Microbiome and pediatric atopic dermatitis

Transcription

1 doi: / Journal of Dermatology 2015; 42: REVIEW ARTICLE Microbiome and pediatric atopic dermatitis Claire E. POWERS, 1 Diana B. MCSHANE, 2 Peter H. GILLIGAN, 3 Craig N. BURKHART, 2 Dean S. MORRELL 2 1 Duke University School of Medicine, Durham, 2 Department of Dermatology, University of North Carolina Chapel Hill, 3 Clinical Microbiology-Immunology Laboratories, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA ABSTRACT Atopic dermatitis is a chronic inflammatory skin condition with drastic impacts on pediatric health. The pathogenesis of this common disease is not well understood, and the complex role of the skin microbiome in the pathogenesis and progression of atopic dermatitis is being elucidated. Skin commensal organisms promote normal immune system functions and prevent the colonization of pathogens. Alterations in the skin microbiome may lead to increased Staphylococcus aureus colonization and atopic dermatitis progression. Despite the evidence for their important role, probiotics have not been deemed efficacious for the treatment of atopic dermatitis, although studies suggest that probiotics may be effective at preventing the development of atopic dermatitis when given to young infants. This review will cover the most recent published work on the microbiome and pediatric atopic dermatitis. Key words: antimicrobial cationic peptides, atopic dermatitis, microbiota, probiotics, Staphylococcus aureus. INTRODUCTION Atopic dermatitis is a chronic inflammatory skin condition that primarily arises in childhood. 1 Worldwide, approximately 2 million children suffer from atopic dermatitis with a lifetime prevalence as high as 20% and rising in affluent countries, which are disproportionally affected. 2 The psychosocial and financial burdens of atopic dermatitis on children and their families are great, with time-consuming treatments, diet and household changes, and a significant financial impact of almost $US 1 billion a year in the USA. 3,4 Eighty-four percent of children with atopic dermatitis report difficulty falling asleep and greater than one-third are embarrassed or angry about their appearance. 3 Atopic dermatitis is a common clinical presentation with multiple interrelated etiologies including inflammatory, barrier function and microbial factors (Fig. 1). Alteration of our skin microbiome due to antibiotics and antimicrobial soaps causes a reduction in microbial antigen exposure. This reduced exposure is theorized as a risk factor for the development of atopic diseases such as atopic dermatitis. 5 Indeed, the recent elucidation of the role of the filaggrin (filament aggregating protein) gene in the pathogenesis of atopic dermatitis in a significant number of people supports associations between barrier function and alteration of the skin microbiome in the development of atopic dermatitis. Approximately 42% of atopic dermatitis patients have a filaggrin mutation and abundant Staphylococcus aureus in comparison with normal skin commensals. 6,7 This review will cover the current evidence on the complex effects of the skin microbiome on the pathogenesis and progression of atopic dermatitis and present recent evidence on probiotic use for treatment of atopic dermatitis. ROLE OF THE MICROBIOME IN NORMAL SKIN At birth, newborns possess a fairly uniform microbiome. Its composition is determined initially by mode of delivery, with newborns born vaginally harboring the mother s vaginal flora, dominated by Lactobacillus, and those born by cesarean section inheriting communities similar to those on their mothers skin. 8 Evolution of the microbiome into distinct anatomical niches occurs after infancy until finally, in early childhood, an individual s microbial community achieves relative long-term stability. 9 The skin microbiota is organized by anatomical structures, with sweat glands, hair follicles and sebaceous glands providing unique microbial niches. 10 The antecubital and popliteal fossae, commonly involved atopic dermatitis sites, contain some of the most diverse microbial populations. 5,9 Overarching phyla that dominate the skin microbiome include Actinobacteria (genus Propionibacterium and Corynebacterium), Firmicutes (genus Staphylococcus), Proteobacteria and Bacteroidetes. 5,9 (Fig. 2) Staphylococcus epidermidis, usually a benign commensal, is ubiquitous on the skin and usually colonizes the head, axilla and nares. 11 Numerous microbial species across the skin perform vast and diverse functions. Namely, our microbiota enhance the skin s innate immune response to unwelcome microbes via the production of antimicrobial peptides 12 such as cathelicidins and b-defensins. 13 Skin commensals further modulate immune system development via promotion of type 1 Correspondence: Dean S. Morrell, M.D., Department of Dermatology, University of North Carolina Chapel Hill, 410 Market Street, Suite 400, Chapel Hill, NC 27516, USA. morrell@med.unc.edu Received 10 May 2015; accepted 10 July Japanese Dermatological Association 1137

2 C.E. Powers et al. Acquired stressors ph, RH, PS Sustained barrier defect Inhereited defects FLG LEKTI Cer, free fatty acids, sphingosine Th1 Th2 Cer synthesis S. aureus colonization AMP AD lesion Specific lge Scratching/excoriations T-B-cell activation Pruritus Toxin- + superantigenproducing S. aureus Folliculitus/ impetigo Keratinocytes protease dysregulation neuropeptides Figure 1. Secondary infections can further aggravate barrier abnormality in atopic dermatitis. AD, atopic dermatitis; AMP, adenosine monophosphate; Cer, ceramide; FLG, filaggrin; LEKTI, lymphoepithelial Kazal-type related trypsin inhibitor; PS, psychological stress; RH, relative humidity; Th1, T-helper 1; Th2, T-helper 2. Reprinted with permission from Macmillan Publishers. 49 Glabella Alar crease External auditory canal Nare Manubrium Axillary vault Antecubital fossa Volar forearm Hypothenar palm Interdigital web space Inguinal crease Umbilicus Retroauricular crease Occiput Back Bu ock Gluteal crease Popliteal fossa Plantar heel T-helper (Th)-cell function through interleukin (IL)-1 signaling pathways 14 while potentially inhibiting the development of type 2 Th-cell functions responsible for allergic conditions including atopic dermatitis, asthma and allergic rhinitis. 15 ROLE OF THE MICROBIOME IN ATOPIC DERMATITIS A child s early skin microbiome may positively influence immune system development away from allergic over-sensitization. 16 Evidence supporting this concept offers one explanation for the pathophysiology of atopic dermatitis in a child with decreased skin microbiome richness or diversity. A wealth of epidemiological data on the prevalence of atopic dermatitis in microbedepleted or microbe-exposed groups also bolsters this relationship. Day-care attendance has been linked to increased microbial antigen exposure and reductions in risk of developing atopic dermatitis in some studies 17,18 while other studies have not observed this relationship. 19,20 Early exposure to bacterial endotoxin in the household environment also appears to be protective against developing atopic dermatitis in some studies, 21,22 yet findings of unclear long-term benefits 23 and an increased risk of atopic reactions in high-risk infants 24 have raised concerns about bacterial endotoxin. An intriguing randomized placebo controlled trial treated 2500 pregnant women in Uganda with albendazole during the third trimester in order to observe the effect of this anti-helminthic treatment on development of the infant s microbiome and eventual risk for atopic dermatitis. They found a double-increased risk of atopic dermatitis in the infants whose mothers received albendazole compared with placebo. 25 Another randomized controlled trial treated over 2000 children directly with albendazole and saw no increase in the incidence of atopic disease. 26 Finally, cesarean section, which exposes infants to a limited microbial population as compared with vaginal delivery, was found to increase the Toe web space Ac nobacteria Corynebacteriaceae Propionibacteriaceae Micrococciaceae Other Ac nobacteria Bacteroidetes Cyanobacteria Firmicutes Other Firmicutes Staphylococcaceae Proteobacteria Divisions contribu ng <1% Unclassified Sebaceous Moist Dry Figure 2. Topographical distribution of bacteria on skin sites. The skin microbiome is highly dependent on the microenvironment of the sampled site. The family-level classification of bacteria colonizing an individual subject is shown, with the phyla in bold. The sites selected were those that show a predilection for skin bacterial infections and grouped as sebaceous or oily (blue circles), moist (typically skin creases) (green circles) and dry, flat surfaces (red circles). The sebaceous sites are: glabella (between the eyebrows); alar crease (side of the nostril); external auditory canal (inside the ear); retroauricular crease (behind the ear); occiput (back of the scalp); manubrium (upper chest); and back. Moist sites are: nare (inside the nostril); axillary vault (armpit); antecubital fossa (inner elbow); interdigital web space (between the middle and ring fingers); inguinal crease (side of the groin); gluteal crease (topmost part of the fold between the buttocks); popliteal fossa (behind the knee); plantar heel (bottom of the heel of the foot); toe web space; and umbilicus (navel). Dry sites are: volar forearm (inside of the mid-forearm); hypothenar palm (palm of the hand proximal to the little finger); and buttock. Reprinted with permission from Macmillan Publishers. 50 risk of atopic dermatitis diagnosis among 2500 infants in Germany, 27 but a meta-analysis of data from 1966 to 2007 concluded there was no excess risk. 28 It appears that larger patient populations may be needed to demonstrate the true effect. Observations that skin microbial communities change during atopic dermatitis flare and recovery periods has sparked inter Japanese Dermatological Association

3 Microbiome and pediatric atopic dermatitis est in the ability of skin commensal organisms to promote skin recovery. Traditional atopic dermatitis treatment with antiinflammatory and antimicrobial medications, even if intermittent, has been linked to greater microbial diversity, specifically increases in the populations of Streptococcus, Corynebacterium and Propionibacterium (Fig. 3). 29 In one study, treatment with emollient creams for 84 days caused clinical improvement in 72% of children, whose skin microbial diversity resembled non-diseased skin at study conclusion. 30 The children in the emollient group also had decreased skin abundance of Staphylococcus species at the end of the study. Beyond the skin microbiota, gastrointestinal microbiota may enhance the development of tolerance to allergens. Analysis of terminal restriction fragment length polymorphism of fecal microbiota diversity found that diversity was lower during the first 18 months of life in infants with atopic dermatitis compared with healthy controls. 31 The large ALLERGY-FLORA project studied 318 infants from Europe using only analyzed culturable intestinal bacteria, a less ideal measure of diversity, and failed to identify such a relationship. 32 It has been well established that tissue from atopic dermatitis lesions produces fewer antimicrobial peptides such as cathelicidins and human b-defensins 13 that defend against unwanted microbes. This deficiency suggests alterations in the commensal skin microbiome, which as mentioned above, are known producers of these antimicrobial peptides. 10 It also explains the increased susceptibility to infection by viral, bacterial and fungal pathogens observed in atopic dermatitis. This risk of infection is much lower in psoriasis, a skin disease also considered to be caused by a defective skin barrier but with increased antimicrobial peptides. 33 Given these differences, variances in the skin microbiome may have a role in individuals inflammatory responses and clinical presentations. ROLE OF MICROBIAL PATHOGENS IN ATOPIC DERMATITIS Atopic dermatitis has long been associated with colonization and frequent infections by the pathogen S. aureus. 34 Ninety percent of chronic dermatitis lesions contain S. aureus. This is in contrast to 5% S. aureus colonization in skin of non-atopic individuals. 35 Beyond causing frequent pyogenic infections, the role of S. aureus in the pathogenesis of atopic dermatitis is being elucidated. S. aureus superantigens may stimulate peripheral T lymphocytes that react to form dermatitis lesions. 36 Superantigens also downregulate the production of antimicrobial peptides by halting Th17 T-cell produced IL-17 and IL-22 which drive antimicrobial peptide production in normal skin. 37 Furthermore, patients with atopic dermatitis frequently have elevated IgE levels and often make IgE specific for these superantigens whose levels are positively correlated with disease severity. 38 The fact that topical corticosteroid treatment alone decreases the colonization of S. aureus on atopic skin supports the idea that inflammation may play an 1.0 (a) Mean proportion (b) 1.0 Mean proportion Flare, Flare, Controls Baseline no intermittent Postflare treatment treatment Actinobacteria Corynebacteriaceae Propionibacteriaceae Bacteroidetes Other Proteobacteria Alphaproteobacteria Betaproteobacteria Comamonadaceae Gammaproteobacteria Firmicutes Clostridia Bacilli Streptococcaceae Staphylococcaceae Non-Staphylococcus Staphylococcus, other S. hominis S. epidermidis S. capitis S. aureus Figure 3. Bacterial taxonomic classifications in the atopic dermatitis skin microbiome. (a) Mean relative abundance of the 14 major phyla order in the antecubital and popliteal creases for controls and atopic dermatitis disease states: baseline, flare (no treatment and intermittent) and post-flare. (b) Mean relative abundances for antecubital and popliteal creases of species-level classifications of staphylococcal species. Order of subjects follows A. Reprinted with permission from Cold Spring Harbor Laboratory Press Japanese Dermatological Association 1139

4 C.E. Powers et al. important role in establishing S. aureus colonization of dermatitis lesions. 39 Staphylococcal protein A has also been demonstrated to have direct chemical irritant properties. 40 Other microbes implicated in the exacerbation of atopic dermatitis include S. epidermidis and the yeast species Malassezia. S. epidermidis may be more abundant in patients with atopic dermatitis 41 and the proportion of S. epidermidis on the skin is higher during atopic dermatitis flares than postflare. 29 Patients with atopic dermatitis have higher levels of IgE antibodies against Malassezia as compared with healthy controls. Furthermore, the severity of atopic dermatitis symptoms can improve in some patients after a 1 2-month daily treatment with oral ketoconazole or itraconazole. 42 While these and other microbes play a pathogenic role in the atopic dermatitis progression, none seem to play as critical a role in pathogenesis and progression as S. aureus. IMPLICATIONS FOR MANAGEMENT As information regarding the potential effects of skin microbiome alteration on the pathogenesis of atopic dermatitis has emerged, a plethora of trials looking at use of oral probiotics to both prevent and treat atopic dermatitis have appeared. 43 Table 1 summarizes six most recent randomized clinical trials performed in children selected based upon a PubMed search atopic dermatitis probiotic with the Therapy/RCT filter applied. A 2008 Cochrane review that analyzed 10 randomized trials comprising 781 children found that probiotics are not an effective treatment for atopic dermatitis and that probiotics do carry a small risk of adverse events including infection and bowel ischemia. 44 A second meta-analysis reviewed 10 trials encompassing 1898 children demonstrated that probiotics may be more efficacious at preventing atopic dermatitis than treating it. 45 This meta-analysis found a significant risk reduction in future incidence of atopic dermatitis as high as 61% associated with the use of maternal prenatal and/or infant postnatal probiotics. One of the recent larger trials looking at prevention of atopic dermatitis provided a Lactobacillus probiotic to 425 mothers from 35 weeks of gestation onward, and then to their infants during the first 2 years of life. They found decreased prevalence of dermatitis in these children at 4 years of age in the probiotic group versus placebo but non-significant reductions in Scoring Atopic Dermatitis severity score (SCORAD). 46 As laid out in Table 1 and demonstrated by the 2008 Cochrane review, multiple trials have failed to see any efficacy in treating atopic dermatitis with oral probiotics. Recently, two posters presented at the American College of Allergy, Asthma and Immunology 2014 meeting offered results of a topical probiotic extract (the exact composition of the probiotic extract has not yet been released by the company that produces it) that Table 1. Recent randomized clinical trials on the efficacy of probiotics in the treatment of pediatric atopic dermatitis yield mixed results First author Study population Probiotic Results Country Yang 51 n = 100, ages 2 9 Lactobacillus and Bifidobacterium Wickens 46 Han 52 n = 425, maternal supplementation 35 weeks gestation to 6 weeks, infant supplementation for first 2 years n = 118, ages 12 months to 13 years Lactobacillus rhamnosus or Bifidobacterium animalis Lactobacillus plantarum CJLP133 Gore 53 n = 208, ages 3 6 months Bifidobacterium lactis or Lactobacillus paracasei Wu 54 n = 60, ages 2 14 years, moderate to severe Lactobacillus salivarius Cytokine levels not significantly different at week 6 (IL-4, P = 0.50; P = 0.58; TNF-a, P = 0.82). Improved clinical severity in both intervention and placebo groups at 6 weeks. Decreased cumulative prevalence of dermatitis by 4 years, hazard ratio 0.57 (95% CI ) with L. rhamnosus. Non-significant reductions in SCORAD scores >10 (HR = 0.74 [95% CI = ]). SCORAD at week 14 was lower in the probiotic group than placebo (P = 0.044). Eosinophil count, IFN-c and IL-4 significantly decreased from baseline in intervention group. No significant difference between SCORAD in placebo and each probiotic group. At 8 and 10 weeks, treatment (synbiotic) group SCORAD scores ( ) were significantly lower than controls (prebiotic) ( ). (P = 0.022) van der Aa 55 n = 90, ages <7 months Bifidobacterium breve No significant differences between the symbiotic and the placebo groups in cytokine production and circulating regulator T-cell percentage. Korea New Zealand Korea UK Taiwan Netherlands CI, confidence interval; HR, hazard ratio; IFN, interferon; IL, interleukin; SCORAD, Scoring Atopic Dermatitis severity score; TNF, tumor necrosis factor Japanese Dermatological Association

5 Microbiome and pediatric atopic dermatitis worked equivalently to topical dexamethasone in treating atopic dermatitis. 47 This promising but speculative topical extract may function to disrupt S. aureus biofilms, a concept that has also recently been demonstrated in vitro by showing that topically applied Lactobacillus rhamnosus GG (10 8 colonyforming units/ml) increases epidermal keratinocyte survival during exposure to S. aureus from 25% to 57% (P = 0.01). 48 CONCLUSION Atopic dermatitis is a chronic inflammatory skin condition in the pediatric population characterized by recurrent pruritic flares of disease activity. Destruction of the skin s normal barrier function is likely involved in the pathogenesis of atopic dermatitis 49 and commensal organisms promote normal skin barrier function through the production of antimicrobial peptides that defend against skin pathogens. A lack of normal microbial skin diversity combined with an overabundance of staphylococcal species in patients with atopic dermatitis further leads to disruption of skin-barrier homeostasis. The ability to analyze the makeup of the human microbiome is expanding rapidly with the use of sensitive high-throughput DNA sequencing 5 rather than data from cultured isolates. Understanding the breadth of the skin microbiome and its protective role offers novel insights into the relationship between the microbiome and atopic dermatitis disease progression. The ability to harness the human microbiome in order to treat common inflammatory conditions such as atopic dermatitis has not yet been fully realized. Randomized clinical trials of probiotics to treat atopic dermatitis have not demonstrated efficacy, especially when compared with traditional treatment modalities. However, more evidence exists for using probiotics to prevent atopic dermatitis development. Most probiotics for atopic dermatitis have only contained one or two microbes, which is in contrast to the normal skin that maintains a plethora of commensal organisms. Therefore, even if deemed effective, the exact composition, along with the route of administration and safety of an eventual probiotic treatment, must be determined. CONFLICT OF INTEREST: None declared. REFERENCES 1 Williams H, Robertson C, Stewart A et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999; 103: Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy 2014; 69: Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB Jr, Manuel JC. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol 2005; 22: Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. 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