The elements, implications, and nuances of the cutaneous microbiome are driving factors in the development, spread, and treatment of skin diseases.
Matthew J. Zirwas, M.D.Sometimes, seeing the big picture means drilling down to consider the smallest components that comprise the overall canvas. This is clearly true when considering the skin and when considering the microbiomes that cooperate to paint the larger picture.
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Matthew J. Zirwas, M.D., director, Ohio Contact Dermatitis Center, says, “We know that the skin is colonized by a variety of organisms (bacteria and yeast primarily), most of which are probably beneficial. The innate immune system protects us from most of the pathogenic organisms and, in different inflammatory diseases, the activity of the innate immune system may be increased (as in psoriasis) or decreased (as in atopic dermatitis). These changes lead to alterations in the cutaneous microbiome which may be a factor in disease activity. It is also possible that changes in the cutaneous microbiome, independent of innate immunity, could be driving factors in some diseases.”
Adam Friedman, M.D.Adam Friedman, M.D., FAAD, associate professor of dermatology, residency program director, director of translational research, department of dermatology, George Washington School of Medicine and Health Sciences, speaks to the science of the cutaneous microbiome. “It’s easy to dismiss this field at first glance as pseudoscience, given the very generalized claims made regarding over-the-counter products containing probiotics-but what are probiotics? They’re live bacteria and yeast (the term is non-specific) and subject, like many other elements making up the cutaneous picture, to mislabeling.
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“So definitions are really important,” Dr. Friedman explains. “The lay and medical communities often refer to this area of study incorrectly. The microbiome is actually the collective genome of all the microorganisms on the skin. It’s not the actual organisms themselves. ‘Microbiota’ is actually the collection of microbial populations. The way we’re identifying the microbiota is through their genetic fingerprint. Through that microbiome. That’s how we identify who is at the party, which can vary tremendously even from one body area to the other.”
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“The cutaneous microbiome is still a highly evolving topic,” Dr. Zirwas says. “Identifying organisms that do not grow on standard culture media is extremely difficult, but new techniques, such as collecting samples then analyzing the DNA present to look for DNA of microorganisms, are making substantial progress.”
Dr. Friedman agrees that understanding of the microbiome is rapidly evolving, and is informed by known science, and sometimes by educated hypotheses. “Much of what we are learning regarding the genetic makeup of the microbiota is through alterations in varying disease states,” he says. “We learn the best from when things go wrong. So a lot of the work that’s been done from the skin perspective on how the alteration of the good microbiota comes from the atopic dermatitis [AD] literature.”
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He cites researchers doing some “incredible work in showing how these population shifts in the microbiota-specifically staph aureus, which is a gram positive bacterium-can cause a lot of problems. We know that in atopic dermatitis especially, there is a love-hate relationship with staph in that staph loves atopic derm but atopic derm doesn’t love it back. S. aureus has numerous virulence factors allowing it to adhere better to the AD dysfunctional skin barrier as well as maintain the TH2 immune milieu, thereby suppressing the innate immune response from effectively clearing this organism. Thus, it instigates and perpetuates active disease, which only further disturbs the barrier and suppresses the TH1 immune response. [So] it is not surprising that S. aureus comprises a much greater percent of the microbiota on AD skin versus normal skin.”
Dr. Friedman explains that researchers have shown by taking swabs from all over the body that the microbiota is different all over the body, but also that in a disease state like dermatitis, it differs from healthy controls.
“So the question for me is, is it the chicken or the egg? Does the imbalance drive the disease, or is it the disease that allows for this imbalance? There are two camps on this. My belief is, when you think about atopic dermatitis, that it is inherently a disease of barrier dysfunction and probably that abnormal topography is what is allowing for the change in the microbiota, and that change in the microbiota drives the disease,” says Dr. Friedman.
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He concedes this makes sense from a topographical view, but that the challenge to this theory is that when you push the immune response-the inflammation-toward atopic dermatitis, “we know that the TH2/TH17 inflammation can also interfere with the production, differentiation and formation of various components of the epidermal barrier. We also know there are certain gene mutations that result in barrier dysfunction, such as filaggrin and occludins, but it may not be enough. It could be that it’s the combination of the genetics plus the change in the microbiome that actually sets this up. So I’m challenging my own theory,” he says, immediately adding that “the best way to learn is to poke holes in your own ideas. But I really think it’s the abnormal landscape that then facilitates the abnormal bacterial landscape which drives the disease.”
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There’s so much we don’t know about genetic and environmental influences. Dr. Friedman cites quorum sensing-bacteria can sense their environment and secrete certain elements to resolve to the “bad guys” in their environment. He observes, “As humans, we are very often egocentric about our place in our environment. But the funny thing is, for every skin cell there are probably 33 bacterium to that one skin cell. So that figures to about a million bacterium that inhabit each square centimeter of our skin. There are so many more of them than there are of us. We are not alone. We are covered! We’re essentially giant petri dishes. It sounds gross, but they need us. And we need them. It’s a real symbiosis.”
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Society’s often unnecessary use of antibiotics is not without consequences. “A good example is yeast infections when antibiotics also kills off the ‘good guys,’ allowing one particular member of that microbiota to proliferate without control, without the normal checks and balances. The same goes for C. difficile infections in hospitals, these horrible enteric infections following antibiotic use (historically Clindamycin)… you’ve killed off the good, and now the bad guys, which are pretty resistant to certain antibiotics, flourish and wreak havoc,” Dr. Friedman says.
Considering what we know and are learning, what are the implications for current and future dermatological treatments? Dr. Zirwas hopes for the discovery of the specific changes in the cutaneous microbiome that are characteristic of different diseases. “Then we will develop therapies that normalize the cutaneous microbiome that lead to clinical benefit in these diseases. Of course we already do this when we put people on antibiotics or anti-yeast agents; however, this is a very non-specific approach that probably doesn’t normalize the microbiome, instead non-specifically killing off both pathogeneic and beneficial organisms. The ideal approach would be to be able to target the organisms that are present in excess while ‘seeding’ the skin with organisms that are beneficial or that have been removed via use of personal care products or antibiotics.”
With such an evolving field and researchers learning so much, Dr. Friedman believes there will be significant implications for future dermatologic understanding, research and treatment. He is excited about a National Institutes of Health (NIH)-funded study on the topic being conducted by Richard Gallo, University of California San Diego. The NIH Research Portfolio for the study, titled “Establishing a Skin Microbiome Transplant,” notes the complex and diverse community of bacteria residing on human skin. The study abstract cites abundant experimental evidence demonstrating that many of these commensal bacteria residing on healthy subjects can be beneficial, noting that these bacteria perform essential functions such as inhibiting survival of pathogenic bacteria, limiting skin inflammation and enhancing skin innate immune defense.
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This has led to the hypothesis that the bacteria that normally inhabit human skin could be beneficially exploited. Gallo’s clinical trial seeks to study the effect of a series of simple interventions to better understand the potential benefits of transplanting commensal bacteria, as part of the microbiome, on human skin. The study will test hypotheses related to key concepts inherent in microbiome transplant such as the function, duration and effects of other microbes. This will, as Dr. Friedman says, provide “answers to key unknown questions about the microbiome of human skin that will be relevant to a wide range of skin disorders. Our specific aims are: 1: Evaluate the capacity of an autologous microbiome transplant to decrease S. aureus colonization. 2: Determine the duration of survival of transplanted bacteria on the skin surface. 3: Measure the influence of the transplanted bacteria on the local microbiome.”
Dr. Friedman believes that this trial, and other research, will greatly influence how scientists and physicians view the smallest elements making up the big picture of the skin.
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Understanding how the cutaneous elements works naturally will pave the way to enabling a normal, sustainable skin microbiome.
“I think a lot of folks will say, ‘so how do we deliver the right probiotics in an effective and safe manner,’” Dr. Friedman posits. “And there’s a theory I think we need to consider-and I think even a lot of dermatologists don’t know this. It’s the idea of prebiotics. Instead of repopulating the skin with the right bacterium or yeast, rather provide a media for the right guys to grow.” That’s how he defines prebiotics: “Providing the tool for the right guys to grow and put that natural checks and balances system back in place.”
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You can think of it in terms of giving a man a fish and he eats for a day versus teaching a man to fish and he eats for a lifetime. “That is exactly the concept,” says Dr. Friedman: “If you throw the good guys back onto an abnormal landscape, you don’t solve the root of the problem. If you put the good microbiota on a hostile home, how long are they going to last? I don’t know the answer to that. But I do know there’s some really interesting data about providing a medium with the various nutrients needed to help the right bacterium grow. And that’s been shown to help push the balance away from that adaptive or allergic response of atopic derm and back toward the middle ground. To me, that’s easier, because how do you regulate probiotics, because you’re delivering living organisms? …I think you’re going to have a much easier time implementing quality assurance if what you’re delivering is just a media for the subject to grow, and in so doing, providing the tools for the good guys to fight the bad guys.”
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There’s a growing societal understanding of the possibility that an overuse of antibacterial agents-in linoleum floors and hand sanitizers, for example-insulates people (children especially) from being exposed to typical agents in the environment and subsequently developing immune responses to them.
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“They’re not developing tolerance, not colonizing appropriately,” Dr. Friedman says. “So it’s possible that the rise in atopic dermatitis, pretty rapidly in the last couple decades, might be a result of that. We were never meant to be taken out of the dirt. I think especially early on, as the skin is developing and the populations are forming and colonizing, [the use of sanitizers, etc.] could be extremely detrimental. In line with that, there’s evidence to show that initializing moisturizer therapy in high risk babies, those with a family history, that you can limit atopic derm. Well, that makes sense because if their barrier is disrupted and you’re kind of restoring it, what happens? The right guys are colonizing it because the skin is of a normal topography from day one. That makes a lot of sense to me. But I think a lot of the cultural practices-the concept that dirt is inherently bad-is a societal attitude that can really hurt us.”
How does what we’re learning now about cutaneous microbiome relate to how the immune system works?
“We take direction from the gastrointestinal (GI) literature, and the knowledge of how the gastrointestinal lining interacts with the gut microbiome,” Dr. Friedman says. “We know a lot about how alterations in that can lead to inflammation and malignancies… the gut lining and the skin are pretty close relatives. They’re very similar in their structure.” So the understanding of the GI microbiome will “help guide us in terms of where we should be looking, of how changes will induce certain elements in the immune system and suppress others. I think the population, whether it be the ‘right’ one or the ‘wrong’ one, will have an influence on the immune system and that can definitely drive diseases: you see it in contact dermatitis but also in malignancies. What is cancer? It’s unrestricted cell growth. And how do those cells that grow relentlessly get to this point? Often due to injury-in skin cancer, from ultraviolet radiation and the free radicals that form from that and the DNA damage. Even low-grade chronic inflammation we know can cause damage resulting in cancers. Some GI cancers and various forms of lymphoma are associated with aberrations in immune regulation. I think this has very broad implications for probably almost all skin diseases, not just inflammatory but also neoplastic because the immune system plays a major role in both restricting but also in allowing or enabling cancers to grow and spread.”
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“We have so much more to go with this” in terms of what we have to learn, Dr. Friedman says. “Many of today’s cutting edge studies will inform also how to ‘kill the bad guys.’ Whenever we look at biology and how nature handles itself, I find we do better in figuring things out. Antibiotics, while they’ve saved countless lives, are really inherently quite simple. They’re targeting one element of the bacterium to inhibit its growth and allow the immune system to take over and take care of the rest. That’s a pretty simplistic approach, but it’s also why bacteria develop resistance. Organisms can develop new metabolic pathways not impacted by the antibiotic, enzymes which degrade the antibiotic, or simply pump the drug out of the cell. So when we learn from the immune system, or how these bacteria naturally kill one another, we can implement new technologies and new drugs that are based on this biology. [For example,] antimicrobial peptides, which are mobilized in response to invading pathogens or injury, and which can literally rip organisms apart. These peptides are so simple but lethal; their positively charged ends bind to the surface of these organisms (which has a strong negative charge), while their negatively charged sides insert inside the pathogen and with a scissoring motion, rip it to pieces. These things are incredible, and there’s been a real push to develop analogs, synthetic versions of these antimicrobial peptides. And you’ll never get resistances to these things because it’s all about electrical charges. Importantly, this is not inhibitory, it’s actually killing the organisms, and you can’t develop resistance to that. And this is what our immune system does, so when we mimic what occurs naturally, we do pretty well.”
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Dr. Friedman adds that “nitric oxide (NO), which is a charged radical, in itself physically destroys bacterium, fungi, viruses, protozoa, parasites, you name it. Furthermore, in various intermediate forms, such as S-nitrosoglutathione (GSNO), NO can be donated onto pathogen structures like DNA and proteins and change their function, inhibit that function, and result in cell death.”
Scientists need to develop ways to attack the “bad guys” that are multi-mechanistic and that mimic natural actions to avoid development of resistances. Dr. Friedman believes the medical community will learn a lot of that from the microbiota.
“We are on the edge of a revolution when it comes to our understanding of the microbiome and microbiota,” Dr. Friedman says. “It is an extremely exciting time! We have an opportunity to really understand and educate what is going on with the microbiome.”
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In short, the medical community will gain a better appreciation of how the mosaic of cutaneous players informs the whole picture.