Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by dry, itchy, and inflamed skin. It is highly prevalent with 15-20% of children and 1-3% of adults in the world affected, and is associated with reduced quality of life, increased health care expenditure, and other atopic diseases such as allergic rhinitis and asthma.1 The pathophysiology of AD is not completely understood, but genetics, skin barrier function, bacterial diversity of skin, and immune dysregulation have all been implicated.2,3
Current treatment of AD depends on the extent and severity of the condition, and should also consider pruritus, sleep disruption, and involvement of sensitive areas such as the face and folds. While powerful systemic agents exist and continue to be developed, treatment of AD relies heavily on topical preparations such as corticosteroids, calcineurin inhibitors, and emollients. Long-term topical corticosteroid use is linked to numerous side effects including skin thinning, telangiectasia, folliculitis, and contact dermatitis.4 Topical calcineurin inhibitors are generally well tolerated, but the FDA has noted concerns about potential links to cancer with a black box warning for these medications.5,6 An even more extensive black box warning adorns the newest non-steroidal topical Janus kinase (JAK) inhibitor, ruxolitinib as well.7 Thus, despite new additions to the therapeutic armamentarium, there is continued demand for alternatives that have decreased risks and side effects.
In recent years, the interplay between immune cells and commensal microbes on the skin has been implicated in AD. Importantly, patients with AD often display decreased microbial diversity.3 Staphylococcus aureus colonization is associated with AD flares and supports the notion that disruption of the normal skin microbiome is implicated in AD.3 This observation has led to a number of research endeavors aimed at investigating the safety and efficacy of probiotics for topical use in AD. Probiotics can be defined as live microorganisms that confer a health benefit.8 Prebiotics, on the other hand, are non-digestible food ingredients that promote growth/activity of the microbiota and thus benefit the host.8 Synbiotics include products with prebiotic and probiotic components in which the prebiotics selectively promote the probiotic bacteria in the same product.8 There are currently several reported and active clinical trials using topical probiotics for AD. The goal of this systematic review is to assess the interventions and data of the clinical trials.
Material and methods
A database search for articles and trials mentioning ‘topical probiotic AND atopic dermatitis’ was developed for the following databases: MEDLINE (PubMed), EMBASE (Embase.com), CINAHL Plus (EBSCO), Cochrane Library (Wiley), Scopus (Elsevier), Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform from inception on October 17, 2021. All abstracts were reviewed using Rayyan by one author (D.F.) and only those describing the use of topical probiotic in atopic dermatitis were retained (Figure 1). Articles written in languages other than English and poster presentations were excluded from consideration. Three additional studies that did not appear in our literature search were discovered by carefully reviewing the references from prior reviews and one clinical trial was added from prior knowledge. A full text screen was then conducted by one author (D.F.).
There were 9 different bacterial strains used in these interventions: Streptococcus thermophiles, Vitreoscilla filiformis, Lactobacillus sakei, Staphylococus hominis, Staphylococcus epidermidis, Lactobacillus johnsonii, Lactococcus lactis, Roseomonas mucosa, and Lactobacillus reuteri. Vitreoscilla filliformis was the only strain with published results in more than one study. In addition to the one published study assessing Lactobacillus reuteri, a clinical trial is currently recruiting to evaluate the safety and efficacy of Lactobacillus reuteri in children with mild or moderate AD. Of the other clinical trials in progress, one study noted that it would be testing Lactobacillus plantarum. The other noted that it would be testing topically applied Lactobacillus but did not specify the strain.
Common objective clinical measures used to assess improvement in patients included scoring atopic dermatitis (SCORAD) index formula (5 studies), transepidermal water loss (TEWL) (3 studies), or the number of S. aureus colony forming units (2 studies). Subjective tools were also used to evaluate the efficacy of the various treatments.
Manipulating the microbiome in AD clearly has potential to be a novel approach to therapy. While there are many potential ways to achieve this goal, topical application of viable probiotics has substantial evidence of a clinical effect, though there are many unanswered questions and much work remains to be done.
While the results of these studies are promising, there are a few potential confounders and limitations to note. First, some studies allowed concomitant treatment with other active agents including topical corticosteroids, antihistamines, omega-3 fatty acids, and calcineurin inhibitors. This can lead to enhancing the placebo group response, especially in more mild cases, and also may affect the microbiome more directly in ways that are not yet elucidated.
Additionally, there is significant heterogeneity between study designs and endpoints. Design ranged anywhere from a one-time transplant to a 16-week treatment course. Some studies used more objective endpoint measurements including SCORAD and TEWL while others used more subjective endpoints such as parental ratings. Thus, while each of the studies showed some benefit, there is minimal ability to compare the results. Moreover, in nine completed studies, eight different probiotic strains were tested. The variety in agents used leads to a lack of meaningful reproducibility between studies. As such, while the results of each individual study point to a promising role for probiotics in AD management, they cannot be used to support each other.
In addition to problems with drawing comparisons between studies, the study designs implemented also pose issues when extrapolating the results to a larger population. Specifically, the study performed by Crespo testing Lactococcus Lactis used exclusively subjective ratings by parents about the cosmetic efficacy of the emollient. The subjective nature of the evaluation severely limits the generalizability of the study.
Overall, these preliminary trials suggest a beneficial effect and a reassuring safety profile for various strains of topical probiotic bacteria. Undoubtedly, further investigation must continue in this area. More studies should be implemented to corroborate the findings thus far.
No funding sources were secured for this study.
Dr. Lio reports research grants/funding from the National Eczema Association, AOBiome, Regeneron/Sanofi Genzyme, and AbbVie; is on the speaker’s bureau for Regeneron/Sanofi Genzyme, Pfizer, Eli Lilly, LEO, Galderma, and L’Oreal; reports consulting/advisory boards for Almirall, ASLAN Pharmaceuticals, Dermavant, Regeneron/Sanofi Genzyme, Pfizer, LEO Pharmaceuticals, AbbVie, Eli Lilly, Micreos, L’Oreal, Pierre-Fabre, Johnson & Johnson, Level Ex,Unilever, Menlo Therapeutics, Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, and Galderma.
The other authors report no conflict of interest.