Table Of ContentNeuro-Immuno-
Gastroenterology
Cris S. Constantinescu
Razvan I. Arsenescu
Violeta Arsenescu
Editors
123
Neuro-Immuno-Gastroenterology
Cris S. Constantinescu
Razvan I. Arsenescu (cid:129) Violeta Arsenescu
Editors
Neuro-Immuno-
Gastroenterology
Editors
Cris S. Constantinescu Violeta Arsenescu
University Hospital Armedica LLC
University of Nottingham Basking Ridge , OH
Nottingham USA
United Kingdom
Razvan I. Arsenescu
Atlantic Digestive Health Institute
Morristown Medical Center
Morristown , OH
USA
ISBN 978-3-319-28607-5 ISBN 978-3-319-28609-9 (eBook)
DOI 10.1007/978-3-319-28609-9
Library of Congress Control Number: 2016941539
© Springer International Publishing Switzerland 2016
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CSC would like to dedicate this book to his
parents, who have inspired his interest in
interdisciplinary science.
RA & VA dedicate this book to their son,
Victor, their beacon of light and constant
source of inspiration.
Pref ace
The multidirectional interaction between the immune system, the gut and the brain
has only become subject of more intense research interest in the last few years.
Much work has been done in neuroimmunology and in the immunology and immu-
nopathogenesis of the gastrointestinal tract, and the infl uence of the nervous system
on both immune functions (neuroimmunomodulation and nerve-driven immunity)
and on gastrointestinal processes has been studied in detail. However, to date, no
dedicated forum exists, either in the form of a scientifi c journal or in the form of a
book, which addresses issues at the interface between the three biological disci-
plines, and in which the dialogue on specifi c common issues between neuroimmu-
nologists and immuno-gastroenterologists can take place.
Recent discoveries in fundamental immunology require an intensifi cation of this
dialogue, so that understanding by scientists of one discipline of processes belong-
ing to the other discipline is possible. For example, the fact that the gut has a critical
function in shaping systemic immune responses, through innate lymphoid cells and
mucosa-associated lymphoid tissues, means that scientists and physicians studying
immune-mediated neurological disease need to gain insight into the immunology of
the gastrointestinal system. Also, as it has recently become clear that the gut micro-
biota has a profound infl uence on the shaping of the immune response, as well as
other processes such as metabolism, not only in the gastrointestinal system but also
in the nervous system, scientists and clinicians in these fi elds require knowledge of
the microbiology of the gastrointestinal tract. Fascinatingly, manipulation of the
microbiota and of the intestinal immune responses can be used to modulate neuro-
logical and other immune-mediated infl ammatory diseases.
Conversely, the nervous system and the psyche have signifi cant effects on the
functioning of the gastrointestinal tract.
Collaboration and communication between neuroscientists, gastrointestinal
researchers, microbiologists and systematic biologists is essential for the advance-
ment of this important fi eld.
This book, an editorial collaboration between a neuroimmunologist and an
immuno-gastroenterologist and nutrition scientist couple, is a fi rst attempt at such a
collaboration and communication. While not being an exhaustive, comprehensive
vii
viii Preface
textbook on the subject, it is a collection of relevant topics that address many impor-
tant issues regarding the interaction between the nervous system, the immune sys-
tem and the digestive system in health and disease.
Introductory chapters into the immunology, the nervous system (enteric nervous
system) and the microbiology of the gastrointestinal system, each written by experts
in their research fi elds, provide necessary fundamentals of knowledge in these areas.
The immunology chapter is written by gastroenterologists (Y Mahida and col-
leagues) with close attention to relevant disease entities. While not intended as a
comprehensive review of the increasingly complicated landscape of the gut immune
system, it provides essential information on this to allow the reader to put it in the
context of immune-mediated infl ammatory diseases. The chapter on the enteric ner-
vous system, by a pathologist, M Constantinescu, in addition to a review of the
anatomy of the nervous system of the gut, provides very useful information on the
anatomic pathology of the enteric nervous system.
I mportant neurotransmitters, such as substance P (J Vilisaar and R Arsenescu)
and vasoactive intestinal polypeptide (VIP, Ganea and colleagues), are discussed in
particular with regard to their effect on the gut immune system and also their role in
gut infl ammation.
The role of stress in the gut-brain connection is expertly reviewed in a thorough,
dedicated chapter by B Bonaz.
F ive chapters deal with how gastrointestinal infections or commensal fl ora infl uence
immune-mediated infl ammatory diseases of the ventral and peripheral nervous system,
while a separate chapter deals with the role of nutrition and macrobiotics in the gut and
brain infl ammation. In this context, the most widely discussed condition is the infl am-
matory demyelinating disease of the central nervous system, multiple sclerosis (MS),
which, almost from its fi rst clinicopathological descriptions by Charcot and his pupils,
was postulated to have an infectious pathogenesis. Infections that potentially have a
protective infl uence such as Helicobacter pylori (K Robinson, B Gran and colleagues)
and intestinal parasites like Necator americanus (R Tanasescu) which is currently used
in a phase II clinical trial of helminth immunotherapy in MS are thoroughly presented in
separate chapters by established investigators in their respective areas, along with their
potential immunomodulatory mechanisms in MS and its experimental model, experi-
mental autoimmune encephalomyelitis (EAE). On the other hand, the negative infl uence
of certain gut bacteria can be inferred from a thorough account of intestinal microbiota
dysregulation in MS, with particular emphasis on Japanese MS (the epidemiology of
which can be explained through major nutritional changes in Japan in the last decades),
presented by a pioneering researcher in the fi eld, T Yamamura, and by a comment on the
role of certain bacteria and bacterial toxins in MS and neuromyelitis optica (NMO) by
I-J Chou and CS Constantinescu. Nutrition and nutritional interventions, discussed in a
chapter by V Arsenescu, for example, in the form of macrobiotics, are increasingly
being studied in the context of infl ammatory diseases of both the gastrointestinal and the
nervous system. In the peripheral nervous system, N Shahrizaila and N Yuki use the best
known example of molecular mimicry in autoimmunity, between Campylobacter and
peripheral nerve glycolipids, to discuss the role of Campylobacter jejuni infection in the
Guillain-Barré syndrome (GBS).
Preface ix
The coexistence between immune-mediated (autoimmune) infl ammatory dis-
eases of the nervous and the gastrointestinal system is another reason to support the
development of neuro-immuno-gastroenterology. For example, MS is thought to
coexist with infl ammatory bowel disease more often than just by chance. Although
this has been challenged by studies suggesting this association is merely due to the
increased susceptibility of women to both of these conditions, the association seems
to be genuine even after correcting for gender in some studies, suggesting common
mechanisms of immunopathogenesis. On the other hand, even if the association
were purely by chance, the frequency of the conditions means that management
issues need considerations when they coexist, and not only common but differing
immunopathogenesis mechanisms are to be taken into account. Demyelinating dis-
ease during or following treatment with anti-TNF agents for infl ammatory bowel
disease (and other immune-mediated diseases) is discussed in a chapter by SY Lim
and CS Constantinescu. This is an unresolved issue, but the chapter provides a
review of the information to date and balances the risk of coexistence of the condi-
tions (with or without treatment) with that of “induction” of MS by anti-TNF
treatment.
Cannabinoids are molecules involved in many biological functions, produced in
large amounts in the central nervous system as endocannabinoids are fulfi lling the
defi nition of neurotransmitters (albeit nonclassical). The plant-derived or synthetic
cannabinoids are also drugs that affect the immune, nervous system and gut func-
tions. A team of pharmacologists led by P Gershkovich discuss novel ways of
exploiting their physicochemical properties (liposolubility) to improve delivery to
the gut lymphoid tissue to achieve and/or enhance neuroimmunological effects.
The last four chapters are dedicated to established neurological disease entities
where the immune system and the gut play essential parts.
G luten intolerance is an immune-mediated condition that is widely known to
gastroenterologists. However, its neurological manifestations are less explored.
Knowledge of these manifestations is important for gastroenterologists, nutrition-
ists and neurologists alike. This is discussed in detail in the chapter by M
Hadjivassiliou and colleagues. A view of pernicious anaemia, with interesting his-
torical details, although the condition is certainly not a disease of the past, and in
which often autoimmune mechanisms are critical, is provided by L Edwards. The
profound effects in which the immune-mediated central nervous system disease,
MS, affects the gut are expertly discussed by D Levinthal and K Bielefeldt. Finally,
R Bassil and C Ionete review the neurological manifestation in the complex immu-
nopathogenesis of the primary gastrointestinal condition of Whipple’s disease.
T he book does not aim to cover all aspects of neuro-immuno-gastroenterology.
Functional neuro-gastroenterological disorders where infl ammation or infection has
been implicated, including irritable bowel syndrome and other motility disorders,
are not discussed in a dedicated chapter. The mucosal immunology of the gut is an
ever-increasing fi eld as is the gut microbiota and its role in physiology and disease,
so all very recent developments cannot be covered in a book like this.
H owever, the novelty of this book and the breadth of subjects covered offer a
background of knowledge and an opening for the development of an important
