Label the Image to Review Important Structures of the Skin
Nat Rev Microbiol. Author manuscript; available in PMC 2013 Jan 3.
Published in last edited class as:
PMCID: PMC3535073
NIHMSID: NIHMS424100
The skin microbiome
Abstract
The skin is the human body'due south largest organ, colonized by a diverse milieu of microorganisms, well-nigh of which are harmless or even beneficial to their host. Colonization is driven by the ecology of the pare surface, which is highly variable depending on topographical location, endogenous host factors and exogenous ecology factors. The cutaneous innate and adaptive immune responses can modulate the skin microbiota, only the microbiota besides functions in educating the allowed organization. The development of molecular methods to place microorganisms has led to an emerging view of the resident peel bacteria equally highly various and variable. An enhanced understanding of the peel microbiome is necessary to gain insight into microbial involvement in human skin disorders and to enable novel promicrobial and antimicrobial therapeutic approaches for their treatment.
The pare is an ecosystem composed of 1.8 m2 of diverse habitats with an affluence of folds, invaginations and specialized niches that support a broad range of microorganisms. The master office of the peel is to serve equally a concrete barrier, protecting our bodies from potential attack by foreign organisms or toxic substances. The skin is besides an interface with the exterior environment and, as such, is colonized by a diverse collection of microorganisms — including bacteria, fungi and viruses — as well as mites1–seven (FIG. i). Every bit we draw, many of these microorganisms are harmless and in some cases provide vital functions that the homo genome has not evolved. Symbiotic microorganisms occupy a wide range of skin niches and protect against invasion by more pathogenic or harmful organisms. These microorganisms may too take a role in educating the billions of T cells that are plant in the pare, priming them to answer to similarly marked pathogenic cousins.
Schematic of skin histology viewed in cross-section with microorganisms and peel appendages
Microorganisms (viruses, leaner and fungi) and mites cover the surface of the pare and reside deep in the hair and glands. On the skin surface, rod and round bacteria — such as Proteobacteria and Staphylococcus spp., respectively — course communities that are deeply intertwined among themselves and other microorganisms. Commensal fungi such as Malassezia spp. abound both as branching filamentous hypha and as individual cells. Virus particles live both freely and in bacterial cells. Skin mites, such every bit Demodex folliculorum and Demodex brevis, are some of the smallest arthropods and live in or near pilus follicles. Skin appendages include pilus follicles, sebaceous glands and sweat glands.
The perception of the pare every bit an ecosystem — composed of living biological and physical components occupying diverse habitats — tin can advance our understanding of the fragile balance betwixt host and microorganism. Disruptions in the balance on either side of the equation tin result in skin disorders or infections. Perturbations affecting the host–microorganism relationship tin can be endogenous (for case, genetic variation that selects for a specific microbial community) or exogenous (for example, hand washing). To farther our understanding of health, disease and infection of the peel, microbiologists, immunologists and dermatologists have partnered with genomic scientists to develop a more complete characterization of the skin microbiota and how it interacts with the host (FIG. 2).
Factors contributing to variation in the skin microbiome
Exogenous and endogenous factors discussed in this Review that contribute to variation betwixt individuals and over the lifetime of an individual.
The habitat of the skin divers
The physical and chemical features of the skin select for unique sets of microorganisms that are adapted to the niche they inhabit. In general, the skin is absurd, acidic and desiccated, but singled-out habitats are determined past pare thickness, folds and the density of pilus follicles and glandsviii. Structurally, the epidermis is a formidable concrete bulwark, resisting penetration by microorganisms and potential toxins while retaining moisture and nutrients within the body9–11. The meridian layer of the epidermis, the stratum corneum (FIG. 1), is composed of terminally differentiated, enucleated keratinocytes, that are known as squames. Squames consist of keratin fibrils and crosslinked, cornified envelopes embedded in lipid bilayers, forming the 'bricks and mortar' of the epidermis11. The pare is a continuously self-renewing organ, and squames are constantly shed from the peel surface as the final stage of last differentiation, having begun their migration from the basal layer ~4 weeks earlier12.
Invaginations and appendages
Cutaneous invaginations and appendages, including sweat glands (eccrine and apocrine), sebaceous glands and hair follicles, are likely to be associated with their own unique microbiota13 (FIG. one). Eccrine glands, which are more than arable than apocrine glands, are institute on nearly all peel surfaces and continuously breast-stroke the skin surface with their secretion, which is composed mainly of water and common salt. The main office of eccrine sweat is thermoregulation through the release of latent heat from the evaporation of h2o. Additional functions of eccrine glands include excretion of water and electrolytes, and acidification of the pare, which prevents the colonization and growth of microorganisms. Apocrine glands, which are located in the axillary vault (armpit), nipple and genitoanal regions, answer to adrenaline by producing milky, sticky, odourless secretions. Apocrine secretions have long been postulated to incorporate pheromones, which are molecules that trigger sure behaviours (for example, sexual or alarm) in the receiving individualfourteen. The stereotypical odour associated with sweat derives from bacterial processing and utilization of apocrine gland secretions15–18.
Sebaceous glands are continued to the pilus follicle, forming the pilosebaceous unit, and secrete the lipid-rich substance sebum. Sebum is a hydrophobic coating that protects and lubricates the peel and hair and provides an antibacterial shield. Sebaceous glands are relatively anoxic and support the growth of facultative anaerobes such equally Propionibacterium acnes, a mutual skin commensal bacteriumiii,13. Full genome sequencing of P. acnes has revealed multiple genes encoding lipases that degrade peel lipids of sebum19. P. acnes hydrolyses the triglycerides present in sebum, releasing free fatty acids onto the pare20,21. The bacterium tin so attach to these complimentary fatty acids, and this peradventure aids in the colonization of the sebaceous gland22. These gratuitous fatty acids also contribute to the acidic pH (~five) of the peel surface4,10. Many common pathogens, such as Staphylococcus aureus and Streptococcus pyogenes, are inhibited by an acidic pH, thus the growth of coagulase- negative staphylococci and corynebacteria is favouredx,23–25. However, skin apoplexy results in an elevated pH, which favours the growth of S. aureus and Southward. pyogenes 24. Because humans produce much greater quantities of triglyceride-containing sebum than other mammals, P. acnes is nowadays in greater abundance on homo skin than on the skin of other mammals26.
Topography
The skin surface varies topographically owing to regional differences in skin beefcake and, according to culture-based studies, these regions are known to support distinct sets of microorganisms. Some regions of the pare are partially occluded, such as the groin, axillary vault and toe spider web. These regions are higher in temperature and humidity, which encourages the growth of microorganisms that thrive in moist weather condition (for instance, Gram-negative bacilli, coryneforms and S. aureus)four. The density of sebaceous glands is another factor that influences the skin microbiota, depending on the region. Areas with a high density of sebaceous glands, such every bit the confront, chest and back, encourage the growth of lipophilic microorganisms (for instance, Propionibacterium spp. and Malassezia spp.)4. Compared with other peel sites, arm and leg skin is relatively desiccated and experiences large fluctuations in surface temperature. Using culture-based methods, these areas were found to harbour quantitatively fewer organisms than moist areas of the skin surface3.
Host factors
Factors specific to the host, such as historic period, location and sex, contribute to the variability seen in the microbial flora of the peel (FIG. 2). Age has a great event on the microenvironment of the skin and, thus, on the colonizing microbiota27,28. In utero, fetal skin is sterile, but colonization occurs immediately afterwards nativity, either during vaginal delivery or in the minutes following birth by caesarian section29,30. I area for future enquiry is to explore how the microbial communities of the pare and other sites are established and stabilized during the start years of life, as a newborn baby explores its environment and matures its immune organization31. During puberty, changes in sebum production parallel the levels of lipophilic bacteria on the pare, as determined by civilisation-based approaches28. Physiological and anatomical differences between male and female cutaneous environments such as sweat, sebum and hormone production, partially business relationship for the microbial differences seen between the genders32–34.
Ecology factors
Environmental factors specific to the private, such as occupation, wear pick and antibiotic usage, may attune colonization by the skin microbiota (FIG. ii). The effect of antibiotic treatment on the gut microbiota has been examined using molecular methods35–37 just, to our knowledge, a similar assessment of skin microbiota in healthy individuals does not exist. Cosmetics, soaps, aseptic products and moisturizers are likewise potential factors contributing to the variation of skin microbiota. These products alter the conditions of the skin bulwark but their effects on skin microbiota remain unclear. Quantitative culture demonstrated that loftier-temperature and high-humidity are associated with increased quantities of bacteria on the dorsum, axillary vaults and feet as compared with loftier-temperature low-humidity conditions38. In the same written report, loftier humidity and low temperature atmospheric condition were associated with a higher frequency of Gram-negative leaner on the back and feet. Ultraviolet (UV) calorie-free is a welld-ocumented bactericidal treatment39, and one tin imagine geographical variability in pare microbiota correlating with the longitudinal and/or latitudinal variation in UV exposure.
Molecular analysis of peel microbiota
Genomic approaches to characterize skin bacteria have revealed a much greater diversity of organisms than that revealed past culture-based methods33,40–43 (BOX i). As defined by 16S ribosomal RNA metagenomic sequencing, most skin bacteria autumn into four different phyla: Actinobacteria, Firmicutes, Bacteroidetes and Proteobacteria. These 4 ascendant phyla also constitute the microbiota that is found on the inner mucosal surfaces (the gastrointestinal tract and oral cavity44–49). Nonetheless, the proportions differ vastly: whereas Actinobacteria members are more arable on skin, Firmicutes and Bacteroidetes members are more arable in the gastrointestinal tract. A common characteristic of gut and skin microbial communities seems to be low diversity at the phylum level, but high diversity at the species level.
Variation by peel site
Molecular approaches examining bacterial diversity have underlined the concept that the pare microbiota is dependent on the body site and that caution should be taken when selecting and comparing sites for skin microbiome studies. Our group and others have demonstrated that colonization of leaner is dependent on the physiology of the skin site, with specific bacteria beingness associated with moist, dry and sebaceous microenvironments (FIG. iii). In full general, bacterial diversity seems to exist everyman in sebaceous sites, suggesting that there is pick for specific subsets of organisms that can tolerate weather condition in these areas. Sebaceous sites that contain low phylotype richness include the forehead (six phylotypes43), the retroauricular crease (behind the ear) (fifteen phylotypes42), the back (17 phylotypes42) and the alar pucker (side of the nostril) (18 phylotypes42). Propionibacterium spp. are the dominant organisms in these and other sebaceous areas, which confirms classical microbiological studies that describe Propionibacterium spp. as lipophilic residents of the pilosebaceous unit. Microbial transplant experiments suggest that the microenvironment of sebaceous areas (such as the forehead) is a stronger force in determining microbial colonization than the microenvironment of dry areas (such as the forearm)43.
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 are grouped every bit sebaceous or oily (blue circles), moist (typically peel creases) (dark-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 breast); 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 spider web space; and umbilicus (navel). Dry out sites are: volar forearm (inside of the mid-forearm); hypothenar palm (palm of the paw proximal to the pinkie); and buttock. Data from REF. 42.
Metagenomic analysis has revealed that Staphylococcus and Corynebacterium spp. are the most arable organisms colonizing moist areas42,43, consequent with civilization information suggesting that these organisms prefer areas of high humidity. These moist sites include the umbilicus (navel), the axillary vault, the inguinal pucker (side of the groin), the gluteal pucker (topmost function of the fold between the buttocks), the sole of the foot, the popliteal fossa (backside the knee) and the antecubital fossa (inner elbow). Staphylococci occupy an aerobic niche on the skin and probably use the urea present in sweat as a nitrogen source. Corynebacteria are extremely fastidious and slow-growing organisms in civilization, and, as such, their role as peel microorganisms has been underappreciated until recently. Processing of apocrine sweat by corynebacteria and staphylococci (forth with other axillary vault microorganisms) results in the characteristic malodour associated with sweat in humans15,16,18,50.
The most diverse skin sites are the dry areas, with mixed representation from the phyla Actinobacteria, Proteobacteria, Firmicutes and Bacteriodetes40,42,43. These sites include the forearm, buttock and various parts of the hand. A surprising characteristic of the microbiota of these sites is the abundance of Gram-negative organisms that are captured by molecular analysis; these were one time thought to colonize the pare just rarely, as contaminants from the alimentary canal1,four. Interestingly these sites too harbour greater phylogenetic diversity than the gut or the oral cavity of the same private43.
Temporal variation
Molecular analysis of skin microbiota has also revealed that the temporal variability of the pare microbiome is dependent on the site sampled. The nigh consistent sites over fourth dimension, when considering bacterial community membership and community structure, were the external auditory canal (within the ear), the nare (within the nostril) and the inguinal crease42. These are all sites that are at least partially occluded. In full general, sites that harbour a greater diversity of microorganisms tend to exist less stable over time in terms of community membership and structure; these sites include the volar forearm (forearm), the popliteal fossa, the antecubital fossa, the plantar heel (the bottom of the heel of the foot) and the interdigital web space (between the fingers) 42. Compared with the microbiome of the gut and the mouth, the microbiome of the skin had the greatest variability over time43
Interpersonal variation
In general, intrapersonal variation in microbial community membership and structure between symmetric skin sites is less than the interpersonal variation, as adamant past 16S rRNA metagenomic sequencing40,42,43. The leaner that populate the sebaceous back are predominantly Propionibacterium spp., with some representation from the Betaproteobacteria (phylum Proteobacteria) and the Flavobacteriales (phylum Bacteroidetes). Although all three of these bacterial taxa are also establish on the antecubital fossa and the plantar heel, the relative amounts of Propionibacterium spp. are much lower at these sites, which have a greater abundance of Betaproteobacteria and Staphylococcus spp., respectively. As shown in FIG. four, the antecubital fossa, back, nare and plantar heel are more like to the same site on another individual than to any other site on the same individual. In this sense, the ecological torso site niche is a greater determinant of the microbiota composition than the individual genetic variation among healthy volunteers (FIG. four). Some sites on an individual are similar, but these are sites such as the antecubital fossa and popliteal fossa that share common ecological features.
Interpersonal variation of the skin microbiome
The microbial distribution of four sites on four salubrious volunteers (HV1, HV2, HV3 and HV4) is depicted at the antecubital fold (inner elbow; part a); the dorsum (role b); the nare (inside the nostril; part c); and the plantar heel (bottom of the heel of the foot; part d). Skin microbial variation is more dependent on the site than on the individual. Bars represent the relative affluence of bacterial taxa as determined by 16S ribosomal RNA sequencing. Data from REF. 42.
A study with larger numbers of patients will be required to statistically define which bacterial species are unique to certain individuals or torso sites. In a written report of six subjects, information technology was shown that only 6.6% of all genera identified were plant on the forearms of all subjects sampled, and 68.ane% of genera identified were nowadays on only one subjectxl. In a study of mitt microbiota, hands from the aforementioned individual shared but 17% of species-level phylotypes, whereas easily from different individuals shared only 13%33. The frequency of hand washing, the degree of exposure to environment elements and handedness preference probably all contribute to the variation that is seen in the skin microbiota of the hand. Comparisons of male and female person skin microbiota advise that females harbour a greater variety of bacteria on their hands, but information technology remains unclear whether this observed difference is due to physiological factors or differences in hygiene and cosmetic usage33,xl. Our piece of work has demonstrated that interpersonal variation, every bit measured by shared community membership and structure, is lowest in sebaceous areas such as the alar crease, the back and the manubrium (upper chest)42. These studies describe the skin microbiota as predominately composed of a scattering of stable inhabitants (Propionibacterium and Staphylococcus spp.). Rare and/or transient species brand up the balance and business relationship for interpersonal variation. Factors driving the variability are unclear, but nosotros propose that they may include external environmental factors (for example, climate and geography), host immune status, host pathophysiology and/or historical exposures.
Further challenges: defining the functional potential of the skin microbiome
Although molecular approaches to surveying bacterial variety provide a less biased depiction of pare microbiota than culture-based assays, they are not without their caveats. The molecular approaches that are currently in apply are unable to distinguish between 16S rRNA genes that are derived from living versus dead organisms. Therefore, molecular studies are technically surveying the history of the skin microbiota. As the skin is an organ that is exposed to the surroundings, it is difficult to determine which of the identified species are transient and which species are resident members of the community. In addition, biases be in the methods that are used to extract, amplify and sequence 16S rRNA genes. Fifty-fifty degenerate PCR primers may not amplify all 16S rRNA genes with equal efficiency. Furthermore, typing of 16S rRNA genes does not provide information regarding the cistron content of flexible, open pan-genomes or plasmids. For example, 16S rRNA gene phylotyping cannot distinguish between methicillin-sensitive and methicillin-resistant Staphylococcus spp. isolates.
Only whole-genome shotgun metagenomic sequencing (WGS metagenomic sequencing) of bacterial communities will ascertain their full genetic variety and enable prediction of the gene functions that are associated with the skin microbiota. WGS metagenomic sequencing has proved to exist useful in identifying the functional potential of gut microbiomes, revealing the increased energy harvesting potential of the obesity-associated gut microbiota51. To date, WGS metagenomic analysis of skin microbiota has not been reported. Several factors delay this blazon of analysis of skin microbiota. One such factor is the lack of reference genome sequences for peel isolates; this is probable to exist due to the difficulty in culturing some peel microorganisms such as the corynebacteria. Furthermore, obtaining the critical corporeality of starting textile required for WGS metagenomic sequencing, free of contaminating host DNA, is challenging for skin. Before skin metagenomic sequencing is tractable on a big calibration, robust methods demand to exist farther developed to separate host Deoxyribonucleic acid from microorganism DNA, followed by unbiased whole-genome distension.
Beyond the bacterial microbiome
Molecular approaches have been used to characterize eukaryotic species colonizing the skin, although these methods are not as well developed. The fungal phylogeny has been established using data from half-dozen genes: 18S rRNA, 28S rRNA, v.8S rRNA, elongation cistron 1α and two RNA polymerase Two subunits52. When performing molecular surveys of fungal diverseness, the most commonly analysed region is the internal transcribed spacer region that separates the small- and large-subunit rRNA genes in eukaryotes53. Most fungal organisms identified on the healthy skin by molecular typing resemble Malassezia spp., closely mirroring civilisation-based information54–56. In one report, Malassezia spp. were calculated to establish 53–eighty% of the total skin fungal population, depending on the peel site, with the retroauricular crease harbouring the highest proportion56. Information technology nevertheless remains unclear which fungal species plant the rest of the population, and farther investigation is warranted. Culture-based analysis suggests that Candida spp. rarely colonize human skin only can cause clinical infection especially in atmospheric condition of allowed deficiency, diabetes or infection following antibody usefour,57. Other types of fungi that, co-ordinate to culture-based analyses, are idea to grow on the skin, include Debaryomyces and Cryptococcus spp.3, although this has not been confirmed past molecular assay of pare fungal biota. Larger, more than all-encompassing studies of the human skin fungi are needed, as well equally improve approaches for identifying and analysing fungal sequences.
Demodex mites (such as Demodex folliculorum and Demodex brevis), which are small arthropods, have historically been associated with rosacea, equally well equally a range of other pare disorders, including facial itching and chronic blephartitis58–sixty. Demodex mites reside in the pilosebaceous units, about commonly of the facial skin, and are considered part of the normal skin microflora60,61. Molecular methods for typing Demodex mites do not exist. Methods for isolating and identifying viruses from skin are simply being adult, such as rolling-circle distension62. These microorganisms are likely to be an important component of the skin ecosystem; thus, farther analysis of their diversity and colonization dynamics are warranted (FIG. i). To our knowledge, archaea have not been identified on the skin, either by culture or past molecular analyses.
Modulation by the cutaneous immune system
In improver to being a physical barrier, the pare is an immunological bulwark63. The skin allowed response is vital in wounding and infection and likewise modulates the commensal microbiota that colonizes the skin. Keratinocytes continuously sample the microbiota colonizing the skin surface through pattern recognition receptors (PRRs), such as Toll-similar receptors (TLRs), mannose receptors and the NOD-similar receptors. These receptors recognize pathogen-associated molecular patterns (PAMPs) including flagellin and nucleic acids, as well as lipopolysaccharide from Gram-negative leaner, mannan and zymosin from fungal jail cell walls, and peptidoglycan and lipoteichoic acid from Gram-positive bacteria. The activation of keratinocyte PRRs by PAMPs immediately initiates the innate allowed response, resulting in the secretion of antimicrobial peptides (AMPs), cytokines and chemokines. Across effecting an adaptive immune response, AMPs also straight kill bacteria, fungi and enveloped viruses64. Therefore, there is a constant interplay among keratinocytes, immune cells and microorganisms that is modulated by AMPs, cytokines, chemokines and microbial peptides.
Despite being constantly exposed to large numbers of microorganisms, the skin can discriminate betwixt harmless commensal microorganisms and harmful pathogenic microorganisms. The mechanism of this discrimination is not fully clear, but may involve the induction of allowed tolerance; TLRs may be desensitized by prolonged exposure to commensal microorganisms, either through decreased TLR expression on the prison cell surface or past activation of the TLR pathway inhibitors interleukin-one receptor-associated kinase 3 (IRAK3; also known as IRAK-M) and suppressor of cytokine signalling 1 (SOCS1)65,66. Specificity may likewise be accomplished by combined recognition of PAMPs by PRRs.
Staphylococcus epidermidis, a commensal bacterium, has recently been demonstrated to modulate the host innate immune response. Phenol-soluble modulins produced by S. epidermidis can selectively inhibit skin pathogens, such as South. aureus and Group A Streptococcus, and can even co-operate with host AMPs to raise killing67,68. Recent studies demonstrate that commensal-induced TLR signalling may be necessary for jail cell survival and repair during infection. Lipoteichoic acid produced by S. epidermidis tin can inhibit skin inflammation through a TLR2- and TLR3-mediated crosstalk mechanism69. In addition, Southward. epidermidis triggers keratinocyte expression of AMPs through a TLR2-dependent mechanism70. This body of work definitively links commensal pare microorganisms with modulation of the innate allowed response.
Dysregulation of the peel immune response is apparent in several skin disorders (for instance, psoriasis, atopic dermatitis (AD; commonly known every bit eczema and contact dermatitis), just how dysregulation affects and/or results from changes in the microbiota remains unclear. AD lesions are characterized past low levels of AMP production as compared with levels from normal skin. This is in sharp contrast to psoriatic lesions, which produce abundant quantities of AMPs and are characterized by an activated innate immune response71–75. Advertising lesions are also regularly infected with pathogens, especially Due south. aureus, and reply to antimicrobial treatment. Upregulation of T helper 2 cytokines in Ad lesional peel is likely to partially account for the apparent suppression of the innate immune response that is observed in AD71,72. There is no clear microbial component to the common form of psoriasis, although the guttate subset of psoriasis has been associated with streptococcal infections76.
The skin microbiome and affliction
Many common peel disorders are postulated to have an underlying microbial contribution because clinical improvement is seen with antimicrobial treatments. Yet, a causative microbial component that fully satisfies Koch'southward postulates has rarely been identified in these skin diseases. We illustrate the different ways in which a skin disease can exist associated with a specific organism with three cases: start, peel disorders with a correlation to microbiota; second, a skin disorder with a currently unidentified microbial component; and third, a skin commensal that can become invasive to cause infection.
Skin disorders with a correlation to microbiota
Seborrhoeic dermatitis is a hyperproliferative, pruritic skin disorder, typically affecting the scalp. A fungal component is postulated to participate in disease pathogenesis, as a wide range of fungicides effectively combat seborrhoeic dermatitis.The presumptive target of these fungicides is Malassezia spp., which are the dominant fungi cultured from the peel and are particularly prevalent in sebaceous areas such as the scalp. Improvements in seborrhoeic dermatitis are associated with reduced levels of Malassezia spp. on the scalp77. However, improvement is non observed when the scalp is treated with antibacterial agents78. The suggested mechanism for comeback implicates Malassezia lipase genes, which process sebum to release complimentary fat acid metabolites (oleic acid). These metabolites then penetrate upper layers of the skin to promote hyperproliferation and inflammation79. As Malassezia spp. are present on healthy skin, and past themselves are not sufficient to cause seborrhoeic dermatitis, other factors probably contribute to their pathogenicity and ability to crusade disease.
The commensal pare bacterium P. acnes is associated with the very common teenage malady acne, an inflammatory disorder of the pilosebaceous unit. The onset of puberty matures the pilosebaceous unit, increasing the preponderance of lipophilic microorganisms, especially P. acnes, which secretes lipases, proteases and hyaluronidases that hurt the tissue lining of the pilosebaceous unit of measurementfourscore. The P. acnes genome encodes various immunogenic factors, including prison cell surface proteins with adherent properties and porphyrins19. Furthermore, the harm caused by P. acnes in the pilosebaceous unit activates the classical and culling complement pathways81,82 and induces product of pro-inflammatory cytokines83,84 and neutrophil chemotactic factors85,86. Yet, the use of molecular methods to examine the bacterial component of acne has been limited, and a minor sequencing study did not place any novel acne-associated leaner87.
Advertising is a chronic relapsing disorder that affects ~15% of US children and ~2% of adults, and is also associated with microbial colonization and infection. The prevalence of Advertisement has doubled or tripled in industrialized countries over the by three decades with no articulate cause. This raises the intriguing possibility that pare microbial fluctuations modulate the gene–environment interaction on the peel surface, resulting in the episodic exacerbations of Advert. Classic AD manifests at stereotypical sites, including the antecubital fossa and the popliteal fossa, which are sites that harbour similar organisms when compared to other trunk sites42. More than than 90% of Advertizing patients are colonized with S. aureus on both lesional and non-lesional skin, compared with <5% of healthy individuals88,89. The most common treatments for Ad include topical or systemic antibiotics, and steroids. Dilute bleach baths to lower the bacterial load are effective in reducing clinical severity90. No specific link has been identified between virulence factors expressed by S. aureus and flare-ups in patients with AD. However, in a mouse model that has reduced skin barrier function (the NC/Nga strain, which is deficient in ceramide production91), awarding of S. aureus immunoglobulin Thou-binding protein A (also known equally Staphylococcus protein A) along with an agitating detergent resulted in a severe AD-similar phenotype92.
Disorder with an unidentified microbial component
Chronic wounds, affecting diabetic, elderly, and immobile individuals, are an example where commensal skin organisms invade and become pathogenic upon breach of the skin bulwark. Although bacteria practise non cause the initial wounding event, they are thought to contribute to the lack of healing and persistent inflammation that is associated with chronic wounds. As for healthy pare, the microbial diversity colonizing chronic wounds is greater when analysed using molecular methods as opposed to civilisation-based methods93. All the same, molecular studies thus far have been unable to place a unique organism that colonizes wounds of the same aetiology (for instance, in diabetic pes ulcers or venous leg ulcers)94–96. This is in dissimilarity to burn down wounds, in which a causative microbiological amanuensis is ordinarily readily identifiable. Fire wounds commonly go infected with S. pyogenes, Enterococcus spp. or Pseudomonas aeruginosa, and tin can also become infected with fungi and/or viruses97.
A major problem in dissecting the clinical relevance of chronic wound microbial variety data sets is the ecology and genetic factors that may confound results, especially when the precise clinical phenotyping data that could exist used to stratify patient populations are absent-minded. One way to circumvent misreckoning factors when analysing host–microorganism relationships is to use an animal model. This arroyo has allowed the identification of a longitudinal selective shift in the microbiota colonizing slow-healing diabetic mouse wounds; the shift is correlated with abnormal expression of skin defense force and inflammatory genes98.
S. epidermidis: an invasive skin commensal that causes infection
The third category is that of skin microorganisms that are normally commensal but that tin sometimes crusade infection and illness, particularly when they invade other sites. S. epidermidis is a very mutual skin commensal, merely information technology is also the most frequent cause of infirmary- acquired infection on in-dwelling medical devices such as catheters or middle valves99. After they gain entry, virulent strains of these organisms can grade biofilms on catheters or other devices, which protects them from the host allowed organisation and antibiotics. Increasing levels antibiotic resistance, particularly to oxacillin or methicillin, complicates treatment of S. epidermidis infections. Furthermore, Due south. epidermidis seems to be a reservoir of antibody-resistance genes that it transfers to the closely related merely more than virulent organism, S. aureus 100.
Conclusions and perspectives
Molecular approaches to characterizing microbial variety accept dramatically inverse our view of the skin microbiome, later on raising many important questions near the host–microorganism relationship and its relevance to skin disease. Although information technology is at present clear that several dominant organisms (that is, Staphylococcus and Propionibacterium spp.) constitute a big proportion of the pare microbiota, little is understood nigh the rare or transient organisms making up the rest. It is unclear what factors drive variation in these organisms, and how fluctuation is associated with skin disease. Metagenomic analysis to elucidate the full complement of microbial genes and their functions should provide insight into these questions. The The states National Institutes of Health Common Fund Human Microbiome Project aims to characterize the human microbiota and its office in health by examining the microbial diversity of 250 healthy volunteers sampled at 18 pare sites, including 2 skin sites, nine oral crenel sites, the nare, the stool and five vaginal samples for women101. These results from healthy volunteers will be used to guide and examine the statistical power of clinical studies, including investigations into the skin disorders acne, Advertizing and psoriasis.
Although at that place is a full general agreement that microorganisms are potential components of many pare disorders, including those described here, footling is understood about their contribution and how it relates to the genetic and ecology variation that besides contributes to the disease. Many mutual skin diseases are associated with a specific stage of life, a specific topographical location and/or specific microorganisms. Whether this specificity is driven by the endogenous microbial community structure remains to be adamant. Several skin sites with a predilection for affliction, such as the glans penis and the eyelids, remain to be sampled and characterized for bacterial diversity.
Another outstanding question is whether ethnic skin microorganisms provide some benefit to the host, and whether they are truly symbiotic, or commensal. In a recent example of host and microorganism joining forces to combat invasion by pathogens, the commensal peel bacteria S. epidermidis was demonstrated to inhibit nare colonization and biofilm formation by S. aureus 102. A subset of Due south. epidermidis express the glutamyl endopeptidase protein (encoded by the esp factor), which can synergize with the human being AMP β-defensin 2 (likewise known as β-defensin 4A) to interfere with S. aureus colonization. This example raises several of import points for consideration, including the possibility of the host and the microorganism evolving together. Furthermore, as our arsenal of antimicrobial weapons falls short in the boxing against South. aureus and other potential pathogens, perhaps therapeutics derived from microorganisms themselves will offering hope every bit viable alternatives. Equally we keep to enhance our knowledge of the skin microbiota, these factors and other unanswered questions volition guide time to come research efforts directed towards understanding the circuitous interactions governing the host–microorganism human relationship.
Acknowledgements
We give thanks H. Kong and E. Hobbs for critical reading of the manuscript and J. Fekecs and D. Leja for graphical assistance. Eastward.A.G. is supported by a Pharmacology Research Associate Training Fellowship, United states of america National Institute of General Medical Sciences. This piece of work was supported by the Usa National Human Genome Enquiry Institute Intramural Inquiry Program and the US National Institutes of Health Common Fund AR057504.
Glossary
| Keratinocyte | The predominant cell type of the epidermis. Keratinocytes produce keratin every bit they terminally differentiate into the squames of the stratum corneum |
| Squame | An enucleated, dead, squamous keratinocyte that is shed from the stratum corneum |
| Sebum | The oily, lipid-containing substance that is secreted past the sebaceous glands of the pare. Sebaceous glands are continued to the pilus follicle and form the pilosebaceous unit. Sebum protects and emolliates the skin and hair |
| 16S ribosomal RNA metagenomic sequencing | Genomic analysis of 16S ribosomal RNA phylotypes from DNA that is extracted directly from bacterial communities in clinical or environmental samples, a process that circumvents culturing |
| Microbiome | All of the genetic material of a microbial customs sequenced together |
| Phylotype | A taxon-neutral way to describe organisms based on their phylogenetic relationships to other organisms. Phylotypes are determined past comparing 16S ribosomal RNA gene sequences. A common threshold used to define species-level phylotypes is 97% sequence identity of the 16S rRNA cistron sequence |
| Whole-genome shotgun metagenomic sequencing | Genomic assay of Dna that is extracted directly from a clinical or environmental sample and whole-genome shotgun (WGS) sequenced to represent the full microbiome |
| Design recognition receptor (PRR) | A receptor present on the surface of keratinocytes and other cells of the innate immune organization that recognizes microorganism-specific molecules (for example, lipopolysaccharide and flagellin) |
| Pathogen-associated molecular pattern (PAMP) | A molecule that is associated with a pathogen and recognized by a pathogen recognition receptor. Examples include lipopolysaccharide, flagellin, lipoteichoic acid, double-stranded RNA, peptidoglycan and unmethylated CpG motifs |
| Atopic dermatitis (AD) | A type of eczema characterized by red, flaky, itchy skin, typically affecting the inner elbows and backside the knees. It is often associated with other atopic diseases such as allergic rhinitis, hay fever and asthma |
| Seborrhoeic dermatitis | An inflammatory, hyperproliferative pare status characterized past red, flaky, skin often affecting sebaceous areas of the face, scalp and trunk. Commonly known as dandruff |
Footnotes
Competing interests statement
The authors declare no competing financial interests.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535073/
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