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Indu Pal Kaur Editor-in-Chief
Parneet Kaur Deol Editor

Probiotic
Research in
Therapeutics
Volume 1: Applications in Cancers and
Immunological Diseases
Probiotic Research in Therapeutics
Indu Pal Kaur
Editor-in-Chief

Parneet Kaur Deol

Editor

Probiotic Research in
Therapeutics
Volume 1: Applications in Cancers
and Immunological Diseases
Editor-in-Chief
Indu Pal Kaur
Panjab University
Chandigarh, Punjab, India

Editor
Parneet Kaur Deol
G.H.G. Khalsa College of Pharmacy
Gurusar Sadhar
Ludhiana, Punjab, India

ISBN 978-981-15-8213-4 ISBN 978-981-15-8214-1 (eBook)

https://doi.org/10.1007/978-981-15-8214-1

# Springer Nature Singapore Pte Ltd. 2021

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, expressed 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.

This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
To my father who taught me to think and write
rationally.
To my mother from whom I get my confidence
and the feature to express clearly.
To my husband who encouraged me to grow
professionally and enjoy finer things in life.
—Prof. Indu Pal Kaur

To the four pillars of my life—my husband, my

daughter, my parents, and my GURU.
—Dr. Parneet Kaur Deol
Foreword

The saying attributed to Hippocrates, the Father of Medicine, that “Let food be thy
medicine, and let medicine be thy food” never felt more valid than now when we are
challenged by a variety of lifestyle diseases. The relevance of holistic healing has
increasingly been related, in recent years, to the gut microbiome, composed of
bacteria, archaea, viruses, and eukaryotic microbes, all of which reside in our gut
and together have a strong potential to impact our physiology, both in health and in
disease. When faced with a variety of diseases, our present-day knowledge lays
emphasis on the importance of a healthy microbiome, not only limited to gut health
but also to metabolic disorders, cancers, immunity, brain health, and skin health. Can
we manipulate the gut microbiota by probiotic intervention toward disease preven-
tion and treatment? That is precisely what is receiving the attention of a large number
of scientists engaged in research on human health. The growing market interest in
the health benefits of probiotics has intensified research and investments in this area.
With an overwhelmingly large number of new products based on probiotics on the
shelves of the supermarkets and pharmacies, it can be inferred that the research in
this area is at a very exciting stage. Though the intricate mechanisms involved in the
importance of gut flora may require some basic scientific expertise but surfing
through scientific claims on the usefulness of probiotic therapy can catch the fancy
of even a general reader.
I have known Prof. Indu Pal Kaur, Editor-in-chief of this book series, for the past
12 years and have been closely following her research interests which essentially
hover around being a formulation scientist, be it for small and large molecules,
phytochemicals and probiotics. I have noticed her deep interest in trying to comple-
ment the observational data compiled in the traditional system of medicine with
scientific rationale from currently available information. I have myself discussed
with her, several times, the human microbiome and its manipulations for useful
therapeutic options. She has been active in the topic of probiotics for a long time and
had, in fact, published her first review on Potential Pharmaceutical Applications of
Probiotics way back in 2002, which has been cited over 500 times till date. Her
passion to bring probiotics into mainstream therapeutics is not limited only to the
ailments of the gut, viz. inflammation, ulcers, and cancers, but is also aimed to
extend it to other lifestyle diseases, such as depression, chronic fatigue syndrome,
vaginal candidiasis, wound healing, and skin health.

vii
viii Foreword

The present e-book series, comprising five volumes, brings the latest information
and key insights on the application of probiotics in cancer and immunological
disorders, gut inflammation and infection, skin ailments, neurodegenerative
disorders, and metabolic disorders. The contributing authors are recognized experts,
which ensures that each chapter affords a critical insight into the topic covered, with
a review of current research and a discussion on future directions in order to
stimulate interest. Each volume itself covers a broad theme in detail by including
chapters disseminating basic information in the field in such a manner that it would
attract the attention of even a stray reader or intending consumers. Of course, the
whole series of five volumes is designed with care so as to not only ignite the minds
of graduating students for future research but also boost the confidence of health
professionals, physicians, dieticians, nutritionists, and those practicing naturopathy
by underlining the integrity of the data documented in the chapters of these volumes
from well-established labs and groups. All in all, a very thoughtful compendium of
probiotics research in therapeutics!

Asia Pacific Academy of Materials J. V. Yakhmi

Mumbai, Maharashtra, India
Homi Bhabha National Institute
Mumbai, Maharashtra, India
Physics Group, Bhabha Atomic Research Centre
Mumbai, Maharashtra, India
Technical Physics and Prototype Engineering Division,
Bhabha Atomic Research Centre
Mumbai, Maharashtra, India
Spectroscopy, Synchrotron and Functional Materials,
Bhabha Atomic Research Centre
Mumbai, Maharashtra, India
Preface

Human beings are metaorganisms comprising the macroscopic host and coexisting
plethora of symbiotic commensal organisms. A vast majority of these
microorganisms coinhabit within the confines of the gastrointestinal tract. Termed
the gut microbiota, they have a collective mass of approximately 1.5 kg, and together
with the gastrointestinal tract they create the most metabolically active system within
the human body. Humans have coevolved with their microbial component over
some two million years, leading to a homeostatic and symbiotic system designed for
optimized production and absorption of essential nutrients, tightly regulated epithe-
lial cell differentiation and renewal, and balance between immune recognition of
pathogens and tolerance of commensal microorganisms. Only 10% of cells of this
superorganism are represented by the Homo sapiens and millions of microbial genes
present in the humans outnumber the “mere” 20–25 thousand genes of the human
genome. The cultural, social, dietary, medical, and technological advances of the last
two centuries tend to challenge this balance resulting in an alteration in the
preexisting microbial composition and metabolic activity of the gut microbiome
contributing to an unhealthy state. The scientific community is thus currently
engaged in exploring approaches to manipulate the human gut microbiota by
probiotic intervention as a means for disease prevention and treatment.
All this information about the gut microbiome and the possibility to manipulate it
by probiotic therapy is highly exciting and full of possibilities. It is said that the next
era therapeutics would involve maneuvering the resident microbiome of the human
body to shift it from dysbiosis to symbiosis. It was in this context that the present
e-book series entitled “Probiotic Research in Therapeutics,” which is a compilation
of five volumes that bring forth the purported benefits of probiotic therapy in a
variety of disease states, was perceived and planned. Each volume encompasses the
potential and mechanism of probiotic therapy in a specific set of pathophysiology.
With state-of-the-art commentaries on all aspects of probiotic research, from
contributors across the globe, the e-book series provides an authoritative and timely
overview of the field.
The first volume of the series comprising of 15 chapters, and expanding on the
potential applications of probiotics in the management of cancer and immunological

ix
x Preface

diseases, is presented here. The introductory chapter discusses in detail the associa-
tion of the gut microbiome with the suppression and progression of cancers. It also
elaborates about the role played by the immune system in this interaction. Chapter 2
highlights the potential protective and therapeutic accountability of probiotics in
combating cancer. The next chapter covers the role of various probiotic strains in
cancer and summarizes the important findings in relation to the probiotic-mediated
suppression of gastrointestinal and extraintestinal cancers. Chapter 4 elaborates on
the future scope of probiotic therapy against a broad array of cancers like colon,
stomach, breast, cervix, and myeloid leukemia cells, as an adjunct to chemotherapy
or radiotherapy. In recent years, various researchers have highlighted the beneficial
health effects of metabiotics, the components of probiotic microorganisms, and/or
their metabolites. Potential of metabiotics as an effective strategy for prophylaxis or
as a therapeutic option in the treatment of colorectal cancer is discussed in detail in
Chap. 5. In the next five chapters (Chaps. 6, 7, 8, 9, and 10), the authors emphasize
the role of probiotics in prophylaxis and management of various cancers, viz.
colorectal, lung, gastrointestinal, and breast cancer. Efforts are made to include the
underlying mechanism of action and a consolidated overview of the preclinical and
clinical status of probiotic therapy in the management and control of these cancers.
Next in line is the chapter highlighting the recent developments on applications of
probiotic bacteriocins (ribosomally synthesized small antimicrobial peptides) along
with other bacteriocins as anticancer agents, their cytotoxicity, efficacy, and mode of
action against cancer cells. Chapter 12 encompasses the positive health effect of
probiotics in autoimmune, inflammatory, and gastrointestinal disorders. It includes
the underlying mechanism and the current market status of probiotics in the above-
mentioned conditions. Elaborate discussion with respect to the status of probiotics in
rheumatoid arthritis is presented in the next chapter.
An interesting perspective of genetically modified probiotics or designer
probiotics is elaborated in Chap. 14. The sophisticated approach of using genetically
engineered probiotic/designer probiotics is based on altering the genetic makeup of
probiotic strains for improving human health, livestock management, and aquacul-
ture industries. The chapter focuses on the current progress in the field of designer
probiotics, safety concerns regarding their practical applications, and the potential
prospects of their clinical translation. Last in the list is a chapter presenting a very
elaborate glance on the patent world of probiotics to get the overall picture of the
business potential of probiotics.
I hope this book will be a useful educational and scientific tool to academicians,
health professionals, students, and pharma/biotech businessmen worldwide. As
editors of the book, we express our sincere thanks to all the authors for their excellent
contribution to the book.

Chandigarh, Punjab, India Indu Pal Kaur

Ludhiana, Punjab, India Parneet Kaur Deol
Contents

1 Gut Microbiota and Cancer Correlates . . . . . . . . . . . . . . . . . . . . . . 1

Alok Malaviya, K. A. Paari, Shruti Malviya,
Vamsi Krishna Kondapalli, Aditi Ghosh, and Riya Ann Samuel
2 Potential Preventive and Therapeutic Accountability of Probiotics
in Cancer: An Insight of Mechanism of Action . . . . . . . . . . . . . . . . 29
Pranav Kumar Prabhakar, Yachana Mishra, and Vijay Mishra
3 Probiotics and Cancer: Boosting the Immune System . . . . . . . . . . . 47
Prashant Upadhaya, Prachi Kharkar, Abhinandan Patil, Shivaji Pawar,
John Disouza, and Vandana B. Patravale
4 Probiotics as Next Generation Strategy for Cancer Therapy . . . . . . 69
Anuradha Mishra, Pragyandip P. Dash, Afreen Usmani,
Satya Prakash Singh, and Anup K. Sirbaiya
5 Metabiotics in Colorectal Cancer: Crosstalk Between Gut
Microbiota and Host Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Monica Gulati, Sachin Kumar Singh, Rajesh Kumar, Kamal Dua,
Simanchal Panda, James Blaxland, and Lipika Chandwani
6 Possibility of Probiotic in Colorectal Cancer: A Specific
Countenance to Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Mohammad Yasir, Ruchi Khare, Pushpendra Singh, Sohni Singh,
and Rahul Shrivastava
7 Probiotics in Lung Cancer: An Emerging Field of Multifarious
Potential and Opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Mallesh Kurakula and Koteswara Rao G. S. N.
8 Probiotics for Prophylaxis and Management of Breast Cancer:
Preclinical and Clinical Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Sheyda Ranjbar, Seyed Afshin Seyednejad, Shahab Edalatian Zakeri,
Hossein Rezaeizadeh, and Roja Rahimi

xi
xii Contents

9 Probiotics for Management of Gastrointestinal Cancers . . . . . . . . . 191

Nilesh Rai, Anurag Kumar Singh, Priyanka Kumari Keshri,
Suvakanta Barik, Swapnil C. Kamble, Santosh Kumar Singh,
Rajiv Kumar, Pradeep Mishra, Deepak Kotiya, and Vibhav Gautam
10 Potential of Probiotics in the Management of Lung Cancer . . . . . . . 211
G. Divyashri, T. P. Krishna Murthy, and Manikanta Murahari
11 Bacteriocins of Probiotics as Potent Anticancer Agents . . . . . . . . . . 231
Pallvi Sharma and Santosh Kumar Tiwari
12 Probiotics in Autoimmune and Inflammatory Diseases . . . . . . . . . . 251
Vivek P. Chavda, Hitesh Prajapati, Punit Zadafiya, and Moinuddin
Soniwala
13 Role of Probiotics in Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . 273
Rahul Shukla, Munindra Ruwali, N. Sharath Pawar, and S. J. S. Flora
14 Genetically Engineered Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Saba Hag and Naresh Poondla
15 A Glance to the Patent World of Probiotics . . . . . . . . . . . . . . . . . . . 329
Vivek P. Chavda, Arumugam Meyyappan, Disha Chavda,
and Moinuddin Soniwala
About the Editors

Indu Pal Kaur is presently the Professor and Chairperson, at the University
Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, India.
She has more than 25 years of teaching and research experience to her credit. She
was Director, Sophisticated Analytical Instrumentation Facility, Panjab University,
from 2012 to 2015 and Dean, Faculty of Pharmaceutical Sciences, from 2017
to 2018.
Her research forte is enhancing the bioperformance of drugs, plant extracts/
phytochemicals, and small/large biomolecules, viz. siRNA and probiotics using
active-tailored delivery systems.
She has been granted seven Indian and one US patents and has filed 19 patents in
the past 10 years. She has produced 23 PhDs and 55 postgraduates. She received
funding to the tune of 72.3 million INR from government agencies and has a couple
of industrial consultancies amounting to 15.3 million INR. Her research work was
funded twice (2017 and 2020) by DST and Science and Technology Facilities
Council, ISIS, UK for SANS characterization at ISIS Facility—Rutherford Appleton
Laboratory, UK.
She has delivered 49 invited talks, published >130 high impact international
publications, and her group has received 31 best paper awards at national and
international conferences.
She is a US-Fulbright fellow (2017–2018) and was awarded Women Scientist
Award 2018 by the Organisation of Pharmaceutical Producers of India (OPPI).
She has also been graced with BRIC Technology Exposition Award, consecu-
tively for 2019 and 2020, Tynor Innovation Award 2019, and Researcher of the Year
award 2019, by Sunpure Research Incubation Center.
The emphasis of her work lies in Industrial and clinical translation and is reflected
through her three technology transfers to two Indian industries.

Parneet Kaur Deol is presently working as Assistant Professor at G.H.G. Khalsa

College of Pharmacy Gurusar Sadhar Ludhiana, Punjab, India. She has more than
10 years of experience in probiotic research and has published her work in highly
reputed peer-reviewed international journals. She has 21 international publications
to her credit with a cumulative impact factor of >50. She has co-edited a special
issue for “Current Pharmaceutical Design” with Prof. Indu Pal Kaur in the year 2019.

xiii
xiv About the Editors

She has presented her work at various national and international platforms. She was
awarded the “Dr. Harpal Singh Buttar and Mrs. Harinder Kaur Buttar Award of
Excellence in Pharmaceutical Sciences” in the year 2016 and Mekaster Young
Scientist Award in 2018 for her research work. Recently, she fetched two research
projects from Department of Science and Technology-Science and Engineering
Research Board (DST-SERB), New Delhi, worth 65 lakh.
Gut Microbiota and Cancer Correlates
1
Alok Malaviya, K. A. Paari, Shruti Malviya, Vamsi Krishna Kondapalli,
Aditi Ghosh, and Riya Ann Samuel

Abstract

The human microbiota is a concoction of bacteria, archaea, fungi, and other

microorganisms. It is necessary to maintain a partnership between the host and
the microbiota in order to maintain the different aspects of human physiology,
such as nutrient absorption, immune function and metabolism. The microbiota
can contribute to both progression and suppression of the disease, including
cancer. A disturbance in this interspecies balance called microbiome dysbiosis
becomes a reason for the host to be more prone to issues such as immunodefi-
ciency and cancer. Gut microbiota could potentially influence the factors that
govern cancer susceptibility and progression through mechanisms such as
immunomodulation, by producing metabolites, such as, bacteriocins, antimicro-
bial peptides involved in tumor suppression, and short-chain fatty acids (SCFA),
and through enzymatic degradation. It is now an established fact that the host
physiology as well as risk of diseases such as cancer could be greatly modulated
by these commensal microbes and the regulation of cancer development, pro-
gression as well as response to anticancer therapy is greatly dependent on the host
microbiota. Therefore, it is being envisaged that by the involvement of

A. Malaviya (*) · V. K. Kondapalli · A. Ghosh

Applied and Industrial Biotechnology Laboratory (AIBL), Department of Life Sciences, CHRIST
(Deemed to be University), Bengaluru, India
e-mail: [email protected]; [email protected]; aditi.
[email protected]
K. A. Paari · R. A. Samuel
Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, India
e-mail: [email protected]; [email protected]
S. Malviya
National Centre for Biological Sciences (NCBS), TATA Institute of Fundamental Research,
Bengaluru, India
e-mail: [email protected]

# Springer Nature Singapore Pte Ltd. 2021 1

P. K. Deol (ed.), Probiotic Research in Therapeutics,
https://doi.org/10.1007/978-981-15-8214-1_1
2 A. Malaviya et al.

microbiome in augmenting antitumor responses to therapeutic approaches, poten-

tially a new era of research with potentially broad implication on cancer treatment
could be established. Better cancer treatment responsiveness can be achieved by
understanding the role of the “tumor microbiome” in shaping the tumor microen-
vironment. This will help us to develop personalized anticancer solution with the
goal to discover a bacterial species or a combination of species that decreases
systemic toxicity and helps in anticancer therapy. This chapter is written in same
context, which focuses on the association of the gut microbiome with the
suppression and progression of cancers, the role of the immune system in this
interaction, the utilization of these organisms for the treatment of cancers, and
future perspectives.

Keywords

Bacteriocins · Cancer · Dysbiosis · Probiotics · Microbiome

1.1 Introduction

There are several different types of bacteria and other microorganisms present in the
human body, which comprise the human microbiota. They inhabit in the epithelial
barrier surfaces of the body exhibiting commensalism with the host. About 31013
bacterial cells are present in the gut microbiota whose composition is shaped by
colonization at the time of birth, host genetics, type of delivery, incidences of
diseases, exposure to antibiotics as well an individual’s lifestyle. The composition
of the microbiota changes during early years of life, which remains relatively
constant throughout life. The gut microbiota impacts various aspects of human
physiology, such as nutrient absorption, metabolism, and immune function. A
continuous crosstalk between the gut microbiota, immune cells, and the mucosal
barrier is necessary to maintain a healthy body (Roy and Trinchieri 2017). There are
strong scientific indications that gut microbiota plays a shielding role against cancer
in animal models and an imbalance of the gut microbiota (dysbiosis) might result in
the development of many disorders, including cancer.
Probiotics are used to address the problem of gut microbiota imbalance, which
when given in balanced quantity can provide health benefits to the host. They are
known to have direct and indirect benefits on host well-being. While the direct
benefit involves gut health improvement, these are also known to indirectly help
with prevention and treatment of cancer, reduction in tumor formation and metasta-
sis by modulating the microbiota, immune response, reduction in bacterial translo-
cation, enhanced gut barrier function, and anti-inflammatory antipathogenic activity
(Yu and Li 2016). Therefore, it has variously been suggested that probiotics could be
used as a dietary supplement against neoplastic predisposition by influencing both
the local and systemic immune processes of the host. It gives the hope that some
probiotic strains can also be developed and used to prevent or treat cancers by
functioning as adjuvants by modulating intestinal microbiota and immune responses.
Owing to the ability of gut microbiota to modulate host metabolism, inflammation,
1 Gut Microbiota and Cancer Correlates 3

and immunity as well as its involvement in the initiation and/or progression of

different cancers, this chapter is written with the aim to discuss various aspects of
gut microbiota and gut dysbiosis and its association with cancer. Additionally, we
have also discussed the various anticancer therapies based on gut microbiota.

1.2 Gut Microbiota, Gut Dysbiosis, and Cancer

Gut microbiota has a significant local as well as systemic effect on the nutrient
absorption, metabolism, and immune function. Maintenance of the epithelial barriers
is crucial for the health of the organism as it provides the surface for microbiota to
reside on (Scott et al. 2013). The epithelial barrier and the commensal
microorganisms maintain a peaceful relationship that mediates the protection of
the host from pathogens and pathobionts. The physiological relationship between
epithelial cells and the microbiota is disrupted by the alteration in the composition of
the microbiota, a condition called dysbiosis (Fig. 1.1). Dysbiosis has been linked to
the breach of the barriers, induction of inflammatory responses as well as initiation
and progression of cancerous conditions (Roy and Trinchieri 2017). These
organisms that comprise the microbiome are also believed to colonize tumors, and
there are several models that suggest the role of the microbiome as a contributor to
carcinogenesis. A healthy individual is said to be associated with high diversity of
gut microbiota, which critically influences bacterial dysbiosis, pathogenesis,
genotoxin production, and host metabolism disruption that controls the host immune
system. Regulation of systemic function by the microbiota is crucial for the survival
and health of the host (Yang et al. 2009). A lot of studies have been done to
understand the metabolic functions of the associated microbes. However, the focus
has shifted toward understanding the interconnections between physiologies of
microbial communities, their host, and the impact of the gut microbiota to maintain
health and disease (Hooper et al. 2007).
Decoding and sequencing of the microbiome have helped the researchers to get a
clear sight of extending the benefits of manipulating the gut microbiota to treat
diseases. Whole-genome shotgun sequencing and 16S ribosomal RNA amplicon
sequencing help to deduce the diversity of particular taxa present in the gut
microbiome. The information gathered will aid in reconstructing the potential
metabolic capacity of the microbiome at strain, species, genus, and taxonomic levels
(Saus et al. 2019). Advancement in metagenomic analyses has provided more
direction to differentiate the gut microbiota present in diseased and healthy
individuals. The past two or three decades have provided a sizable functional data
relating to the presence of gut microbes in numerous physiological processes,
including digestion of food substances and maturation of the immune system (Qin
et al. 2010; Wong et al. 2019; Sender et al. 2016). Imbalance of microbiota or an
impaired microbiota can result in the development of cancer, disturbing the host
physiological functions through the interference with the immune system. Modula-
tion of cancer treatment can be done by certain factors like antibiotic ingestion,
defined microbiome transplantation, and change in lifestyle (Raza et al. 2018). The
mechanisms using which these organisms affect the systemic function are less
4 A. Malaviya et al.

Fig. 1.1 Mechanism of gut microbiota in development and inhibition of carcinogenesis. Bacterial
translocation happens because of imbalance in bacterial diversity (dysbiosis) causing chronic
inflammation, resulting in the overexpression of proinflammatory cytokines and generation of
reactive oxygen species causing oxidative stress and DNA damage resulting in carcinogenesis. In
the presence of healthy microbial community (eubiosis), short-chain fatty acids (SCFAs) such as
acetate, butyrate, and propionate are secreted, which create an immune homeostasis state
influencing the process of cancer cell attenuation by limiting c-myc expression and by regulating
P57 levels

understood when compared to the localized functions (Belkaid and Naik 2013).
Following section briefly deals with an overview of gut microbiota and gut dysbiosis
and its role in cancer.

1.2.1 Gut Microbiota and Its Interaction with Host

The human gut is a concoction of different bacteria, archaea and protozoa, which
collectively constitute the microbiota (Gharaibeh and Jobin 2019). Constant
crosstalk between these microbes, the mucosal barrier, and the immune system
results in an efficient gut epithelial barrier (Ma et al. 2019). The central nervous
system (CNS) and the “gut brain axis” (GBA) communicate and connect bidirec-
tionally through the “gut brain axis” (GBA). Various components of GBA include
(1) the autonomic nervous system (ANS), (2) the central nervous system (CNS),
(3) the enteric nervous system (ENS), (4) the entero-endocrine system (EES), and
1 Gut Microbiota and Cancer Correlates 5

(5) the hypothalamic–pituitary–adrenal (HPA) axis (Vivarelli et al. 2019). Here the
gut is a part of an interface between the resident microbiota of the gastrointestinal
tract and the human body. In a bidirectional crosstalk between the human body and
GBA, the gut microbiota acts as doorkeeper for such communications to happen
(Neuman et al. 2015). It has variously been reported that the gut microbiome
composition gets modified based on the host’s hormones and neurohormones. For
example, there are several peptide hormones secreted by the gastrointestinal entero-
endocrine cells that could be sensed by the gut bacteria and in turn the gut microbiota
composition is tuned. Similarly, gut microbiota also secretes some active molecules
that are sensed by host’s gut cells and translation of corresponding signals to GBA. It
has been reported that gut microbiota can (1) produce vitamin K, vitamin B, and
linoleic acid, (2) produce short-chain fatty acids, and (3) transform molecules such as
glutamate to gamma-aminobutyric acid or histidine to histamine, affecting various
aspects of the host health such as (1) modulation of host’s immune system, (2) main-
tenance of host’s gut barrier integrity, (3) modulation of host’s metabolism, (4) xeno-
biotic and drug metabolism by host, and (5) host’s protection against gastrointestinal
pathogens (Vivarelli et al. 2019).
This partnership between the microbiota and the host is an essential element of
health, and this interspecies balance is termed as eubiosis (Lazar et al. 2018). A
disturbance in eubiosis termed microbiome dysbiosis is the alteration of the
microbiota composition, which is associated with disrupting the microbiota–epithe-
lial cell interaction. Switching of eubiosis to dysbiosis in the host becomes a reason
for the host to be more prone to issues, such as immunodeficiency and cancer (Lazar
et al. 2018, 2019). The role of gut microbiome in cancer is dual in nature as they play
a role both in tumorigenesis and in the prevention and treatment of cancer. Cancer
progression may alter the microbiome, and microbiome may also affect the progres-
sion of cancer. In diseases such as colorectal cancer, composition of bacteria in the
host intestine was shown to be different in patients with colorectal cancer compared
to healthy subjects (Gharaibeh and Jobin 2019). Intestinal epithelial cells function to
provide mechanical protection and to regulate immunity by secreting chemokines,
cytokines, and antimicrobial peptides (Wu and Wu 2012). Cytokines are soluble
signaling proteins produced in immune cells such as macrophages, neutrophils, and
B and T cells for the regulation of immune responses (Stenken and Poschenrieder
2015). They are also associated with maintaining a microbiota homeostasis. The
cytokine interleukin-18 (IL-18) facilitates the protection of the intestinal mucosa,
and mice deficient in IL-18 demonstrate dysbiosis that increases susceptibility to
colon carcinogenesis (Roy and Trinchieri 2017). In a similar study carried out by
Elinav et al. (2011), wild-type mice showed symptoms of dysbiosis after fecal
microbiota of mice deficient in IL-18 were transferred to the wild-type mice.

1.2.2 Gut Microbiota as Cancer Promoter

The first bacterial protein to have been associated with human cancer is CagA
produced by Helicobacter pylori (Vivarelli et al. 2019). Fusobacterium nucleatum
(Fn), when present in abundance, has been associated with colorectal carcinoma
6 A. Malaviya et al.

(Zhou et al. 2018). Fn contributes to colorectal cancer by using its FadA adhesin to
bind to E-cadherin and causes the activation of host β-catenin–WNT signaling.
Thus, FadA is a potential diagnostic and therapeutic target (Rubinstein et al.
2013). Certain bacterial pathogens make the host prone to cancer by promoting
dysbiosis and altering the host’s immune system and thus triggering the growth of
tumor. Metalloproteinase toxin (MP toxin) by Bacteroides fragilis also plays a role
by disrupting intercellular junctions and activating β-catenin signaling (Vivarelli
et al. 2019). Bacteria such as Bacteroides fragilis, Escherichia coli, and
Peptostreptococcus anaerobius have been associated with colorectal cancer through
the activation of Th17 cell response and direct DNA damage (Wong et al. 2019).
Helicobacter hepaticus has been reported to activate the WNT/β-catenin pathway as
well as nuclear factor-kappa B (NF-κB)-regulated and Th-1 immune network
resulting in hepatocellular carcinoma (Fox et al. 2010). Injuries to the epithelial
barrier, inflammation, and chronic infections can trigger carcinogenesis in
individuals. Infections due to various pathogenic microorganisms in the gut have
been correlated with an increased risk of tumor development. Individuals with a
Salmonella typhi infection are at the risk of developing gallbladder carcinoma;
similarly, chronic Streptococcus bovis infection may lead to the development of
colon cancer (Hooper et al. 2007). In the case of H. pylori and S. typhi infections,
correlation between microorganisms and their tendency to initiate cancer in the hosts
varies for different individuals (Mager 2006).
On the contrary, there are other organisms in the gut microbiota that are of great
interest to the cancer researchers to mediate the effects of anticancer therapies (Wong
et al. 2019). H. pylori has been reported to increase the risk of gastric cancer in some
people and reduce the risk of esophageal cancer in others; however, the cause is still
unclear (Whiteman et al. 2010). Salmonella typhimurium has been associated with
gallbladder cancer, and it has also been used as a carrier of therapeutic agents for
different types of cancers; as being a facultative anaerobe, it can easily survive in the
anoxic environment often found in tumors (Mager 2006). They are made to migrate
toward the tumor sites by rendering them auxotrophic for compounds found in high
concentrations at the tumor sites such as by the removal of metabolic gene purI from
mutants such as VNP20009. This forces the organism to move toward the tumor for
survival (Low 2004). S. typhimurium destroys tumors by (1) using bacterial toxins to
activate Caspase-3 for apoptosis, (2) delivering anticancer compounds, and
(3) sensitizing the immune system to the tumors (Wall et al. 2010).
Several preclinical, clinical, and meta-analyses of clinical studies have explored
the possibilities of manipulating the microbiota to change the host’s response to
different diseases, including cancer. One of the key mechanisms that scientists have
tried to explore is immunomodulation (Ma et al. 2019). Immunomodulators change
the way the immune system responds to the tumors by increasing
(immunostimulators) or decreasing (immunosuppressive) antibody production
(Bascones-Martinez et al. 2014). Recent studies have discovered that the bacteria
in the gut impact the way cancer patients respond to immune checkpoint blockade
therapy by using antibodies targeting co-inhibitory receptors to enhance the activity
of T cell response (Gharaibeh and Jobin 2019)
1 Gut Microbiota and Cancer Correlates 7

1.2.3 Gut Microbiota as Cancer Suppressor

Several researchers have attempted to describe the mechanism by which gut

microbiome influences the host physiology. The gut bacteria show anticancer effect
either by increasing host immunity or by preventing gut dysbiosis. The bacteria
L. rhamnosus GG (LGG) can counteract cancer growth in tumor models of ovarian,
colorectal, breast, hepatic, cervical, and oral squamous cancers through its influence
on mTOR or WNT pathways (Vivarelli et al. 2019; Nagy et al. 1998). One of the
mechanisms involves short-chain fatty acids (SCFA), which are products of bacterial
fermentation of undigested dietary fibers (Nagpal et al. 2018; Mager et al. 2005).
They are associated with several functions such as intestinal repair, maintenance of
intestinal homeostasis, inhibition of cancer cell proliferation, activation of G-
protein-coupled receptors (GPCRs), etc. (Lazar et al. 2018; Nagpal et al. 2018;
Arun et al. 2019). Butyrate and propionates show anticancer effect by inhibiting
the histone deacetylases (Vivarelli et al. 2019; Ohland and Jobin 2015).
Probiotic bacteria such as lactic acid bacteria help the growth of SCFA-producing
gut bacteria (Wang et al. 2019). Reduced production of SCFAs has been associated
with an increase in the incidence of colorectal cancer (CRC) (Nagpal et al. 2018).
Butyrate is an essential SCFA as it plays a key role in homeostasis (Lazar et al.2018).
By inhibiting histone deacetylase (HDAC), it increases the acetylation of histone,
which in turn regulates the transcriptional activity of tumor suppressors, resulting in
a reduction of inflammation and CRC risk (Wang et al. 2019). Escherichia coli
Nissle 1917 administered as mutaflor in combination with intestinal antibiotic
rifaximin shows anti-inflammatory activity. Other probiotics such as L. casei trigger
apoptosis and inhibit tumor growth by secreting a ferrichrome metabolite (Vivarelli
et al. 2019). The association between microbiome and cancer is complex and has not
been completely characterized. Additionally, various factors such as lifestyle, diet,
and host immune system strongly influence the activity of the microbiota. Hence, it
is difficult to conclude if their role is as promoters of cancer or as inhibitors.

1.2.4 Gut Microbiota as Immune Checkpoint Inhibitors

The gut microbiota helps the host immune system to develop tolerance toward
beneficial microbiota and prompt an immune response against the gut pathogens
as indicated in Fig. 1.2 (Vivarelli et al. 2019). The role of recognizing and attacking
tumor cells is played by many cells of the immune system including T cells (Sharma
and Allison 2015). In the presence of an antigen, T cells receive stimulatory signals
for proliferation. T cells also receive inhibitory signals to downregulate their popu-
lation once the infection is under control. Inhibitory signals can limit the response of
T cells against cancer and hinder the process of tumor eradication (Andersen et al.
2006). CTLA-4 gene, programmed cell death protein 1 (PD-1) and its ligand
(PD-L1) modulate down regulation of T cell response (Seidel et al. 2018). Thus,
by targeting this inhibitory interaction, they can cause the T cells to remain activated for
a period long enough for tumor eradication. The U.S. Food and Drug Administration
Another random document with
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 FLORAL EMBLEMS.
The cross is the principal emblem of Easter, and is used in
connection with many displays, being suitable for any line of
merchandise. To be most effective it should be a floral cross, and
may be formed from natural or artificial flowers. However, natural
flowers are so scarce in most towns, and artificial flowers so
inexpensive, that we need consider only the latter. Of these, violets
are easily procurable, and are pretty and appropriate. Festoons, or
bunches of them, always brighten a display. Such set pieces as the
cross, crown, star, the “gates ajar” may be covered with masses of
mixed flowers, in which the tint of the violet predominates, and the
purity of the Easter or calla lily affords a soothing relief.
Wire netting, supported by a light framework of thin lumber, is the
ground for all these floral emblems. The mesh should be much
smaller than it is drawn in the accompanying design, for there is only
need of space to push the stem through. Begin at one end, thrust a
flower through the netting so that it covers the edge, and wind a
thread around the stem from the back of the netting. When the next
flower is placed in position and the thread given a turn around it,
both flowers are firmly fastened. One thread unwound from the
spool as needed, will fasten the entire design securely. Floral
emblems made in this way are remarkably light in weight, and may
be suspended in the window or placed in any desired position.
EASTER DESIGN.
EASTER DISPLAY.—Hannaford.
EASTER DISPLAY.—Hannaford.
 EASTER EGGS.
Easter would not be Easter without eggs, and therefore eggs will be
used in many window designs. Mammoth eggs may be constructed
and decorated in a hundred different ways. The mechanical egg,
which opens into two or four parts, is old but always attractive. A
clever idea is to build several large eggs, over light wood or wire
framework, break in the front sides and show a recess in each egg in
which is a “nest” of the goods you wish to call attention to. White
paper cambric—the shiny side out—is the best representation of an
egg shell.
Cut small price cards the shape of eggs, and place them in your
Easter display; or use real eggs, with the prices neatly painted upon
them.
Another idea is to blow out the insides of a number of eggs, run a
thread through them and suspend them in your window at different
heights. Or, cover your window floor with hay, to represent a hay
mow, and put nests of decorated or dyed eggs here and there. Or,
make a mammoth egg of papier mache (or a framework), covered
with cloth, and use it for the center of your window. This may be
made to open by dividing it into sections which are hinged a short
distance from the bottom, and connecting each section with a string
running to a main cord. A boy can operate it from back of the
window, or it may be connected with a motor. Put a prettily dressed
baby doll, or a chicken, in the center of the egg.
 RABBITS AND CHICKS.

A simple way to make these, in any desired size, is to cut from

heavy cardboard or thin lumber the outline of the rabbit or chicken.
Then cut cloth, to extend one-fifth beyond the edge of the outline
(see dotted lines), leaving more margin where the body is thickest.
Glue or tack the edges, and stuff with cotton or excelsior, as shown in
the end section. Paint in eyes, etc., and color with water colors.
 THE MECHANICAL LILY.
To render an Easter lily mechanical, so that the petals will open
and close, a small circle of wood is securely fastened to the standard
rising from the floor. Each leaf (there should be six) is then hinged to
this circular piece, a few inches from the lower end of the leaf. At the
extreme lower point of each leaf is now fastened a cord, and all the
cords are gathered into one a short distance down. Run the main
cord through the floor of your window and attach it to the pivot of
your water wheel. As the cord is drawn downward the leaves all
close; when it is released the leaves open by their own weight. In the
center of the lily may be placed any design or arrangement of goods.
Sometimes the figure of a doll clinging to a cross is used.
 EASTER DESIGNS.
The reader will find here a collection of beautiful designs for
Easter displays, all being photographed from life. These will all be
useful in conveying ideas for the arrangement of your own displays.
It should be borne in mind that no window display can be accurately
reproduced; yet often you will find a way to improve upon the
suggestion offered you.
 CHAPTER XXIII.
MEMORIAL DAY DISPLAYS.

A pretty custom it is to set apart one day in memory of our nation’s

fallen heroes, and May 30 is always held in loving, if sad,
remembrance by our people.
Much advice has been offered in past years concerning the
appropriate decorations for this day. Some favor depicting the joy
and triumph resulting from our wars, and the glory of a life given for
the nation’s defense. Others see the sadness of mourning friends
only, and think the flower strewn grave the best recognition of the
day. So the matter of design must be left to the taste and disposition
of the decorator. It is well, however, to bear in mind that mixed with
the sorrow of the people is a strain of pride and exaltation that their
loved ones died so nobly and heroically.
Flowers in profusion should be used, and the national colors are
not inappropriate.
Since our late wars there are more soldiers’ and sailors’ graves to
decorate than ever before, and a new interest in Memorial day has
been aroused. Therefore the wise merchant, who persistently caters
to the moods and whims of the great public, will see that his show
windows pay a fitting tribute to the occasion.
 A FLORAL FLAG.
A national flag composed of flowers is made by running wires
across a frame for stripes and pinning red and white flowers to them.
Wire netting does nicely for this purpose, and if natural flowers are
not available, red, white and blue artificial flowers may readily be
procured.
 RIBBON FLAGS.
Another way to make a flag is to use ribbon for the stripes and
puffed blue silk with white knots of baby ribbon for the stars. I have
seen some handsome flags made entirely of baby ribbons. You can
make red, white and blue backgrounds by using these colors of
Velvelette, which is easily applied. Velvelette is a “flock” which comes
in various colors and can be had at paint stores.
 ILLUSTRATIONS.
The illustrations accompanying this chapter are appropriate
designs for Memorial Day. By studying them you will get ideas for
your own display, the details being readily carried out through the
instructions furnished in the opening chapters of this book.
 FOURTH OF JULY DISPLAY.
Trimmers will find no difficulty in securing appropriate subjects
for Independence Day, as our recent history abounds in striking
incidents. But it must not be forgotten that July 4 is dedicated to the
heroes of the revolution and to the signers of the Declaration of
Independence.

MEMORIAL DAY WINDOW.—Tobias.

MEMORIAL DAY WINDOW.
MEMORIAL DAY WINDOW.—Feckenscher.
MEMORIAL DAY DISPLAY.—Eman.
 MEMORIAL DAY WINDOW.—Cornwell.

For this reason July 4th is the great patriotic occasion and the
national colors, the national flag and shield and the national heroes
are appropriately employed for decoration. “The Spirit of the Times”
and “The Birth of the Flag,” are grand subjects for window display,
and both of these we illustrate. Other window trims of a patriotic
character also accompany this chapter.
 EXAMPLE OF PATRIOTIC DISPLAY.

FRONT VIEW OF PATRIOTIC DISPLAY.

Many people, I know, place an electric fan where its powerful

breeze moves the flag in quick waves; but after all, that is not a
natural method of waving “Old Glory.” The sweep of the flag pole
itself in a semi-circle is the proper method of waving the star
spangled banner, and this effect may easily be procured in a show
window.
 In the first illustration is a large frame of red, white and blue, in
the center being a battleship, or whatever else your fancy may dictate
for a trim. You can make this frame and keep it to inclose various
incidents of the war as they may occur. The section of frame marked
“white” is beveled, or placed on an incline, to better carry out the
effect of a picture frame. Above your picture three flags are naturally
and continually waved, and the effect is well worth the slight trouble
required to produce it.
“4th OF JULY” WINDOW.—Morton.
JULY 4th DISPLAY.—Goldsman.
JULY 4th DISPLAY.—Goldsman.
PATRIOTIC WINDOW.—McElwain.
PATRIOTIC DISPLAY.—Cornwell.
PATRIOTIC DISPLAY.—Weber.
 PATRIOTIC DISPLAY.—Mueller.

The second illustration, which is the rear plan, explains the waving
of the flags. Three circular slots (3) are cut in the frame, through
which the flag staffs (2) are placed. These are weighted at the ends
(7) to make them balance. Place the pulleys (4) as shown in the cut,
and run a cord over the pulleys connecting with the flags. Opposite
each connection place a rubber cord or weak spring, fastened to the
framework in such a position that as the cord slacks it will pull the
flag to the opposite side. The pin and block (5) for the flag to work on
should be loose enough for free motion. The wheel (6) gives the
motion to the cord, and is operated by a small motor. The apparatus
is very easily constructed, and works perfectly. In front of the picture
place stacks of arms and a cannon, to fill in the foreground. The
cannon is made as follows: Cover a frame with oilcloth or carpet
paper and apply black or yellow cloth or paint, to make it resemble
iron or brass.
 THANKSGIVING DISPLAYS.
While much labor, time and expense is devoted to Christmas
windows the trimmer often neglects his Thanksgiving displays. For
this reason hardly anything strictly new is ever seen on this occasion.
As a matter of fact, it is much easier to scheme for Christmas than for
Thanksgiving displays, as the trimmer has a greater variety of
attractive material for his work at his disposal and more liberal
allowances are made on his employer’s side for the occasion. Yet we
can without any great expenditure produce many attractive and new
Thanksgiving displays. Winter scenes of different character can
easily, quickly and economically be gotten up and are very adaptable.
On Thanksgiving Day we have usually snowy, wintry weather; should
it happen, however, that this year this is not the case, do not let the
weather interfere with your work. Thanksgiving Day being the
opening day of the season a winter scene is always appropriate, very
effective and makes a winning, pleasing impression upon the
passerby.