PracticalDermatology

Atopic Dermatitis (AD or eczema) is a chronic and pruritic inflammatory skin disorder that is characterized by recurrent eczematous lesions and intense itching. It is typically treated with combinations of topical or systemic anti-inflammatory agents, moisturizers, and avoidance of triggering factors.¹ It affects approximately 20 percent of children and as many as 10 percent of adults in developed countries.² The pathophysiology is complex, as both genetic and environmental factors affect the presentation of allergic diseases such as AD.³ For example, mutations in the gene encoding the skin barrier protein filaggrin (FLG) are associated with AD, but infants who have greater presence of coagulase-negative staphylococci have a decreased risk of developing AD.^4,5

The skin microbiome plays a key role in the pathogenesis of atopic dermatitis. AD has been heavily associated with Staphylococcus aureus colonization of the skin.6 Kong et al specifically commented in a 2012 study that there exists, “a strong association between worsening disease severity and lower skin bacterial diversity.”¹ They also determined that this shift in the microbiome was not present over the entire skin but was localized to specific sites of disease. In addition, chronic itching and subsequent dysbiosis with colonization by S. aureus are considered essential for the maintenance of AD. Thus, clinical evidence suggests that IL-4 and IL-13 serve a central role in the chronicity of AD by driving a type 2 inflammation loop.7

Other species of bacteria, such as Streptococcus, Corynebacterium, and Propionibacterium species, are varied across the AD disease states, seemingly overpowered by S. aureus colonization.8 Thus, beyond treatments aimed solely at reducing S. aureus levels, there may be therapeutic options that may help restore the more diverse and consequently more resilient microbiome state.

EDITOR'S NOTE: Read Part 1 of this series, The Microbiome in Acne: Where are We Now?

Microbes and Atopic Dermatitis

Though S. aureus is the most discussed microbe in the field of AD, the relationship between host and bacteria is complex and multifaceted. S. aureus exhibits multiple virulence factors, including superantigens like enterotoxins (i.e. SEA, SEB), toxic shock syndrome toxin 1 (TSST1), exotoxins, phenol soluble modulins (PSMs), as well as proteases that trigger inflammation alongside skin barrier dysfunction in AD.^9–11 FLG mutations are thought to increase skin pH and facilitate proliferation of S. aureus as well.

Beyond staphylococcal species, Malassezia spp. are the most abundant fungi on mammalian skin and are associated with AD.^12,13 There are increased levels of Malassezia-specific IgE in AD patients,¹⁴ and there is a correlation of AD severity with an increased amount of Malassezia species present.¹⁵

In healthy skin, there is generally a diverse community of different microbes. Specifically, within the Staphylococcal species, commensals such as Staphylococcus epidermidis, Staphylococcus hominis, and Staphylococcus lugdunensis are of clear importance. Strains of S. epidermidis were found to carry and express the gene that produces serine protease glutamyl endopeptidase, which inhibits the production of biofilms and colonization by S. aureus.¹⁶S. lugdunensis was found to inhibit S. aureus growth through the production of lugudinin, a novel class of macrocyclic thiazolidine peptide antibiotics.¹⁷ Other non-staphylococci microbes have shown antagonistic properties towards S. aureus as well. Streptococcus spp. was shown to have an inhibitory effect on S. aureus growth,¹⁸ while Corynebacterium spp. was shown to constrain S. aureus through accessory gene regulatory inhibition.¹⁹

The integrity of the gut microbiome plays an important role in AD pathogenesis. Several factors, including psychological stress, sleep disruption, diet composition, and antibiotic use, affect the gut microbiota.²⁰ A study assessing fecal samples of 98 infants found that microbial diversity was significantly lower in infants with eczema compared to eczema-free infants at 12 months of age.²¹ Within the gut of children with AD there were more Clostridia and fewer Bifidobacteria and Lactobacilli species.²² Bifidobacteria and Lactobacilli induce T regulatory cells, followed by IL-10 and TGF-Β production, which reduces inflammation and inhibits the growth of S. aureus. Despite understanding these relationships between microbes and AD, many questions still remain regarding the relationship of the entire microbiome and the pathogenesis of AD.

Manipulating the Microbiome

The microbiome of each individual is often unique, like a fingerprint. Thus in therapeutics for AD, more personalized manipulation of the microbiome may be required. Broadly speaking, there are four main forms of microbial restoration: prebiotics, probiotics, parabiotics, and postbiotics. Probiotics are the viable commensal microorganisms, while prebiotics fuel commensal bacterial growth and are indigestible by humans. Symbiotics are another class, which combines prebiotics and probiotics, allowing both the microbes and its nutrients or substrates to be delivered for growth. Postbiotics are the byproducts of bacteria that are secreted by live bacteria or released following their lysis or death. Parabiotics are intact but inactivated probiotic bacteria.^26,27

Oral Probiotic Therapies

The effect of oral probiotic formulations on AD pathology has been assessed, and the evidence is mixed. Probiotics may stimulate anti-inflammatory cytokines, such as IL-10 and TGF-Β, and this can induce signaling to produce IL-12, IL-18, and TNF-α.²⁸ Certain commensal microbes, such as Lactobacillus species and Bifidobacterium species, produce γ-aminobutyric acid (GABA), which inhibits itch. Supplementation with 1x1010 CFU of Lactobacillus paracasei has been shown to reduce skin sensitivity and transepidermal water loss in healthy adults.²⁹ Additionally, a randomized trial found an initial reduction in eczema in infants aged 4-13 months given Lactobacillus paracasei has been shown to reduce skin sensitivity and transepide108 CFU versus placebo. However, despite this improvement, a follow up at eight to nine years of age showed no difference in the number of AD patients in both groups, suggesting only delayed onset.³⁰

Another lactic acid producing bacterium that has been heavily studied among AD infants is Lactobacillus rhamnosus GG. A systematic review of various nutrient supplements found moderate evidence for the use of Lactobacillus rhamnosus GG in mothers and infants for preventing development and reducing severity of AD.³¹ However, Huang et al conducted a systematic review of studies that utilized Lactobacillus strains and did not find a difference in outcomes with use of Lactobacillus rhamnosus GG. Despite this finding, an analysis of probiotic mixtures demonstrated a significant decrease in AD severity, thus providing evidence towards combined therapy being more effective.³² Additionally, a Cochrane review in 2008 found that probiotics slightly reduced investigator rated eczema severity scores.³³ However, they did not find evidence that probiotics impacted quality of life or patient-rated symptoms of AD.

Though these findings may have been mixed and not as promising overall, the unique nature of the microbiome and heterogeneity of patients involved in the studies may dilute the effects. The various strains of probiotics, the dosages, and the patients themselves may well be variables affecting the outcome of probiotic treatments for AD. Randomized-controlled trials with set dosing, strain or strains, and careful patient selection may be required until we have a more precise understanding of the factors involved.

Topical Microbial Therapies

Topical probiotic treatments have also been of interest in treatment for AD. One study looked at the effect of topical application of Roseomonas mucosa from healthy volunteers in 10 adults and five pediatric AD patients. Despite the sample size being smaller than desired, the study demonstrated a significant decrease in SCORAD (p < 0.01, p < 0.05), regional pruritus (p < 0.01), and steroid application in both cohorts (p < 0.05). Additionally, a significant decrease was seen in the relative proportion of S. aureus in the antecubital fossa area of the pediatric cohort (p < 0.05).³⁴ Unfortunately, a larger follow up study of topical Roseomonas mucosa failed to meet its primary endpoint.³⁵

Recently, there have been developments in bioactive moisturizers that often contain bioactive ingredients. Bioactive moisturizers contain ingredients such as cannabinoids, bioactive lipids, microbiome modulators, and antioxidant enzymes. These moisturizers intend to confer the same functions of traditional moisturizers but with additional biological effects aimed at improving skin function by upregulating lipid synthesis, decreasing neurosensory transmission of itch signals, reversing oxidative stress, decreasing inflammatory cell activity and cytokine release, and modulating skin microbiota.²⁶

An open label study utilized heat-treated Lactobacillus johnsonii NCC 533 lotion (0.93 x 109 CFU/mL) on 31 AD patients, 15 of whom were S. aureus carriers.³⁶ This study demonstrated that the lotion used twice daily for three weeks led to a decrease in mean SCORAD and a significant decrease of S. aureus on treated lesions. Double blind studies have demonstrated efficacy of topical Lactobacillus sakei, Vitreoscilla filiformis, and Lactobacillus reuteri with success in improving severity of AD.^37–39

Overall, there is very promising evidence for the use of topical probiotics, both live or heat inactivated, in therapy of AD. However, similar to oral probiotic treatments, many questions remain and larger blinded randomized trials are needed to ensure efficacy. As a result of the many complexities in treatment, it is reasonable to conclude that re-establishing a robust and diverse microbiome may not be as simple as selecting a single probiotic strain, formulation, or therapy.

Other Promising Therapies

Phage therapy is a newly studied therapy that may be applicable in the treatment of AD. Phage therapy treats bacterial diseases by utilizing the lytic activity of bacteriophages. Phages often only target a specific type of bacteria, which makes it a promising therapy for the selective elimination of bacteria where there exist several types of bacteria, such as on the skin.⁴⁰ A study examined the use of a S. aureus phage in the treatment of AD and found that the phage was able to inhibit the growth of S. aureus. Researchers were able to improve the symptoms and presentation of the skin on mice with AD, despite not achieving complete restoration.⁴¹ Another more recent study was able to demonstrate that a cream formulation with a phage against S. aureus was able to produce a clinically and statistically significant reduction in AD severity in both children and adults.⁴²

Similar to these phages are lantibiotics. Lantibiotics are ribosomally-synthesized antimicrobial peptides produced by Gram-positive bacteria that are characterized by the presence of lanthionine and/or methyllanthionine residues.⁴³ They are of key interest in therapies for AD, as they are observed to have antimicrobial activity against S. aureus.⁴⁴ These lantibiotics were constitutively secreted by bacteria at concentrations that are sufficient to kill S.aureus on the skin surface and highly synergistic with LL-37, an important human antimicrobial peptide.^5,45 These therapies show promising results for potential future treatments that can specifically target S. aureus without severely affecting the rest of the microbiome.

Future Directions

The evidence for oral and topical probiotic formulations continues to expand. We are now also seeing evidence of new agents, such as lantibiotics, bioactive moisturizers, and phage therapies, that may be utilized to combat S. aureus in AD. However, future studies must consider the tremendous complexity of the microbiome and potentially trial multiple treatments at once. AD and its severity are heavily impacted by both skin microbiome diversity, gastrointestinal colonization, and external factors, such as personal exposure to the environment and allergens. Beyond microbial colonization, both gastrointestinal and skin barrier integrity remain vital foundational considerations. Future research may aim to tackle disease severity through these various mechanisms by accounting for nutritional factors, moisturizer utilization, oral and topical probiotics, as well as commensal application, among others.

Future treatments may involve more than just targeting S. aureus and restoring an individual’s unique “microbiome fingerprint.” This may require personalized treatment designed for each patient’s case that may require having knowledge of an individual’s microbiome make up. Having knowledge of an individual’s specifical intestinal, skin, and fecal microbe population may help answer future questions about the difference in severity among AD patients and why certain individuals may be more predisposed to it. It seems increasingly likely that microbes will play a central role in understanding AD and its treatments.

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