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Gastrointestinal Physiology
Menizibeya Osain Welcome

Gastrointestinal Physiology
Development, Principles and Mechanisms
of Regulation

123
Menizibeya Osain Welcome
Department of Physiology, Faculty of Basic
Medical Sciences
College of Health Sciences, Nile University
of Nigeria
FCT-Abuja
Nigeria

The Figures in this book were designed with help of Motifolio Biomedical Drawing Toolkit
Suite (Motifolio Inc., Ellicott City, USA).

ISBN 978-3-319-91055-0 ISBN 978-3-319-91056-7 (eBook)

https://doi.org/10.1007/978-3-319-91056-7
Library of Congress Control Number: 2018940411

© Springer International Publishing AG, part of Springer Nature 2018

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Preface

The digestive system is responsible for about 60–90% of diseases that affect
humans, making the digestive system one of the most important systems in life
processes. This book is a review of key findings of the last two and present mil-
lennia on the area of digestion. This text is a leading textbook and most compre-
hensive review ever written in the field of gastrointestinal (GI) physiology.
This book is written to address the gaps in other texts. This book provides key
information, yet robust, required to have a detailed and contemporary under-
standing of GI physiology. This text incorporates key concepts of translational
physiology by systematically examining pertinent areas of the GI system, including
anatomy, embryology, histology, biochemistry, pharmacology, biophysics, behav-
ioral science, bioinformatics, pathophysiology, public health, genetics, epigenetics,
and therapeutics, in accordance with physiology. The text provides crucial infor-
mation on the molecular, cellular, tissue, organ, and system levels of functioning
of the GI tract in health and disease.
This book thoroughly explains the normal functioning of the digestive system in
humans, relates the concepts to how diseases develop, and unravels the mechanisms
and basis of medical approach to treatment of the different ailments of the GI tract.
This text apart from incorporating historical information on developmental
course of GI physiology from antiquity to the contemporary era also outlines
contemporary trends and gives a comprehensive description of developmental path
that determined the study of digestive functions in the present-day world.
New data that have accumulated over the past decades on the functioning of the
digestive system are systematically reviewed, and emphases are made on break-
through studies. This book incorporates latest information on functional commu-
nication network between the gut and other organs and tissues of the body such as
the brain, lungs, kidney, heart, pancreas, skin, bone, and adipose tissue. New
information on the roles of the gut as endocrine, exocrine, and neural organ is not
pretermitted. History of over 60 hormones and neurotransmitters currently dis-
covered in the gut alone as well as their functional aspects are discussed. This book
also provides detailed historical and functional information on all digestive
enzymes. New information on mechanisms of enzymatic breakdown of food

v
vi Preface

substances is also discussed. Recently discovered enzymes of the GI tract identified

to play useful role in digestion are also reviewed.
The text strategically highlights key functions of the gut microbiota. Both tra-
ditional and emerging roles of H. pylori in gastric physiology are discussed.
This book is carefully designed for biomedical, medical, and health science
students, scientists, and researchers. It also serves as an inevitable reference text for
clinicians and other medical, health, and allied professionals.
For beneficial comprehension, the book is systematically divided into topics and
subtopics. There are also numerous color illustrations. Recommended readings are
separated into original articles, review articles, guidelines, books, and Nobel
lectures.
The book contains special in-text references on some high-quality publications.
Key information or exceptional discoveries of global significance are systematically
outlined as “Spotlights.” Concepts traditionally used in science, originating from
historians or other areas of science other than physiology, are briefly described as
“Reference Note.” This is needed to provide an adequate and broader understanding
of the information applied in physiology.
To aid comprehension of the association between the physiological concepts,
principles, and clinical presentations, clinical examples such as pathologies that link
basic science with clinical practice are outlined in special sections “Clinical
Correlates.” Contemporary approaches to the basis of treatment of some GI tract
diseases are systematically outlined.
In addition to providing an adequate and broader understanding of the infor-
mation applied in GI physiology, this approach addresses the challenges of trans-
lational physiology. It also provides the necessary background for application of
basic science information to medical practice, as well as utilization of bedside
clinical data and application to produce a solid knowledge base in physiology. This
approach represents a high-quality evidence-based delivery of physiological
information to the learner and allows the learner to appreciate the value and use-
fulness of physiology to nature and human existence.
Thus, the book applies the basic concepts of translational physiology. This
design of the text is aimed at closing the gap between basic science and its
application (such as in the clinics, public health), which is largely due to the
reductionist approach, rather than an integrative in addressing human maladies.
Finally, I would like to take this opportunity to express my sincere gratitude to
Prof. Vladimir Alexeevich Pereverzev MD, Ph.D., DSc, Head of Department of
Normal Physiology of the Belarusian State Medical University, Minsk, Belarus, and
the editorial team of Springer for all their support and encouragement.

FCT-Abuja, Nigeria Menizibeya Osain Welcome

March 2018
Key Features

• Most comprehensive, up-to-date text ever written in the field of gastrointestinal

physiology in the world
• Basic and reference text for medical and allied health science students, as well as
practicing doctors and other health professionals
• Provides a detailed analysis of the trend of development of knowledge on all
aspects of gastrointestinal physiology from antiquity to the contemporary world
• Provides detailed mechanisms of regulation of gastrointestinal functioning in
normal and pathology
• Outlines groundbreaking studies of the past centuries in the field of gastroin-
testinal physiology and provides contemporary information on the direction of
future investigations
• Numerous color illustrations.

vii
Target Groups

• Undergraduates and graduates of medicine, dentistry, pharmacy, nursing, human

biology, science, and other allied health professions
• Interns, residents, and other practicing medical doctors as well as health
professionals
• Academicians
• Researchers and scientists
• Policy makers.

ix
Contents

1 History of Development of Gastrointestinal Physiology:

From Antiquity to Modern Period and the Birth of Modern
Digestive Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3
1.2 Organization of the GI System, Periods of Development
of Knowledge on the Digestive Physiology . . . . . . . . . . . . . . 5
1.3 Evolutionary Emergence of the Gastrointestinal System . . . . . . 8
1.4 Digestive Physiology in Antiquity . . . . . . . . . . . . . . . . . . . . . 9
1.5 Digestive Physiology During the Renaissance . . . . . . . . . . . . . 14
1.6 Digestive Physiology in Modern History . . . . . . . . . . . . . . . . 20
1.7 The Beginning of Modern Digestive Physiology . . . . . . . . . . . 30
1.8 Current and Emerging Trends in the Study of Physiology . . . . 40
1.8.1 The Pendulum of Investigation of Physiological
Systems Is Swinging Toward Integrative Approach.
The Physiome and Giome Projects . . . . . . . . . . . .. 40
1.8.2 Bedside-to-Bench or Bench-to-Bedside
Physiology—The Cornerstone of Translational
Physiology or Medicine . . . . . . . . . . . . . . . . . . . .. 42
1.9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 43
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 46
2 Structural and Functional Organization of the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
2.2 Structural Architecture of the Gastrointestinal Tract . . . . . . . . . 54
2.2.1 Regions of the Gastrointestinal Tract . . . . . . . . . . . . 59
2.2.2 Layers of the Gastrointestinal Tract . . . . . . . . . . . . . 62
2.2.3 Epithelium of the Gastrointestinal Tract . . . . . . . . . . 66
2.2.4 Microarchitecture of the Mucosa . . . . . . . . . . . . . . . 68
2.2.5 Accessory Organs of Digestion . . . . . . . . . . . . . . . . 71

xi
xii Contents

2.3 Gastrointestinal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . 72

2.3.1 Gastrointestinal Venous Circulation . . . . . . . . . . . . . 72
2.3.2 Gastrointestinal Blood (Arterial) Supply . . . . . . . . . . 74
2.3.3 Gastrointestinal Perfusion . . . . . . . . . . . . . . . . . . . . 74
2.4 Gastrointestinal Lymphatic Drainage . . . . . . . . . . . . . . . . . . . 81
2.4.1 Brief Historical Background . . . . . . . . . . . . . . . . . . 81
2.4.2 Anatomical Architecture of the Lymphatic
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2.4.3 Pattern of Lymphatic Drainage of the Gut . . . . . . . . 84
2.5 Nerve Supply of the Gastrointestinal Tract . . . . . . . . . . . . . . . 87
2.6 Functions of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . 87
2.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3 Cellular Organization of the Gastrointestinal Tract . . . . . . . . . . . . 107
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
3.2 Brief Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . 109
3.3 Types of Gastrointestinal Tract Cells . . . . . . . . . . . . . . . . . . . 111
3.3.1 Muscle Cells of the Gut . . . . . . . . . . . . . . . . . . . . . 111
3.3.2 Neurons and Glial Cells of the Gut . . . . . . . . . . . . . 113
3.3.3 Connective Tissue Cells . . . . . . . . . . . . . . . . . . . . . 113
3.3.4 Accessory Cells of the Gastrointestinal Tract . . . . . . 115
3.3.5 Cells of the Accessory Organs of the Digestive
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
3.3.6 Major Types of Gastrointestinal Epithelial Cells . . . . 118
3.4 Structural Composition and Functions of the Cell . . . . . . . . . . 124
3.4.1 Plasma Membrane . . . . . . . . . . . . . . . . . . . . . . . . . 124
3.4.2 Intracellular Components . . . . . . . . . . . . . . . . . . . . . 147
3.5 Polarity of the Epithelial Cell . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
4 Intercellular Network of Junctions of the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.2 Brief Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.3 Gastrointestinal Epithelial Cells Are Structurally and
Functionally Attached to Each Other via Intercellular
Network of Junctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
4.3.1 Gap Junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
4.3.2 Tight Junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
4.3.3 Adherens Junction . . . . . . . . . . . . . . . . . . . . . . . . . 215
Contents xiii

4.3.4 Desmosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

4.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
5 Molecular Mechanisms of Gastrointestinal Signaling . . . . . . . . . . . 227
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
5.2 Brief Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . 232
5.3 Classification of Receptors and Their Signal Transduction
Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
5.3.1 Ion Channel Receptors . . . . . . . . . . . . . . . . . . . . . . 242
5.3.2 G Protein-Coupled Receptor . . . . . . . . . . . . . . . . . . 256
5.3.3 Receptors with Intrinsic Enzymatic Activities . . . . . . 269
5.3.4 Morphogen Receptors . . . . . . . . . . . . . . . . . . . . . . . 276
5.3.5 Integrin Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . 284
5.4 Gut Nutrient Sensing and Nutrient Receptor Signaling
(Gastrointestinal Chemosensation) . . . . . . . . . . . . . . . . . . . . . 287
5.4.1 Carbohydrate Sensing in the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
5.4.2 Amino Acid Sensing . . . . . . . . . . . . . . . . . . . . . . . . 289
5.4.3 Lipid (Fatty Acid) Sensing . . . . . . . . . . . . . . . . . . . 290
5.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
6 Gastrointestinal Growth and Development: From Embryo to
Adult. The Aging Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
6.2 Development of the Gastrointestinal System: From Embryo
to Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
6.2.1 The Primitive Gut, the Mesenchyme–Epithelial
Transition and the Derivatives of the Muscle
Layers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
6.2.2 Development of Gastrointestinal Organs and
Supportive Tissues . . . . . . . . . . . . . . . . . . . . . . . . . 323
6.2.3 Development of Gastrointestinal Nervous System . . . 325
6.2.4 Separation of Larynx and Trachea from the
Pharynx and Esophagus . . . . . . . . . . . . . . . . . . . . . 327
6.2.5 Nutrients Required for Embryonic and Fetal
Growth and Development . . . . . . . . . . . . . . . . . . . . 334
6.3 Digestive Functions of a Newborn in the First Few Hours
of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
6.4 Digestive Functions of a Neonate in the Postnatal Period
During the First *48 h of Life . . . . . . . . . . . . . . . . . . . . . . . 336
6.5 Digestive Functions of a Neonate in the Postnatal Period
After *48 h of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
xiv Contents

6.6 Gastrointestinal Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

6.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
7 Gastrointestinal Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
7.2 Historical Background: The Implication of Discovery of
Animal Electricity on Future Understanding of
Gastrointestinal Motor Functions . . . . . . . . . . . . . . . . . . . . . . 356
7.2.1 Emergence of the Phenomenon of Electricity in
Living Systems and the Pioneer Investigations on
the Motor Functions of the Gastrointestinal Tract—
From Galvani to Alvarez and Beyond . . . . . . . . . . . 356
7.2.2 The First Measurement of Gastrointestinal Motility
Using an Electrical Device and the Origin of
Spontaneous Slow Waves . . . . . . . . . . . . . . . . . . . . 364
7.3 Physiologic Anatomy of the Muscles of the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
7.3.1 Overview of the Structural and Functional
Architecture of Gastrointestinal Smooth Muscle
Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
7.3.2 The Contractile Unit of Gastrointestinal Muscles . . . 376
7.4 Gastrointestinal Smooth Muscle Contraction
and Relaxation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
7.4.1 Stimulators and Inhibitors of Gastrointestinal
Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
7.4.2 Pacemaker Cells of the Gut: Interstitial Cells of
Cajal, CD34-Positive and PDGFRa-Positive
Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
7.4.3 Neurogenic and Myogenic Tone of Gastrointestinal
Muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
7.4.4 Mechanisms of Gastrointestinal Smooth Muscle
Contraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
7.4.5 Mechanisms of Muscle Relaxation . . . . . . . . . . . . . . 389
7.4.6 Motor Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
7.5 Motor Patterns of the Gastrointestinal Tract . . . . . . . . . . . . . . 392
7.5.1 Motor Functions of the Mouth . . . . . . . . . . . . . . . . . 392
7.5.2 Motor Functions of the Esophagus . . . . . . . . . . . . . . 394
7.5.3 Motor Functions of the Stomach . . . . . . . . . . . . . . . 405
7.5.4 Motor Function of the Small Intestine . . . . . . . . . . . 414
7.5.5 Motor Functions of the Large Intestine . . . . . . . . . . 417
7.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Contents xv

8 Gastrointestinal Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
8.2 Discovery of Internal Secretion of the Gut: Origin of the
Endocrine Concept of Regulation of Functions . . . . . . . . . . . . 458
8.3 Gut as the Largest Neuroendocrine Organ in the Human
Body: An Integral Part of the Diffuse Neuroendocrine System
(DNES)/Amine Precursor Uptake Decarboxylase (APUD)
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
8.4 The Changing Views on the Origin of Humoral and
Neurohumoral Secretions of the Gut: The Origin of
Enteroendocrine Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
8.5 The Paraneuron Concept: Is an Enteroendocrine Cell a Type
of Neuron? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
8.6 Classification of Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . 504
8.7 Gastrointestinal Hormones: Timeline on History of
Discovery, Their Structural and Functional Characteristics,
as well as Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . 505
8.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
9 Neural Secretions and Regulation of Gut Functions . . . . . . . . . . . . 527
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
9.2 The Extrinsic Nervous System of the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
9.2.1 Parasympathetic Innervation of the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
9.2.2 Sympathetic Innervation of the Gastrointestinal
Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
9.2.3 Central Transmission and Processing of Visceral
Signals of the Gastrointestinal Tract . . . . . . . . . . . . . 548
9.2.4 Descending Neural Pathways Regulating
Gastrointestinal Tract Activities . . . . . . . . . . . . . . . . 556
9.2.5 Gastrointestinal Reflexes—Automatic Responses to
Stimuli, Regulating Gastrointestinal Functioning . . . . 559
9.2.6 Gastrointestinal Motility Responses to Stimuli . . . . . 561
9.2.7 Mechanosensitive Responses of Enteric Neurons to
Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
9.3 Intrinsic (Enteric) Nervous System . . . . . . . . . . . . . . . . . . . . . 563
9.3.1 Enteric Nervous System and its
Anatomo-functional Characteristics . . . . . . . . . . . . . 563
9.3.2 Types of Cells in the Enteric Nervous System . . . . . 564
9.3.3 Synthesis of Neural Secretions (Neurotransmitters,
Neuromodulators, Neurohormones) and Packaging
for Export, Exocytosis, and Recycling . . . . . . . . . . . 614
xvi Contents

9.3.4 Types of Neural Signaling . . . . . . . . . . . . . . . . . . . . 617

9.3.5 Modes of Neural Signaling . . . . . . . . . . . . . . . . . . . 620
9.3.6 Neural Network of the Enteric Nervous
System—The Plexuses . . . . . . . . . . . . . . . . . . . . . . 624
9.3.7 Afferent and Efferent Nerve Fibers Connecting the
Enteric Nervous System . . . . . . . . . . . . . . . . . . . . . 629
9.3.8 Enteric Neurons Synapse with Smooth Muscle and
Interstitial Cells of Cajal to Mediate Exocytosis and
Other Physiological Processes . . . . . . . . . . . . . . . . . 629
9.4 Gastrointestinal Neurotransmitters: Course of Discovery,
Their Structural–Functional Properties, Mechanisms of
Action, and Clinical Application . . . . . . . . . . . . . . . . . . . . . . 632
9.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
10 Immunomodulatory Functions of the Gastrointestinal Tract . . . . . . 685
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
10.2 Gut-Associated Lymphoid Tissue . . . . . . . . . . . . . . . . . . . . . . 694
10.2.1 Peyer’s Patch—Structural and Functional
Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
10.2.2 Gastrointestinal Lymph Nodes—Sites of Induction
of Immune Response or Tolerance . . . . . . . . . . . . . . 698
10.3 The Gastrointestinal Tract as an Anatomical Barrier to
Potential Pathogenic Invaders—First Line of Defense . . . . . . . 699
10.3.1 Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
10.4 The Reticuloendothelial System—Cells of the Innate Immune
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
10.4.1 Origin of Immune Response Cells . . . . . . . . . . . . . . 723
10.5 Digestive Machinery of Phagocytotic Cells . . . . . . . . . . . . . . . 724
10.5.1 Phagocytosis and Antigen Presentation . . . . . . . . . . . 724
10.5.2 Major Histocompatibility Complex: A Key
Component of the Digestive Machinery of
Phagocytotic Cells . . . . . . . . . . . . . . . . . . . . . . . . . 725
10.5.3 Killer Receptor Signaling: To Die or
Not To Die? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
10.5.4 Antibodies: Origin, Structure, Functions, and
Signaling Mechanisms . . . . . . . . . . . . . . . . . . . . . . 733
10.6 Initiation of Antibody Production Is Cooperatively Linked to
the Induction of Adaptive Immunity . . . . . . . . . . . . . . . . . . . . 741
10.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
Contents xvii

11 Gastrointestinal Exocrine (Lumencrine) Secretions. The

Reception Theory as the Basis for Developing the First
Antisecretory Pharmacotherapy Drugs . . . . . . . . . . . . . . . . . . . . . . 773
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
11.2 Components of Gastrointestinal Lumencrine Secretions . . . . . . 775
11.2.1 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
11.2.2 Ions, Mucus, Enzymes, and Other Biologically
Active Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . 777
11.3 Synthesis of Gastrointestinal Secretory Molecules . . . . . . . . . . 778
11.3.1 Cellular Signaling Pathways Regulating
Gastrointestinal Secretory Activity . . . . . . . . . . . . . . 778
11.3.2 Exocytic Machinery of Secretory Vesicles of the
Gastrointestinal Cells . . . . . . . . . . . . . . . . . . . . . . . 779
11.4 Regional Gastrointestinal Secretions . . . . . . . . . . . . . . . . . . . . 780
11.4.1 Salivary (Buccal) Secretions . . . . . . . . . . . . . . . . . . 780
11.4.2 Esophageal Secretions . . . . . . . . . . . . . . . . . . . . . . . 809
11.4.3 Gastric Secretions . . . . . . . . . . . . . . . . . . . . . . . . . . 814
11.4.4 Intestinal Secretions . . . . . . . . . . . . . . . . . . . . . . . . 832
11.4.5 Secretions of the Colon . . . . . . . . . . . . . . . . . . . . . . 842
11.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
12 Chemical Digestion, Absorption, and Transport . . . . . . . . . . . . . . . 871
12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
12.2 Brief History of Chemical Digestion and Digestive
Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
12.3 Sources of Enzymes for Chemical Digestion . . . . . . . . . . . . . . 901
12.3.1 Autolytic Digestion . . . . . . . . . . . . . . . . . . . . . . . . . 901
12.3.2 Symbiotic Digestion . . . . . . . . . . . . . . . . . . . . . . . . 902
12.3.3 Digestion Proper . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
12.4 Digestion of Carbohydrate . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
12.4.1 Carbohydrate-Digesting Enzymes . . . . . . . . . . . . . . . 903
12.4.2 Chemical Cleavage of Carbohydrate . . . . . . . . . . . . 903
12.4.3 Carbohydrate Absorption and Transport . . . . . . . . . . 904
12.4.4 The Fate of Absorbed Hexoses . . . . . . . . . . . . . . . . 907
12.5 Protein-Digesting Enzymes and Chemical Processing
of Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
12.5.1 Protein-Digesting Enzymes . . . . . . . . . . . . . . . . . . . 908
12.5.2 Chemical Cleavage of Protein . . . . . . . . . . . . . . . . . 908
12.5.3 Amino Acid and Peptide Absorption and Transport
in the Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 908
xviii Contents

12.6 Lipid-Digesting Enzymes and Chemical Processing

of Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 912
12.6.1 Lipid-Digesting Enzymes . . . . . . . . . . . . . . . . . . . . 912
12.6.2 Lipid Digestion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 912
12.6.3 Lipid Absorption and Transport Mechanism . . . . . . . 914
12.6.4 Resynthesis of TGA and the Synthesis of
Chylomicrons in the Enterocyte . . . . . . . . . . . . . . . . 917
12.6.5 Basolateral Exocytosis and Transport of
Chylomicrons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
12.6.6 Fate of Absorbed Lipids . . . . . . . . . . . . . . . . . . . . . 919
12.7 Absorption and Transport of Dietary Elements . . . . . . . . . . . . 919
12.7.1 Historical Background of Intestinal Epithelial Ion
Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
12.7.2 Absorption and Transport of Calcium . . . . . . . . . . . 920
12.7.3 Absorption and Transport of Iron . . . . . . . . . . . . . . 921
12.7.4 Absorption and Transport of Magnesium . . . . . . . . . 926
12.7.5 Absorption and Transport of Zinc . . . . . . . . . . . . . . 926
12.7.6 Absorption and Transport of Other Metals . . . . . . . . 927
12.8 Absorption and Transport of Anions . . . . . . . . . . . . . . . . . . . 927
12.9 Absorption and Transport of Toxic Metals . . . . . . . . . . . . . . . 928
12.10 Absorption and Transport of Pharmacological Drugs . . . . . . . . 929
12.11 Absorption and Transport of Vitamins . . . . . . . . . . . . . . . . . . 932
12.11.1 Water-Soluble Vitamins . . . . . . . . . . . . . . . . . . . . . 932
12.11.2 Lipid-Soluble Vitamins . . . . . . . . . . . . . . . . . . . . . . 936
12.12 Absorption and Transport of Bile Acids. Enterohepatic
Recirculation of Bile Acids . . . . . . . . . . . . . . . . . . . . . . . . . . 936
12.13 Absorption and Transport of Water . . . . . . . . . . . . . . . . . . . . 939
12.14 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
13 Excretory Functions of the Gastrointestinal Tract. Defecation . . . . 973
13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
13.2 Ammonia Handling in the Gut . . . . . . . . . . . . . . . . . . . . . . . . 974
13.3 Urea Handling in the Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . 975
13.4 Prebiotics, Probiotics, Synbiotics and Gut Ammonia
and Urea Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
13.5 Excretion of Bilirubin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
13.5.1 Diagnostic Usefulness of Conjugated and
Unconjugated Bilirubin . . . . . . . . . . . . . . . . . . . . . . 977
13.6 Gastrointestinal Excretion of Some Chemicals and Drugs . . . . 979
13.7 Defecation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979
13.7.1 Mechanism of Defecation: Defecation Reflex . . . . . . 981
13.7.2 Pathological Conditions that Are Associated with
Defecation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
Contents xix

13.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
14 Helicobacter Pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
14.2 Pathogenicity of H. Pylori: Cytotoxin-Associated Gene
Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
14.3 H. Pylori Urease, Urease Transporter, and Physiology of
Gastric Microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
14.4 H. Pylori Acid Chemoreceptor Sensing . . . . . . . . . . . . . . . . . 993
14.5 H. Pylori and Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
14.6 H. Pylori and Gastric Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . 996
14.7 H. Pylori and Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 999
14.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
15 Functional Relationship Between the Gut and Other
Tissues/Organs of the Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
15.2 Composition and Classification of the Gut Microbiota . . . . . . . 1011
15.3 Gut–Liver Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
15.4 Gut–Pancreas Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
15.5 Gut–Brain Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014
15.6 Gut–Heart Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
15.7 Gut–Kidney Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
15.8 Gut–Lung Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
15.9 Gut–Bone Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
15.10 Gut–Skin Axis and Gut–Brain–Skin Triangle . . . . . . . . . . . . . 1019
15.11 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
 About the Author

Dr. Menizibeya Osain Welcome, MD, Ph.D. is a Senior Lecturer in the

Department of Physiology, Faculty of Basic Medical Sciences, College of Health
Sciences, Nile University of Nigeria, FCT-Abuja. He earned the Doctor of
Medicine in 2011 and his Ph.D. in Medicine (Physiology) in 2013. He is the author
or co-author of over 200 papers and holds several awards.

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