Episode 32: The inflammation-microbiome connection and how new therapies can correct both.
Biological therapies like dupilumab target type 2 inflammation, now new research shows they also modify the skin microbiome. In this episode we discuss what type 2 inflammation is, why it matters in eczema, and how these therapies modify the skin microbiome with Dr. Lisa Beck, Co-Director, Center for Allergic Disease Research, University of Rochester Medical Center, NY. (If you like our podcast consider supporting it with a tax deductible donation.) Check out the transcript here.
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Korey: [00:00:00] Thank you everybody and welcome to the Eczema Breakthroughs Podcast. With us today is Dr. Lisa Beck, who is co-director of the Center for Allergic Disease Research at the University of Rochester Medical Center in New York.
For 25 years, she has dedicated her career to studying eczema, to finding safe and effective treatments for patients, and understanding why some eczema patients are susceptible to skin infections. So Dr. Beck, welcome to the podcast.
Lisa: Thank you very much. It's great to be here.
Korey: So we have a lot to cover today and I think we wanna get to some of the interesting results that you've published related to systemic treatment and the relationship with the skin barrier and the skin microbiome. But before we get there, I think there's some key concepts to cover.
What is type 2 inflammation?
Korey: And the first one is really this idea of inflammation, and we hear people talk about [00:01:00] type two inflammation. Could you talk a little bit about what type two inflammation is and why it's relevant to eczema,
Lisa: Sure. That's a great We've named inflammation three different types, primarily type one, type two, and type three. And the reason we've given them different names is because when the body sees an antigen, or an allergen that could be, a viral antigen, a bacterial antigen, or something like dust mite. The human responds with a specific type of inflammation. When it is allergens, the immune response is what we call type two.
And it has specific mediators that are being released in the tissue and often in the blood as well. Type two mediators are interleukin four and interleukin 13. Type one inflammation is often what we respond to when we see a virus. The characteristic mediator of type one inflammation is interferon [00:02:00] gamma. So almost all inflammatory human diseases can be characterized into type one, type two, and type three, type two, which we think is what predominates, in eczema patients , is seen within the lesion.
But interestingly, it's even seen in non-lesional skin and is also detectable in the circulation. And this type two inflammation is not just unique to atopic
dermatitis or eczema, but it's also seen with asthma, hay fever or allergic rhinitis, food allergy, eosinophilic esophagitis, nasal polyposis and chronic rhinosinusitis. So a host atopic conditions would be characterized by this type two inflammation.
Korey: That was great. Thank you. And I'll, I'll try to summarize please, correct me as I go, but, type two inflammation is the type of response that the immune system has in response to allergens and the way that it responds is through these specific channels or pathways. [00:03:00] Which in the case of type two inflammation is interleukin four and interleukin 13. So that's why we hear about those when we talk about treatments for eczema. And you mentioned that these pathways and this type of response is common among all allergic diseases. And so that helps explain why children who have eczema atopic dermatitis also are more prone to things like food allergy and asthma and those sorts of things because it's a common pathway and response.
Lisa: That's perfect.
Inside out / Outside in hypothesis
Korey: Okay, great. So when we talk about this response that's going on in the immune system, this inflammation that's occurring in response to an allergen, how does that then affect the skin barrier?
Lisa: That's a good question, that debate surrounds the notion about this disease being an inside out disease or an outside in disease. What people mean by that.
If you are thinking this as an inside out, [00:04:00] you believe that the type two inflammation starts first and then that causes barrier disruption. And the microbial changes that we now know are so characteristic of the skin surface of our eczema patients. And There's a lot of evidence that type two cytokines, interleukin four, 13, can disturb the skin barrier So that's arguing that it's the primary inflammatory type two cytokines that drive all of that.
The outside in hypothesis says, no, no, no. This all starts with a barrier disruption that leads to making the skin more susceptible to pathogens like staph aureus and altering the microbiome.
There are many ways that the barrier gets disrupted in eczema patients. We cause some of the barrier disruption scratching, like so many researchers, I had eczema and asthma, so, uh, you know, I was part of causing my own barrier
disruption without a doubt. The [00:05:00] microbes, produce a lot of factors that disturb the barrier function. And the consequence would be type two inflammation developing in the tissue.
The truth is we don't know which of those hypothesis is true and my honest thought after getting a lot of grey hair is studying this disease is that it varies patient by patient.
Why /what causes eczema?
Korey: I guess you know, the question that I think vexes parents who have kids with eczema, is like, why?
Why did my baby show up with this? But, this idea that there's one pathway maybe is not right, maybe it's both, it takes the, the inside out and the outside in, more of a tipping point model where if there hadn't been these various things that came together, maybe the child wouldn't have eczema. But when, there're additive, maybe that's when it develops. And there's the perfect storm of things, maybe that's when we see eczema.
Lisa: I think you bring up an incredibly important point that many of [00:06:00] these complex human inflammatory diseases it is clearly a gene environment interaction that leads to manifesting the disease.
And we're still trying to understand which are the most important genes and what are the key environmental signals that, occurring very early in life and potentially even in utero.
Korey: We've been talking about type two inflammation and how it affects the skin barrier, but it also affects the skin microbiome, which is related to the skin barrier. Can you talk a little bit about what we know about that relationship and how inflammation is altering the skin microbiome and the interplay with something like staph bacteria?
Lisa: Yeah, so when we say that the skin microbiome is abnormal, really what we mean is there's a lot of a skin bacteria that we think of as a pathogen, which is staphylococcus aureus.
Most of us have very little staph [00:07:00] aureus on our skin. Now, 30% of us will have it in the nose. That's not that unusual, but we think less than 5% of people have it on their skin. But Atopic dermatitis patients do culture this out,
and it's not just on their lesional skin.
Again, this is another thing that's abnormal in non-lesional skin. So most of what's wrong is too much staph aureus. It's actually quite simple.
Biologics improving the microbiome
So, and now we have a bunch of new treatments available for eczema and even for kids. Can you talk about how these new treatments that target type two inflammation. Are also able to bring about changes in the skin microbiome
Lisa: So we had two publications this last year where therapies that target type two inflammation that are approved to treat atopic dermatitis patients.
And both of these are biologics. Dupilumab was the first one, which targets and blocks the actions of [00:08:00] both type two cytokines, interleukin four and interleukin 13, and tralokinumab, which has been approved a little bit more recently. And that blocks just 13, which we think is probably the relevant cytokine of these two type two cytokines.
So when treating our atopic derm patients with either of those biologics, a four 13 blocker or a 13 blocker alone, we saw a big drop in the amount of staph aureus on the skin surface.
And so that was, not entirely expected.
In Tralokinumab, we saw changes in the microbiome by eight weeks. But, we didn't look at earlier time points. So different study design was used to study this effect with dupilumab. And quite shockingly three days after the loading dose of dupilumab, the amount of staph on lesional and non-legal skin dropped. So we think that's a very [00:09:00] important effect of these two drugs. We think it's part of what leads to some of the clinical improvement you see at later time points.
Korey: Do you think that blocking of IL four and IL 13 in some way kills the staph? Is it shoring up the skin barrier or is it amplifying the body's natural ability to take care of staff
Lisa: we don't think four in 13 and maybe 13 alone does anything to the bacteria. We think this effect is by altering the epithelial surface to either allowing the epithelial barrier to recover or maybe blocking four and 13 allows
the epithelium to eradicate the staph aureus. And a third hypothesis here is maybe when you block I four and L 13, you make the epithelium more hospitable to good bacteria. And several Good bacteria, which we call commensals. Produce proteins that kill staph [00:10:00] aureus.
Korey: It's curious that these effects were seen within three days. I mean, that makes me think it's not the epithelial barrier being restored. 'cause it seems like that type of repair would take longer, don't you think?
Lisa: The improvement we saw at day three was not likely a barrier repair.
So we asked the question of, of the proteins that the skin can produce that would fight staph aureus, could we see that they were enhanced in their expression?
So by day seven, you would've thought if it was due to improvement in some of these proteins that we can produce from our epithelium, we would see them at that point.
And we didn't. So then we went on to ask whether there was a chance that we were seeing some switch in our type of inflammation.
So remember there are three major types of inflammation, type one, type two, and type three. Type two seems to really predominate and initiates most allergic and atopic [00:11:00] conditions in the really chronic phases of these diseases. There are a little bit of a mixture of all three of these, but still type two dominates.
We know if you have a lot of type two it blocks type three inflammation. If you have a lot of type three it blocks type two. And so what we think honestly is happening is that we've dampened the type two inflammation with these drugs pretty well and that allows the body to feel more of the type three inflammation.
So if we lower with our biologic therapies, type two, it allows the biologic actions of type three to be felt. Well, type three is the pathway that fights bacteria. And so we were seeing more of that. And that's consistent with the observations that sometimes, dupilumab treated patients have features that are a little bit like psoriasis and sometimes [00:12:00] arthritis, Those are type three diseases. So it's consistent with this notion that if you've dropped type two, you feel type three more. And so I think that we hit, the perfect ratio to finally get rid of this staph aureus.
And not too surprisingly, some psoriasis patients where they now have targeted therapies toward type three. Some of the patients have developed some eczema, so we can no longer think of these inflammatory pathways in isolation. We have to start thinking about them as relative ratios.
Korey: Yeah. That's really fascinating. The way a new treatment can really open the window to how the immune system works. Right. Because it’s, revealing all these things. It's, it's really interesting.
Lisa: It is fantastic because this latest atopic dermatitis research with dupilumab is continuing to teach us things. And I can tell [00:13:00] you there's still new papers being develop from that trial because we're really understanding all the different interactions of skin barrier and the microbiome and the underlying inflammation, and how this all relates to disease activity and itch.
Korey: That's great. That's great news. I do wonder though, so many kids are on biologics now, even as young as like
Lisa: Six months and up.
Korey: Right? And, our family has experience using a biologics and, as a parent, I wonder like, do we really entirely know what the consequences are gonna be in a developing immune system?
Lisa: A good question, with dupilumab we’re now down at an age where there's tremendous amount of physical growth but also there's tremendous amount of immunologic growth and we don't even fully know all of that yet right, but there are a number of trials looking at that. Type two inflammation is somewhat important [00:14:00] for antibody responses, so there's some rationale why we'd want to keep an eye on that.
Having said that though, we believe we had type two inflammation to treat op parasites and for good or for bad. We don't have a lot of those anymore, in, industrialized countries.
So blocking it may not be that big a deal because we have these other arms, type one and type three that help protect us from viruses fungi and bacteria. So, that’s probably why dupilumab specifically is now down to six months of age. But, we see that marching to younger age groups occurring much more slowly in the psoriasis world that are blocking the type three and sometimes the type one pathway.
The other thing that I feel very strongly about I think that with children we need to always think about backing off on the dose when they're better, I'm gonna see a lot of them space out their frequency and be able to get off the drug.
And why? Well, [00:15:00] we still think 50 to 60% of them outgrow this disease, so we want to be sure that. We aren't keeping them on a drug that we don't need to anymore. So we start doing that pretty quickly.
Korey: Yeah, the only time when don't see that eagerness to get off it is when you had a kid with really severe eczema and then for time in their life, they're living without it, and then those, patients are sometimes hesitant to risk going back to that time when they were, just constantly plagued by the itch and so on.
I really appreciate your comment about what the type two immune system was designed to do, because I know that. It's really helpful to me personally, and helps me put in context like, how important is this type two response? And maybe it's one of these outmoded things that is less relevant to modern society?
I want to go back because, Staph is so persistent on kids with eczema, and you get rid of it, but then it comes back.
And we've heard from our microbiologist guests that it hides [00:16:00] out, like you said, in the nose and in the hair follicle. Did your studies look at that at all?
Like was Staph eradicated or is it just, hiding out to come out when it can.
Lisa: Yeah, that's great question. We did not do that. And I can tell you we regret that so much, but these trials were so complex already. And so that is one of the things we propose trying to do.
When you stop dupilumab, patient's disease did not roar back. And that was quite surprising to us because if you stop systemic steroids like prednisone or, you treated them with cyclosporine or oral JAK inhibitors, like Rinvoc, the disease roars back within days. So that was why it was so surprising when people stopped dupilumab. And most patients, even three or four months later, were not back at their baseline. So that alone is fascinating. And to study how the disease comes back and what happens first, is it the barrier [00:17:00] disruption? Is it primarily a dominance of staph? Are there itch mediators that come back really quickly? Is it type two inflammation coming back? So it'd be so interesting to sort of understand that.
Korey: Yeah. And on that topic, is there some possibility that, early in life, a high risk infant is given a systemic and we're able to prevent ad?
Lisa: You're not the only one thinking that we have no therapy at this point that cures you of the disease, but maybe we have therapies that not just work really well, but might be slightly disease modifying, meaning you could go off of it and maybe you could be managed with good moisturizing And topical steroids pretty well.
And this speaks to the notion that is very real. And that's the atopic march. And The Idea that food allergy and atopic dermatitis are early allergic diseases. And quite predictive [00:18:00] of those that will go on to develop upper airway, which is hay fever, allergic rhinitis, sinusitis, and lower airway or asthma. And we could add a whole host of other ones, so I do think that there is tremendous promise if you treat these kids with atopic dermatitis really early.
Korey: Yeah it's interesting 'cause talking to adult patients, they'll say, yeah, my food allergies are a pain but it's the eczema that makes me insane.
And you hear that too with kids with the atopic march without exception, eczema is the thing that is most damaging to their quality of life.
Lisa: Absolutely. I have not yet had one parent say no to dupilumab for a six month to one year of age, moderate to severe deep child. Surprised me when this was the case. It highlighted how highly disruptive this is. Not just for the child, watching a child itch and scratch and cry [00:19:00] and not be able to focus on learning and daily activities and fun. But it also affects the whole family environment and actually always gets me choked up. 'cause I know how horrible this is for families. So that's why the yes is there, nobody wants to have their kid get a shot.
It's the most rewarding thing in 30 years of practice. To be able to help a whole household sleep and have the parents be able to focus on the other children and get back to work and sleep themselves. It's just, it's, it's great.
Korey: I'm not at all surprised to hear that your patients are eager to take that risk and try something it's incredibly difficult on both children and families. Because you're at your wit's end usually. So to have something for them when before you just didn't have great solutions has gotta be fantastic.
I know we're at time and it was such a great [00:20:00] discussion.
Lisa: Well, thank you, the questions were really spot on and, very timely.
Korey: Thank you
