NEA and PeDRA to team up on new research project with $250,000 grant money designated for future work.
Published On: Dec 6, 2021
Last Updated On: Dec 7, 2021
Human skin is colonized by a diverse system of bacteria, fungi and other organisms which interact both with each other and with the human body (Figure 1). In fact, more than 1000 different bacterial species live on the skin.1 This is called the skin microbiome, which is part of the total human microbiome that lives on the skin, in the respiratory system, in the urinary system, vagina and in the gut. Dr. Richard Gallo, PhD, of the University of California San Diego states, “Healthy skin depends on the microbiome to maintain its normal functions. Bacteria on the skin can actually act like a part of the immune system and is important for controlling the skin barrier and environment.” The skin is not just a flat surface, but is made up of hair follicles and sweat glands, giving the skin microbiome approximately 25 m2 of surface on which to live.2 The Human Microbiome Project was launched by the National Institutes of Health in 2007, allowing the first studies to learn about which bacteria colonize the skin and how the skin microbiome changes over time and depending on body site (i.e. moist vs. dry body sites).3 Previously, we discussed how JAK inhibitors and biologics are potentially changing the future of eczema treatment. In this final article in the series about potential new treatment options for atopic dermatitis (AD), we explore how the microbiome is affected in AD and how manipulating the skin microbiome is being investigated as a new type of treatment approach.
Scientists have been exploring what kinds of organisms make up the healthy skin microbiome, and how the microbiome impacts and is affected by the development and progression of AD. Several significant observations have come from research to date, including:
To show that the skin microbiome is altered in AD, a study was performed with 12 pediatric patients with moderate-to-severe AD and 11 healthy controls, aged 2–15 years.7 Skin from different AD disease states (baseline disease state, disease flare and post-treatment for disease flare) were sampled for bacteria and compared to each other and to the bacteria from skin of healthy controls. While the number of patients in this study was small, AD treatments varied (e.g. corticosteroids, antibiotics and calcineurin inhibitors were all used), and methods for sampling skin to collect microbial populations have since advanced, this study found that the amount of S. aureus was greater during disease flares than at baseline or post-treatment and correlated with worsened disease severity.7
A subsequent study additionally showed that the skin microbiome is different in pediatric (ages 2-12) versus teenage (ages 13-17) and adult (ages 18-62) AD patients (teenage and adult patients were grouped).8 In AD non-lesional (i.e. skin visibly unaffected by AD), the microbiome diversity was significantly higher in young children than in adults-teenagers. In general, research has demonstrated it is better to have a diverse microbiome than to lose bacterial diversity. A diverse microbiome helps the skin barrier function properly and acts as one of the major communicators with the human immune system.1
Finally, increased presence of S. aureus was shown to precede AD in a study with newborn infants. Bacteria first colonize our skin when we are born – studies have shown that birth by passage through the birth canal versus by Caesarian section can alter a person’s microbiome.9,10 Scientists asked the question whether skin colonization at infancy by the pathogenic bacteria S. aureus could contribute to the development of AD. Indeed, in 149 white infants whose microbiomes were analyzed at birth and at seven time points over their first two years of life, it was found that at age three months S. aureus was more prevalent on skin of infants who later went on to develop AD.10 This evidence, together with studies performed in mouse models, led to the conclusion that changes to the skin microbiome can promote or be a driver of AD.11 Further studies have since added strength to this conclusion, showing down to the species level that increases in specific types of S. aureus associate with worsened AD severity.12
In addition to the microbiome being different in AD compared to healthy skin, the way that the microbiome interacts with the skin and immune system is also different. For example, in skin actively involved in AD (i.e lesional skin) S. aureus was found to reside in the dermis, a deeper layer of skin, which can increase inflammation and result in skin swelling.13 This ability of S. aureus to penetrate further into the skin has been shown to be due to a protein it makes called a “protease” that can break down connections between skin cells and allow the bacteria to push deeper into the skin. Once the bacteria has broken through the skin barrier, the body reacts by releasing immune system-associated chemical messengers called interleukins (IL), in this case IL-4, IL-13, IL-22, thymic stromal lymphopoietin, and others, resulting in inflammation. If the skin barrier is already compromised, like in patients with filaggrin mutations, more bacteria can penetrate the skin and increase these immune messengers even more.13
The above study in mice also found that use of moisturizers or barrier repair products resulted in less ability for S. aureus to move into the skin and the interleukin differences were partially restored to more normal levels.13 Similar results have been seen in humans. In a more therapeutically targeted approach, AD patients treated with dupilumab (a monoclonal antibody (biologic) that blocks the IL-4 receptor on cells) showed increases in microbial diversity (a sign of healthier skin) and a decreased level of S. aureus on the skin.14 A recent study confirmed and extended these findings, demonstrating that AD patients on dupilumab saw microbiome changes in both lesional and non-lesional skin and in the nose.15 Together, these data show that not only does the microbiome influence the human immune system, but modulating the human immune system has impacts on bacterial survival and colonization.
How does S. aureus colonize the skin in AD? While the answer to this is complicated, studies have shown that antimicrobial proteins naturally found in the skin are reduced in AD skin compared to healthy skin.1 The outer skin layer, the stratum corneum, is naturally slightly acidic and S. aureus grows poorly in acidic conditions. However, AD patients have lost this skin acidity, giving the chance for S. aureus to overgrow. S. aureus isolated from AD patients also is more “sticky,” binding more strongly to AD skin. This is even more of a problem in skin of people with filaggrin mutations who have deformed cells in their stratum corneum, making it even easier for these sticky S. aureus to bind.1
What if other members of the microbial community on the skin fought back? Members of bacterial colonies on the skin surface talk to each other and sometimes the commensal bacteria can push back the pathogenic bacteria.1 An example of this is that the presence of other staphylococci besides S. aureus at two months of age protected infants against later developing AD.1 The more commensal bacteria S. epidermidis, S. hominis and S. lugdunensis all produce molecules that target S. aureus, but these bacteria are reduced in AD.16 One study in mice found that if S. aureus were exposed to a particular protein secreted by other commensal bacteria on the skin, S. aureus was unable to exert its pathogenic effects that lead to damage and inflammation.17 This observation led to a great deal of excitement and further study of the ability of commensal bacteria (or their products) to be used therapeutically against S. aureus to treat AD.
After learning how the skin microbiome can influence the severity of AD and impact the skin barrier as well as the immune system, scientists wondered if they could therapeutically change the microbiome to improve skin health. Several methods have been used to try to reduce S. aureus in AD including topical steroids in combination with antibiotics, oral antibiotics and use of emollients and bleach baths (which have been shown not to have antimicrobial effects18). However, despite the known pathogenic contributions of S. aureus in AD, none of the attempts to reduce S. aureus itself have really improved AD over the long-term.19 General antimicrobial or antibiotic approaches also impact commensal bacteria in addition to pathogens. Dr. Jennifer Schoch, FAAD of the University of Florida pointed out that “trying to ‘eradicate’ Staph doesn’t really work, so instead we’d like to see more microbial diversity as a sign of a “better” skin microbiome in patients with AD.”
Another area of investigation was to try to use a topical probiotic approach to support commensal bacteria and thereby improve skin bacterial diversity. These types of approaches include use of emollients that contain bits of proteins, called peptides, that act to support certain bacterial growth6 or emollients containing bacterial lysates (all the contents of bacterial populations),20 or by transplanting a specific type of commensal bacteria such as Roseomonas mucosa onto the skin.21 The transplantation approach appeared promising in its Phase I/II clinical trial with transplantation of this bacteria resulting in decreased AD severity, topical steroid requirement and S. aureus burden.21 Preclinical and clinical trial results regarding transplant with other commensal microbes support their potential use as an AD therapy. However, these studies remain preliminary, and the effect on the cutaneous microbiome and safety, including long-term safety, of commensal organisms that target S aureus is unknown.1 Dr. Gallo suggested that, “There should be distinctions made between the different approaches for targeting the skin microbiome, some of which utilize more broad tactics which may or may not be guided by known mechanisms of action and others, such as the bacteriotherapy technology approach, which requires a very detailed and comprehensive understanding of microbe-host behaviors.”
Bacteriotherapy technology is defined as the purposeful use of bacteria or their products in treating an illness and can include modifying the bacteria to have a desired trait. A very small trial (five people) was conducted where multiple strains of bacteria with antimicrobial activity were applied to the skin resulting in a significant decrease in S. aureus at the site of application.16 One specific type of bacteria, S. hominis A9, which had been previously found to be capable of inhibiting S. aureus growth and is found in the skin of 21% of healthy subjects but only 1% of AD patients, was isolated from healthy human skin and placed on mice using a lotion.22 This resulted in reduced skin redness and inflammation and improved eczema-like symptoms in the mice.
To follow up, a small Phase I clinical trial in humans was done to assess how S. hominis A9 would work in 54 moderate-to-severe AD patients, 36 of who used S. hominis A9-containing lotion and 18 who used control lotion. S. hominis was applied to the arms of the 36 patients twice daily for seven days and the microbiome of these patients was sampled before treatment and on days four and seven of the treatment.22 S. aureus colonization was found to be reduced at both days four and seven, and the local inflammation at the site of application was improved. The AD microbiome also stayed improved for 96 hours after treatment was stopped. This one-week application of the bacteria and the small number of people in the study did not allow the researchers to observe clinical improvement of AD symptoms, but future studies are planned to test this.22 Dr. Gallo said, “Picking the bacterial strain and species is really important for this type of therapy to be successful. The choice of bacteria should have a low infection possibility and be bacteria that have evolved to live on the skin.” There remains a good deal of promise with trying to alter the skin microbiome for AD patients and increase bacterial diversity as part of the battery of treatment options for AD. The field of microbiome research is rapidly advancing. Some of the additional approaches to utilizing or targeting the human microbiome therapeutically in AD can be found on NEA’s Eczema Treatments in Development web page. Dr. Schoch said, “Increasing bacterial diversity and healthy skin bacteria will likely be an exciting new way to treat AD. I am particularly excited to see if, eventually, we can use similar techniques to reduce the incidence of AD by applying these therapies early in childhood even before AD has a chance to develop.”
Take Home Points:
Biologic: A drug made from biological (living) sources like humans, animals, plants, fungi, or microbes. Biologic drugs are sometimes called “biologic response modifiers” because they change a process already occurring in cells or in a disease. In atopic dermatitis, new biologic drugs like monoclonal antibodies can modify the immune reaction driving the disease.
Colonization: The term colonization related to bacteria means the action of the bacteria establishing itself in a particular body location. Bacteria can colonize the skin, the inside of the nose, the gut and other body areas.
Commensal bacteria: The term “commensal” means when two organisms live together and benefit from each other. In terms of commensal bacteria, this means all the human microbiome that interact with the environment and human systems, helping to promote overall human health.
Pathogenic bacteria: The term “pathogen” means disease causing and a pathogenic bacteria is one which causes disease or helps set up conditions for disease. We are familiar with this when someone gets a case of food poisoning from a bacteria called Escherichia coli in raw or undercooked meat. On the skin, Staphylococcus aureas or S. aureus is a pathogenic bacteria involved in AD.
Interleukins: Small proteins made and secreted by cells of the immune system that send a signal to another cell to respond in a certain way.They are abbreviated “IL” and numbered (IL-1, IL-4, IL-12, IL-23, etc.)
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