The Human Microbiota and Chronic Disease
Dysbiosis as a Cause of Human Pathology

Microbiota-associated pathology can be a direct result of changes in general bacterial composition, such as might be found in periodontitis and bacterial vaginosis, and/or as the result of colonization and/or overgrowth of so called keystone species. The disruption in the composition of the normal human microbiota, or dysbiosis, plays an integral role in human health and human disease.

The Human Microbiota and Human Chronic Disease: Dysbioses as a Cause of Human Pathology discusses the role of the microbiota in maintaining human health. The text introduces the reader to the biology of microbial dysbiosis and its potential role in both bacterial disease and in idiopathic chronic disease states.

Divided into five sections, the text delineates the concept of the human bacterial microbiota with particular attention being paid to the microbiotae of the gut, oral cavity and skin. A key methodology for exploring the microbiota, metagenomics, is also described. The book then shows the reader the cellular, molecular and genetic complexities of the bacterial microbiota, its myriad connections with the host and how these can maintain tissue homeostasis. Chapters then consider the role of dysbioses in human disease states, dealing with two of the commonest bacterial diseases of humanity ? periodontitis and bacterial vaginosis. The composition of some, if not all microbiotas can be controlled by the diet and this is also dealt with in this section.  The discussion moves on to the major ?idiopathic? diseases afflicting humans, and the potential role that dysbiosis could play in their induction and chronicity. The book then concludes with the therapeutic potential of manipulating the microbiota, introducing the concepts of probiotics, prebiotics and the administration of healthy human faeces (faecal microbiota transplantation), and then hypothesizes as to the future of medical treatment viewed from a microbiota-centric position.

• Provides an introduction to dysbiosis, or a disruption in the composition of the normal human microbiota
• Explains how microbiota-associated pathology and other chronic diseases can result from changes in general bacterial composition
• Explores the relationship humans have with their microbiota, and its significance in human health and disease
• Covers host genetic variants and their role in the composition of human microbial biofilms, integral to the relationship between human health and human disease

Authored and edited by leaders in the field, The Human Microbiota and Human Chronic Disease will be an invaluable resource for clinicians, pathologists, immunologists, cell and molecular biologists, biochemists, and system biologists studying cellular and molecular bases of human diseases.

List of contributors xvii

Preface xxi

Section 1 An introduction to the human tissue microbiome 1

1 The human microbiota: an historical perspective 3
Michael Wilson

1.1 Introduction: the discovery of the human microbiota: why do we care? 3

1.2 The importance of the indigenous microbiota in health and disease 3

1.3 The development of technologies for characterising the indigenous microbiota 8

1.4 Culture‐independent approaches to microbial community analysis 29

1.5 Determination of microbial community functions 31

1.6 Closing remarks 32

Take‐home message 32

References 33

2 An introduction to microbial dysbiosis 37
Mike Curtis

2.1 Definition of dysbiosis 37

2.2 The ‘normal’ microbiota 38

2.3 Main features of dysbiosis 45

2.4 Conclusions 49

Take‐home message 53

Acknowledgment 53

References 53

3 The gut microbiota: an integrated interactive system 55
Hervé M. Blottière and Joël Doré

3.1 Introduction 55

3.2 Who is there how is it composed? 56

3.3 A system in interaction with food 58

3.4 A system highly impacted by the host 61

3.5 A system in interaction with human cells 62

3.6 Conclusion: an intriguing integrated interactive system deserving further study 63

Take‐home message 63

References 63

4 The oral microbiota 67
William G. Wade

4.1 Introduction 67

4.2 Composition of the oral microbiome 68

4.3 The oral microbiota in health 71

4.4 Role of oral microbiome in disease 73

4.5 Future outlook 75

Take‐home message 75

References 76

5 The skin microbiota 81
Patrick L.J.M. Zeeuwen and Joost Schalkwijk

5.1 Normal skin 81

5.2 Skin diseases 83

5.3 Experimental studies 87

5.4 Dynamics of the skin microbiome 87

5.5 Axillary skin microbiome transplantation 89

5.6 Mouse skin microbiome studies 89

5.7 Concluding remarks 90

Take‐home message 90

References 90

6 Metagenomic analysis of the human microbiome 95
Luis G. Bermúdez‐Humarán

6.1 Introduction 95

6.2 The human microbiome 96

6.3 Changes in microbiota composition during host life cycles 97

6.4 The human microbiome and the environment 98

6.5 Disease and health implications of microbiome 99

6.6 Conclusions 105

Take‐home message 105

References 106

Section 2 Microbiota-microbiota and microbiota-host interactions in health and disease 113

7 Systems biology of bacteria‐host interactions 115
Almut Heinken Dmitry A. Ravcheev and Ines Thiele

7.1 Introduction 115

7.2 Computational analysis of host‐microbe interactions 118

7.3 Network‐based modeling 121

7.4 Other computational modeling approaches 127

7.5 Conclusion 129

Take‐home message 130

Acknowledgments 130

References 131

8 Bacterial biofilm formation and immune evasion mechanisms 139
Jessica Snowden

8.1 Introduction 139

8.2 Biofilms in human disease 139

8.3 Biofilm formation 141

8.4 Immune responses to biofilms 143

8.5 Biofilm immune evasion strategies 147

8.6 Vaccines and biofilm therapeutics 148

8.7 Conclusions 149

Take‐home message 149

References 150

9 Co‐evolution of microbes and immunity and its consequences for modern‐day life 155
Markus B. Geuking

9.1 Introduction 155

9.2 Symbiosis in eukaryotic evolution 156

9.3 Evolution of the (innate and adaptive) immune system 157

9.4 Hygiene hypothesis 159

9.5 What drives the composition of the microbiota? 160

9.6 The pace of evolution 161

Take‐home message 162

References 162

10 How viruses and bacteria have shaped the human genome: the implications for disease 165
Frank Ryan

10.1 Genetic symbiosis 165

10.2 Mitochondria: symbiogenesis in the human 167

10.3 Viral symbiogenesis 169

10.4 HERV proteins 172

Take‐home message 174

References 174

11 The microbiota as an epigenetic control mechanism 179
Boris A. Shenderov

11.1 Introduction 179

11.2 Background on epigenetics and epigenomic programming/ reprograming 180

11.3 Epigenomics and link with energy metabolism 184

11.4 The microbiota as a potential epigenetic modifier 185

11.5 Epigenetic control of the host genes by pathogenic and opportunistic microorganisms 188

11.6 Epigenetic control of the host genes by indigenous (probiotic) microorganisms 189

11.7 Concluding remarks and future directions 191

Take‐home message 193

References 193

12 The emerging role of propionibacteria in human health and disease 199
Holger Brüggemann

12.1 Introduction 199

12.2 Microbiological features of propionibacteria 199

12.3 Population structure of P. acnes 201

12.4 Propionibacteria as indigenous probiotics of the skin 202

12.5 Propionibacteria as opportunistic pathogens 203

12.6 Host interacting traits and factors of propionibacteria 205

12.7 Host responses to P. acnes 206

12.8 Propionibacterium‐specific bacteriophages 208

12.9 Concluding remarks 209

Take‐home message 210

References 210

Section 3 Dysbioses and bacterial diseases: Metchnikoff’s legacy 215

13 The periodontal diseases: microbial diseases or diseases of the host response? 217
Luigi Nibali

13.1 The tooth: a potential breach in the mucosal barrier 217

13.2 The periodontium from health to disease 217

13.3 Periodontitis: one of the most common human diseases 219

13.4 Periodontal treatment: a non‐specific biofilm disruption 220

13.5 Microbial etiology 220

13.6 The host response in periodontitis 221

13.7 Conclusions 223

Take‐home message 223

References 223

14 The polymicrobial synergy and dysbiosis model of periodontal disease pathogenesis 227
George Hajishengallis and Richard J. Lamont

14.1 Introduction 227

14.2 A (very) polymicrobial etiology of periodontitis 229

14.3 Synergism among periodontal bacteria 230

14.4 Interactions between bacterial communities and epithelial cells 232

14.5 Manipulation of host immunity 233

14.6 Conclusions 237

Take‐home message 238

References 239

15 New paradigm in the relationship between periodontal disease and systemic diseases: effects of oral bacteria on the gut microbiota and metabolism 243
Kazuhisa Yamazaki

15.1 Introduction 243

15.2 Association between periodontal and systemic diseases 244

15.3 Issues in causal mechanisms of periodontal disease for systemic disease 249

15.4 New insights into the mechanisms linking periodontal disease and s ystemic disease 252

15.5 Effect of oral administration of P. gingivalis on metabolic change and gut microbiota 252

15.6 Conclusions 254

Take‐home message 255

References 255

16 The vaginal microbiota in health and disease 263
S. Tariq Sadiq and Phillip Hay

16.1 What makes a healthy microbiota 263

16.2 The vaginal microbiota in disease 265

16.3 Conclusions 269

Take‐home message 269

References 270

Section 4 Dysbioses and chronic diseases: is there a connection? 273

17 Reactive arthritis: the hidden bacterial connection 275
John D. Carter

17.1 Introduction 275

17.2 Reactive arthritis 276

17.3 Pathophysiology of ReA 277

17.4 Questions remain 279

17.5 Conclusion 280

Take‐home message 280

References 280

18 Rheumatoid arthritis: the bacterial connection 283
Jacqueline Detert

18.1 Preclinical rheumatoid arthritis 283

18.2 Predisposition to RA 284

18.3 MCH‐HLA and genetic predisposition to RA 284

18.4 Molecular mimicry in RA 285

18.5 Innate immune system and RA 285

18.6 Bystander activation and pattern recognition receptors 286

18.7 Antibodies and neoepitopes 287

18.8 Superantigens 287

18.9 Lps 287

18.10 Bacterial DNA and peptidoglycans 288

18.11 Heat‐shock proteins 288

18.12 Toll‐like and bacterial infections 288

18.13 Proteus mirabilis 288

18.14 Porphyromonas gingivalis and RA 289

18.15 Gastrointestinal flora and RA 290

18.16 Smoking lung infection and RA 291

18.17 Where to go from here? 291

Take‐home message 291

References 292

19 Inflammatory bowel disease and the gut microbiota 301
Nik Ding and Ailsa Hart

19.1 The microbiota in inflammatory bowel disease 301

19.2 Dysbiosis and IBD pathogenesis 301

19.3 Environmental factors affecting microbiome composition 302

19.4 Genetics and application to the immune system and dysbiosis in IBD 303

19.5 An overview of gut microbiota studies in IBD 305

19.6 Specific bacterial changes in IBD 306

19.7 Functional composition of microbiota in IBD 308

19.8 Challenges 310

19.9 Conclusion 310

Take‐home message 310

References 310

20 Ankylosing spondylitis klebsiella and the low‐starch diet 317
Alan Ebringer, Taha Rashid and Clyde Wilson

20.1 Introduction 317

20.2 Clinical features of AS 317

20.3 Gut bacteria and total serum IgA 318

20.4 Molecular mimicry in AS 319

20.5 Pullulanase system and collagens 320

20.6 Specific antibodies to Klebsiella in AS patients 321

20.7 The low‐starch diet in AS 322

20.8 Conclusions 324

Take‐home message 325

References 325

21 Microbiome of chronic plaque psoriasis 327
Lionel Fry

21.1 Introduction 327

21.2 Microbiota in psoriasis 329

21.3 Variation of microbiota with site 331

21.4 Swabs versus biopsies 331

21.5 Psoriatic arthritis 331

21.6 Microbiome and immunity 332

21.7 Evidence that the skin microbiome may be involved in the pathogenesis of psoriasis 332

21.8 New hypothesis on the pathogenesis of psoriasis 334

Take‐home message 334

References 335

22 Liver disease: interactions with the intestinal microbiota 339
Katharina Brandl and Bernd Schnabl

22.1 Introduction 339

22.2 Non‐alcoholic fatty liver disease 339

22.3 Qualitative and quantitative changes in the intestinal microbiota 340

22.4 Endotoxin 341

22.5 Ethanol 342

22.6 Choline 342

22.7 Alcoholic liver disease 343

Take‐home message 346

References 346

23 The gut microbiota: a predisposing factor in obesity diabetes and atherosclerosis 351
Frida Fåk

23.1 Introduction 351

23.2 The “obesogenic” microbiota: evidence from animal models 351

23.3 The “obesogenic” microbiota in humans 352

23.4 A leaky gut contributing to inflammation and adiposity 352

23.5 Obesity‐proneness: mediated by the gut microbiota? 353

23.6 Bacterial metabolites provide a link between bacteria and host metabolism 353

23.7 Fecal microbiota transplants: can we change our gut bacterial profiles? 354

23.8 What happens with the gut microbiota during weight loss? 354

23.9 The “diabetic” microbiota 355

23.10 The “atherosclerotic” microbiota 356

23.11 Conclusions 357

Take‐home message 357

References 357

24 The microbiota and susceptibility to asthma 361
Olawale Salami and Benjamin J. Marsland

24.1 Introduction 361

24.2 The microenvironment of the lower airways 361

24.3 Development of the airway microbiota in the neonate 362

24.4 Upper airway microbiota 364

24.5 What constitutes a healthy airway microbiota 365

24.6 Microbiota and asthma 365

24.7 Dietary metabolites and asthma 366

24.8 Conclusion future perspectives and clinical implications 367

Take‐home message 367

References 367

25 Microbiome and cancer 371
Ralph Francescone and Débora B. Vendramini‐Costa

25.1 Introduction 371

25.2 Microbiome and cancer: where is the link? 374

25.3 Microbiome and barrier disruption 376

25.4 Microbiome and different types of cancer 377

25.5 Microbiota and metabolism: the good and the bad sides 382

25.6 Chemotherapy the microbiome and the immune system 384

25.7 Therapeutic avenues 385

25.8 Unresolved questions and future work 387

Take‐home message 387

References 387

26 Colorectal cancer and the microbiota 391
Iradj Sobhani and Séverine Couffin

26.1 Introduction 391

26.2 Colon carcinogenesis and epidemiological data 392

26.3 The microbiota 394

26.4 Bacteria and CRCs links 395

26.5 Hypotheses and perspectives 402

Take‐home message 405

References 405

27 The gut microbiota and the CNS: an old story with a new beginning 409
Aadil Bharwani and Paul Forsythe

27.1 Introduction 409

27.2 The microbiota‐gut‐brain axis: a historical framework 410

27.3 The microbiota‐gut‐brain axis: an evolutionary perspective 411

27.4 The gut microbiota influence on brain and behavior 413

27.5 Microbes and the hardwired gut brain axis 415

27.6 Hormonal pathways to the brain 418

27.7 Microbes and immune pathways to the brain 420

27.8 Metabolites of the microbiota: short‐chain fatty acids 421

27.9 Clinical implications of the microbiota‐gut‐brain axis 422

27.10 Conclusion 422

Take‐home message 423

References 423

28 Genetic dysbiosis: how host genetic variants may affect microbial b iofilms 431
Luigi Nibali

28.1 The holobiont: humans as supra‐organisms 431

28.2 Genetic variants in the host response to microbes 432

28.3 Genetic dysbiosis 434

28.4 Summary and conclusions 438

Take‐home message 438

References 438

Section 5 Mirroring the future: dysbiosis therapy 443

29 Diet and dysbiosis 445
Mehrbod Estaki, Candice Quin and Deanna L. Gibson

29.1 Introduction 445

29.2 Coevolution of the host‐microbiota super‐organism 445

29.3 Gut microbiota in personalized diets 446

29.4 The evolution of diet 447

29.5 Plasticity of the microbiota and diet 447

29.6 Interaction among gut microbiota host and food 448

29.7 Consequences of diet‐induced dysbiosis for host health 450

29.8 The role of gut microbes on the digestion of macronutrients 451

29.9 Diet induces dysbiosis in the host 452

29.10 The effect of maternal diet on offspring microbiota 456

29.11 The effects of post‐natal diet on the developing microbiota of neonates 457

29.12 Conclusion 459

Take‐home message 459

Host-food 460

References 460

30 Probiotics and prebiotics: what are they and what can they do for us? 467
Marie‐José Butel Anne‐Judith Waligora‐Dupriet

30.1 The gut microbiota a partnership with the host 467

30.2 Probiotics 467

30.3 Prebiotics 470

30.4 Synbiotics 471

30.5 Pro‐ pre‐ and synbiotics in human medicine today 471

30.6 Concluding remarks 477

Take-home message 478

References 478

31 The microbiota as target for therapeutic intervention in pediatric intestinal diseases 483
Andrea Lo Vecchio and Alfredo Guarino

31.1 Introduction 483

31.2 Use of probiotics in pediatric intestinal diseases 484

31.3 Fecal microbiota transplantation for treatment of intestinal diseases 488

31.4 Conclusion 492

Take‐home message 493

References 493

32 Microbial therapy for cystic fibrosis 497
Eugenia Bruzzese, Vittoria Buccigrossi, Giusy Ranucci and Alfredo Guarino

32.1 Introduction: pathophysiology of cystic fibrosis 497

32.2 Intestinal inflammation in CF 498

32.3 Dysbiosis in CF 499

32.4 Microbial therapy in CF 502

32.5 Conclusion 504

Take‐home message 504

References 504

Index 507

Brian Henderson is a Professor of Microbial Diseases in the School of Life and Medical Sciences at University College London in London, UK.