The book provides a comprehensive detailed summary of current status on skin microbiome research in health and disease as well as key regulatory and legal aspects.
In the past decade, interest and technology have greatly advanced to unravel the nature and effect of skin microbiome on our health. Diseases such as atopic dermatitis and acne are at the forefront of this research, but also other conditions such as skin cancer are under investigation. In addition, mapping of the skin microbiome has gone from basic to more detailed with attempts to correlate it to various ages, ethnicities and genders. In parallel to mapping it, a great deal of research is dedicated to understanding its functionality and communication (and hence effect) on human cells.
The Skin Microbiome Handbook is a summary of current status of knowledge, research tools and approaches in skin microbiome, in health and disease. It contains the following categories: healthy skin microbiome and oral-skin interaction; skin microbiome observational research; skin microbiome in disequilibrium and disease; skin's innate immunity; testing and study design; regulatory and legal aspects for skin microbiome related products. The 18 chapters of the book are written by carefully selected leaders in the academia and industry exhibiting extensive experience and understanding in the areas of interest.
Table of Contents
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. Dubé 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
