439244 1 En BookFrontmatter 1. - ResearchGate
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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/325881209 Gastrointestinal Physiology Book · June 2018 DOI: 10.1007/978-3-319-91056-7 CITATION 1 READS 4,161 1 author: Some of the authors of this publication are also working on these related projects: Stem Cells View project Geriatric Physiology View project Menizibeya Osain Welcome Nile University of Nigeria 192 PUBLICATIONS 426 CITATIONS SEE PROFILE All content following this page was uploaded by Menizibeya Osain Welcome on 22 June 2018. The user has requested enhancement of the downloaded file.
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439244_1_En_BookFrontmatter 1..21See discussions, stats, and author
profiles for this publication at:
https://www.researchgate.net/publication/325881209
Gastrointestinal Physiology
1 author:
Some of the authors of this publication are also working on these related projects:
Stem Cells View project
Geriatric Physiology View project
SEE PROFILE
All content following this page was uploaded by Menizibeya Osain Welcome on 22 June 2018.
The user has requested enhancement of the downloaded file.
123
Menizibeya Osain Welcome Department of Physiology, Faculty of Basic Medical Sciences
College of Health Sciences, Nile University of Nigeria
FCT-Abuja Nigeria
Library of Congress Control Number: 2018940411
© Springer International Publishing AG, part of Springer Nature 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Printed on acid-free paper
This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
The Figures in this book were designed with help of Motifolio Biomedical Drawing Toolkit Suite (Motifolio Inc., Ellicott City, USA).
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
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
vi Preface
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.
• 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
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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
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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
Contents xiii
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
xiv Contents
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
Contents xv
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
xvi Contents
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
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
xviii Contents
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
Contents xix
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.
xxi
Gastrointestinal Physiology
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Menizibeya Osain Welcome Department of Physiology, Faculty of Basic Medical Sciences
College of Health Sciences, Nile University of Nigeria
FCT-Abuja Nigeria
Library of Congress Control Number: 2018940411
© Springer International Publishing AG, part of Springer Nature 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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
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
vi Preface
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.
• 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
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
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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
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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
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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
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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
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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
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
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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
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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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