just to put things in context a little bit. There's been probably a dozen or so studies done at this point trying to prevent atopic dermatitis in children, and most of them have to do with applying emollients to improve the skin barrier. And many of the studies either don't show an effect or show a mild effect, and often show an improvement of about 20 % to as much as 50%. By applying the emollients, which are often things like petrolatum.
So one of the first studies that we did with a large population was actually looking at a data set that had about 800,000 pregnant women in it. And in the U.S., when you're pregnant, shortly before delivery, people often have a group B strep culture. It's usually a vaginal swab. And our idea was that if women with atopic dermatitis had different microbiomes, then perhaps we should be able to find this in a large database, where group B strep is coded.
And in fact, women with atopic dermatitis who are pregnant are about 23 percent more likely to have group B strep. And group B strep often gets treated with antibiotics. There's been other people who have also tried to look at some of this as well. And there were some differences between people who received antibiotics and those who didn't.
And then our study, which actually looked at a million people, moms and babies. And we were able to link the mom's exposures to the baby's exposures and then see what actually happened to them. Now, as one might expect, if a mom has atopic dermatitis, the baby is about 70 percent more likely to have atopic dermatitis.
However, she received penicillin during her pregnancy. And again, penicillin is often used for group B strep. That risk is about 60%. What's also interesting about this is if you looked at the moms who had atopic dermatitis versus those who didn't, This risk actually was higher in moms who didn't have atopic dermatitis to begin with, so it appeared to be an independent risk factor.
The same was similarly true for the babies themselves. So previous studies had looked at any sort of antibiotic exposure during childhood and whether the child was more likely to develop atopic dermatitis. And the problem with that is that they weren't always looking early and they weren't always looking before atopic dermatitis might have occurred.
If the child was exposed to antibiotics in the first 90 days they were in fact 70% more likely to develop atopic dermatitis. So the exposure is very early in life, and this is a time frame where children are developing illnesses, but they're often viral illnesses and perhaps don't need antibiotics.
And the same thing is perhaps true if they were born to moms who did not have atopic dermatitis. That risk was 70% versus 45% if they did. So, so again, the risk was higher amongst those who were born to moms who didn't have atopic dermatitis. So they weren't, let's say, genetically predisposed to developing it, so it appeared to be an independent risk.
So what do we know from these studies and other studies is that pregnant women with a history of atopic dermatitis are more likely to be colonized with group B strep. But what that's really confirming is the notion that individuals with atopic dermatitis, that their skin microbiome, is persistently different than people who don't.
It's been well known that pregnant women and infants are more likely to receive antibiotics. And there's been multiple studies that show women in pregnancy, especially later in their pregnancy, because of group B strep, up to 60 percent of women will receive antibiotics, and anywhere from about 10 to 40% of infants will receive antibiotics in the first 3 months of life.
The risks appear to be greatest during specific periods of time for the children, but anytime during pregnancy appears to be at risk. And this begins to beg the question as whether or not we could do something to prevent atopic dermatitis that has a similar effect as the moisturizer studies.
Why do we talk about antibiotics and stopping antibiotics since everybody views them as being sort of life savings and saving diseases? Well, there's been campaigns in the US and in Europe for at least the last 20 years with concerns that antibiotics are being used to treat diseases that they don't treat.
This is especially true in children with ear infections, or sore throats in that most of them are viral, and the antibiotics aren't going to do much at all. We also have a little bit of confirmatory information from lab studies where we can show that uh, mice conceived in germ free environments that their skin barriers are delayed in terms of development. And we can create the same delay by taking a mouse that's not born in a germ free environment and exposing them to antibiotics.
There's some European countries that have gotten the rates of antibiotic use in early childhood down very, very small as compared to the U.S. over logic that the risk of the antibiotic is greater than the potential risk that it's a bacterial infection and that the antibiotics will treat it. I don't have a proper answer and I want to be clear about that.. but it does appear to have some sort of direct effect. And with that, I think my time is up and I thank you all for having me here today.
Korey: Terrific. Thank you Dr. Margolis for that excellent presentation. So your presentation indicates that antibiotic use in pregnancy and early childhood. Could really be predisposing children for atopic dermatitis, but how often do we really have a choice? About whether or not we should take those antibiotics.
Dr. Margolis: We still want to do studies to see if the antibiotics are causing microbiome changes our hypothesis is they are, but we still need funding to actually show that. But I do know that we tend to ask for treatments for diseases that sometimes can't be treated.
Korey: Right? So better antibiotic stewardship may get us there as well in terms of improving this particular thing.
Dr. Margolis: Yeah.
Korey: It seems like the working hypothesis is that taking these oral antibiotics are altering the gut microbiome in some way.
Dr. Margolis: We don't know, but I think we have other speakers that that may help with that.
Korey: Very true. Okay. Well, great segue. Now I'll introduce our next speaker, Nikole Kimes, PhD, who is joining us from Siolta Therapeutics. She is the founder and CEO, and she's going to be talking to us about her biotherapeutic products for the prevention of allergic disease. Thank you, Nikole.
Dr. Kimes: Thank you very much for the opportunity to be here. It's an honor and quite thrilling to talk to parents and patients themselves. I am a scientist by training and have co-founded Siolta Therapeutics with my mentor, Dr. Susan Lynch, who remains a professor of microbiology at the University of California, San Francisco. And we are developing live biotherapeutic products for the prevention of allergic disease.
I want to start very briefly with the power of the microbiome. I hope most of you recognize that the microbiome does not only include pathogens, but includes lots of very important microbes to human physiology, and you are actually only half human, the other half of your cells in and on your body are microbial cells. But even more importantly and exciting than that is if you actually look at the gene content of our microbiome, it represents a hundred times more genes than your human genome, which is why it has such an outsized impact on so many parts of human physiology, including our immune systems, our neurological development, and very importantly, the way we metabolize nutrition, which impacts all of these other things.
I use the term live biotherapeutic products, because the FDA regulates products based on their intended use. Probiotics are regulated as food dietary supplements that target healthy populations. If you are looking at a product that is used to diagnose, prevent, treat, mitigate or cure disease, the FDA sees those as drugs or biologics, and that means that we're held to a much higher standard for both manufacturing as well as safety, which in our case, going after prevention in infants, we thought was a really important aspect of development.
So let's focus on the problem at hand, which you all know much better than anybody else is the increasing incidence of allergic disease and David talked about the atopic march and what I wanted to highlight is that these Allergic diseases all have a common biological underpinning, so allergen is introduced to the system and the adaptive immune system results in producing IgE antibodies and upon restimulation with that allergen. Those IgE antibodies then kick off an innate immune cascade of inflammation, and this can happen locally on the skin dermatitis, but it also occurs systemically. So this is happening in the gut as well.
Over the last couple of decades, we've established that there are many early life exposures, as were mentioned, that are associated with allergic disease. And these exposures are all known to impact the gastrointestinal microbiome. So we do see antibiotic use, and formula feeding, Cesarean section births, also lack of exposure to pets. All of these have an impact on the developing gastrointestinal system. For us that meant that there's a glimmer of hope in that the microbiome might actually move us towards causation.
So Dr Lynch in her early work was able to start showing not only that there is a microbial association with the development of allergic disease: So in healthy infants, we see organisms that are keystone early species that really help pave the way for the diversification that happens over the first three years of life. And many of these species are lacking in the most at risk infants. Inversely, we actually see an increase in opportunistic fungal pathogens in those infants. But even more importantly than just what microbes are there, we really started to be able to drill into some of the mechanisms.
So we take in food and our microbes process this food into different molecules that then have different impacts on human physiology. And one example is, uh, linoleic acid. Depending on what microbes are in the infant's gastrointestinal system, can either be oxidized into inflammatory molecules or biosynthesized into polyunsaturated fatty acids. So it's not just the food going in, it's the microbes working with the food. And we started seeing these consistencies across different global studies, which made us really want to focus on translating this knowledge into an actual solution. And that's when we decided to found Siolta Therapeutics because we didn't see any pharmaceutical companies really going after this approach, whether it be prevention or using the microbiome as a therapeutic tool.
So we always started with clinical data. It's really important that we're using human data to rationally design these consortia of microbes from the gastrointestinal system, and then really looking at how the different organisms work together so that we could try and design a minimal consortia that had maximal functional potential. And these organisms work with one another to really fulfill a synergistic functional potential and move that into more empirical studies for proof of concept.
In the case of the early animal studies. We were able to induce allergic inflammation while providing oral supplementation of those missing microbes that I have mentioned previously. And in these animal models, we really focused on the IGE mechanism of action underlying allergic disease. And we were able to show that we can impact and mitigate the downstream inflammation.
What was even more exciting was when we started recognizing that we were actually impacting upstream of that and able to deplete the IgE that is produced during this. And even further upstream, we could show that we are rebalancing the immune cells that typically drive a TH2 allergic response.
And with that, it really made us start to believe that we could look at prevention using this type of model. And that's when we went to the FDA, and they got it. They understood number one the need, and number two the potential for fulfilling that unmet need in a relatively safe manner. So, our first in human studies, simply safety studies but we did these in adults, adolescents and children down to the age of four, they were treated for four weeks. And we were able to show that by impacting the gastrointestinal microbiome, we are impacting metabolic changes, and we could see biomarkers of reduced inflammatory signaling.
So, with that, the FDA gave us permission to move into what is our current phase two proof of concept study in newborn babies. This is for the prevention of allergic disease, including atopic dermatitis, we do also include food sensitization and atopic wheeze in our clinical endpoints.
We treat over the first year of life. It's an oral supplement that's taken daily. And then we follow these children out to the age of two. And we will be looking at both incidence and severity at one year of age for initial prevention and at two years of age for durability. And that study completes in December of next year. So we are very excited about the coming year and about contributing a solution to this incalcitrant issue that we're all experiencing. Thank you.
Korey: Really wanted to highlight the novelty of this approach, which is to look at the gut of babies and figure out what was different between a healthy baby and one that went on to develop allergic conditions. Noting which species were missing in those babies and then backfilling them with this oral probiotic therapeutic that was just outlined. So I think it's really exciting. Any questions?
Angela: When you're following them, are you doing stool swabs ? And anything else besides the stool swabs?
Dr. Kimes: We are collecting blood, so we'll be looking at IgE levels. We are collecting stool in two different ways, which allows us to look at sequencing of stool for community analysis, as well as preserving it so that we can do metabolic analysis and look at the metabolic changes. We are also doing skin tape, looking at different RNA sequencing and different cytokines associated with atopic dermatitis as well. That's stool, skin, and blood, along with the clinical endpoint.
Korey: Yeah, and how do you account for dietary differences?
Dr. Kimes: We do follow diet, and we actually are randomizing based on the intention to breastfeed versus formula feed. And then we have questionnaires throughout the two years: Who is actually getting formula versus breast milk. And then once foods are introduced, the main different food groups and when they're being introduced, it will no doubt have an impact.
Korey: Yeah, that one seems important. Do we know what's causing the gut microbiome of these babies to show up different?
Dr. Kimes: We don't know definitively, but we know it's not solely genetics, right? We know that all of these different environmental exposures are having an impact on the development of the gut microbiome early on. So, we would say the vast majority of this is really from environmental exposures. There's also familial exposures. One could certainly posit an allergic mother is going to seed a different vaginal microbiome, because they are experiencing systemic inflammation as well. So environmental exposures and familial microbiome exposures would be the top two.
Lynita: Great food for thought. As the speakers have shown, a healthy gut microbiome is essential to our overall health and hopefully this research will one day help prevent kids getting eczema in the first place.
