Microbiome, Immunity, Digestive Health

and Nutrition: Epidemiology,

Pathophysiology, Prevention and
Treatment Debasis Bagchi
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Microbiome, Immunity, Digestive Health and
Nutrition
Epidemiology, Pathophysiology, Prevention and Treatment
This page intentionally left blank
Microbiome, Immunity,
Digestive Health and
Nutrition
Epidemiology, Pathophysiology, Prevention
and Treatment

Edited by
Debasis Bagchi
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States;
Department of Biology, Adelphi University, Garden City, NY, United States; Department of R&D,
Victory Nutrition International, Inc., Bonita Springs, FL, United States

Bernard William Downs

Division of Precision Nutrition, Victory Nutrition International, Inc.,
Bonita Springs, FL, United States
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 Dedication

Dedicated this legendary book to Mr. Tapan Kumar Pain, my beloved and
respected guide, philosopher, and friend for his esteemed contribution,
encouragement, and inspiration in my life.

Debasis Bagchi

This book is dedicated with love and awe-struck admiration to Kim, my wife.
She is the most amazing woman I know and a source of constant inspiration
to me. She achieves extraordinary accomplishments and makes them seem
simply like routine occurrences.

Bernard William Downs
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Contents

List of contributors xix Author disclosure statement 21

Preface xxv References 21

3. Impact of the gut microbiome on

Section I human health and diseases 25
Microbiome and human health: Samudra Prosad Banik, Shalini Sehgal,
Rituparna Banik Ghosh and Ahana Das
an introduction
3.1 Introduction 25
1. Oral microbiome: a gateway to your 3.1.1 Definition of microbiome 25
health 3 3.1.2 Uneven distribution of microbiota
across various sites and organs of the
Na-Young Song, Se-Young Park, body: reasons and implications 25
Won-Yoon Chung, Young-Joon Surh, 3.2 The gut as the most significant niche of
Kyung-Soo Chun and Kwang-Kyun Park the human microbiome 26
1.1 Introduction 3 3.2.1 Establishment of the gut microbiome:
1.2 Oral microbiome and oral disease 3 journey from womb to adulthood 26
1.2.1 Caries 3 3.2.2 Heritable component of the gut
1.2.2 Periodontal disease 4 microbiome 26
1.2.3 Oral cancer 4 3.2.3 Role of diet and other environmental
1.3 Oral microbiome and systemic disease 5 factors in shaping the gut
1.3.1 Alzheimer’s disease 5 microbiome 27
1.3.2 Cardiovascular disease 6 3.3 Physiological roles of the gut microbiome 27
1.3.3 Diabetes 6 3.3.1 Gut Microbiota in metabolism 27
1.4 Concluding remarks 7 3.3.2 Gut microbiota in boosting immune
Acknowledgments 8 response: role of short-chain fatty
References 8 acids and cross-talk with diet 28
3.3.3 The role of the gut microbiome in
the development of gut-associated
2. Influence of microbiome in shaping lymphoid tissue 29
the newborn immune system: 3.3.4 Gut microbes as a defense
an overview 11 mechanism against pathogens 30
3.3.5 Role in cognitive development:
Manoj Kumar Kingsley and B. Vishnu Bhat
the gut-brain axis 30
2.1 Introduction 11 3.3.6 The gut microbiome as a human
2.2 How the microbiota shapes the organ 32
development of immunity in early life 11 3.4 Dysbiosis of normal flora: implications in
2.3 Influence of the microbiota on the human diseases and intervention strategies 32
development and function of specific 3.4.1 Gut microbiome in human ailments 32
immune cell subsets in early life 13 3.4.2 How to keep the gut happy: prebiotics,
2.3.1 Myeloid cells 13 probiotics, postbiotics, and synbiotics 34
2.3.2 Lymphoid cells 14 3.5 Concluding remarks 35
2.3.3 Epithelial cells 20 Acknowledgments 36
2.4 Conclusion 21 References 36

vii
viii Contents

4. The gut microbiome, human 5.1.4 Microbiome formation and early

nutrition, and immunity: colonization 54
visualizing the future 41 5.1.5 The endocannabinoid axis: the
microbiome as a mechanism by
Soching Luikham and Jhimli Bhattacharyya which lifestyle affects various
4.1 Introduction 41 aspects of metabolism, which in
4.2 Studying the gut microbiome and its turn can lead to metabolic
importance 42 syndrome and metabolic disorders 54
4.3 The role of the microbiome in nutrition 44 5.2 Brief methodology overview 55
4.3.1 Digestion of breast milk 45 5.3 Biomarker validation: metabolic
4.3.2 Digestion of Fiber 45 syndrome and cardiovascular diseases 55
4.3.3 Enhancement of immune 5.3.1 Limited clinical trial: person-oriented
competence 45 treatment of type 2 diabetes 55
4.3.4 Promotion of brain health 45 5.4 Results and discussion 55
4.3.5 Boosting of cardiovascular health 45 5.4.1 Patterns of clinically validated
4.3.6 Potentiation of insulin sensitization biomarkers in the gastrointestinal
and decrease in the risk of diabetes 45 microbiome for patients with
4.3.7 Prebiotic foods and dietary fiber 45 metabolic syndrome, obesity, type 2
4.3.8 Probiotic foods 46 diabetes, and cardiovascular diseases 55
4.4 The role of the microbiome in immune 5.4.2 Data from human trials: treatment
system development 46 by individual nutrition and
4.5 Various ways to improve our gut biopreparation with pharmabiotics 56
microbiome 47 5.4.3 IT tools for implementation of 3P
4.5.1 Eat a diverse diet 47 medicine and individual nutrition 58
4.5.2 Consider fermented foods 47 5.4.4 Databases 58
4.5.3 Avoid artificial sweeteners 47 5.4.5 IT tools 59
4.5.4 Consume prebiotic foods 47 5.4.6 Mechanisms involved and
4.5.5 Breastfeed for six months 47 prospective research 59
4.5.6 Include whole grains 48 5.4.7 Biological active compounds as
4.5.7 Include plant-based foods 48 potential modern prebiotics 59
4.5.8 Consume polyphenol-containing 5.4.8 Early health programming 62
food 48 5.5 Conclusion 65
4.5.9 Take antibiotics when required 48 References 66
4.6 Future areas of research 48
4.7 Conclusion 48
Acknowledgments 48
References 49 Section II
Microbiome and digestive health
5. Individual microbiota correction and
human health: programming and 6. The etiology of gut dysbiosis and
reprogramming of systemic and its role in chronic disease 71
local immune response 53 Alvin H. Danenberg
Tamara Meleshko, Oleksandra Pallah and
6.1 Introduction 71
Nadiya Boyko
6.2 First things first 71
5.1 Introduction 53 6.3 Diet and the gut 72
5.1.1 What is known and what is new? 6.4 Short-chain fatty acids 72
Beneficial microbes: a new concept? 53 6.5 Fasting and the gut 72
5.1.2 The concept of a healthy human 6.6 The effect of unhealthy diets on the gut 72
microbiome 53 6.7 The benefit of healthy diets for the gut 73
5.1.3 The basic concept of a healthy 6.7.1 Mediterranean diet 74
normal microbiota and concepts of 6.7.2 Low-carbohydrate diets 74
early formation of the microbiome 54 6.7.3 Ketogenic diets 74
 Contents ix

6.7.4 Paleolithic diet 74 7.5 Contribution of human intestinal

6.8 Inflammation 74 microbes in causing diseases 96
6.8.1 Acute inflammation 75 7.5.1 Clostridium difficile infection 97
6.8.2 Chronic inflammation 75 7.5.2 Inflammatory bowel disease 97
6.9 Gluten 75 7.5.3 Colorectal cancer 97
6.10 Gliadin 75 7.5.4 Rheumatoid arthritis 98
6.11 Leaky gut 76 7.5.5 Obesity 98
6.12 Other irritants to the gut 76 7.5.6 Esophageal cancer 98
6.13 A closer look into the inner tube of 7.6 Microorganism that can prevent human
the gut 77 disease 99
6.13.1 The gut microbiome and 7.6.1 Colorectal cancer 99
infections 78 7.6.2 Gastric cancer 99
6.13.2 Cross-talk between microbes 78 7.6.3 Inflammatory bowel diseases 100
6.14 Chronic inflammatory and autoimmune 7.6.4 Obesity 100
diseases 79 7.6.5 Hepatic encephalopathy 100
6.14.1 Type 1 diabetes 79 7.7 Dietary modulation of the gut
6.14.2 Rheumatoid arthritis 79 microbiota 100
6.14.3 Celiac disease 79 7.8 Conclusion 102
6.14.4 Inflammatory bowel disease 80 References 102
6.14.5 Allergic diseases 80
6.14.6 Systemic lupus erythematosus 80
6.14.7 Skin-related autoimmune
pathologies 80 Section III
6.14.8 Neurological inflammatory Microbiome and metabolic syndrome
diseases 80
6.14.9 Periodontal disease 80 8. The beneficial role of healthy
6.14.10 Cancer 81 microbiome in metabolic syndrome
6.15 Unraveling the mystery of treatment 82 and cardiovascular health 109
6.15.1 Treatment for active infections 82
6.15.2 Understanding periodontal Smriti Arora, Nitika Bhambri, Samikshha Puri,
disease 82 Anamika, Nandini Dasgupta, Shradha Khater
6.15.3 Repairing and restoring the gut 82 and Gautam Das
6.15.4 Spore-based bacillus probiotics 83 8.1 Introduction 109
6.15.5 Prebiotics 83 8.2 Gut microbiota and metabolic syndrome 110
6.15.6 The mucosal layer 83 8.2.1 Obesity 111
6.15.7 The importance of the mouth 84 8.2.2 Gut microbiota and hyperglycemia
6.15.8 Personal oral hygiene protocol 84 and diabetes 112
6.16 Concluding remarks 85 8.2.3 Gut microbiota and dyslipidemia 112
References 85 8.2.4 Gut microbiota and hypertension 113
8.2.5 Gut microbiota and cardiovascular
7. Role of the microbiome in the disease 113
function and diseases of the 8.2.6 Early gut microbiota and MetS 114
digestive system 93 8.3 Mechanism at the molecular level 114
8.3.1 The gut barrier 114
F A Dain Md Opo, Addisu Demeke Teklemariam,
8.3.2 Energy metabolites 115
Rokeya Pervin and Md. Akil Hossain
8.4 Metabolic syndrome therapy by
7.1 Introduction 93 managing gut microbiota 117
7.2 Microbes in gastrointestinal tract 93 8.4.1 Influence of diet 117
7.3 Development of the gut flora 94 8.4.2 Influence of prebiotics 118
7.4 Physiological functions of gut microbes 95 8.4.3 Influence of probiotics 118
7.4.1 Metabolism 95 8.4.4 Influence of exercise 119
7.4.2 Immune system development 96 8.5 Conclusion 119
7.4.3 Central nervous system development 96 References 119
x Contents

9. The role of the intestinal microbiota 11.4.4 Intestinal microbiota in

in weight loss in overweight and cardiovascular diseases:
obese humans 125 the heart-gut axis 156
11.5 Influence of dietary components in
Isabel Sospedra López, Gema Alfonso Sigüenza, boosting a healthy microbiome and
Estela González Rodrı́guez, Mar Lozano Casanova reducing the risk of metabolic
and José Miguel Martı́nez-Sanz syndrome 157
9.1 Causes of overweight and obesity 125 11.5.1 Carbohydrates 158
9.2 The microbiota and obesity 125 11.5.2 Proteins 158
9.3 The bacterial composition of the 11.5.3 Fats 159
microbiota according to weight status 126 11.5.4 Fatty acids 159
9.4 Effect of dietary interventions on the 11.5.5 Polyphenols 160
microbiota 127 11.5.6 Spices 160
9.5 Conclusions 133 11.5.7 Prebiotics 160
References 133 11.5.8 Probiotics 161
11.5.9 Selective diets 161
11.6 Conclusion 162
10. Role of microbial metabolites in
References 162
cardiovascular and human health 137 Further reading 165
Abhilasha Singh
Abbreviations 137 12. Restoring gut biome balance for
10.1 Introduction 137 weight loss: clinical applications 167
10.2 Gut microbial metabolites and
cardiovascular disease 138 Naras Bhat, Jyoti Bhat, Kusum Bhat,
10.2.1 Short-chain fatty acids 139 Imran Junaid, Anita Bhat and Joy Bhat
10.2.2 Other metabolites of clinical 12.1 Introduction 167
significance 143 12.2 Gut microbiome resiliency 167
10.3 Conclusions 145 12.3 Obesogenic features of the gut
References 145 microbiome 168
12.3.1 Obesogenic gut microbiome is
11. Beneficial role of gut microbiome in transferrable 168
metabolic syndrome, obesity, and 12.3.2 Mother-to-child transmission of
cardiovascular diseases 149 obesity 168
12.4 Dysbiosis as obesogenic signature 168
Pradipta Banerjee, Sriya Choudhury, Komal Jalan,
12.4.1 Decreased diversity 168
Amitava Das, Nandini Ghosh and Debasis Bagchi
12.4.2 Firmicutes/bacteroidetes ratio 168
11.1 Introduction 149 12.4.3 Keystone bacteria 168
11.1.1 Gut microbiome 149 12.4.4 Gut barrier permeability 169
11.1.2 Dietary intake for reducing the risk 12.4.5 Concept of prebiotics,
factor of metabolic syndrome, probiotics, and postbiotics 169
obesity, and cardiovascular 12.5 Obesogenic metabolic endotoxemia
disease 149 and insulin resistance 170
11.2 Metabolic syndrome 150 12.5.1 Diet-induced lipopolysaccharide
11.3 Composition of a healthy gut endotoxemia 170
microbiome 150 12.5.2 Insulin resistance and
11.4 Beneficial role of a healthy microbiome inflammation 172
in preventing metabolic syndrome 154 12.5.3 Stress and metabolic
11.4.1 How the microbiome is related endotoxemia 172
to health and diseases 154 12.5.4 Immune activation 172
11.4.2 Gut microbiome and metabolic 12.6 Effect of dietary components on
syndrome 154 metabolic endotoxemia 172
11.4.3 Gut microbiome: a new strategy 12.6.1 Effect of fasting on metabolic
to treat obesity 155 endotoxemia 172
 Contents xi

12.6.2 Exercise and metabolic 13.4 Dysbiosis 187

endotoxemia 172 13.5 Gut microbiome and inflammation 188
12.6.3 How long does it take to 13.6 Future: harnessing the gut microbiota
change the gut biome? 172 to treat metabolic disorders 188
12.7 Microbial regulation of host energy 13.7 Intestinal transplantation 188
balance 173 13.8 Oral butyrate 189
12.7.1 Microbiota-associated energy 13.8.1 Probiotics 189
harvest 173 13.9 Heat-killed probiotics 190
12.7.2 Cross-talk between the gut 13.10 Prebiotics 190
microbiota and the host 13.11 Synbiotics 190
metabolism 173 13.12 Postbiotics 190
12.7.3 Gut-brain axis of eating behavior 173 13.13 Summary and concluding remarks 190
12.7.4 Gut-muscle axis and energy References 191
output 173
12.7.5 Gut-adipose-liver axis and 14. The effect of resveratrol-mediated
energy storage 173 gut microbiota remodeling on
12.7.6 Gut biome and circadian rhythm 174 metabolic disorders 193
12.7.7 Fasting and autophagy 174
12.8 Western lifestyle as a menace to the Marzena Wojcik and Lucyna Wozniak
gut biome 174 14.1 Introduction 193
12.9 Pragmatic mitigation of western 14.2 Gut microbiota and obesity 194
lifestyle effects on the gut biome 176 14.2.1 Resveratrol, the gut microbiota,
12.10 Eating and fasting 176 and obesity 196
12.10.1 What to eat? 176 14.3 Gut microbiota and type 2 diabetes
12.10.2 Clinical protocol for mellitus 199
microbiome-centered eating 178 14.3.1 Resveratrol, the gut microbiota,
12.10.3 When to eat? Intermittent and type 2 diabetes mellitus 200
fasting 178 Acknowledgments 200
12.10.4 Clinical protocol for fasting- References 200
mimicking time-restricted
eating 179
12.11 Physical activity versus physical
inactivity 179 Section IV
12.11.1 Exercise versus nonexercise 179
12.11.2 Sedentary versus sitting disease 179
Microbiome and immune health
12.11.3 Clinical protocol for physical
activity 180
15. The microbiome, immunity,
12.12 Wake-sleep circadian rhythm 180 anaerobism, and inflammatory
12.12.1 Clinical protocol for circadian conditions: a multifaceted systems
rhythm balance 180 biology intervention 205
12.13 Conclusion 181 Bernard William Downs, Samudra Prosad Banik,
References 181 Manashi Bagchi, Rituparna Banik Ghosh,
Further reading 184 Steve Kushner and Debasis Bagchi
13. Harnessing gut friendly microbiomes 15.1 Introduction 205
to combat metabolic syndrome 185 15.2 Restoring the ideal biological
environment and optimal
Chitra Selvan and Satinath Mukhopadhyay
homeostatic equilibrium 205
13.1 Introduction 185 15.3 Digestion: the first step in metabolism 206
13.2 Gut microbiome 185 15.4 Antioxidant therapy: firing at the
13.3 Gut microbiota and metabolic wrong target 206
disorders: mechanisms 187 15.5 Role of the microbiome 207
13.3.1 Gut microbiome and energy 15.6 Epigenetic influences 209
homeostasis 187 15.7 Microbiome functional competence 209
xii Contents

15.8 Inflammatory events 210 17.4 Gut-hypothalamic homeostatic energy

15.9 Multifaceted systems biology regulation 234
intervention: conceptual overview 210 17.4.1 The set point dilemma 235
15.10 Microbial dysbiosis 211 17.4.2 Homeostatic systems 235
15.11 Functions of microbial strains 212 17.4.3 Feeding behavior regulation by
15.12 Microbial restoration 212 dopaminergic systems 235
15.13 Butyric acid 213 17.4.4 Food and drug addiction
15.14 Conclusion 213 identification of common
References 214 neurobiological mechanisms 236
Further reading 216 17.5 Summary 237
17.6 Conclusion 239
16. Preclinical data support the strong References 239
specificity and advertising ability to
control the immune reactions at 18. Influence of gut microbial flora in
mucosal sites 217 body’s serotonin turnover and
associated diseases 245
Tamara Meleshko, Oleksandra Pallah and
Nadiya Boyko Sabyasachi Choudhuri, Jyotirmoy Panda and
Sayantan Maitra
16.1 Introduction 217
16.2 Microbiota detection tools 218 List of abbreviation 245
16.2.1 Technological approaches 218 18.1 Introduction 245
16.2.2 Mice models 218 18.2 The gut microbiota 246
16.2.3 Schaedler’s E. coli induces 18.3 Role of the gut microbiota in
diminished translocation of maintaining the body’s normal
Lactobacillus salivarius into the physiological homeostasis 249
lung: the role of surfactant 18.4 Influence of neurotransmitters on
protein D 221 the gut microbiome population
16.3 Conclusion 225 through the gut-brain axis 251
References 225 18.4.1 Role of biogenic amines in the
gut microbiota 252
18.4.2 Role of esters in the gut
microbiota 256
Section V 18.4.3 Role of miscellaneous
neurotransmitters in the gut
Microbiome and cognitive health microbiota 257
18.5 Association between the microbiome-
17. Achieving dopamine homeostasis to gut-brain axis and serotonin
combat brain-gut functional turnover 257
impairment: behavioral and 18.6 Dysregulation in the occurrence of gut
neurogenetic correlates of reward microbiota and its implications in
deficiency syndrome 229 diverse pathological conditions 259
18.7 Conclusion 262
Kenneth Blum, Bernard William Downs,
References 262
Debasis Bagchi, Gene-Jack Wang,
Panyotis K. Thanos, Igor Elman, Rehan Jalali,
19. The connection between diet, gut
Abdalla Bowirrat, David Baron, Diwanshu Soni,
Rajendra D. Badgaiyan and Mark S. Gold
microbes, and cognitive decline 265
Abhai Kumar, Smita Singh and
17.1 Introduction 229
Rameshwar Nath Chaurasia
17.2 Understanding endorphin deficiency
syndrome and opioid deficiency 19.1 Introduction 265
syndrome 232 19.2 Microbiome composition and
17.3 Understanding obesity as a evolution 265
hypodopaminergia 233 19.3 Microbiota and brain functioning 266
 Contents xiii

19.4 Microbiome-gut-brain axis 267 20.5 Summary 290

19.5 Microbiome and cognitive decline 268 References 291
19.6 Diet and cognition 268
19.7 Conclusion 269 Section VI
References 269
Microbiome, dermal health and
wound healing
20. Role of the gut microbiome in Rett
syndrome 273 21. Skin microbiota and its role in health
and disease with an emphasis on
Carly Albright, Amanda Friend, Benjamin Peters,
Miranda Reed, Vishnu Suppiramaniam and
wound healing and chronic wound
Subhrajit Bhattacharya
development 297
J.H. Kim, A. Ahamed, K. Chen, E.G. Lebig,
20.1 Introduction to the gut microbiome 273
B. Petros, S. Saeed and M. Martins-Green
20.1.1 Digestion and the gut microbiome 273
20.1.2 Absorption, distribution, 21.1 Introduction 297
metabolism and excretion 274 21.2 Skin structure and function 298
20.1.3 Gut microbiome altering 21.3 Skin microbiome diversity in
medication efficacy 274 different parts of the body 299
20.1.4 Medication-induced gut 21.4 Microbial dysbiosis in skin-related
microbiome dysbiosis 276 diseases 300
20.2 Diseases of the gut 276 21.4.1 Atopic dermatitis 300
20.2.1 Diseases central to the gut 276 21.4.2 Acne vulgaris 300
20.2.2 Diseases distant from the gut: 21.4.3 Rosacea 301
psychiatric and neurological 21.4.4 Psoriasis 301
disorders 277 21.4.5 Skin cancers 302
20.3 The gut microbiome and Rett syndrome 280 21.5 The microbiome and cutaneous
20.3.1 Background and history of Rett wound healing 302
syndrome 280 21.5.1 The microbiome and cutaneous
20.3.2 Pathology, symptoms, and chronic wound development 303
progression 281 21.5.2 Specific chronic wounds and
20.3.3 Genetic links 281 their wound microbiome 304
20.3.4 DNA methylation in Rett 21.6 Common techniques for surveying
syndrome 282 the skin microbiota 306
20.3.5 Biogenic amine systems in Rett 21.7 Manipulation of the skin microbiota to
syndrome 282 prevent or treat skin-associated
20.3.6 Rett syndrome in males 282 ailments 307
20.3.7 Role of different excitatory and 21.7.1 Probiotics 307
inhibitory receptor systems: 21.7.2 Skin microbiota transplant 307
GABA, NMDAR, and AMPAR 283 21.7.3 Prebiotics 307
20.3.8 Treatment paradigm 283 21.8 Perspectives 308
20.4 Relationship between gut microbiome References 308
and Rett syndrome 284
20.4.1 Effect on gut microbiome
diversity and dysbiosis 285
Section VII
20.4.2 Recent and past studies 286 Microbiome and cancer
20.4.3 Rett syndrome and other
neurological and psychiatric 22. Healthy gut microbiome in the
disorders that share gut prevention of colorectal cancer 315
microbiome alterations 287
Marufa Rumman, Misako Nagasaka,
20.4.4 Intestinal inflammation in Rett
Bayan Al-Share, Asfar S. Azmi and
syndrome 289
Md. Hafiz Uddin
20.4.5 Rett syndrome therapeutics and
the gut microbiome 289 22.1 Introduction 315
xiv Contents

22.2 The gut microbiome in the Section IX

progression
of colorectal cancer 315
Environmental pollutants and
22.3 Factors affecting the gut microbiome 317 gut microbiome
22.3.1 Dietary fats 317
22.3.2 Red and processed meats 317 24. Microplastic toxicity and the gut
22.3.3 Alcohol consumption 318 microbiome 345
22.3.4 Smoking 318
Muhammad Manjurul Karim, Pooja Shivappa,
22.3.5 Obesity 318
Nadiya Dileep, Tania Akter Jhuma and
22.3.6 Physical activity 319
Ashfaque Hossain
22.4 The gut microbiome in the protection
against colorectal cancer 319 24.1 Introduction 345
22.5 Prevention of colorectal cancer by 24.2 History of microplastics 345
enhancing healthy gut flora 320 24.3 Microplastics pollution and the
22.5.1 Prebiotics 320 threat to habitats 346
22.5.2 Probiotics 321 24.4 Gut microbiome 347
22.5.3 Synbiotics 322 24.4.1 Dysbiosis and eubiosis 348
22.6 Conclusion and future perspectives 322 24.4.2 Short-chain fatty acids and
Conflict of interest 322 branched-chain fatty acids 349
References 322 24.4.3 Virome and microplastics 349
24.4.4 Akkermansia muciniphila 351
24.5 Toxic effects of microplastics on human
systems 351
Section VIII 24.5.1 Microplastic modulation of
cellular pathways 352
Microbiome, arthritis and 24.5.2 Microplastics-induced reactive
multiple sclerosis oxygen species 352
24.5.3 Accumulation of microplastic
23. Regulatory roles of the microbiome particles in different tissues 353
in arthritis, fibromyalgia, and 24.6 Plastisphere: biofilm on microplastics 353
multiple sclerosis 331 24.7 Microplastics as pathogen carriers 354
24.8 Conclusion and perspectives 354
Liz J. Vázquez-Chinea, Savannah N. Johnson
References 354
and Elizabeth A. Lipski
23.1 Introduction 331
23.2 Rheumatoid arthritis 331 Section X
23.2.1 Microbiome profile of individuals Molecular and immunological
with rheumatoid arthritis 332
23.2.2 Probiotic supplementation in
mechanisms associated with
individuals with rheumatoid healthy gut microbiome functions
arthritis 332
23.3 Fibromyalgia 334 25. Role of the gut microbiome and
23.3.1 Pain and fibromyalgia 334 probiotics for prevention and
23.3.2 Gut microbiota and management of tuberculosis 361
fibromyalgia 334
Tejaswini Baral, Shilia Jacob Kurian, Sonal Sekhar M.,
23.4 Multiple sclerosis 335
Murali Munisamy, Chandrashekar Udyavara Kudru,
23.4.1 Gut microbiota and multiple
Bidita Khandelwal, Mithu Banerjee, Chiranjay
sclerosis 335
Mukhopadhyay, Kavitha Saravu, Jitendra Singh,
23.4.2 Multiple sclerosis and
Sarman Singh and Mahadev Rao
modifiable factors 336
23.5 Discussion 338 25.1 Introduction 361
23.6 Conclusion 340 25.2 Gut-lung axis 362
References 340 25.3 Gut-liver axis 362
 Contents xv

25.4 Gut
immune system axis 363 27. Prospective role of prebiotics and
25.5 Role of the human gut microbiome in probiotics in gut immunity 387
tuberculosis 363
25.6 Role of probiotics in tuberculosis 363 Saptadip Samanta
25.6.1 Probiotics as immunomodulator 365 27.1 Introduction 387
25.6.2 Probiotics as an antiinfective 27.2 The gut microbiota and its beneficial
mediator 366 effects 388
25.6.3 Preclinical and clinical evidence 27.2.1 Shape of the gut microbiota 388
of the effects of probiotics in 27.2.2 Role of the microbiota in the
managing tuberculosis 366 synthesis of essential metabolites
25.7 Role of probiotics in preventing and bioactive components 388
anti-TB drug-induced adverse effects 367 27.3 Impacts of dysbiosis 390
25.7.1 Amelioration of adverse 27.3.1 Inflammatory bowel diseases 391
gastrointestinal effects 367 27.3.2 Clostridium difficile infection 391
25.7.2 Amelioration of drug-induced 27.3.3 Metabolic disorders 391
hepatotoxicity 367 27.3.4 Role in cancer progression 391
25.8 Probiotics in the improvement of 27.3.5 Gastric cancer 392
nutritional status in tuberculosis 368 27.3.6 Colorectal cancer 392
25.9 Dose and dosage of probiotic 27.3.7 Hepatocellular carcinoma 392
formulations for dietary supplements 368 27.3.8 Other cancers 392
25.10 Conclusion 369 27.4 Prebiotics 393
References 369 27.5 Probiotics 394
27.6 Role of prebiotics and probiotics in
26. Lactic acid bacteria
based immunomodulation 394
beverages in the promotion of 27.6.1 Prebiotics and immune-boosting
gastrointestinal tract health 373 effects 394
27.6.2 Production of short-chain fatty
Luı́s Cláudio Lima de Jesus, Tales Fernando da acids and their
Silva, Rafael de Assis Glória, Andria dos Santos immunomodulatory effects 394
Freitas, Monique Ferrary Américo, Lucas Jorge da 27.6.3 Protective role against
Silva Fernandes, Gabriela Munis Campos, inflammation 396
Gabriel Camargos Gomes, Rhayane Cristina Viegas 27.6.4 Role of bile acids 396
Santos, Rodrigo Dias de Oliveira Carvalho, 27.6.5 Effect on development of gut-
Debmalya Barh and Vasco Azevedo associated lymphoid tissue and
26.1 Introduction 373 expansion of gut immunity 396
26.2 Lactic Acid Bacteria 373 27.6.6 Protective role of probiotic
26.3 LAB-derived bioactive compounds 374 organisms against pathogenesis 397
26.4 The LAB fermentation process 375 27.6.7 Role in innate immunity 398
26.5 Organoleptic characteristics of 27.6.8 Probiotic bacteria and
LAB-fermented foods 375 modulation of cytokine profile 398
26.6 Commercial products from LAB 27.6.9 Role in enhanced secretion of
fermented foods 376 IgA 398
26.7 Application of LAB-fermented 27.6.10 Role in immunosurveillance-
beverages in gastrointestinal mediated cancer prevention 399
tract
related diseases 376 27.7 Additional benefits of probiotics 399
26.7.1 Antibiotic-associated diarrhea 378 27.8 Concluding remarks 399
26.7.2 Constipation 378 References 399
26.7.3 Inflammatory Bowel Diseases 380
26.7.4 Intestinal mucositis 381 28. Gut
brain communication: a novel
26.7.5 Colorectal cancer 382 application of probiotics 405
26.7.6 Enteric infections 382
Sujit Das, Trupti J. Undhad and Subrota Hati
26.8 Final considerations 383
References 383 28.1 Introduction 405
xvi Contents

28.2 The gut-brain axis: a concept 405 steroid hormone
microbiota-

28.3 Factors regulating the microbiota- inflammation axis 424
gut-brain axis 407 References 427
28.3.1 Genetics and epigenetics 407
28.3.2 Mode of delivery at birth 407
28.3.3 Fats 407
28.3.4 Medications and the 30. Role of mushroom polysaccharides
microbiome 407 in improving gut health and
28.4 Interactions within the gut-brain axis 407 associated diseases 431
28.4.1 Neuronal pathway 408 Divya Yadav and Pradeep Singh Negi
28.4.2 Endocrine pathway 408
28.4.3 Humoral/metabolic pathway 408 30.1 Introduction 431
28.4.4 Immune pathway 409 30.2 The gut microbiome 432
28.5 Function of the microbiota in the 30.3 Mushroom polysaccharides 432
gut-brain-axis 409 30.3.1 D-glucan 433
28.5.1 From the gut microbiota to the 30.4 Proteoglycan 437
brain 409 30.4.1 Glycoprotein 438
28.5.2 From the brain to the gut 30.5 Prebiotic efficiency of mushroom
microbiota 410 polysaccharides 438
28.6 The gut-brain axis in the regulation 30.6 Hydrolysis of mushroom
of food intake 411 polysaccharides by intestinal
28.7 Behavior and the microbiota bacterial enzymes 439
gut-brain axis 411 30.7 Impact of mushroom polysaccharides
28.7.1 Animal studies 411 on the gut microbiome 439
28.7.2 Human studies 413 30.8 Prevention of various diseases by
28.8 Conclusions and future perspectives 413 prebiotic mushroom polysaccharides
References 413 through modulation of the gut
microbiota 440
30.8.1 Inflammatory bowel disease 440
30.8.2 Antitumor effect 444
29. Flaxseed has a pronounced effect
30.8.3 Immunomodulatory effect 445
on gut microbiota 417 30.9 Conclusion and future perspectives 445
M.N. Sharath Kumar and S. Devaraja References 445
29.1 Introduction 417
29.2 Flaxseed oil prevents alcoholic liver
disease by modulating the gut
microbiota through its antiinflammatory Section XI
property 418
29.3 Flaxseed oil reduces the severity
Microbiome and immunomodulatory
of type 2 diabetes mellitus by peptides
modulating the gut microbiota via its
antiinflammation effect 419 31. The role of the microbiome in
29.4 By altering the composition of the sports nutrition 451
gut microbiota, flaxseed oil has
Estela González-Rodrı́guez, Laura Albero Montava,
beneficial immunological and
Isabel Sospedra López and José Miguel
metabolic effects 421
Martı́nez-Sanz
29.5 Flaxseed polysaccharide modulates the
composition and structure of the gut 31.1 Introduction 451
microbiota by altering the firmicutes- 31.2 The microbiome and sport 451
bacteroidetes ratio 423 31.3 Research related to the microbiome
29.6 Flaxseed oil ameliorated polycystic and athletic performance 452
ovary syndrome through the sex 31.4 Conclusion 457
References 457
 Contents xvii

Section XII 33.3 Outcome measure 482

33.4 Sample data: hydroxycitric acid study 482
Study design and statistical 33.5 Method for analyzing the intervention
interpretation effect without adjusting for the
pre-value effect 482
32. Food-derived immunomodulatory 33.6 Method for analyzing an intervention
peptides: science to applications 461 effect, adjusting for the effect of the
pre-value: analysis of covariance 485
Chopada Kevalkumar Dineshbhai,
33.7 Change point regression model 489
Pratik Shukla, Amar Sakure, Brij Pal Singh,
References 492
Sujit Das, Sreeja V. and Subrota Hati
32.1 Introduction 461
32.2 Immunomodulation and
immunomodulatory peptides 462
Commentary from the Editor’s
32.3 Mechanism of immunomodulatory Desk 495
peptide 463
32.4 Sources of some immunomodulatory A treatise on a healthy microbiome:
peptides 463 contribution to human health and
32.4.1 Milk and milk products 464 disease prevention 497
32.4.2 Fish 467
Debasis Bagchi, Samudra Prosad Banik and
32.4.3 Marine organisms 468
Bernard William Downs
32.4.4 Eggs 468
32.4.5 Plants 468 A.1 Microbiome terminology: the origin 497
32.5 Bioavailability of bioactive peptides in A.2 Microbiota, microorganisms, and
foods 470 microbiome 497
32.5.1 Absorption 471 A.3 Microbiome: human health and disease
32.5.2 Distribution 471 pathology 498
32.5.3 Metabolism 472 A.4 Microbiome and metabolic syndrome 499
32.5.4 Elimination 472 A.5 Microbiome and obesity 500
32.6 Methods used to assay A.6 Microbiome and diabetes 500
immunomodulatory activity 472 A.7 Microbiome and cancer 500
32.7 Clinical studies 474 A.8 Microbiome, brain health, and
32.7.1 Related to COVID-19 474 advancing age 500
32.7.2 Impact of probiotics strains on A.9 Summary and conclusions 501
T cell response 474 References 501
32.8 Applications 474
32.9 Conclusion 475 Index 503
References 475

33. Clinical intervention, study design,

and statistical methodology:
statistical approaches for
pre-post studies 481
Kohsuke Hayamizu
33.1 Introduction 481
33.2 Pre-post design 481
This page intentionally left blank
List of contributors
A. Ahamed Department of Molecular, Cell and Systems
Biology, University of California, Riverside, CA,
United States
Laura Albero Montava Nursing Department, Faculty of
Health Sciences, University of Alicante, Alicante,
Spain
Carly Albright Department of Drug Discovery and
Development, Auburn University, Auburn, AL, United
States
Bayan Al-Share Department of Oncology, Karmanos
Cancer Institute, Wayne State University School of
Medicine, Detroit, MI, United States
Monique Ferrary Américo Laboratório de Genética
Celular e Molecular (LGCM), Instituto de Ciências
Biológicas, Departamento de Genética, Ecologia e
Evolução, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte, Minas Gerais, Brazil
Anamika Department of Allied Health Sciences,
University of Petroleum and Energy Studies (UPES),
Dehradun, Uttarakhand, India
Smriti Arora Department of Allied Health Sciences,
University of Petroleum and Energy Studies (UPES),
Dehradun, Uttarakhand, India
Vasco Azevedo Laboratório de Genética Celular e
Molecular (LGCM), Instituto de Ciências Biológicas,
Departamento de Genética, Ecologia e Evolução,
Universidade Federal de Minas Gerais (UFMG), Belo
Horizonte, Minas Gerais, Brazil
Asfar S. Azmi Department of Oncology, Karmanos
Cancer Institute, Wayne State University School of
Medicine, Detroit, MI, United States
Rajendra D. Badgaiyan Department of Psychiatry,
South Texas Veteran Health Care System, Audie L.
Murphy Memorial VA Hospital, and Long School of
Medicine, University of Texas Health Science Center,
San Antonio, TX, United States; Department of
Psychiatry, MT. Sinai School of Medicine, New York,
NY, United States
Debasis Bagchi College of Pharmacy and Health
Sciences, Texas Southern University, Houston, TX,
United States; Department of Biology, Adelphi
University, Garden City, NY, United States;
Department of R&D, Victory Nutrition International,
Inc., Bonita Springs, FL, United States
Manashi Bagchi Department of R&D, Dr. Herbs LLC,
Concord, CA, United States
Mithu Banerjee Department of Biochemistry, All India
Institute of Medical Sciences, Jodhpur, Rajasthan,
India
Pradipta Banerjee Department of Biochemistry and
Plant Physiology, Centurion University of Technology
and Management, Parlakhemundi, Odisha, India;
Department of Surgery, Indiana University School of
Medicine, Indianapolis, IN, United States
Samudra Prosad Banik Department of Microbiology,
Maulana Azad College, Kolkata, West Bengal, India
Tejaswini Baral Department of Pharmacy Practice,
Manipal College of Pharmaceutical Sciences, Manipal
Academy of Higher Education, Manipal, Karnataka,
India
Debmalya Barh Laboratório de Genética Celular e
Molecular (LGCM), Instituto de Ciências Biológicas,
Departamento de Genética, Ecologia e Evolução,
Universidade Federal de Minas Gerais (UFMG), Belo
Horizonte, Minas Gerais, Brazil; Centre for Genomics
and Applied Gene Technology, Institute of Integrative
Omics and Applied Biotechnology (IIOAB),
Nonakuri, West Bengal, India
David Baron Department of Psychiatry, College of
Osteopathic Medicine of the Pacific, Western University
of Health Sciences, Pomona, CA, United States
Nitika Bhambri Department of Allied Health Sciences,
University of Petroleum and Energy Studies (UPES),
Dehradun, Uttarakhand, India
Anita Bhat Jivahealth Clinics, Concord, CA, United
States
B. Vishnu Bhat Director-Medical Research, Professor of
Pediatrics and Neonatology, Aarupadaiveedu Medical
College and Hospital, Vinayaka Mission’s Research
Foundation-DU, Puducherry, India
xix
xx List of contributors
Joy Bhat Jivahealth Clinics, Concord, CA, United States
Jyoti Bhat Jivahealth Clinics, Concord, CA, United
States
Kusum Bhat Jivahealth Clinics, Concord, CA, United
States
Naras Bhat Jivahealth Clinics, Concord, CA, United
States
Subhrajit Bhattacharya School of Pharmacy and Health
Sciences, Keck Graduate Institute, Claremont, CA,
United States
Jhimli Bhattacharyya Department of Chemistry,
National Institute of Technology Nagaland, Dimapur,
Nagaland, India
Kenneth Blum Department of Psychiatry, College of
Osteopathic Medicine of the Pacific, Western University
of Health Sciences, Pomona, CA, United States
Abdalla Bowirrat Department of Molecular Biology,
Adelson School of Medicine, Ariel University, Ariel,
Israel
Nadiya Boyko Department of Clinical Laboratory
Diagnostics and Pharmacology, Faculty of Dentistry,
Uzhhorod National University, Uzhhorod, Ukraine;
Research Development and Educational Centre of
Molecular Microbiology and Mucosal Immunology,
Uzhhorod National University, Uzhhorod, Ukraine;
Ediens LLC, Velyki Lasy, Ukraine
Gabriela Munis Campos Laboratório de Genética
Celular e Molecular (LGCM), Instituto de Ciências
Biológicas, Departamento de Genética, Ecologia e
Evolução, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte, Minas Gerais, Brazil
Rodrigo Dias de Oliveira Carvalho Laboratório de
Genética Celular e Molecular (LGCM), Instituto de
Ciências Biológicas, Departamento de Genética,
Ecologia e Evolução, Universidade Federal de Minas
Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
Mar Lozano Casanova Nursing Department, Faculty of
Health Sciences, University of Alicante, Alicante,
Spain
Rameshwar Nath Chaurasia Department of Neurology,
Institute of Medical Sciences, Banaras Hindu
University, Varanasi, India
K. Chen Department of Molecular, Cell and Systems
Biology, University of California, Riverside, CA,
United States
Sabyasachi Choudhuri Department of Pharmaceutical
Science and Technology, Maulana Abul Kalam Azad
University of Technology, Haringhata, West Bengal,
India
Sriya Choudhury Department of Biochemistry,
Institute of Biomedical Sciences, The West Bengal
University of Health Sciences, Kolkata, West
Bengal, India
Kyung-Soo Chun College of Pharmacy, Keimyung
University, Daegu, South Korea
Won-Yoon Chung Department of Oral Biology, Yonsei
University College of Dentistry, Seoul, South Korea;
Department of Applied Life Science, The Graduate
School, Yonsei University, Seoul, South Korea; BK21
Four Project, Yonsei University College of Dentistry,
Seoul, South Korea
Tales Fernando da Silva Laboratório de Genética
Celular e Molecular (LGCM), Instituto de
Ciências Biológicas, Departamento de Genética,
Ecologia e Evolução, Universidade Federal de Minas
Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
Alvin H. Danenberg Balanced Metabolic Coaching,
Periodontist, Certified Functional Medicine
Practitioner, Certified Primal Health Coach,
Charleston, SC, United States
Ahana Das Department of Microbiology, Maulana Azad
College, Kolkata, West Bengal, India
Amitava Das Department of Surgery, Indiana
University School of Medicine, Indianapolis, IN,
United States
Gautam Das miBiome Therapeutics LLP, Mumbai,
Maharashtra, India
Sujit Das Department of Rural Development and
Agricultural Production, North-Eastern Hill
University, Tura, Meghalaya, India
Nandini Dasgupta miBiome Therapeutics LLP,
Mumbai, Maharashtra, India
Luı́s Cláudio Lima de Jesus Laboratório de Genética
Celular e Molecular (LGCM), Instituto de
Ciências Biológicas, Departamento de Genética,
Ecologia e Evolução, Universidade Federal de
Minas Gerais (UFMG), Belo Horizonte, Minas
Gerais, Brazil
S. Devaraja Department of Studies and Research in
Biochemistry, Tumkur University, Tumkur,
Karnataka, India
Nadiya Dileep Department of Medical Microbiology
and Immunology, RAK Medical and Health
Sciences University, Ras Al Khaimah, United Arab
Emirates
Chopada Kevalkumar Dineshbhai Department of Dairy
Microbiology, SMC College of Dairy Science,
Kamdhenu University, Anand, Gujarat, India

Bernard William Downs Division of Precision
Nutrition, Victory Nutrition International, Inc., Bonita
Springs, FL, United States
Igor Elman Behavioral Neuropharmacology and
Neuroimaging Laboratory on Addictions, Clinical
Research Institute on Addictions, Department of
Pharmacology and Toxicology, Jacobs School of
Medicine and Biosciences, State University of New
York at Buffalo, Buffalo, NY, United States
Lucas Jorge da Silva Fernandes Laboratório de
Genética Celular e Molecular (LGCM), Instituto de
Ciências Biológicas, Departamento de Genética,
Ecologia e Evolução, Universidade Federal de
Minas Gerais (UFMG), Belo Horizonte, Minas
Gerais, Brazil
Andria dos Santos Freitas Laboratório de Genética
Celular e Molecular (LGCM), Instituto de Ciências
Biológicas, Departamento de Genética, Ecologia e
Evolução, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte, Minas Gerais, Brazil
Amanda Friend Department of Drug Discovery and
Development, Auburn University, Auburn, AL, United
States
Nandini Ghosh Department of Surgery, Indiana
University School of Medicine, Indianapolis, IN,
United States
Rituparna Banik Ghosh Department of Physiology,
Bhairab Ganguly College, Kolkata, West Bengal, India
Rafael de Assis Glória Laboratório de Genética Celular e
Molecular (LGCM), Instituto de Ciências Biológicas,
Departamento de Genética, Ecologia e Evolução,
Universidade Federal de Minas Gerais (UFMG), Belo
Horizonte, Minas Gerais, Brazil
Mark S. Gold Department of Psychiatry, Washington
University School of Medicine, St. Louis, MO, United
States
Gabriel Camargos Gomes Laboratório de Genética
Celular e Molecular (LGCM), Instituto de Ciências
Biológicas, Departamento de Genética, Ecologia e
Evolução, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte, Minas Gerais, Brazil
Estela González-Rodrı́guez Nursing Department, Faculty
of Health Sciences, University of Alicante, Alicante,
Spain
Subrota Hati Department of Dairy Microbiology, SMC
College of Dairy Science, Kamdhenu University,
Anand, Gujarat, India
Kohsuke Hayamizu Yokohama University of Pharmacy,
Yokohama, Japan
List of contributors xxi
Ashfaque Hossain Department of Medical
Microbiology and Immunology, RAK Medical and
Health Sciences University, Ras Al Khaimah,
United Arab Emirates
Md. Akil Hossain Department of Pharmacology and
Experimental Therapeutics, School of Medicine,
Boston University, MA, United States
Rehan Jalali Division of Nutrigenomics, The Kenneth
Blum Behavioral Neurogenetic Institute, Austin, TX,
United States
Komal Jalan Department of Agriculture, University of
Calcutta, Kolkata, West Bengal, India
Tania Akter Jhuma Department of Microbiology,
University of Dhaka, Dhaka, Bangladesh
Savannah N. Johnson Department of Clinical Nutrition,
Maryland University of Integrative Health, Laurel,
MD, United States
Imran Junaid Jivahealth Clinics, Concord, CA, United
States
Muhammad Manjurul Karim Department of
Microbiology, University of Dhaka, Dhaka, Bangladesh
Bidita Khandelwal Department of General Medicine,
Sikkim Manipal Institute of Medical Sciences, Sikkim
Manipal University, Gangtok, Sikkim, India
Shradha Khater miBiome Therapeutics LLP, Mumbai,
Maharashtra, India
J.H. Kim Department of Molecular, Cell and Systems
Biology, University of California, Riverside, CA,
United States
Manoj Kumar Kingsley Department of Neonatology,
JIPMER, Puducherry, India
Chandrashekar Udyavara Kudru Department of
Medicine, Kasturba Medical College and Hospital,
Manipal Academy of Higher Education, Manipal, India
Abhai Kumar Department of Neurology, Institute of
Medical Sciences, Banaras Hindu University,
Varanasi, India
Shilia Jacob Kurian Department of Pharmacy Practice,
Manipal College of Pharmaceutical Sciences, Manipal
Academy of Higher Education, Manipal, Karnataka, India
Steve Kushner Department of R&D, ALM R&D,
Oldsmar, FL, United States
E.G. Lebig Department of Molecular, Cell and Systems
Biology, University of California, Riverside, CA,
United States
Elizabeth A. Lipski Faculty Advisor, Department of
Clinical Nutrition, Maryland University of Integrative
Health, Laurel, MD, United States
xxii List of contributors
Isabel Sospedra López Nursing Department, Faculty of
Health Sciences, University of Alicante, Alicante,
Spain
Soching Luikham Department of Chemistry, National
Institute of Technology Nagaland, Dimapur,
Nagaland, India
Sayantan Maitra Institute of Pharmacy, Jalpaiguri,
Government of West Bengal, Department of Health
and Family Welfare, West Bengal, India
José Miguel Martı́nez-Sanz Nursing Department,
Faculty of Health Sciences, University of Alicante,
Alicante, Spain
M. Martins-Green Department of Molecular, Cell and
Systems Biology, University of California, Riverside,
CA, United States
Tamara Meleshko Department of Clinical Laboratory
Diagnostics and Pharmacology, Faculty of
Dentistry, Uzhhorod National University, Uzhhorod,
Ukraine; Research Development and Educational
Centre of Molecular Microbiology and Mucosal
Immunology, Uzhhorod National University,
Uzhhorod, Ukraine
Chiranjay Mukhopadhyay Department of
Microbiology, Coordinator, Center for Emerging and
Tropical Diseases, Kasturba Medical College and
Hospital, Manipal Academy of Higher Education,
Manipal, Karnataka, India
Satinath Mukhopadhyay Department of Endocrinology,
Institute of Postgraduate Medical Education &
Research, Kolkata, West Bengal, India
Murali Munisamy Department of Translational
Medicine, All India Institute of Medical Sciences,
Bhopal, Madhya Pradesh, India
Misako Nagasaka Department of Oncology, Karmanos
Cancer Institute, Wayne State University School of
Medicine, Detroit, MI, United States
Pradeep Singh Negi Department of Fruit and
Vegetables Technology, CSIR-Central Food
Technological Research Institute, Mysuru, India;
Academy of Scientific and Innovative Research
(AcSIR), Ghaziabad, India
F A Dain Md Opo Department of Biological Sciences,
King Abdulaziz University, Jeddah, Saudi Arabia
Oleksandra Pallah Department of Clinical Laboratory
Diagnostics and Pharmacology, Faculty of Dentistry,
Uzhhorod National University, Uzhhorod, Ukraine;
Research Development and Educational Centre of
Molecular Microbiology and Mucosal Immunology,
Uzhhorod National University, Uzhhorod, Ukraine
Jyotirmoy Panda Department of Pharmaceutical Science
and Technology, Maulana Abul Kalam Azad
University of Technology, Haringhata, West Bengal,
India
Kwang-Kyun Park Department of Oral Biology, Yonsei
University College of Dentistry, Seoul, South Korea
Se-Young Park Department of Oral Biology, Yonsei
University College of Dentistry, Seoul, South Korea;
Department of Applied Life Science, The Graduate
School, Yonsei University, Seoul, South Korea; BK21
Four Project, Yonsei University College of Dentistry,
Seoul, South Korea
Rokeya Pervin Foot and Mouth Disease Division,
Animal and Plant Quarantine Agency, Gimcheon-si,
South Korea
Benjamin Peters Department of Drug Discovery and
Development, Auburn University, Auburn, AL, United
States
B. Petros Department of Molecular, Cell and Systems
Biology, University of California, Riverside, CA,
United States
Samikshha Puri Department of Allied Health Sciences,
University of Petroleum and Energy Studies (UPES),
Dehradun, Uttarakhand, India
Mahadev Rao Department of Pharmacy Practice,
Coordinator, Center for Translational Research,
Manipal College of Pharmaceutical Sciences, Manipal
Academy of Higher Education, Manipal, Karnataka,
India
Miranda Reed Department of Drug Discovery and
Development, Auburn University, Auburn, AL, United
States; Center for Neuroscience Initiative, Auburn
University, Auburn, AL, United States
Estela González Rodrı́guez Nursing Department,
Faculty of Health Sciences, University of Alicante,
Alicante, Spain
Marufa Rumman Department of Microbiology,
National Center for Toxicological Research, US Food
and Drug Administration, Redfield, AR, United States
S. Saeed Department of Molecular, Cell and Systems
Biology, University of California, Riverside, CA,
United States
Amar Sakure Deparment of Agriculture Biotechnology,
Anand Agricultural University, Anand, Gujarat, India

Saptadip Samanta Department of Physiology,
Midnapore College, Midnapore, West Bengal, India
Rhayane Cristina Viegas Santos Laboratório de
Genética Celular e Molecular (LGCM), Instituto de
Ciências Biológicas, Departamento de Genética,
Ecologia e Evolução, Universidade Federal de Minas
Gerais (UFMG), Belo Horizonte, Minas Gerais,
Brazil
Kavitha Saravu Department of Infectious Diseases,
Coordinator, Manipal Center for Infectious Diseases,
Kasturba Medical College and Hospital, Manipal
Academy of Higher Education, Manipal, Karnataka,
India
Shalini Sehgal Department of Food Technology,
Bhaskaracharya College of Applied Sciences,
University of Delhi, New Delhi, India
Sonal Sekhar M. Department of Pharmacy Practice,
Manipal College of Pharmaceutical Sciences, Manipal
Academy of Higher Education, Manipal, Karnataka, India
Chitra Selvan Department of Endocrinology, Ramaiah
Medical College, Bengaluru, Karnataka, India
M.N. Sharath Kumar Department of Studies and
Research in Biochemistry, Tumkur University,
Tumkur, Karnataka, India
Pooja Shivappa Department of Basic Sciences, RAK
Medical and Health Sciences University, Ras Al
Khaimah, United Arab Emirates
Pratik Shukla Department of Dairy Microbiology, SMC
College of Dairy Science, Kamdhenu University,
Anand, Gujarat, India
Gema Alfonso Sigüenza Nursing Department, Faculty of
Health Sciences, University of Alicante, Alicante, Spain
Abhilasha Singh Cardiovascular Research Centre,
Massachusetts General Hospital, Harvard Medical
School, Boston, MA, United States
Brij Pal Singh Deparment of Microbiology, Central
University of Haryana, Mahendragarh, Haryana, India
Jitendra Singh Department of Translational Medicine,
All India Institute of Medical Sciences, Bhopal,
Madhya Pradesh, India
Sarman Singh All India Institute of Medical Sciences,
Bhopal, Madhya Pradesh, India
Smita Singh Department of Geriatric Medicine, Institute
of Medical Sciences, Banaras Hindu University,
Varanasi, India
Na-Young Song Department of Oral Biology, Yonsei
University College of Dentistry, Seoul, South Korea;
Department of Applied Life Science, The Graduate
School, Yonsei University, Seoul, South Korea; BK21
List of contributors xxiii
Four Project, Yonsei University College of Dentistry,
Seoul, South Korea
Diwanshu Soni Department of Psychiatry, College of
Osteopathic Medicine of the Pacific, Western University
of Health Sciences, Pomona, CA, United States
Vishnu Suppiramaniam Department of Drug Discovery
and Development, Auburn University, Auburn, AL,
United States; Center for Neuroscience Initiative,
Auburn University, Auburn, AL, United States
Young-Joon Surh College of Pharmacy, Seoul National
University, Seoul, South Korea; Department of
Molecular Medicine and Biopharmaceutical Sciences,
Graduate School of Convergence Science and
Technology, Seoul National University, Seoul, South
Korea; Cancer Research Institute, Seoul National
University, Seoul, South Korea
Addisu Demeke Teklemariam Department of Biological
Sciences, King Abdulaziz University, Jeddah, Saudi
Arabia
Panyotis K. Thanos Department of Psychology and
Behavioral Neuropharmacology and Neuroimaging
Laboratory on Addictions (BNNLA), Research
Institute on Addictions, University at Buffalo, Buffalo,
NY, United States
Md. Hafiz Uddin Department of Oncology, Karmanos
Cancer Institute, Wayne State University School of
Medicine, Detroit, MI, United States
Trupti J. Undhad Department of Dairy Microbiology,
SMC College of Dairy Science, Kamdhenu
University, Anand, Gujarat, India
Sreeja V. Department of Dairy Microbiology, SMC
College of Dairy Science, Kamdhenu University,
Anand, Gujarat, India
Liz J. Vázquez-Chinea Department of Clinical
Nutrition, Maryland University of Integrative Health,
Laurel, MD, United States
Gene-Jack Wang Laboratory of Neuroimaging, National
Institute of Alcohol Abuse and Alcoholism, National
Institutes of Health, Bethesda, MD, United States
Marzena Wojcik Department of Structural Biology,
Medical University of Lodz, Lodz, Poland
Lucyna Wozniak Department of Structural Biology,
Medical University of Lodz, Lodz, Poland
Divya Yadav Department of Fruit and
Vegetables Technology, CSIR-Central Food
Technological Research Institute, Mysuru, India;
Academy of Scientific and Innovative Research
(AcSIR), Ghaziabad, India
This page intentionally left blank
Preface

This book explores a wide range of topics related to the role of nutrition in boosting a healthy microbiome in chapters
written by leading experts in the field. To provide a comprehensive approach to the emerging field of nutrition, gut
health, food recommendations, and the human microbiome, this book covers a wide spectrum of agents including food,
minerals, vitamins, dietary fibers, prebiotics and probiotics, nutraceutical supplements, and phytonutrients that boost
overall human health and performance by improving the health of the microbiome. This book specifically addresses the
causes and pathological manifestations of microbiome dysbiosis and the molecular and cellular mechanisms and path-
ways involved by which nutritional components contribute to the physiology and functionality of a healthy microbiome
and consequential human health. In addition to an extensive review of a variety of functional ingredients and dietary
supplements, this book addresses information regarding nutritional guidelines and healthy lifestyle that are important to
correct, boost, and maintain a healthy gut microbiome for optimal human health.
Digestion and metabolism are the most important steps in human physiology. It is important to note that 70%
80%
of the lymphatic tissue in humans resides in the gastrointestinal tract. Moreover, there is more neurotransmitter activity
in the gut than in the brain, prompting labels of the gastrointestinal tract as “the second brain.” Proper nutrition is essen-
tial for optimal human health, daily activities, and performance. The microbiota that resides in the gastrointestinal tract
performs functions that are essential to overall health, including the synthesis and/or metabolization of certain vitamins,
fatty acids, fibers, and amino acids. The health of the GI tract is ultimately foundational to maintaining good health and
appropriately regulating immune function and maintaining metabolic homeostasis. Otherwise, unhealthy lifestyle
choices and disruptions of health can cause drastic alterations of these gut microbial communities, which ultimately
leads to dysbiosis and the potential for a range of disorders, including but not limited to immune dysregulation, mental
dysfunction, and even autoimmune disorders. Therefore there is a growing need for a comprehensive appraisal of the
proper nutritional benefits in boosting the human microbial ecosystem, which ultimately promotes optimal gastrointesti-
nal health, immunity, and mental function.
This textbook is divided into 12 major section comprising of 33 chapters. The book starts with, the editorial preface,
which was crafted by the editors to provide an overview of this book. Section I “Microbiome and Human Health: An
Introduction” is comprised of five chapters. The first chapter, “Oral Microbiome: A Gateway to Your Health,” demon-
strates the intricate aspects of the oral microbiome and its association with human health, while the second chapter
highlights how a healthy microbiome is involved in shaping the newborn immune system. The third chapter demon-
strates the impact of diverse gut microbiota on human health and prevention against diverse degenerative diseases, and
the fourth and fifth chapters discusses how the individual microbiota participates in programming and reprogramming
both systemic and local immune responses to modulate immune health.
Section II, “Microbiome and Digestive Health,” is composed of two chapters. The first of these chapters discusses
the etiology of gut dysbiosis and its role in chronic diseases, and the second chapter explores the role of microbiome in
the function and diseases of the digestive system. Section III, “Microbiome and Metabolic Syndrome,” is composed of
seven independent chapters. These chapters discuss diverse aspects on the roles of a healthy microbiome in obesity,
weight management, and cardiovascular health. The fourteenth chapter demonstrates the beneficial roles of resveratrol
in remodeling the gut microbiota to prevent metabolic disorders. Section IV, “Microbiome and Immune Health,” is
composed of two chapters. These two chapters emphasize the regulatory roles of the microbiome in immune compe-
tence, anaerobism, and inflammatory conditions.
Section V, “Microbiome and Cognitive Health,” is composed of four chapters. The first of these chapters demon-
strates the importance of achieving dopamine homeostasis to combat brain-gut functional impairment and discusses the
behavioral and neurogenetic correlation with reward deficiency syndrome. The second chapter discussed the influence
of the gut microbial flora in the body’s serotonin turnover and its associated diseases. The third chapter explores the
connection between diet, gut microbes, and cognitive decline, while the fourth chapter discusses the role of the gut
microbiome in Rett syndrome, a rare genetic mutation that affects brain development in some girls. Section VI,

xxv
xxvi Preface

“Microbiome, Dermal Health, and Wound Healing,” discusses the roles of the skin microbiota in dermal health, devel-
opment of chronic wounds, and wound healing. Section VII, “Microbiome and Cancer,” is composed of one chapter
discussing the roles of a healthy gut microbiome in the prevention of colorectal cancer.
Section VIII, “Microbiome, Arthritis, and Multiple Sclerosis,” explains the regulatory roles of the microbiome in
arthritis, fibromyalgia, and multiple sclerosis in one independent chapter. Section IX, “Environmental Pollutants and
Gut Microbiome,” explores the consequences of microplastic exposure on the gut microbiome.
Section X, “Molecular and Immunological Mechanisms Associated With Healthy Gut Microbiome Functions,” ela-
borates on the subject in seven independent chapters. The first three of these chapters discuss the beneficial roles of a
healthy gut microbiome, prebiotics, and probiotics, while the second chapter highlights the roles of lactic acid bacteria
in diverse foods and beverages in the promotion of gastrointestinal health. The fourth chapter explores demonstrates the
novel application of probiotics in enhancing gut-brain communication. The following two chapters demonstrate the ben-
eficial effects of flaxseeds, dietary flavonoids, and mushroom polysaccharides in improving the gastrointestinal micro-
biome and human health. The last chapter in this section demonstrates the roles and importance of healthy gut
microbiome in sports nutrition.
Section XI, “Microbiome and Immunomodulatory Peptides,” details the beneficial roles of immunomodulatory pep-
tides in human health. Section XII, “Study Design and Statistical Interpretation,” demonstrates the aspects of clinical
intervention, study design, and different statistical methodologies for pretest
posttest studies.
The book concludes with a commentary entitled “A Treatise on a Healthy Microbiome,” which summarizes a vivid
scenario of diverse aspects of a healthy microbiome.
We would like to express our sincere gratitude and thanks to all our eminent contributors as well as the helpful
Elsevier/Academic Press editorial team members including Megan R. Ball, Lindsay Lawrence, and Praveen
Sachidanandam for their continued support, cooperation, and assistance.

Debasis Bagchi
Bernard William Downs
Section I

Microbiome and Human

Health: An Introduction
This page intentionally left blank
Another random document with
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The Project Gutenberg eBook of Ralph Trulock's
Christmas Roses
This ebook is for the use of anyone anywhere in the United States and
most other parts of the world at no cost and with almost no restrictions
whatsoever. You may copy it, give it away or re-use it under the terms of
the Project Gutenberg License included with this ebook or online at
www.gutenberg.org. If you are not located in the United States, you will
have to check the laws of the country where you are located before
using this eBook.

Title: Ralph Trulock's Christmas Roses

Author: Annette Lyster

Release date: September 21, 2023 [eBook #71699]

Language: English

Original publication: London: The Religious Tract Society, 1921

*** START OF THE PROJECT GUTENBERG EBOOK RALPH

TRULOCK'S CHRISTMAS ROSES ***
Transcriber's note: Unusual and inconsistent spelling is as printed.

"WISHING YOU MANY HAPPY RETURNS OF THE DAY."

RALPH TRULOCK'S CHRISTMAS
ROSES

BY

ANNETTE LYSTER

Author of

"The Boy who never lost a Chance," etc.

LONDON

THE RELIGIOUS TRACT SOCIETY

4 Bouverie Street & 65 St. Paul's Churchyard

 CONTENTS.

CHAPTER

I. LADY MABEL'S REST

II. RALPH TRULOCK'S STORY

III. MAY CLOUDESLEY SPEAKS HER MIND

IV. A SMALL SEAMSTRESS

V. RALPH'S DINNER PARTY

VI. HOW THE CHRISTMAS ROSES BEGAN TO TAKE ROOT

VII. RALPH'S NURSE

VIII. MRS. CRICKLADE

IX. RALPH'S LETTER

X. RALPH'S CHRISTMAS ROSES BLOOM AT LAST

XI. MONSIEUR OLIVER

 RALPH TRULOCK'S CHRISTMAS
ROSES

CHAPTER I.

LADY MABEL'S REST.

IN one of the midland counties of England, there is a village of

considerable size; of such size indeed that the inhabitants sometimes
call it a town; but it must be confessed that, in spite of this, it is
straggling of aspect. I think myself that it is a mistake to call it a town,
because as a village it is a large place, whereas, considered as a town,
it is disappointing; but no doubt this is a matter of opinion. The name of
the place is Fairford, and it is divided by a shallow stream into two parts,
High and Low Fairford. It took its name from the existence of a ford,
which but is not much used, as there has long been an excellent stone
bridge over the river. None but the Low Fairford boys, on their way to
school in High Fairford, ever use the ford now, but they seem to prefer it
to this day.

High Fairford contains not only the school but the post-office, the
market-place, shops, and several houses of respectable size and
appearance, which all cluster round the church and parsonage. Then
Low Fairford, to which you go by a street so steep that it is like the roof
of a house, and across the little bridge at the foot of the hill,—is merely a
straggling street of cottages, which stand farther and farther apart until
they are lost altogether, and you reach the border of a great piece of
wood, the remains of a very celebrated forest in which Robin Hood once
carried on business in the very "taking" fashion peculiar to that class of
hero.
In a large flat space, close to the forest, there are twelve pretty houses
all in a row. They stand separate, each in a little garden, and a broad
road sweeps all round them, bounded on one side by the low walls of
the gardens, on the other by a high wall with two gates, one in front and
one at the back. That into the forest is seldom opened, but the one
which faces the village is open all day.

These twelve houses were built more than a hundred and fifty years
ago, by a lady who owned all the land in those parts, and who was the
last of her race and name. Hers had been a grand family, and though
active enough in all the troubles of their times, they had contrived to
keep their property together. But if the property did not diminish, the
family did, and ended at last in one young orphan girl, Mabel Greatrex;
whose name will outlive those of all the rest of her house. This young
girl, being rich and fair, had no lack of suitors for her hand. But she was
a long time before she met with one to her mind; so long that people had
begun to say that she would never marry at all. But the right man came
at last, and married she was, in the church of High Fairford; and the
wedding party was coming gallantly down the hill and over the ford, on
horseback, according to the fashion of the day, when the bridegroom's
horse slipped on a stone in the water, grew frightened and restive,
struggled out of the stream on the Low Fairford side, and scoured away
towards the forest. No one was alarmed, for Sir Henry was a gallant
rider; but while they watched how he was bringing his horse under
control again, they saw him carried under the branch of great tree, which
swept him from the saddle and left him dead for his bride to find when
she galloped up.

Mabel never married again, though she was still young. And when she
had somewhat recovered the first shock of her grief, she caused these
houses to be built on the spot which had been so fatal to her—and she
called the place "Lady Mabel's Rest." It was built, said the legend over
the gate, "To the glory of God and the good of His poor." There were six
men and six women, with a warden to see after them, who had
comfortable rooms over the principal gate; and Lady Mabel framed the
rules herself, and secured to them many privileges before she passed
away, leaving her great possessions to distant kindred who did not bear
her name, but leaving (as she said in her will) "to her native place
something by which to remember kindly the last of her race."
So wisely and so well had Lady Mabel done her work, that the
machinery she set going is going on well to this day. The rector of the
parish for the time being manages the affairs of the charity, and is well
paid for so doing. The only conditions for election are, respectability,
poverty, and being a native of Fairford; the most deserving person of
those whose names are sent in is to have the preference. As a general
rule the selection is wisely made, but an occasional mistake occurs once
in a way, of course.

Two vacancies had just been filled up when my story opens: a man and
a woman having been chosen to fill them. It happened that the two
vacant houses stood together at the end of the row. The rector, who had
been abroad with his delicate wife, had come home to arrange about the
selection, and had then returned to the South of France, leaving his
curate and his curate's wife to make acquaintance with the new-comers.

The curate was a young man, and this was the first time that he had
been left in sole charge, so he was naturally anxious to do his best, and
his sweet little bride was anxious to make every one as happy as she
was herself. So, on Christmas Eve, this young couple betook
themselves to Lady Mabel's Rest, to visit the ten families they already
knew, and to see the two new inmates for the first time.

Mrs. Cloudesley had provided herself with a quantity of Christmas roses

from the rectory garden, which she had made up into twelve nosegays,
one for each family. "Let them be ever so proud," said she, "a few
flowers cannot offend them."

Ten of the nosegays were disposed of when the pair knocked at the
door of the last house but one, and awaited with some interest the
appearance of Mrs. Short, of whom they knew nothing but the name,
and the fact that she was a widow.

The door was opened after a short pause by a round little woman, with a
round face, a round nose, a round mouth, and a pair of—no, her eyes
were not round, because they were almost invisible, lost in the
plumpness of her face. But she opened them as wide as she could
when she saw her visitors; and then they completed the series of O's
which composed her features. She wore a cherry-coloured merino
dress, warm, and a snowy apron and cap: the latter with a cherry-
coloured rosette on the top, the last round thing about her. She smiled
and curtsied, and looked very picturesque, thought Mrs. Cloudesley.

"You are Mrs. Short, I think?" said that young lady, after waiting in vain
for her husband to speak. He said afterwards that he thought she could
manage it better than he could; and I daresay he was right.

"Yes, miss, I am; and will you walk in, miss? For it's bitter cold, surely;
and though I haven't got my furniture settled quite to my mind yet,
perhaps you and the young gentleman will excuse that."

"Oh, yes; we know you only came two days ago. This is Mr. Cloudesley,
you know, and I am Mrs. Cloudesley; and we promised Mrs. Barton to
call and see you as soon as we could."

The round woman burst into a fat, smothery laugh, as she answered,—

"A married lady, and me calling of you miss; but re'lly you do look so
young, you must excuse it. Walk in, ma'am, and you, sir, if you'll be so
good."

She opened the door of her little parlour as she spoke, and in they all
walked. Mr. Cloudesley felt a little surprised at the furniture; for though
many of the old inmates of the Rest were well off in that respect, it was
not usual for a new-comer to possess such comforts as he saw here. A
carpet covered the floor, a handsomely gilt clock stood on the
chimneypiece, reflected in a mirror of some size; warm curtains hung
over the window, a bright fender, thick rug,—everything, in fact, of the
best; and also, it must be confessed, of the most hideous, so gaudy was
the colour of each article, where colour was possible. A large, luxurious
easy chair stood close to the fire, which burned brightly, and a small
round table was drawn up beside it. The other chairs were of the
common shape, and were covered with Berlin wool flowers which made
Mrs. Cloudesley feel quite uncomfortable, they were so brilliant. Into the
easy chair the fat lady sank, having first drawn forward two of the less
comfortable ones for her guests.

Mrs. Cloudesley looked about for something to talk about; not a book
was to be seen, not even a newspaper.
"You are making your sitting-room very comfortable," said she, looking
round again.

"Ah, yes, indeed, ma'am; the furniture is very 'andsome, thanks be to

'evin. Yet it do make me sad-like to look at it—but there! That's me all
over! As my poor Matthew, that's dead and buried, poor fellow, used to
say of me. I'm too good-natured for my own 'appiness."

Mrs. Cloudesley, failing to see the connection between the furniture and
the good-nature, looked inquiringly at the speaker.

"You know, miss,—leastways, ma'am, only it's ridiculous,—I'm a Fairford

woman, of course, or I couldn't be here; but I married a Londoner, and
never saw Fairford for thirty year! My 'usbin were a baker, and my son,
—the only child I have, I may fairly say; for as to my daughter Jane, poor
thing she's lost to me, and may be dead or may be alive, I know no
more than if I was dead myself,—he's a baker, too, and has a very good
shop—and of course I've lived with him and kep' his places beautiful.
But there, young men is fools,—he goes and marries! And I haven't a
word to say against her, a civil little body, and decent in her ways, but
selfish, very selfish, poor Seliner is, and ever will be; a boy the first year,
and a girl the next, and then a girl again, and then a boy again, and so
on, and this year twins! No, miss,—ma'am, I mean,—the twins done it;
the 'ouse is small, and when one twin ain't crying the other is, and I'm
not so young as once I were, and I said I'd like a little rest and time to
mind on my latter end—" (with a glance at the curate, who was listening
gravely), "before my time came to die. My good Matthew left me but little
money, and that little is gone now; and, of course, he never thought I
should have to leave my 'ome in my old age; but the furniture was mine,
some he left me by will, and some I bought myself since he was took,
and that's what I meant just now, miss—ma'am—I'm feared they'll miss
it, though I left them everything I could do without—I'm that good-
natured."

She smiled her fat smile, and closed her little twinkling eyes, as if the
contemplation of her good-nature was too much for her. But if she had
stated that her gorgeous purchases had been made with her son's
money; that her right had only extended to taking furniture for two
rooms; and had also described what she had left for the use of her son's
family, adding that "Seliner" had said, "Let her take it all, if she will only
go," perhaps the Cloudesleys might have opened their eyes with quite a
different feeling. As it was, Mrs. Cloudesley felt a little puzzled.

"Do you care for reading?" she said, presently. "For we can lend you
books, if you wish."

"Indeed, I'm no great reader, ma'am. I like to have a bit of work on 'and
as will be a credit to me—them flower pieces are all my own, cross-
stitch every bit of 'em; but I think I shall have no time for it now. By the
time I get my places as nice as I like to have 'em, and my little meal
cooked and ate, there'll be little time for idling."

"Well, but reading is not idling," said Gilbert Cloudesley.

"Ain't it, sir? Well, I don't know. A-settin' with a book in my 'and, doing
nothing, I should be asleep in five minutes, sir, that's certing; even, as I
said, if I had time."

"But you'll keep a girl, won't you?" asked the lady. "Miss Jones—your
neighbour, you know,—she regularly trains girls for service, and so well
that they always get good places when they leave her."

"Well, but you see, miss, I'm very pertic'ler, and gels is so careless and
dirty, and breaks and eats so much; and I never could bear to be
scolding; that's me all over, as my poor Matthew used to say. I'd rather
do the work than be scolding for ever, as Miss Jones do. Besides, I like
to do summut myself; I'm none of your idle ones, nor do I set up to be a
fine lady."

"Miss Jones," said the curate, "says she would rather do the work
herself, too; but, you see, it is a way in which she can be of use, and so
she goes on with it."

"Of course, sir; and I'll think of it," said Mrs. Short smoothly. "Won't you
read a little to me, sir, before you go?" she added, folding her fat hands
and smiling encouragingly at him.

"Not to-day," he said, quietly; "it is late, and we must leave you now."
"And I have brought you these flowers, Mrs. Short—Christmas roses,
you see. I am so fond of them. They come to tell us that we are never
forgotten at any time of the year, and that summer will come again."

"Thank you, ma'am, I'm much obliged," Mrs. Short replied, taking the
flowers and laying them on the table without a glance at their fair, fragile
faces.

"I have a bunch for your neighbour, too, you see," Mrs. Cloudesley went
on, seeing that she eyed the basket curiously.

Mrs. Short laughed. "For Ralph Trulock!" said she. "Flowers and he
won't go well together. Poor Trulock! Such a cross-grained body! Are
you going, ma'am? Well, I hope you'll come again some day. I'm greatly
obliged for the visit,—and the posy," she added, after a moment's
pause.

She opened the door for them, bidding them good-bye again with great
cordiality. A poor lad had ventured into her little front garden, and
seemed inclined to address them, but Mrs. Short retreated hastily,
crying,—

"Oh, what a miserable-looking creetur! I must run in, ma'am, or the sight
of him will spoil my appetite for my tea, I'm that good-natured."

The Cloudesleys looked at each other, the lady puzzled, the gentleman
amused.

"A kind-hearted woman, May?"

"Yes, Gilbert," in a doubtful voice. "I dare say she is. Do give that boy
sixpence, dear."

"No, Mrs. Cloudesley; that is an extravagant notion, quite unfit for a

curate's wife. Besides, I will not encourage begging; but we'll see who
he is. Very likely he wants work rather than charity."

A few words with the boy, and then they went on to the next house, and
knocked at the door of Mr. Trulock's home. It was opened after a little
while by a tall, stooping man with grey hair and a thin, grave face,—
more than grave, indeed, for it was both stern and sad. He was decently
dressed, but not warmly; and he looked cold, and not particularly glad to
see them, little Mrs. Cloudesley thought, as she held on tight to her
husband's arm, and gave it a little pinch, as much as to say, "You must
speak this time."

"Mr. Trulock?" said the curate.

"That is my name, sir," said the tall man, in a sad, toneless voice, as if
speaking were a trouble to him.

"I am Mr. Cloudesley, the curate of this parish; and this is my wife. We
came to pay you a visit this Christmas Eve, that we may not be quite
strangers when we meet to-morrow."

"Thank you, sir, and you, madam. If you will walk in,—but I have no
place fit to bring a lady to."

Mr. Cloudesley was so struck with the unwilling air of this invitation, that
he was about to say "some other day," and leave the place, when his
wife surprised him by walking in. Something in the forlorn man touched
little May's warm heart, and leaving her husband's side she entered the
house quickly, saying:

"It is too cold to stand talking at the door."

The little parlour was in size and shape exactly the same as the one
they had just left. But here there was no carpet, no curtain, no easy
chair, and—worst of all—no fire. Four cane chairs and a small table
formed the furniture.

"I was sitting in the kitchen, madam," said Mr. Trulock, looking at the
bonnie, pleasant face of his little visitor, "and there is a fire there, though
not a good one."

May followed him to the kitchen, which certainly was less cold than the
parlour, and contained rather more furniture, though of the plainest and
cheapest kind. A windsor chair, with arms, but no cushions, was drawn
up close to the struggling fire, and in this Mr. Trulock placed the lady,
and then slowly brought forward a seat for Mr. Cloudesley, and another
for himself.

"You will want a nice tidy girl to keep you comfortable," said May. "Miss
Jones will find you one—she knows all the nice girls in the place."

"Thank you, madam, but I want no girl. It is my wish to do without one, if

I can at all."

"You have some relative who will live with you, then? No! Surely you will
not live quite alone."

"Madam, I must be alone," he said sadly. "A servant would make no

difference."

Then he seemed to repent having said so much, and May could get no
more out of him. He was civil enough, but only answered, "Yes,
madam," or, "No, madam," except that he admitted that he was fond of
reading, and they promised to lend him books.

Then May took out the last of her twelve nosegays.

"Do you care for flowers, Mr. Trulock?"

"No, madam." Then he saw that she had brought him some, and added,
with a mournful smile, "You mean these for me? Thank you, madam,
'twas a kind thought. I will get a glass to put them in. What are they? 'Tis
a strange time of the year for flowers."

"They are Christmas roses, Mr. Trulock."

"It seems unnatural for flowers to blossom now," the old man said, as he
placed them in water. "Summer and youth and flowers—winter and old
age and no flowers at all; that's how things go, madam."

May had risen to say good-bye, she put her small hand into his, and
looking up with tears in her eyes, for his voice was very sad, she said,—

"Yet there are Christmas roses, you see."

"For such as you," he answered.

"For you," she said earnestly. "Only have faith and patience, and open
your heart to the sunshine God sends, and the sweet flowers of charity
—I like the word, even though love may be more correct—will blossom
round your path."

When they were gone, Trulock sat gazing at the fair, pure blossoms, but
he murmured, "Not for me! Not for me!"

Mrs. Short forgot to put her flowers in water, and threw them out the next
morning, muttering contemptuously,—

"Rubbishy things! If it had even been a bit of holly, now, to stick in my

pudding!"

CHAPTER II.
RALPH TRULOCK'S STORY.

BONNIE May Cloudesley caught cold on that Christmas Day, and was
so ill that as soon as she was fit to travel, her husband took her home to
her mother to be nursed for a while. Very dreary and uncomfortable the
poor fellow was during her absence; and when she came home, quite
recovered, he informed her that she must never be ill again, as he could
not possibly get on without her.

"Nonsense, Gilbert! Why, we have not been married a year—and how

did you get on all the thirty-four years before you even knew me?"

"I don't know, May. But it just shows how short a time it takes to spoil a
man; for I was really rather a jolly kind of bachelor."
But at the notion of her shy, silent, grave Gilbert ever having been a jolly
bachelor, May laughed in the most unkind and disrespectful way.

"You may laugh," said Gilbert; and May seemed to agree with him, for
she did laugh very heartily. Then she said,—

"How are all the poor people, Gilbert. How is the boy we met at Lady
Mabel's Rest? And oh! How are the two new people there going on?"

"I have seen Mrs. Short several times, and she always tells me what a
good kind of woman she is. I've nothing to say against it—she ought to
know, of course. Mr. Trulock I have only seen in church; he is always out
when I call."

"I must go there to-morrow. When does Mr. Barton come home?"

"Not until June, I think," replied Mr. Cloudesley.

May kept her word, and the next day, putting on her warmest wraps, for
it was bitter February weather, she trotted down the hill, over the bridge,
and away to Lady Mabel's Rest. She paid one or two visits—one to Miss
Jones. Miss Jones was that unnatural thing, a very disagreeable
Christian. She had a heart of gold, loved her Master and served Him for
love's sake, but she had a queer temper and a natural love of fault-
finding. If she had not been a good woman, she would have been a
most censorious one; as it was, she never permitted herself to speak ill
of the absent, but she "took it out" in scolding. She was greatly pleased
to see Mrs. Cloudesley, and had a hundred questions to ask about Polly
Burr, a girl whom she had trained, and who was now Mrs. Cloudesley's
cook.

"Polly is a really good girl," said May, "and an excellent servant. You
really have a gift for training servants, Miss Jones."

Miss Jones's dark, solemn face softened into a pleased smile.

"A poor gift, ma'am," said she.

"Not poor at all," replied May. "How many Fairford girls have you trained
for service, now?"
"Seventeen altogether, ma'am. Three are married, two died, three
emigrated, and the rest are doing well in their place—all but one. One,
poor thing—well, well, we don't know the end yet."

"No, indeed," said May; "and we can pray, you know. That's always a
comfort, isn't it? Have you made acquaintance with your new
neighbours yet?"

"I knew them both long ago, ma'am."

"I was in hopes that Mrs. Short would follow your good example, and
take a girl to train."

"Martha Short will never take that much—No, ma'am, she has no girl."

"Do you find her a pleasant neighbour?"

"We don't see much of each other, ma'am."

"You knew Mr. Trulock also, didn't you say?"

"Yes, ma'am, and his wife—she was a schoolfellow of mine. A decent

man, Ralph always was, and at one time a very rich one; but there was
something about the son—I never heard the rights of it. It killed poor
Annie, I believe; and Ralph looks heartbroken himself. I see very little of
him—he is out all day. There never was such a man for going about the
country."

Mrs. Cloudesley's next visit was to Mr. Trulock, or rather to his door, for
her knock brought no one to let her in. Mrs. Short's door opened, and
that dumpy dame put out her round head and called out:

"You need not knock again, ma'am, for Mr. Trulock is out; and out he
always is, I may truly say. I couldn't abear to see you knocking, standing
there in the bitter wind, you that has lately had a cold too; I'm that good-
natered. 'Do as you'd be done by,' is my motter, and I wouldn't fancy
standing out in the cold;—you're welcome back, Mrs. Cloudesley,—and
won't you walk in?"
"I was coming to see you," replied May, going round to the door, and
following the waddling steps of Mrs. Short into the parlour. If that room
had surprised her on her first visit, it fairly astounded her now! The
handsome chiffonier with glass doors, the wax flowers under a bell
shade, the pictures in their massive gilt frames! These last were three in
number, and one of them represented Mrs. Short—a shade less round
than Mrs. Short was now, but still an undeniable likeness,—looking
sentimental with all her might at a miniature which she held out straight
before her—so straight, in fact, that only half the miniature could be got
into the picture at all. The second picture represented the late Mr. Short,
a thin little man with a deprecating smile upon his face, carrying in his
hand a bunch of flowers, of which he seemed mortally afraid. The third
was that of the youthful son of this worthy couple, a fat, staring boy with
crimson cheeks, hard and shiny as two rosy apples. He was depicted
drawing by a string a toy horse—black with red spots. The horse was
very well done: it was quite as wooden and as little like a real horse as
the original had been.

"You're looking at my picter, ma'am! Ah, I'm greatly altered since that
was done. It was a minnychure of my poor diseased—" (probably meant
for deceased) "father that I 'ad in my 'and, ma'am, and I requested of the
artiss to put in my poor father's face, but would you believe it, he
refused! He said I wanted to get two 'eads out of him for the price of
one! Some folks is wonderful ill-natered. That's my poor Matthew, as is
dead and buried, poor man! Very like him it is, but you never saw him.
And that's my son Matt; and I hope he'll do well and be 'appy, though
he's not been quite the son he might have been to his widowed mother,
as did for him for years, and kept his places like a 'pictur.' But there! I'll
never mention it to mortal, nor remember it against him—I'm too good-
natured for that!"

"How is Mr. Trulock getting on?" said May, longing to interrupt the flow of
words. "Has he got a servant yet?"

"No, ma'am, nor won't! I've been at him about it dozens of times, for it
spoils my disjection to see him look the way he does—half-starved—
half-clothed, too, I may say; for though decent, yet very threadbare and
scant, ma'am, as your own heyes may tell you. But there! I might as well
talk to a stone, the best I get is, 'You've no gel yourself'; and it's vain to