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Dr Lio on the Microbiome and AD
The microbiome is a promising new area for investigation for various inflammatory diseases, including atopic dermatitis (AD). While the evidence is still conflicting on the efficacy of probiotics for the treatment of AD, studies suggest that the microbiome of the skin, and maybe even the gut, play a role in the development of AD.
Peter Lio, MD, discussed current research on the microbiome, the potential of probiotics for treatment of AD, and areas of future research in an interview with The Dermatologist.
The Dermatologist: As of now, what do we know about the microbiome and its relationship to the development and/or prevention of AD?
Dr Lio: I think we are in the early days of understanding this relationship. As we come to terms with the fact that we are outnumbered 10:1 by bacteria, it becomes increasingly clear that our understanding of certain diseases, drugs, and pathways may be severely limited by not fully integrating the role of our microbiota.
Clearly the microbiome is abnormal in patients with AD, both on the skin and in the gut. There is compelling work that demonstrates low microbiota diversity in the gut at day 7 of life can predict the future development of AD.1 For nearly 20 years, we have known that oral probiotics can prevent, or at least delay, AD in high-risk individuals.2
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We are now realizing that impaired skin barrier—what I like to call “leaky skin”—is a serious risk factor for AD and, if treated with moisturizers from birth in high-risk patients, we can actually prevent the development of AD in as many as half of these patients!3 That is a game changer for sure, and may have more to do with the microbiome than we realize at this early stage.
The Dermatologist: How has understanding of the dysfunctions in the skin barrier and colonization of the skin by Staphylococcus aureus contributed to knowledge on the microbiome and potential development of future treatments of AD?
Dr Lio: It is a remarkable time because we are still in the middle of a transformation in our thinking about the role of S aureus in AD. We are moving from the idea that it is “just” a colonizer that can sometimes cause trouble, to becoming the primary, or at least a primary, driver of the disease. Perhaps even more exciting, we are witnessing the birth of myriad new approaches to address AD—from topical antibiotics mixed with corticosteroids, to topical probiotics and prebiotics, to futuristic-sounding anti-bacterial enzymes that selectively destroy S aureus. Diluted bleach baths may have started this endeavor but have been shown to not effectively work against Staphylococcus directly. However, other ideas are filling this need.
What if we find out that the great dermatologist, Paul Unna, MD, was correct so many years ago when he opined that the etiology of AD was due to “the inoculation of a germ”?4 Wouldn’t it be incredible if this terrible, chronic, inflammatory disease could be stopped just by fixing the bacterial balance?
The Dermatologist: What is the role of probiotics in the treatment of AD? Have there been any new developments on whether topical or oral probiotics are beneficial to patients? What strains have shown potential for treating the skin barrier?
Dr Lio: The story of probiotics in AD is really interesting to me and is a beautiful example of the limits of evidence-based medicine as we currently understand it. More than anything, it makes me long for precision medicine, where we so deeply understand the underlying mechanisms, that we do not need to take an average population and use statistics to help us know what is going on. From the perspective of precision medicine, such population studies seem crude, don't they?
Specifically, we see a huge variability in studies of probiotics to treat existing AD. Now, even the positive ones are relatively modest, I admit, but there are some studies that truly seem to show benefit while others do not.
At the end of the day, large meta-analyses generally seem to conclude that there is not much effect on existing AD.5 However, some of the more recent meta-analyses do seem to find a signal, and this makes me think that we simply need to better understand the population of patients with AD. I suspect that it is a more heterogeneous disease than we realize at this point. This means that depending on the subtype of individuals enrolled in a given study, the results could be quite different.
An analogy might be something like this: I could make a bold statement: “I do not think antibiotics treat bacterial infections.” A reasonable person would chuckle and say, “What do you mean? We have amazing evidence that they work!” And I might reply: “Well, I treated 600 people with S aureus infections with an antibiotic or placebo and the groups were equal in that only 20% improved.” If you stopped there, you might conclude that, gosh, maybe they do not work. However, obviously we cannot stop there! We must then ask: “Well, which antibiotic did you use?” And if the answer was penicillin, we would immediately understand why the study was flawed! “Wait!” we would yell, “S aureus makes penicillinase so is resistant to penicillin! You cannot conclude that the entire universe of antibiotics does not work from your goofy, flawed study!” That is kind of how I think we will look back on studies that make such sweeping and myopic conclusions like: “Probiotics do not seem to improve existing AD.”
We need better understanding of the patients, the types of bacterial strains needed, the dosing, the frequency, and so on. For now, I remain cautiously optimistic that there is some sort of signal here and I think it is reasonable to stay tuned.
The Dermatologist: Your presentation at the 2019 American Academy of Dermatology annual meeting discusses the potential for coconut oil for improving the skin barrier. Are there other alternative therapies that show benefits for improving AD symptoms and/or the skin barrier?
Dr Lio: Coconut oil is one of my favorite natural products for AD because it is a pretty good moisturizer and also has an amazing anti-staph property that really seems to decrease the S aureus on the skin of patients with AD. It is sort of a “one-two punch.” Sunflower seed oil is also really neat because it seems to possess some anti-inflammatory properties along with the ability to stimulate ceramide fat production in the skin, again, both very beneficial for our patients.
More recently, I came across a study about L-histidine supplementation orally that can improve the skin barrier, presumably by increasing filaggrin production.6 I find this extremely compelling and want to study this more for sure.
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The Dermatologist: How do you discuss the microbiome with patients and options for improving the skin barrier?
Dr Lio: We are still in the early days and there are far more questions than answers. I caution patients that anyone who “seems to have all the answers” is probably not being honest or is deluded. There are just far too many good ideas for one to say that everything is solved at this point. Most importantly, however, I stress that it may be wise to look at things more holistically. If the skin barrier is damaged, we know S aureus tends to grow, which means we have dysbiosis. Inflammation contributes to barrier dysfunction and, thus, to dysbiosis.
In other words, it is all connected so that when we use our techniques, such as good moisturizers, anti-inflammatory medications, and anti-bacterial preparations to help break the vicious cycle of AD, we also help the microbiome, even if we do not have a magic spray of healthy bacteria. In this way, we know we can help restore the proper bacterial balance, even if it is, relatively speaking, “the hard way.” And, I think patients take some comfort in that.
References
1. Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low diversity of the gut microbiota in infants with atopic eczema. J Clin Allergy Immunol. 2012;129(2):434-440.e2. doi:10.1016/j.jaci.2011.10.025
2. Kalliomäki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357(9262):1076-1079. doi:10.1016/S0140-6736(00)04259-8
3. Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of emollient therapy for the primary prevention of atopic dermatitis. J Am Acad Dermatol. 2010;63(4):587-593. doi:10.1016/j.jaad.2009.11.011
4. Stelwagon L. Prurigo infantum; psoriasis-eczema; primary pigmented sarcoma of the skin; xeroderma pigmentosum; dermatitis herpetiformis. On the nature and treatment of eczema. Am J Med Sci. 1891;101:95-96.
5. Lee J, Seto D, Bielory L. Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol. 2008;121(1):116-21.e11. doi: 10.1016/j.jaci.2007.10.043
6. Tan SP, Brown SB, Griffiths CEM, Weller RB, Neil K Gibbs NK. Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. Clin Cosmet Investig Dermatol. 2017;10:403-411. doi:10.2147/CCID.S146760
