The skin microbiome

Elizabeth A Grice, Julia A Segre, Elizabeth A Grice, Julia A Segre

Abstract

The skin is the human body's largest organ, colonized by a diverse milieu of microorganisms, most of which are harmless or even beneficial to their host. Colonization is driven by the ecology of the skin surface, which is highly variable depending on topographical location, endogenous host factors and exogenous environmental factors. The cutaneous innate and adaptive immune responses can modulate the skin microbiota, but the microbiota also functions in educating the immune system. The development of molecular methods to identify microorganisms has led to an emerging view of the resident skin bacteria as highly diverse and variable. An enhanced understanding of the skin 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.

Figures

Figure 1. Schematic of skin histology viewed…
Figure 1. Schematic of skin histology viewed in cross-section with microorganisms and skin appendages
Microorganisms (viruses, bacteria and fungi) and mites cover the surface of the skin and reside deep in the hair and glands. On the skin surface, rod and round bacteria — such as Proteobacteria and Staphylococcus spp., respectively — form communities that are deeply intertwined among themselves and other microorganisms. Commensal fungi such as Malassezia spp. grow both as branching filamentous hypha and as individual cells. Virus particles live both freely and in bacterial cells. Skin mites, such as Demodex folliculorum and Demodex brevis, are some of the smallest arthropods and live in or near hair follicles. Skin appendages include hair follicles, sebaceous glands and sweat glands.
Figure 2. Factors contributing to variation in…
Figure 2. Factors contributing to variation in the skin microbiome
Exogenous and endogenous factors discussed in this Review that contribute to variation between individuals and over the lifetime of an individual.
Figure 3. Topographical distribution of bacteria on…
Figure 3. 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 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. Data from REF. 42.
Figure 4. Interpersonal variation of the skin…
Figure 4. Interpersonal variation of the skin microbiome
The microbial distribution of four sites on four healthy volunteers (HV1, HV2, HV3 and HV4) is depicted at the antecubital fold (inner elbow; part a); the back (part 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 abundance of bacterial taxa as determined by 16S ribosomal RNA sequencing. Data from REF. 42.

References

    1. Chiller K, Selkin BA, Murakawa GJ. Skin microflora and bacterial infections of the skin. J. Investig. Dermatol. Symp. Proc. 2001;6:170–174.
    1. Fredricks DN. Microbial ecology of human skin in health and disease. J. Investig. Dermatol. Symp. Proc. 2001;6:167–169.

    1. Marples M. The Ecology of the Human Skin. Bannerstone House, Springfield, Illinois: Charles C Thomas; 1965. A seminal and comprehensive work of classical dermatological microbiology.

    1. Roth RR, James WD. Microbial ecology of the skin. Annu. Rev. Microbiol. 1988;42:441–464.
    1. Noble WC. Skin microbiology: coming of age. J. Med. Microbiol. 1984;17:1–12.
    1. Roth RR, James WD. Microbiology of the skin: resident flora, ecology, infection. J. Am. Acad. Dermatol. 1989;20:367–390.
    1. Cogen AL, Nizet V, Gallo RL. Skin microbiota: a source of disease or defence? Br. J. Dermatol. 2008;158:442–455.
    1. Tagami H. Location-related differences in structure and function of the stratum corneum with special emphasis on those of the facial skin. Int. J. Cosmet Sci. 2008;30:413–434.
    1. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable barrier. Exp. Dermatol. 2008;17:1063–1072.
    1. Elias PM. The skin barrier as an innate immune element. Semin. Immunopathol. 2007;29:3–14.
    1. Segre JA. Epidermal barrier formation and recovery in skin disorders. J. Clin. Invest. 2006;116:1150–1158.
    1. Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nature Rev. Genet. 2002;3:199–209.
    1. Leeming JP, Holland KT, Cunliffe WJ. The microbial ecology of pilosebaceous units isolated from human skin. J. Gen. Microbiol. 1984;130:803–807.
    1. Cohn BA. In search of human skin pheromones. Arch. Dermatol. 1994;130:1048–1051.
    1. Emter R, Natsch A. The sequential action of a dipeptidase and a β-lyase is required for the release of the human body odorant 3-methyl-3-sulfanylhexan-1-ol from a secreted Cys-Gly-( S ) conjugate by Corynebacteria. J. Biol. Chem. 2008;283:20645–20652.
    1. Decreau RA, Marson CM, Smith KE, Behan JM. Production of malodorous steroids from androsta-5,16-dienes and androsta-4,16-dienes by Corynebacteria and other human axillary bacteria. J. Steroid Biochem. Mol. Biol. 2003;87:327–336.
    1. Martin A, et al. A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. J. Invest. Dermatol. 2010;130:529–540.
    1. Natsch A, Gfeller H, Gygax P, Schmid J, Acuna G. A specific bacterial aminoacylase cleaves odorant precursors secreted in the human axilla. J. Biol. Chem. 2003;278:5718–5727.
    1. Bruggemann H, et al. The complete genome sequence of Propionibacterium acnes a commensal of human skin. Science. 2004;305:671–673.
    1. Marples RR, Downing DT, Kligman AM. Control of free fatty acids in human surface lipids by Corynebacterium acnes. J. Invest. Dermatol. 1971;56:127–131.
    1. Ingham E, Holland KT, Gowland G, Cunliffe WJ. Partial purification and characterization of lipase (EC 3.1.1.3) from Propionibacterium acnes. J. Gen. Microbiol. 1981;124:393–401.
    1. Gribbon EM, Cunliffe WJ, Holland KT. Interaction of Propionibacterium acnes with skin lipids in vitro. J. Gen. Microbiol. 1993;139:1745–1751.
    1. Korting HC, Hubner K, Greiner K, Hamm G, Braun-Falco O. Differences in the skin surface pH and bacterial microflora due to the long-term application of synthetic detergent preparations of pH 5.5 and pH 7.0. Results of a crossover trial in healthy volunteers. Acta Derm. Venereol. 1990;70:429–431.
    1. Aly R, Shirley C, Cunico B, Maibach HI. Effect of prolonged occlusion on the microbial flora, pH, carbon dioxide and transepidermal water loss on human skin. J. Invest. Dermatol. 1978;71:378–381.
    1. Hentges DJ. The anaerobic microflora of the human body. Clin. Infect. Dis. 1993;16:S175–S180.
    1. Webster GF, Ruggieri MR, McGinley KJ. Correlation of Propionibacterium acnes populations with the presence of triglycerides on nonhuman skin. Appl. Environ. Microbiol. 1981;41:1269–1270.
    1. Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Age-related changes in the resident bacterial flora of the human face. J. Invest. Dermatol. 1975;65:379–381.
    1. Somerville DA. The normal flora of the skin in different age groups. Br. J. Dermatol. 1969;81:248–258.
    1. Dominguez-Bello MG, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA. 2010;107:11971–11975.
    1. Sarkany I, Gaylarde CC. Bacterial colonisation of the skin of the newborn. J. Pathol. Bacteriol. 1968;95:115–122.
    1. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5:e177.
    1. Marples RR. Sex, constancy, and skin bacteria. Arch. Dermatol. Res. 1982;272:317–320.
    1. Fierer N, Hamady M, Lauber CL, Knight R. The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proc. Natl Acad. Sci. USA. 2008;105:17994–17999.
    1. Giacomoni PU, Mammone T, Teri M. Genderlinked differences in human skin. J. Dermatol. Sci. 2009;55:144–149.
    1. Dethlefsen L, Relman DA. Microbes and Health Sackler Colloquium: Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA. 2010 Sep 16;
    1. Antonopoulos DA, et al. Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect. Immun. 2009;77:2367–2375.
    1. Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6:e280.
    1. McBride ME, Duncan WC, Knox JM. The environment and the microbial ecology of human skin. Appl. Environ. Microbiol. 1977;33:603–608.
    1. Faergemann J, Larko O. The effect of UV-light on human skin microorganisms. Acta Derm. Venereol. 1987;67:69–72.
    1. Gao Z, Tseng CH, Pei Z, Blaser MJ. Molecular analysis of human forearm superficial skin bacterial biota. Proc. Natl Acad. Sci. USA. 2007;104:2927–2932.
    1. Grice EA, et al. A diversity profile of the human skin microbiota. Genome Res. 2008;18:1043–1050.

    1. Grice EA, et al. Topographical and temporal diversity of the human skin microbiome. Science. 2009;324:1190–1192. A comprehensive analysis of skin microbiota across 20 sites.

    1. Costello EK, et al. Bacterial community variation in human body habitats across space and time. Science. 2009;326:1694–1697. A comprehensive analysis of skin, gut and oral microbiota in the same individuals.

    1. Eckburg PB, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–1638.
    1. Dewhirst FE, et al. The human oral microbiome. J. Bacteriol. 2010;192:5002–5017.
    1. Zaura E, Keijser BJ, Huse SM, Crielaard W. Defining the healthy ‘core microbiome’ of oral microbial communities. BMC Microbiol. 2009;9:259.
    1. Bik EM, et al. Bacterial diversity in the oral cavity of 10 healthy individuals. ISME J. 2010;4:962–974.
    1. Pei Z, et al. Bacterial biota in the human distal esophagus. Proc. Natl Acad. Sci. USA. 2004;101:4250–4255.
    1. Bik EM, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc. Natl Acad. Sci. USA. 2006;103:732–737.
    1. Leyden JJ, McGinley KJ, Holzle E, Labows JN, Kligman AM. The microbiology of the human axilla and its relationship to axillary odor. J. Invest. Dermatol. 1981;77:413–416.

    1. Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. An important study demonstrating the functional potential of the human microbiome.

    1. James TY, et al. Reconstructing the early evolution of Fungi using a six-gene phylogeny. Nature. 2006;443:818–822.
    1. Chase MW, Fay MF. Ecology. Barcoding of plants and fungi. Science. 2009;325:682–683.
    1. Paulino LC, Tseng CH, Blaser MJ. Analysis of Malassezia microbiota in healthy superficial human skin and in psoriatic lesions by multiplex real-time PCR. FEMS Yeast Res. 2008;8:460–471.
    1. Paulino LC, Tseng CH, Strober BE, Blaser MJ. Molecular analysis of fungal microbiota in samples from healthy human skin and psoriatic lesions. J. Clin. Microbiol. 2006;44:2933–2941.
    1. Gao Z, Perez-Perez GI, Chen Y, Blaser MJ. Quantitation of major human cutaneous bacterial and fungal populations. J. Clin. Microbiol. 2010;48:3575–3581.

    1. Peleg AY, Hogan DA, Mylonakis E. Medically important bacterial-fungal interactions. Nature Rev. Microbiol. 2010;8:340–349. This review describes the clinical and molecular characteristics of bacterium–fungus interactions that are relevant to human disease with a focus on Candida spp.

    1. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br. J. Dermatol. 2007;157:474–481.
    1. Georgala S, et al. Increased density of Demodex folliculorum and evidence of delayed hypersensitivity reaction in subjects with papulopustular rosacea. J. Eur. Acad. Dermatol. Venereol. 2001;15:441–444.
    1. Elston DM. Demodex mites: facts and controversies. Clin. Dermatol. 2010;28:502–504.
    1. Hay R. Demodex and skin infection: fact or fiction. Curr. Opin. Infect. Dis. 2010;23:103–105.

    1. Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe. 2010;7:509–515. An investigation of the preponderance of Merkel cell polyomavirus, and a methodology to isolate circular DNA viral genomes from human skin swabs.

    1. Borkowski AW, Gallo RL. The coordinated response of the physical and antimicrobial peptide barriers of the skin. J. Invest. Dermatol. 2011;131:285–287.
    1. Braff MH, Bardan A, Nizet V, Gallo RL. Cutaneous defence mechanisms by antimicrobial peptides. J. Invest. Dermatol. 2005;125:9–13.
    1. Strober W. Epithelial cells pay a Toll for protection. Nature Med. 2004;10:898–900.
    1. Fukao T, Koyasu S. PI3K and negative regulation of TLR signaling. Trends Immunol. 2003;24:358–363.
    1. Cogen AL, et al. Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis a normal resident of the skin. J. Invest. Dermatol. 2010;130:192–200.
    1. Cogen AL, et al. Staphylococcus epidermidis antimicrobial δ -toxin (phenol-soluble modulin-γ) cooperates with host antimicrobial peptides to kill Group A Streptococcus. PLoS ONE. 2010;5:e8557.

    1. Lai Y, et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nature Med. 2009;15:1377–1382. This analysis demonstrated that products of a skin commensal can modulate the innate immune response.

    1. Lai Y, et al. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defence against bacterial skin infections. J. Invest. Dermatol. 2010;130:2211–2221.
    1. Nomura I, et al. Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J. Allergy Clin. Immunol. 2003;112:1195–1202.
    1. Nomura I, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J. Immunol. 2003;171:3262–3269.
    1. Gudjonsson JE, et al. Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin. J. Invest. Dermatol. 2009;129:2795–2804.
    1. Ong PY, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 2002;347:1151–1160.
    1. de Jongh GJ, et al. High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis. J. Invest. Dermatol. 2005;125:1163–1173.
    1. Owen CM, Chalmers RJ, O’Sullivan T, Griffiths CE. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br. J. Dermatol. 2001;145:886–890.
    1. Pierard GE, Arrese JE, Pierard-Franchimont C, De Doncker P. Prolonged effects of antidandruff shampoos — time to recurrence of Malassezia ovalis colonization of skin. Int. J. Cosmet. Sci. 1997;19:111–117.
    1. Leyden JJ, McGinley KJ, Kligman AM. Role of microorganisms in dandruff. Arch. Dermatol. 1976;112:333–338.
    1. Gupta AK, Batra R, Bluhm R, Boekhout T, Dawson TL., Jr Skin diseases associated with Malassezia species. J. Acad. Dermatol. 2004;51:785–798.
    1. Dessinioti C, Katsambas AD. The role of Propionibacterium acnes in acne pathogenesis: facts and controversies. Clin. Dermatol. 2010;28:2–7.
    1. Scott DG, Cunliffe WJ, Gowland G. Activation of complement — a mechanism for the inflammation in acne. Br. J. Dermatol. 1979;101:315–320.
    1. Webster GF, Leyden JJ, Nilsson UR. Complement activation in acne vulgaris: consumption of complement by comedones. Infect. Immun. 1979;26:183–186.
    1. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inflammatory events are involved in acne lesion initiation. J. Invest. Dermatol. 2003;121:20–27.
    1. Kim J. Review of the innate immune response in acne vulgaris: activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses. Dermatology. 2005;211:193–198.
    1. Puhvel SM, Sakamoto M. Cytotaxin production by comedonal bacteria (Propionibacterium acnes, Propionibacterium granulosum and Staphylococcus epidermidis ) J. Invest. Dermatol. 1980;74:36–39.
    1. Webster GF, Leyden JJ. Characterization of serum-independent polymorphonuclear leukocyte chemotactic factors produced by Propionibacterium acnes. Inflammation. 1980;4:261–269.
    1. Bek-Thomsen M, Lomholt HB, Kilian M. Acne is not associated with yet-uncultured bacteria. J. Clin. Microbiol. 2008;46:3355–3360.
    1. Hanifin JM, Rogge JL. Staphylococcal infections in patients with atopic dermatitis. Arch. Dermatol. 1977;113:1383–1386.
    1. Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br. J. Dermatol. 1974;90:525–530.
    1. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics. 2009;123:e808–e814.
    1. Aioi A, et al. Impairment of skin barrier function in NC/Nga Tnd mice as a possible model for atopic dermatitis. Br. J. Dermatol. 2001;144:12–18.
    1. Terada M, et al. Contribution of IL-18 to atopic-dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice. Proc. Natl Acad. Sci. USA. 2006;103:8816–8821.
    1. Frank DN, et al. Microbial diversity in chronic open wounds. Wound Repair Regen. 2009;17:163–172.
    1. Dowd SE, et al. Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol. 2008;8:43.
    1. Smith DM, et al. Evaluation of the bacterial diversity of Pressure ulcers using bTEFAP pyrosequencing. BMC Med. Genomics. 2010;3:41.
    1. Price LB, et al. Community analysis of chronic wound bacteria using 16S rRNA gene-based pyrosequencing: impact of diabetes and antibiotics on chronic wound microbiota. PLoS ONE. 2009;4:e6462.
    1. Polavarapu N, Ogilvie MP, Panthaki ZJ. Microbiology of burn wound infections. J. Craniofac. Surg. 2008;19:899–902.

    1. Grice EA, et al. Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defence response. Proc. Natl Acad. Sci. USA. 2010;107:14799–14804. This study showed that a selective shift in microbiota is associated with an altered innate immune response.

    1. Uckay I, et al. Foreign body infections due to Staphylococcus epidermidis. Ann. Med. 2009;41:109–119.
    1. Otto M. Staphylococcus epidermidis — the ‘accidental’ pathogen. Nature Rev. Microbiol. 2009;7:555–567.

    1. Peterson J, et al. The NIH Human Microbiome Project. Genome Res. 2009;19:2317–2323. A detailed description of the Human Microbiome Project and its objectives.

    1. Iwase T, et al. Staphylococcus epidermidis esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature. 2010;465:346–349. An important paper demonstrating the mechanism by which S. epidermidis inhibits S. aureus colonization of the nare.

    1. Dunbar J, Barns SM, Ticknor LO, Kuske CR. Empirical and theoretical bacterial diversity in four Arizona soils. Appl. Environ. Microbiol. 2002;68:3035–3045.
    1. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clin. Microbiol. Rev. 2001;14:244–269.
    1. Davies CE, et al. Use of molecular techniques to study microbial diversity in the skin: chronic wounds reevaluated. Wound Repair Regen. 2001;9:332–340.
    1. Hugenholtz P, Pace NR. Identifying microbial diversity in the natural environment: a molecular phylogenetic approach. Trends Biotechnol. 1996;14:190–197.

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