The skin microbiome: current perspectives and future challenges.

Complex communities of bacteria, fungi, and viruses thrive on our skin. The composition of these communities depends on skin characteristics, such as sebaceous gland concentration, moisture content, and temperature, as well as on host genetics and exogenous environmental factors. Recent metagenomic studies have uncovered a surprising diversity within these ecosystems and have fostered a new view of commensal organisms as playing a much larger role in immune modulation and epithelial health than previously expected. Understanding microbe-host interactions and discovering the factors that drive microbial colonization will help us understand the pathogenesis of skin diseases and develop new promicrobial and antimicrobial therapeutics.

[1]  David M. Berman,et al.  Tissue repair and stem cell renewal in carcinogenesis , 2004, Nature.

[2]  S. Salminen,et al.  Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. , 2001, The Journal of allergy and clinical immunology.

[3]  A. Witney,et al.  The Distribution of Mobile Genetic Elements (MGEs) in MRSA CC398 Is Associated with Both Host and Country , 2011, Genome biology and evolution.

[4]  Takaaki Ohtake,et al.  Biology and clinical relevance of naturally occurring antimicrobial peptides. , 2002, The Journal of allergy and clinical immunology.

[5]  Martin J Blaser,et al.  Bacterial biota in the human distal esophagus , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Lindsay,et al.  Staphylococcus aureus Strains That are Hypersusceptible to Resistance Gene Transfer from Enterococci , 2007, Antimicrobial Agents and Chemotherapy.

[7]  N. Woodford.  Vancomycin resistant Staphylococcus aureus in the United States , 2002 .

[8]  B. Kreiswirth,et al.  Community-Acquired Methicillin-Resistant Staphylococcus aureus: An Emerging Pathogen , 2003, Infection Control & Hospital Epidemiology.

[9]  Giovanna Morelli,et al.  Distinguishing human ethnic groups by means of sequences from Helicobacter pylori: lessons from Ladakh. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Handelsman,et al.  Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. , 1998, Chemistry & biology.

[11]  J. Handelsman,et al.  Metagenomics: genomic analysis of microbial communities. , 2004, Annual review of genetics.

[12]  D. Kasper,et al.  The yin yang of bacterial polysaccharides: lessons learned from B. fragilis PSA , 2012, Immunological reviews.

[13]  B. Finlay,et al.  Shifting the balance: antibiotic effects on host–microbiota mutualism , 2011, Nature Reviews Microbiology.

[14]  Elisabeth M Bik,et al.  Molecular analysis of the bacterial microbiota in the human stomach. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Somerville.  THE EFFECT OF AGE ON THE NOEMAL BACTERIAL FLORA OF THE SKIN † , 1969, The British journal of dermatology.

[16]  J. Lederberg,et al.  `Ome Sweet `Omics--A Genealogical Treasury of Words , 2001 .

[17]  J. Wiesner,et al.  Antimicrobial peptides: The ancient arm of the human immune system , 2010, Virulence.

[18]  S. Salminen,et al.  Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial , 2003, The Lancet.

[19]  M. Blaser,et al.  Molecular analysis of human forearm superficial skin bacterial biota , 2007, Proceedings of the National Academy of Sciences.

[20]  H. Wichmann,et al.  Elder siblings enhance the effect of filaggrin mutations on childhood eczema: results from the 2 birth cohort studies LISAplus and GINIplus. , 2010, The Journal of allergy and clinical immunology.

[21]  D. Modai,et al.  Iatrogenic arterial aneurysm associated with ergotamine therapy. , 1981, Lancet.

[22]  H. Matsuda,et al.  Recent findings in mouse models for human atopic dermatitis. , 2012, Experimental animals.

[23]  M. Stephens,et al.  Traces of Human Migrations in Helicobacter pylori Populations , 2003, Science.

[24]  J. Leyden,et al.  Staphylococcus aureus in the lesions of atopic dermatitis , 1974, The British journal of dermatology.

[25]  F. Götz,et al.  Staphylococcal lipases: molecular characterisation, secretion, and processing. , 1998, Chemistry and physics of lipids.

[26]  F. Forastiere,et al.  Mortality among workers at municipal waste incinerators in Rome: a retrospective cohort study. , 1997, American journal of industrial medicine.

[27]  D. Somerville.  THE NORMAL FLORA OF THE SKIN IN DIFFERENT AGE GROUPS , 1969, The British journal of dermatology.

[28]  J. Neu,et al.  Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns , 2011 .

[29]  R. Gallo,et al.  AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. , 2009, Trends in immunology.

[30]  N. Pace,et al.  Identifying microbial diversity in the natural environment: a molecular phylogenetic approach. , 1996, Trends in biotechnology.

[31]  Gabriel Renaud,et al.  A diversity profile of the human skin microbiota. , 2008, Genome research.

[32]  R. Reading.  Probiotics in primary prevention of atopic disease: a randomised placebo‐controlled trial. , 2001 .

[33]  H. Williams,et al.  Overview of Reviews The prevention of eczema in infants and children: an overview of Cochrane and non-Cochrane reviews. , 2011, Evidence-based child health : a Cochrane review journal.

[34]  M. Kanehisa,et al.  Whole genome sequencing of meticillin-resistant Staphylococcus aureus , 2001, The Lancet.

[35]  P. Naaber,et al.  The intestinal microflora in allergic Estonian and Swedish 2‐year‐old children , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[36]  J. Norton,et al.  Lessons from Coley's Toxin. , 2006, Surgical oncology.

[37]  D. Relman,et al.  An ecological and evolutionary perspective on human–microbe mutualism and disease , 2007, Nature.

[38]  H. Hayashi,et al.  Detection of potentially novel bacterial components of the human skin microbiota using culture-independent molecular profiling. , 2005, Journal of medical microbiology.

[39]  Daniel Falush,et al.  An African origin for the intimate association between humans and Helicobacter pylori , 2007, Nature.

[40]  A. Kennedy,et al.  Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA , 2007, Nature Medicine.

[41]  U. Nübel,et al.  From types to trees: reconstructing the spatial spread of Staphylococcus aureus based on DNA variation. , 2011, International journal of medical microbiology : IJMM.

[42]  J. Patel,et al.  Vancomycin-resistant Staphylococcus aureus in the United States, 2002-2006. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[43]  E. Charlesworth.  Probiotics in primary prevention of atopic disease , 2003 .

[44]  R. Marples.  Sex, constancy, and skin bacteria , 2004, Archives of Dermatological Research.

[45]  D. Gevers,et al.  The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. , 2012, The Journal of allergy and clinical immunology.

[46]  H. Akaza,et al.  Expression of antitumor response role of attachment and viability of bacillus calmette—guérin to bladder cancer cells , 1993, Cancer.

[47]  S. Sicherer.  Treatment of Staphylococcus aureus Colonization in Atopic Dermatitis Decreases Disease Severity , 2009, Pediatrics.

[48]  J. Gustafsson,et al.  Gut flora, Toll‐like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine , 2008, Cellular Microbiology.

[49]  R. Gallo,et al.  Microbial Symbiosis with the Innate Immune Defense System of the Skin , 2011, The Journal of investigative dermatology.

[50]  L. Perini,et al.  Helicobacter pylori: Bacterial Factors and the Role of Cytokines in the Immune Response , 2010, Current Microbiology.

[51]  H. Suto,et al.  Molecular Analysis of Malassezia Microflora on the Skin of Atopic Dermatitis Patients and Healthy Subjects , 2001, Journal of Clinical Microbiology.

[52]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[53]  N. Klopp,et al.  Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. , 2006, The Journal of allergy and clinical immunology.

[54]  A. Chervonsky.  Microbial influences on immune function and more , 2012, Immunological reviews.

[55]  S. Dowd,et al.  Diversity of the Human Skin Microbiome Early in Life , 2011, The Journal of investigative dermatology.

[56]  G. Sensabaugh,et al.  Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus , 2006, The Lancet.

[57]  Julia Oh,et al.  Shifts in human skin and nares microbiota of healthy children and adults , 2012, Genome Medicine.

[58]  C. Walsh,et al.  The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA) , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[59]  N. Pace.  A molecular view of microbial diversity and the biosphere. , 1997, Science.

[60]  A. Witney,et al.  Design, Validation, and Application of a Seven-Strain Staphylococcus aureus PCR Product Microarray for Comparative Genomics , 2005, Applied and Environmental Microbiology.

[61]  J. Ravel,et al.  Community Analysis of Chronic Wound Bacteria Using 16S rRNA Gene-Based Pyrosequencing: Impact of Diabetes and Antibiotics on Chronic Wound Microbiota , 2009, PloS one.

[62]  J. Izard,et al.  The Human Oral Microbiome , 2010, Journal of bacteriology.

[63]  C. Zouboulis,et al.  Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes. , 2006, Microbes and infection.

[64]  H. Hayashi,et al.  Characterization of skin microbiota in patients with atopic dermatitis and in normal subjects using 16S rRNA gene-based comprehensive analysis. , 2007, Journal of medical microbiology.

[65]  Samuel V. Angiuoli,et al.  Insights on Evolution of Virulence and Resistance from the Complete Genome Analysis of an Early Methicillin-Resistant Staphylococcus aureus Strain and a Biofilm-Producing Methicillin-Resistant Staphylococcus epidermidis Strain , 2005, Journal of bacteriology.

[66]  K. T. Holland,et al.  Inhibition of erythromycin‐resistant propionibacteria on the skin of acne patients by topical erythromycin with and without zinc , 1994, The British journal of dermatology.

[67]  C. Starnes.  Coley's toxins in perspective , 1992, Nature.

[68]  S. Salminen,et al.  Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial , 2001, The Lancet.

[69]  H. Kong,et al.  Skin microbiome: genomics-based insights into the diversity and role of skin microbes. , 2011, Trends in molecular medicine.

[70]  H. Kong,et al.  Skin Microbiome: Looking Back to Move Forward , 2011, The Journal of investigative dermatology.

[71]  Denise E. Waldron,et al.  Sau1: a Novel Lineage-Specific Type I Restriction-Modification System That Blocks Horizontal Gene Transfer into Staphylococcus aureus and between S. aureus Isolates of Different Lineages , 2006, Journal of bacteriology.

[72]  H. Tlaskalova-Hogenova.  Faculty Opinions recommendation of Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. , 2010 .

[73]  B. Barrell,et al.  Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  A. Friedrich,et al.  spa typing for epidemiological surveillance of Staphylococcus aureus. , 2009, Methods in molecular biology.

[75]  S. Raimer.  Null Mutations in the Filaggrin Gene (FLG) Determine Major Susceptibility to Early-Onset Atopic Dermatitis that Persists into Adulthood , 2008 .

[76]  C. D. Long,et al.  Bacterial diversity in the oral cavity of 10 healthy individuals , 2010, The ISME Journal.

[77]  T. Sugita,et al.  Genotype Analysis of Malassezia restricta as the Major Cutaneous Flora in Patients with Atopic Dermatitis and Healthy Subjects , 2004, Microbiology and immunology.

[78]  P. Graham,et al.  Hospital transmission of community-acquired methicillin-resistant Staphylococcus aureus among postpartum women. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[79]  S. Dowd,et al.  Evaluation of the bacterial diversity among and within individual venous leg ulcers using bacterial tag-encoded FLX and Titanium amplicon pyrosequencing and metagenomic approaches , 2009, BMC Microbiology.

[80]  A. Witney,et al.  Microarrays Reveal that Each of the Ten Dominant Lineages of Staphylococcus aureus Has a Unique Combination of Surface-Associated and Regulatory Genes , 2006, Journal of bacteriology.

[81]  M. Kilian,et al.  Acne is Not Associated with Yet-Uncultured Bacteria , 2008, Journal of Clinical Microbiology.

[82]  N. Pace,et al.  Culture-Independent Molecular Analysis of Microbial Constituents of the Healthy Human Outer Ear , 2003, Journal of Clinical Microbiology.

[83]  A M Kligman,et al.  Control of free fatty acids in human surface lipids by Corynebacterium acnes. , 1971, The Journal of investigative dermatology.

[84]  D. Elston.  Community-acquired methicillin-resistant Staphylococcus aureus. , 2007, Journal of the American Academy of Dermatology.

[85]  Lionel Fry,et al.  Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin , 2011, Archives of Dermatological Research.

[86]  M. Zervos,et al.  Plasmid Content of a Vancomycin-Resistant Enterococcus faecalis Isolate from a Patient Also Colonized by Staphylococcus aureus with a VanA Phenotype , 2003, Antimicrobial Agents and Chemotherapy.

[87]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[88]  C. Aylsworth,et al.  Intestinal protozoa are hypothesized to stimulate immunosurveillance against colon cancer. , 2008, Medical hypotheses.

[89]  W J Cunliffe,et al.  The cutaneous microflora of adolescent, persistent andlate‐onset acne patients does not differ , 2000, The British journal of dermatology.

[90]  R. Knight,et al.  The influence of sex, handedness, and washing on the diversity of hand surface bacteria , 2008, Proceedings of the National Academy of Sciences.

[91]  C. von Mering,et al.  Like Will to Like: Abundances of Closely Related Species Can Predict Susceptibility to Intestinal Colonization by Pathogenic and Commensal Bacteria , 2010, PLoS pathogens.

[92]  R. Knight,et al.  Bacterial Community Variation in Human Body Habitats Across Space and Time , 2009, Science.

[93]  Henry F. Chambers,et al.  Waves of resistance: Staphylococcus aureus in the antibiotic era , 2009, Nature Reviews Microbiology.

[94]  E. Mutius,et al.  The environmental predictors of allergic disease. , 2000 .

[95]  J. T. Staley,et al.  Measurement of in situ activities of nonphotosynthetic microorganisms in aquatic and terrestrial habitats. , 1985, Annual review of microbiology.

[96]  J. Kopecký,et al.  Active and total microbial communities in forest soil are largely different and highly stratified during decomposition , 2011, The ISME Journal.

[97]  Y. Umesaki,et al.  Differential induction of major histocompatibility complex molecules on mouse intestine by bacterial colonization. , 1992, Gastroenterology.

[98]  A. Macpherson,et al.  Interactions between commensal intestinal bacteria and the immune system , 2004, Nature Reviews Immunology.

[99]  R. Knight,et al.  The Human Microbiome Project , 2007, Nature.

[100]  Xiao Xue Ma,et al.  Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: genomic island SCC. , 2003, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[101]  J. Lindsay,et al.  The distribution of plasmids that carry virulence and resistance genes in Staphylococcus aureus is lineage associated , 2012, BMC Microbiology.

[102]  Anders F. Andersson,et al.  Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome , 2010, PloS one.

[103]  I. Sarkany,et al.  Bacterial colonisation of the skin of the newborn. , 1968, The Journal of pathology and bacteriology.

[104]  J. Gordon,et al.  Creating and Maintaining the Gastrointestinal Ecosystem: What We Know and Need To Know from Gnotobiology , 1998, Microbiology and Molecular Biology Reviews.

[105]  K. Julge,et al.  Allergy development and the intestinal microflora during the first year of life. , 2001, The Journal of allergy and clinical immunology.

[106]  Yoshimitsu Mizunoe,et al.  Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization , 2010, Nature.

[107]  S. Webb,et al.  Nosocomial bacterial infections in Intensive Care Units. I: Organisms and mechanisms of antibiotic resistance , 2005, Anaesthesia.

[108]  R. Knight,et al.  Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns , 2010, Proceedings of the National Academy of Sciences.

[109]  Courtney J. Robinson,et al.  Antibiotic administration alters the community structure of the gastrointestinal microbiota , 2010, Gut microbes.

[110]  Thomas Mammone,et al.  Gender-linked differences in human skin. , 2009, Journal of dermatological science.

[111]  Susan M. Huse,et al.  Defining the healthy "core microbiome" of oral microbial communities , 2009, BMC Microbiology.

[112]  W J Cunliffe,et al.  Acne vulgaris: an investigation into the number of anaerobic diphtheroids and members of Micrococcaceae the in normal and acne skin , 1977, The British journal of dermatology.

[113]  Julia Oh,et al.  Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis , 2012, Genome research.

[114]  C. Zouboulis,et al.  Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill propionibacterium acnes. , 2008, The Journal of investigative dermatology.

[115]  J. Handelsman.  Metagenomics: Application of Genomics to Uncultured Microorganisms , 2004, Microbiology and Molecular Biology Reviews.

[116]  M. C. Bastos,et al.  Staphylococcal antimicrobial peptides: relevant properties and potential biotechnological applications. , 2009, Current pharmaceutical biotechnology.

[117]  V. Nizet,et al.  Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. , 2010, The Journal of investigative dermatology.

[118]  N. Pace,et al.  Microbial diversity in chronic open wounds , 2009, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[119]  N. Socci,et al.  Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. , 2010, The Journal of clinical investigation.

[120]  Y. Nagai,et al.  Genome and virulence determinants of high virulence community-acquired MRSA , 2002, The Lancet.

[121]  Gérard Eberl,et al.  Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis , 2008, Nature.

[122]  Colin N A Palmer,et al.  Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis , 2006, Nature Genetics.

[123]  Lu Wang,et al.  The NIH Human Microbiome Project. , 2009, Genome research.

[124]  O. Bottasso,et al.  The use of mycobacterial adjuvant-based agents for immunotherapy of cancer. , 2008, Vaccine.

[125]  H. Goossens.  European Status of Resistance in Nosocomial Infections , 2005, Chemotherapy.

[126]  C. Deming,et al.  Compartmentalized Control of Skin Immunity by Resident Commensals , 2012, Science.

[127]  R. Rylander.  Environmental exposures with decreased risks for lung cancer? , 1990, International journal of epidemiology.

[128]  J. Lindsay.  Genomic variation and evolution of Staphylococcus aureus. , 2010, International journal of medical microbiology : IJMM.

[129]  V. Nizet,et al.  Staphylococcus epidermidis Antimicrobial δ-Toxin (Phenol-Soluble Modulin-γ) Cooperates with Host Antimicrobial Peptides to Kill Group A Streptococcus , 2010, PloS one.

[130]  C. Deming,et al.  Topographical and Temporal Diversity of the Human Skin Microbiome , 2009, Science.

[131]  Allen F Ryan,et al.  Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. , 2010, The Journal of investigative dermatology.

[132]  Chi-Hong Tseng,et al.  Molecular Analysis of Fungal Microbiota in Samples from Healthy Human Skin and Psoriatic Lesions , 2006, Journal of Clinical Microbiology.

[133]  W D James,et al.  Microbial ecology of the skin. , 1988, Annual review of microbiology.

[134]  R. Donlan,et al.  High-Level Vancomycin-Resistant Staphylococcus aureus Isolates Associated with a Polymicrobial Biofilm , 2006, Antimicrobial Agents and Chemotherapy.

[135]  Eunseog Youn,et al.  A Comparison of Bacterial Composition in Diabetic Ulcers and Contralateral Intact Skin , 2010, The open microbiology journal.

[136]  Allison D. Griggs,et al.  Comparative Genomics of Vancomycin-Resistant Staphylococcus aureus Strains and Their Positions within the Clade Most Commonly Associated with Methicillin-Resistant S. aureus Hospital-Acquired Infection in the United States , 2012, mBio.

[137]  J. Shetty,et al.  Genetic Analysis of a High-Level Vancomycin-Resistant Isolate of Staphylococcus aureus , 2003, Science.

[138]  A HarfoushRAOmarNYAliH,et al.  Molecular typing of methicillin resistant Staphylococcus aureus clinical isolates on the basis of protein a and coagulase gene polymorphisms , 2014 .

[139]  J. Sýkora,et al.  ENDOTOXINS, COTTON DUST, AND CANCER , 1985, The Lancet.

[140]  P. Askenase,et al.  Development of Atopic Dermatitis-like Skin Lesion with Ige Hyperproduction in Nc/nga Mice , 2022 .

[141]  Michael Mitzenmacher,et al.  Detecting Novel Associations in Large Data Sets , 2011, Science.

[142]  Martin J. Blaser,et al.  Substantial Alterations of the Cutaneous Bacterial Biota in Psoriatic Lesions , 2008, PloS one.

[143]  J. Strauss,et al.  Topical clindamycin treatment of acne. Clinical, surface lipid composition, and quantitative surface microbiology response. , 1980, Archives of dermatology.

[144]  Katherine H. Huang,et al.  A framework for human microbiome research , 2012, Nature.

[145]  A. Rudensky,et al.  The effects of commensal microbiota on immune cell subsets and inflammatory responses , 2012, Immunological reviews.

[146]  Daniel H. Huson,et al.  Simultaneous Assessment of Soil Microbial Community Structure and Function through Analysis of the Meta-Transcriptome , 2008, PloS one.