The Role of Cutaneous Microbiota Harmony in Maintaining a Functional Skin Barrier PDF

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To order reprints or e-prints of JDD articles please contact [email protected] January 2017 12 Volume 16 Issue 1 Copyright © 2017 ORIGINAL ARTICLES Journal of Drugs in Dermatology SPECIAL TOPIC The Role of Cutaneous Microbiota Harmony in Maintaining a Functional Skin Barrier Hilary E. Baldwin MD,a Neal D. Bhatia MD,b Adam Friedman MD,c Richard Martin Eng,d and Sophie Seité PhDe The Acne Treatment and Research Center, Morristown, NJ a b Therapeutics Clinical Research Inc., San Diego, CA c George Washington School of Medicine and Health Sciences, Washington, DC d L’Oréal Research and Innovation, Tours, France e La Roche-Posay Dermatological Laboratories, Asnières, France ABSTRACT The skin is constantly exposed to various endogenous and exogenous factors that may impact its barrier function at the physical, me- chanical, immunological, and microbial levels. These factors have the potential to initiate or exacerbate a variety of inflammatory skin Do Not Copy conditions, especially those associated with barrier dysfunction. The barrier function of the skin depends upon a symbiotic relationship between resident microbial communities and host tissue. This symbiosis results from complex signals involved in both the innate and adaptive immune responses. Recent research indicates that both bacterial diversity and the relative abundance of different microbes Penalties Apply present on and in the skin, may contribute to skin barrier stability or dysfunction. The objectives of this review are to discuss the rela- tionship between the skin microbiota and skin barrier function and to consider mechanisms that may help its preservation. J Drugs Dermatol. 2017;16(1):12-18. INTRODUCTION H uman skin is a complex barrier organ that provides an considered to be the most important living organisms in this ecological niche for a wide range of microorganisms. ecosystem. Bacteria are present on the skin surface, deeper lay- The majority of these microflora are harmless or ben- ers of the epidermis, the dermis, and dermal adipose tissue.5 eficial, providing protection against pathogens and playing an important role in modulating the host’s cutaneous innate and Evolution in Understanding of Skin Bacteria adaptive immune systems.1 The symbiosis between the skin Our understanding of microorganisms living on and in the skin and its microbiota (microorganisms on and in the skin, typi- has changed dramatically in the last several years. Culture- cally identified by 16S ribosomal RNA surveys)2 depends on a based studies indicated that Staphylococcus epidermidis, other complex “dialogue” and is necessary for healthy skin and an coagulase-negative staphylococci, and coryneforms of the Acti- efficient skin barrier function.1,3 nobacteria phylum were primary bacterial colonizers of the skin.6 However, many organisms may be present that are said to be The skin is constantly exposed to external and internal envi- uncultivable or are outcompeted by organisms that grow more ronmental factors (eg, ultraviolet radiation, pollution, topical readily in culture. The development of culture-independent mo- medications, and skin care products) that can alter the balanced lecular techniques for identification and quantitation of microbial relationship between the skin and its microbiota.3 Such disruption organisms has revolutionized our view of the skin microbiome. may result in increased risk for infections, chronic inflammatory Genomic characterization of bacterial diversity relies on amplifi- skin diseases (eg, atopic dermatitis, psoriasis, rosacea, acne), cation of the 16S ribosomal RNA (16S rRNA) gene by polymerase and complaints of sensitive, pruritic, and irritated skin.4 chain reaction (PCR) directly from skin samples. The 16S rRNA gene exists in all bacteria and archaea but not in eukaryotes ex- The objectives of this paper are to review recent information about cepted for mitochondria. The bacterial landscape obtained by the relationship between skin microbiota and barrier function, and 16S rRNA sequencing is a first step in knowing skin microbiota to consider mechanisms that may aid in its preservation. and then skin microbiome. The main fault of this technology is that it is blind to difference between dead bacteria and living THE SKIN MICROBIOTA bacteria. Secondly, bacteria have inducible genes that can be A single square centimeter of the human skin contains up to expressed and others that are always running. That means that one million microorganisms, including diverse communities even when we get a global picture of what is there, we ignore of viruses, bacteria, fungi, and mites.5 While bacteria account the active genes and how this community works. The 16S rRNA for only 0.1% of this total (1 million/cm2), they are generally contains both conserved regions that serve as binding sites for © 2017-Journal of Drugs in Dermatology. All Rights Reserved. This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD). No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD. JO0117 If you feel you have obtained this copy illegally, please contact JDD immediately at [email protected]  To order reprints or e-prints of JDD articles please contact [email protected] 13 Journal of Drugs in Dermatology H.E. Baldwin, N.D. Bhatia, A. Friedman, et al January 2017 Volume 16 Issue 1 PCR primers and variable regions for taxonomic classification af- of the cutaneous bacterial flora are said to be influenced by ter high-throughput sequencing of the PCR products.6,7 Another gender, age, and ethnicity. Climate, ultraviolet radiation, pol- crucial point is that there is no international standardization for lution, and lifestyle factors including diet, hygiene habits, and sampling methods. Because of this, comparisons between dif- drug and alcohol consumption may also influence the compo- ferent papers can be biased due to the sampling method, the sition of the skin microbiota.19-27 variable 16S rRNA region used, and sometimes by the databases used. Standardization of sampling methods remains a key prob- STRUCTURE AND FUNCTION OF THE SKIN BARRIER lem in comparing results from different studies. The skin barrier, as well as the microbiota, protects the body against a wide range of external dangers. This barrier consists Composition of the epidermis and several layers below it that influence Molecular methods arising from advances in genomic technology function and harbor microbes.3,28,29 The physical barrier of the have permitted a detailed description of the skin microbiota.6,8-11 skin is formed mainly by the stratum corneum, which is com- Bacteria on the skin are from four main bacterial phyla, Actino- posed of dead keratinocytes or corneocytes and proteinaceous bacteria, Firmicutes, Proteobacteria, and Bacteroidetes, and the crosslinking filaments.30,31 The corneocytes are surrounded by three most common genera are Corynebacteria, Propionibacteria, a proteinaceous structure called the cornified envelope. This and Staphylococci.12 The microbiota of the skin varies across its surface, and four main “environments” have been described: 1) Do Not Copy structure consists of a layer of highly crosslinked insoluble proteins covalently bound to a layer of lipids. The lipid matrix Penalties Apply Moist (the axilla, the inner elbow, or the inguinal fold), harbor- forms the main permeability barrier against the invasion of bac- ing mostly Staphylococci and Corynebacteria12; 2) Sebaceous teria and other hazardous substances.31-33 Filaggrin (filament (the forehead, the malar crease, the retroauricular crease, and the aggregating protein) also contributes to the barrier function of back), having a higher density of Propionibacteria13,14; 3) Dry (eg, the epidermis. The breakdown of filaggrin results in the produc- the upper buttock area), hosting predominantly Staphylococci, tion of alanine, pyrrolidone carboxylic acid, and urocanic acid, Propionibacteria, Micrococci, Corynebacteria, Enhydrobacter, and which act as natural moisturizers in the stratum corneum and Streptococci15; and 4) Others (sweat glands or hair follicles), host- lower skin surface pH. Histidine released from filaggrin deg- ing facultative anaerobes, such as Propionibacterium spp.12,16,8 The radation provides protection against ultraviolet light.33,32 The distribution of follicles, eccrine, apocrine, and sebaceous glands S-100 calcium binding domain in the molecular structure of contribute to the variable cutaneous microenvironments as do profilaggrin may play a role in calcium signaling.33 skin pH, moisture, and temperature. This likely selects subsets of bacteria that can thrive in each ecosystem.17 Nucleated keratinocytes in the stratum granulosum and stra- tum spinosum form cell–cell adhesion junctions that also Factors Influencing Bacterial Growth contribute to barrier function.30,31 Importantly, the condition of The skin provides a “culture medium” for the growth of bac- the epidermal barrier depends on physical properties that in- teria. These microorganisms require water, sources of carbon, clude the amount of sebum produced, hydration, and pH.30 nitrogen, and macro-, and microelements. Water is crucial to microbial growth on the skin, and the amount of water avail- The skin also has a chemical barrier that is comprised of defense able to support this growth is referred to as water activity molecules that are expressed constitutively or induced and can (aw). Water activity varies from 0 (no free water available) to either directly inhibit microbial growth or serve as activators and 1.0 (all molecules of water are free).18 Water activity strongly mediators of the innate and adaptive immune responses.34 Kera- influences the growth of microorganisms and differs consider- tinocytes protect against infection via the innate production and ably between the main environments of human skin described release of antimicrobial peptides (AMPs).These molecules, which above.16 Staphylococcus aureus is able to grow until aw of 0.83, are also produced by mast cells, neutrophils, and sebocytes, pro- Staphylococcus epidermidis is less resistant (unable to grow vide innate microbicidal action against infectious pathogens (as below aw of 0.87), and Pseudomonas fluorescens is unable opposed to antibiotics which have more of a static, or inhibitory, to grow below aw of 0.97. Dry skin therefore favors growth of effect). Some AMPs (eg, cathelicidin) also function by triggering potentially invasive Staphylococci and inhibits the growth of inflammatory cell recruitment and cytokine release.35,36 AMPs commensal organisms. Thus, moisturizers play two important can be produced constitutively, or actively induced by proinflam- roles in the barrier function of the skin: 1) Preservation of the matory cytokines or signaling from pattern recognition receptors physical barrier; and 2) Maintenance of the normal composition (eg, Toll-like receptors [TLRs]).35 of the skin microbiota. Role of Skin Microbiota in Protection from Infection and The skin’s bacterial landscape is highly dynamic with both Inflammation the composition and relative abundance of bacteria varying It is becoming increasingly accepted that commensal species considerably across individuals. The diversity and abundance of microorganisms that naturally reside on the surface of the © 2017-Journal of Drugs in Dermatology. All Rights Reserved. This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD). No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD. JO0117 If you feel you have obtained this copy illegally, please contact JDD immediately at [email protected]  To order reprints or e-prints of JDD articles please contact [email protected] 14 Journal of Drugs in Dermatology H.E. Baldwin, N.D. Bhatia, A. Friedman, et al January 2017 Volume 16 Issue 1 skin are an integral part of the innate immune system. These affected by intrinsic (host) and extrinsic (environmental) factors bacteria contribute to protection against pathogen growth by (Figure 1). These factors alter the composition of the skin micro- competing for nutrients and space.3 Some bacteria directly organism community and may influence skin barrier function restrict the growth of competitors via production of antimicro- by inducing an unbalanced microbial state or dysbiosis that bial compound peptides (AMPs) that can inhibit reproduction may be evidenced in chronic inflammatory skin diseases, such of closely related species without affecting the organisms pro- as atopic dermatitis, psoriasis, rosacea, or acne.20,16,39,40 ducing them.3 Those AMPs are called bacteriocins and are very similar to β-defensins secreted by skin cells to regulate specific The composition of bacterial communities depends on skin bacterial population that are overrepresented and detected by characteristics, such as sebaceous gland concentration, mois- the immune system via toll-like receptors (TLR) TLR2 and TLR4, ture content, and temperature, as well as on host genetics and respectively, for gram-positive and gram-negative bacteria.3 exogenous environmental factors.7 For example, defects in the skin structural barrier permit penetration of the epidermis by Commensal bacteria can also provide protection against in- chemical, allergic, and/or infectious agents. This may result in flammation. Bacteria from normal skin, such as S. epidermidis, chronic inflammation and a loss of microbial diversity with an have been shown to suppress inflammation by inducing the associated increase in Staphylococci, including S. aureus.41 Skin secretion of interleukin-10, an anti-inflammatory cytokine, by antigen-presenting cells.37,38 S. epidermidis, as all gram-positive Do Not Copy cells can also affect microbiota by providing specific nutrients or through the synthesis of antimicrobial peptides (Table 1).10 Penalties Apply bacteria, also secretes specific lipoteichoic acids that inhibit both inflammatory cytokine release from keratinocytes and The microorganisms that are living on the skin are also under inflammation triggered by injury through a TLR2-dependent the influence of its water content.18 The influences of other fac- mechanism.38,35 tors are less well understood,39 but there is limited information about the effects of some of them. Antibiotics, corticosteroids, Interplay Between Skin Cells and Bacteria in Host Defense and radiotherapy, and chemotherapy can all influence the composi- Inflammation tion of the skin microbiota.42,12,6,8,4,43,44 It has also been shown that There is a balanced interplay between the host cells and resi- frequent hand washing disturbs skin barrier function, resulting in dent and/or transient bacterial populations that is continuously irritation and changes in the hand skin microbiota.42 FIGURE 1. Current model of relationship between skin barrier and skin microbiota. Barrier disruption Epidermis Inflammation & Skin immunity Dermis impairment Healthy Skin with Damaged Skin Barrier Normal Microbiota with Dysbiosis Sensitive & reactive skin – Key: Atopy & acne & rosacea aggravation... Commensals Pathogenic Bacteria © 2017-Journal of Drugs in Dermatology. All Rights Reserved. This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD). No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD. JO0117 If you feel you have obtained this copy illegally, please contact JDD immediately at [email protected]  To order reprints or e-prints of JDD articles please contact [email protected] 15 Journal of Drugs in Dermatology H.E. Baldwin, N.D. Bhatia, A. Friedman, et al January 2017 Volume 16 Issue 1 TABLE 1. Relationship Between Skin Barrier and Skin Microbiota How Skin Microbiota Interact With Human Skin Barrier May affect corneocytes desquamation and many skin proteins (ie, filaggrin) involved in Proteases stratum corneum cohesion Lipases Break down surface lipids with potentially irritant by-products including fatty acids Virulence factor found in various pathogenic bacteria; essential in host colonization and Ureases in maintenance of bacterial cells in tissues Biofilm Protect bacterial colonies on the skin Bacteriocins Bactericidal peptides regulating bacterial population Quorum sensing Needed for microbiota balance; effect not known on the skin Skin nutrition Supports commensal bacterial growth Immunology by lipopolysaccharides (Gram-negative bacteria) and teichoic acids (Gram- Do Not Copy Skin education positive bacteria) How Human Skin Barrier Interacts With Skin Microbiota Provides nutriments Control climate Penalties Apply Specific culture medium depending on microenvironment (moist, sebaceous, dry) pH, temperature, moisture, and sweat controlled depending on skin area Climate and nutriments Counter-select bacteria growth Bacterial balance regulation β-defensins production Skin microbiota can affect skin barrier function via bacterial of the skin and so changes the growth of a wide range of bac- enzymes, such as proteases, that may impact corneocyte des- teria with the potential to compete with potentially pathogenic quamation or lipases that may break down skin surface lipids organisms.53,54 (Table 1).10 Colonization by pathogenic bacteria may play a sig- nificant role in the breakdown of the skin barrier in patients with Actions of Moisturizers skin diseases.45 S. aureus colonization on the skin is found in up Moisturizers bind water to the stratum corneum, improving to 90% of patients with atopic dermatitis.46 This organism pro- the skin surface hydration. This has been shown repeatedly duces ceramidase, which breaks down ceramides, an essential to improve the epidermal barrier function and reduce sting- component of the skin barrier.47,48 ing, scaling, redness, and cracks associated with xerosis.55 “To moisturize” does not only mean providing moisture, it The Importance of Maintaining Bacterial Diversity also signifies preventing moisture evaporation from the skin. Changes in the normal composition of the skin microbiota can Moisturizers can be formulated with emollient, humectant, contribute to the development of inflammation. In patients with moisturizing, or occlusive agents; and some formulations inflammatory skin disorders, increasing disease severity corre- have potential prebiotic activity since they may provide food lates with decreased microbial diversity overall and an elevated for the skin microbiota.56 Emollient agents also make the skin prevalence of Staphylococci, including both S. epidermidis and softer and more pliable by filling the space between corneo- S. aureus. Several skin disorders (eg, atopic dermatitis and pso- cytes and restoring the physical barrier function. Humectants or riasis) are characterized by shifts in the skin microbiota, most moisturizing agents are water-soluble substances that help the notably loss of protective bacteria and outgrowth of patho- stratum corneum capture water and rebalance the cutaneous genic organisms.5,49,50 This shift has the potential to contribute hydrolipidic film. Occlusive agents create a sealed barrier and to chronic inflammation. For example, S. aureus-associated prevent moisture evaporation from the surface of the epider- molecular patterns bind to TLR2 to initiate long-lasting cutane- mis. Moisturizers may also have anti-inflammatory properties ous inflammation driven by T helper cells.51 that potentially impact the skin microbiota since inflammation has been associated with dysbiosis.57,58 MOISTURIZERS FOR MAINTENANCE OF THE SKIN BARRIER AND A NORMAL SKIN MICROBIOTA Formulation of Skin Care Products Maintaining the normal, highly diverse skin microbiota appears An important focus for the development of skin care products is to be important for skin health, and moisturizers may help to maintaining an ecological balance in each skin niche.59,58,5 Classi- maintain this diversity.52 Moisturizer modifies the water activity cal moisturizers are able to protect the skin, but new-generation © 2017-Journal of Drugs in Dermatology. All Rights Reserved. This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD). No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD. JO0117 If you feel you have obtained this copy illegally, please contact JDD immediately at [email protected]  To order reprints or e-prints of JDD articles please contact [email protected] 16 Journal of Drugs in Dermatology H.E. Baldwin, N.D. Bhatia, A. Friedman, et al January 2017 Volume 16 Issue 1 formulations have been specifically developed to manage in- containing VFB prepared with selenium-rich TSW vs another flammation and preserve or restore both the skin barrier and recommended emollient yielded greater clinical improvements the skin microbiota diversity. with the VFB emollient that were associated with significantly increased genus Xanthomonas. In contrast, the comparator Water product was associated with increases in Staphylococci.41 This Moisturizers can be formulated with deionized water or thermal has been evaluated via high-throughput sequencing approach water. The physicochemical characteristics of thermal water de- that targets the V1-V3 region of the bacterial 16S rRNA gene pend on the nature of the geologic materials through which the as recommended by Meisel JS et al, 2016.72 While inclusion of groundwater has moved. Common soluble minerals include prebiotics in skin preparations appears promising, much more calcium (Ca2+), bicarbonate (CO3H-), silicates, iron compounds, research is required to learn their benefits and limitations. sodium and magnesium salts, sulphur compounds, and met- als.61 Trace elements, including selenium or strontium, as well Other Components as purity and pH are also important parameters that may in- Occlusive agents, such as ceramides, included in moisturizers fluence the specific biological activities of thermal waters. For may be good carbon and nitrogen sources for bacteria. Ce- example, presence of selenium has free-radical scavenging ramidase activity has been detected in bacterial skin flora and and anti-inflammatory properties and also provides protection against toxic heavy metals.61-65 Do Not Copy it has also been noted that skin ceramide levels are reduced in patients with atopic dermatitis.47 These results suggest that Penalties Apply increasing levels of skin ceramides may be important for main- Thermal waters have a unique microbial signature related to tenance of skin health. their specific mineral content. In comparison to deionized wa- ter, thermal water can be viewed as containing prebiotic active Niacinamide (vitamin B3) is combined with emollients in some ingredients (ie, non-viable food components that confer health skin products and it is also employed in culture media for some benefits associated with a modulation of the microbiota).56 The bacteria. It may promote skin health as it has been shown to presence of specific trace elements in thermal water can drive inhibit the growth of methicillin-resistant S. aureus.73 the growth of beneficial bacterial species particularly if they are already found in its natural microbial content.54 CONCLUSION Understanding the complex relationship between normal skin The importance of thermal water is supported by results which barrier function and the skin microbiome is critical for the showed that an emollient containing 50% selenium-rich ther- rational development of new skin care products.42,59,60,53,58,54 mal spring water (TSW) or the use of selenium-rich TSW alone Appropriately developed formulations have the potential to during balneotherapy reduced disease severity and increased selectively increase the activity and growth of beneficial micro- the diversity of skin microbiota in patients with either atopic biota, prevent skin dysbiosis, and restore or maintain efficient dermatitis or psoriasis.66,54 In both groups of patients, there was skin barrier function.41 This is particularly important for condi- an increase in keratolytic bacteria of the Xanthomonadaceae tions in which barrier dysfunction may occur, such as with dry, family that are naturally present at low levels on the skin and in sensitive, and reactive skin; exposure to aggressive cosmetic TSW and a decrease in Staphylococcus spp.66,54 or hygienic routines; after aesthetic procedures; or when taking therapeutics including antibiotics and corticosteroids. The stud- Prebiotics ies reviewed in this paper suggest that inclusion of prebiotics Prebiotics were initially defined as non-digestible food ingredi- eg, ceramides, niacinamide, selenium-rich thermal spring wa- ents that beneficially affect the host by selectively stimulating ter may all increase the efficacy of moisturizers and that some the growth and/or activity of one or a limited number of bac- of this benefit may be due to positive effects on skin microbiota. teria.67 Prebiotics that might be included in skin products also have the potential to support maintenance of the normal skin ACKNOWLEDGMENTS microbiome.60 Relatively little is known about the benefits of The authors would like to thank Tom Prunty and Bob Rhoades this approach, but it has been shown that application of a bio- of AraMed Strategies for medical writing assistance. Their mass lysate of the non-pathogenic gram-negative bacterium, support was funded by La Roche-Posay Dermatological Vitreoscilla filiformis, helped to restore the skin microbiota Laboratories, USA. in patients with atopic or seborrheic dermatitis.68-70 It is inter- esting to note that V. filiformis biomass (VFB) prepared from DISCLOSURES organisms grown in a medium enriched with TSW resulted in S. Seité is an employee of La Roche-Posay, France. more potent stimulation of mRNA expression for and levels of antimicrobial peptides in reconstructed epidermis.71 Treat- This review was supported by La Roche-Posay Dermatological ment of patients with atopic dermatitis using an emollient Laboratories, USA. © 2017-Journal of Drugs in Dermatology. All Rights Reserved. This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD). No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD. JO0117 If you feel you have obtained this copy illegally, please contact JDD immediately at [email protected]  To order reprints or e-prints of JDD articles please contact [email protected] 17 Journal of Drugs in Dermatology H.E. Baldwin, N.D. Bhatia, A. Friedman, et al January 2017 Volume 16 Issue 1 32. López O, Cócera M, Wertz PW, et al. New arrangement of proteins and lipids in the stratum corneum cornified envelope. Biochim Biophys Acta. REFERENCES 2007;1768(3):521-9. 33. De D, Handa S. Filaggrin mutations and the skin. Indian J Dermatol Venereol 1. Salava A, Lauerma A. Role of the skin microbiome in atopic dermatitis. Clin Leprol. 2012;78(5):545-51. Transl Allergy. 2014;4:33. 34. Christensen GJ, Brüggemann H. Bacterial skin commensals and their role as 2. Whiteside SA, Razvi H, Dave S, et al. The microbiome of the urinary tract—a host guardians. 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Skin Pharmacol Physiol. 2015;28(5):269-279. AUTHOR CORRESPONDENCE Sophie Seité PhD E-mail:................……................................. [email protected] © 2017-Journal of Drugs in Dermatology. All Rights Reserved. This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD). No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD. JO0117 If you feel you have obtained this copy illegally, please contact JDD immediately at [email protected]