Skin Microbiome Handbook

Nava Dayan Ph.D. Pharm D. is a research scientist who has specialized in skin product development for nearly 3 decades. She is the owner of Dr. Nava Dayan L.L.C, a skin science and research consultancy serving the pharmaceutical, cosmetic, and personal care industries; dermal and transdermal. The uniqueness of Dr. Dayan's approach is in its comprehensiveness since she covers biology, physics, efficacy, toxicology, formulations product development, and bio-availability. With her many years of experience in the skin care sector, she has produced more than 150 publication credits in numerous industry-respected journals and in four books. Her research focus is on feasibility in skin care, composition of R&D plans covering efficacy and toxicology; planning, execution and data interpretation into claims, formulations, delivery for improved efficacy and attenuated toxicity, drug-skin interaction, bio-markers, skin/age related sensitivities, inflammatory skin disorders, innate immunity and skin microbiome. This is her fifth book and her 2nd with the Wiley-Scrivener imprint.

Preface xvii


Part 1: Healthy Skin Microbiome and Oral-Skin Interactions 1


1 The Microbiome of Healthy Skin 3


Samantha Samaras and Michael Hoptroff


1.1 Introduction 3


1.1.1 Retrospective 3


1.1.2 Next Generation Sequencing 6


1.2 The Skin Microbiome in Health 7


1.2.1 Composition 7


1.2.2 Diversity 10


1.2.3 Uniqueness 13


1.3 Healthy Skin is the Foundation of a Balanced Skin Microbiome 14


1.3.1 Physical Aspects of Skin Impacting the Microbiome 14


1.3.2 Biochemical and Defensive Aspects of Skin Impacting the Microbiome 16


1.3.2.1 The Acid Mantle 16


1.3.2.2 Antimicrobial Lipids (AMLs) 16


1.3.2.3 Antimicrobial Peptides (AMPs) 17


1.3.3 Nutritional and Microenvironmental Aspects of Skin Impacting the Microbiome 18


1.3.3.1 Amino Acids 18


1.3.3.2 Sebaceous Lipids 19


1.3.3.3 Organic Acids and Other Materials 19


1.4 A Balanced Skin Microbiome Supports the Normal Functioning of Healthy Skin 20


1.4.1 Pathogen Exclusion 20


1.4.2 Contribution to Skin pH 20


1.4.3 Microbial Contribution to Skin Barrier Integrity 21


1.5 Conclusion 22


Acknowledgments 23


References 23


2 The Gut Microbiome-Skin Axis: Impact on Skin and Systemic Health 33


David Drake


2.1 Introduction 34


2.2 The Gut-Skin Microbiome Axis 35


2.3 The Gut-Skin Microbiome Axis: Principle Pathways 35


2.4 Dysbiosis of the Gut Microbiome and Skin Dyshomeostasis 37


2.4.1 Acne Vulgaris 38


2.4.2 Atopic Dermatitis 39


2.5 Summary and Future Directions 39


References 40


3 The Skin and Oral Microbiome: An Examination of Overlap and Potential Interactions between Microbiome Communities 45


Sandra Buerger


3.1 Introduction 45


3.1.1 Focus of the Chapter 45


3.1.2 Definition of Skin Microbiome 47


3.1.3 Definition of Oral Microbiome 48


3.2 Characterization of the Microbiome 48


3.2.1 Variability and Stability of Skin and Oral Microbiome 48


3.2.2 Microbial Community 49


3.2.2.1 Permeant Mutualistic or Commensal Microbes 49


3.2.2.2 Non-Pathogenic Transient Microbes 50


3.2.2.3 Pathogenic Microbes 50


3.3 The Core Skin and Oral Microbiomes 51


3.3.1 Taxonomic Methodology 51


3.3.2 Subgroups of the Microbiome 52


3.3.2.1 Bacteriome 52


3.3.2.2 Mycobiome (and Other Eukaryotic Microbial Members) 52


3.3.2.3 Virome 53


3.4 Interactions Between Skin and Oral Microbiomes 54


3.4.1 Potential for Interactions 54


3.4.2 Quorum Sensing 54


3.4.3 Immune System Development 54


3.4.4 Future Directions 55


3.5 Conclusion 55


Acknowledgments 56


References 56


Part 2: Skin Microbiome Observational Research 59


4 Skin Microbiome Alterations in Skin Diseases 61


Travis Whitfill, Gilles R. Dube and Julia Oh


4.1 Introduction and Background 61


4.2 Interactions Between Microbes and Host 62


4.3 Summary of Known Associations Between Skin Dysbioses and Skin Diseases 64


4.3.1 The Role of S. Aureus in Skin Disease 64


4.3.2 Atopic Dermatitis 64


4.3.3 Acne Vulgaris 66


4.3.4 Psoriasis 67


4.4 Skin Dysbioses in Skin Health 68


4.5 Other Skin Conditions 68


4.6 Therapeutic Approaches to Dysbiosis-Associated Skin Diseases 69


4.6.1 Traditional Methods of Treating Dysbiosis-Associated Skin Diseases 69


4.6.1.1 Atopic Dermatitis 69


4.6.1.2 Acne Vulgaris 69


4.6.2 Emerging Therapeutic Approaches to Treating Dysbiosis-Associated Skin Diseases 70


4.7 Conclusion and Future Directions 71


Acknowledgements 71


References 71


5 The Axillary Microbiome and its Relationship with Underarm Odor 79


Alexander Gordon James


5.1 Introduction 80


5.2 Composition of the Axillary Microbiome 86


5.3 16-Androstene Steroids and Axillary Malodour 95


5.4 The Axillary Microbiome, VFAs and Malodour 96


5.5 The Axillary Microbiome, Thioalcohols and Malodour 100


5.6 Perturbation of the Axillary Microbiome 108


5.7 Human Genetics - Influence on Malodour and the Axillary Microbiome 112


5.8 Conclusions and Future Perspectives 115


Acknowledgements 122


References 122


6 Infant Skin Microbiome 131


Georgios N. Stamatas


6.1 Introduction 131


6.2 Infant Skin Maturation 132


6.3 Infant Immune System Maturation 133


6.4 Infant Skin Microbiome Dynamics 134


6.5 Mother-Infant Microbial Transmission 137


6.6 Conclusion 138


References 139


Part 3: Skin Microbiome in Disequilibrium and Disease 143


7 Microbiome of Compromised Skin 145


Sara Farahmand


7.1 Atopic Dermatitis 146


7.2 Psoriasis 148


7.2.1 Diversity 149


7.2.2 Microbiome Composition 151


7.3 Acne 152


7.4 Rosacea 153


7.5 Seborrheic Dermatitis and Dandruff 155


7.6 Exposome, Skin Barrier, and Skin Microbiome 157


7.6.1 Skin Irritation and Microbiome 157


7.6.2 Diaper Dermatitis 157


7.6.3 Occupational Hand Dermatitis 158


7.6.4 Allergic Contact Dermatitis (ACD) and Skin Microbiome 159


7.7 Conclusion 160


References 163


8 Human Cutaneous Ectoparasites: A Brief Overview and Potential Therapeutic Role for Demodex 171


Stephen L. Strobel


8.1 Introduction 171


8.2 Chiggers (Trombiculidae) 172


8.3 Bedbugs (Cimex lectularius and Hemipterus) 173


8.4 Lice 173


8.5 Scabies (Sarcoptes scabiei) 174


8.6 Demodex 175


8.7 The Association Between Demodex, Rosacea and Blepharitis 176


8.8 Hypothesis 177


8.9 Demodex Folliculorum as a Drug Delivery Agent for Early Skin Cancer 177


8.10 Limitations 179


8.11 Conclusion 180


8.12 Future Considerations 181


References 182


9 Dysbiosis of the Skin Microbiome in Atopic Dermatitis 185


Joyce Cheng and Tissa Hata


9.1 Introduction 185


9.2 The Healthy Skin Microbiome 186


9.3 The Skin Microbiome in Atopic Dermatitis 187


9.4 Microbiome-Targeted Treatment Strategies 195


9.5 Conclusion 196


References 196


10 The Skin Microbiome of Inverse Psoriasis 203


Jennifer Chung, Bruce E. Strober and George M. Weinstock


10.1 Introduction 204


10.2 Methods 205


10.2.1 Subject Population 205


10.2.2 Patient Diagnosis and Characteristics of Populations 206


10.2.3 Specimen Collection 206


10.2.4 Sample DNA Extraction and Sequencing 207


10.2.5 Downstream Sequence Processing and Analysis 207


10.3 Results 208


10.3.1 Cohort Metadata 208


10.3.2 Sequencing Information 208


10.3.3 The Skin Microbiome of Intertriginous Lesion and Non-Lesional Sites on Inverse Psoriasis Subjects 208


10.3.3.1 Psoriasis Lesional Status is Associated with Relative Abundance and Presence of Specific Species 208


10.3.3.2 Psoriatic Lesions Trend to Decrease Taxonomic Diversity 210


10.3.3.3 Psoriatic Lesions are Characterized by Greater Intragroup Variability 212


10.3.4 Inverse Psoriasis vs. Plaque Psoriasis vs. Healthy (All Non-Lesion Sites) 212


10.4 Conclusions & Future Plans 212


Acknowledgements 213


References 214


Part 4: Skin's Innate Immunity 217


11 Effects of Endogenous Lipids on the Skin Microbiome 219


Carol L. Fischer and Philip W. Wertz


11.1 Introduction 219


11.2 Sebaceous Lipids -- Source of Fatty Acids 221


11.3 Stratum Corneum Lipids - Source of Long-Chain Bases 223


11.4 Antimicrobial Activity of Fatty Acids 226


11.5 Antimicrobial Activity of Long-Chain Bases 230


11.6 Conclusion 231


References 231


12 Innate Immunity in Epidermis 237


Miroslav Blumenberg


12.1 Introduction 237


12.2 Skin Acts as an Anatomical Physical and Chemical Barrier to Infectious Agents 238


12.3 Epidermal Cells Recognize Conserved Features of Pathogens, as well as the Indicators of Tissue Damage 239


12.4 Defensive Antimicrobial Proteins AMPs 240


12.5 Cytokines, Specific Signals that Activate Inflammation and Further Cellular Protective Mechanisms 242


12.6 Specialized White Blood Cells Identify and Remove Pathogens 243


12.7 Complement System 246


12.8 Innate Immune System Activates the Adaptive Immune System 246


12.9 Antiviral Defenses 247


12.10 Innate Immunity Memory? 247


12.11 Cutaneous Microbiome: A Newly Surfaced Contributor to Innate Immunity 248


12.12 Conclusion 251


12.13 Future Perspectives 252


References 254


Part 5: Testing and Study Design 261


13 Next Generation Sequencing Reveals the Skin Microbiome 263


Niamh B O'Hara


13.1 Introduction 263


13.2 Current Approaches to Test the Microbiome 265


13.3 The Genomics Revolution and Metagenomics 266


13.4 Metagenomics and the Skin Microbiome 267


13.5 Our Work at Biotia 268


13.6 Challenges and Solutions in Metagenomics 269


13.7 The Microbial World is our Oyster 272


13.8 The Future of Metagenomics 273


Acknowledgements 273


References 274


14 Three-Dimensional Human Skin Models to Investigate Skin Innate and Immune-Mediated Responses to Microorganisms 277


Marisa Meloni and Silvia Balzaretti


14.1 State-of-the-Art and Limits of Skin Microbiota Research 277


14.2 Mechanism-Based Approach to Study Host Response to Associated Microbiome: 3D Skin Models 279


14.3 Understanding S. epidermidis and S. aureus Behavior


and Role on Reconstructed Human Epidermis (RHE) 281


14.4 Immuno-Competent Atopic Dermatitis Model 284


14.5 Conclusion and Future Perspectives 286


References 286


15 Cutibacterium acnes (formerly Propionibacterium acnes) In-Vivo Reduction Assay: A Pre-Clinical Pharmacodynamic Assay for Evaluating Antimicrobial/Antibiotic Agents in Development for Acne Treatment 289


Stuart R. Lessin and James J. Leyden


15.1 Acne Pathogenesis and the Role of Cutibacterium acnes (formerly Propionibacterium acnes) 290


15.1.1 Introduction 290


15.1.2 Pathogenesis 290


15.1.3 The Role of C. acnes and its Microbiome 290


15.2 Current Therapies and Regulatory Approval 293


15.3 In-Vivo C. acnes Reduction Assay 294


15.4 Correlations of C. acnes Reduction and Clinical Efficacy 297


15.5 Conclusion 300


References 300


Part 6: Regulatory and Legal Aspects for Skin Microbiome Related Products 303


16 Intellectual Property Tools for Protecting, Developing and Growing a Skin Microbiome Brand 305


Jeffrey K. Mills


16.1 Introduction 305


16.2 The Tools of Intellectual Property 306


16.2.1 Patents 306


16.2.2 Trademarks 307


16.2.3 Copyrights 308


16.2.4 Trade Secrets/Know-How 309


16.3 Building an Intellectual Property Portfolio for a Skin Microbiome Brand 310


16.3.1 Patents to Define "The Fence" 310


16.3.1.1 Patents "As Sticks" - Enforcement of Infringement 313


16.3.1.2 Patents "As Financial Boosts" - Licensing and Other Agreements 314


16.3.2 Trademarks to Establish Brand Recognition 315


16.3.3 Copyrights to Maintain Information 317


16.3.4 Trade Secrets/Know-How to Keep A Competitive Edge 318


16.4 Conclusion 320


17 Regulatory Aspects of Probiotics and Other Microbial Products Intended for Skin Care: The European Approach 321


Atte von Wright


17.1 Introduction 322


17.2 The Governing Bodies and Decision-Making in the EU 322


17.2.1 The Legal Instruments of the EU 323


17.3 Probiotic Foods and the European Regulations 324


17.3.1 The Safety Assessment of Microorganisms by EFSA, The QPS Concept 324


17.3.1.1 The Safety Assessment of Non-QPS Microorganisms 327


17.3.2 The Case of GMMs 328


17.3.3 Microorganisms as Novel Foods 329


17.3.4 Human Probiotics and Functional Claims 329


17.4 Probiotic Skin Care Products as Pharmaceuticals 330


17.4.1 The Authorization Procedure for Medicines 331


17.4.1.1 The Centralized Procedure 332


17.4.1.2 National Authorizations and Authorizations by Mutual Recognition or Decentralized Procedures 333


17.4.2 Bacteria as Medical Devices 334


17.5 Probiotics in Cosmetics 335


17.5.1 Safety Aspects 336


17.5.1.1 Microorganisms on Skin - Problems of Safety Evaluation 337


17.5.2 The Permissible Cosmetic Claims in the EU 338


17.6 Conclusions 338


References 340


Legal Acts and Guidance Documents 340


18 Regulation of Probiotic and Other Live Biologic Products: The United States Approach 343


Ronie M. Schmelz


18.1 Introduction 343


18.1.1 U.S. Legislative Landscape 344


18.1.2 Foods 345


18.1.2.1 Permissible Food Claims 350


18.1.2.2 Additional Regulatory Considerations 354


18.1.3 Dietary Supplements 355


18.1.3.1 Permissible Dietary Supplement Claims 357


18.1.3.2 Additional Regulatory Considerations 359


18.1.4 Drugs 360


18.1.4.1 Drug Approval Process 361


18.1.4.2 Additional Regulatory Considerations 364


18.1.5 Cosmetics 364


18.2 Summary of Product Categorization and Regulatory Requirements 365


18.3 Resources 369


18.4 Endnotes 369


19 A Future Research Perspective Is There a Connection Between Sun Exposure, Microbiome and Skin Cancer? 377


Nava Dayan


19.1 Introduction 378


19.2 Ultraviolet Light (UV) - The Skin Microbiome and Cancer 378


19.3 Conclusion 386


Acknowledgment 386


References 387


Glossary 389


Index 399