Anis Larbi

Ciriaco A Piccirillo

Danilo Pagliari

Rossella Cianci

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Editorial
The Interactions between Innate Immunity and
Microbiota in Gastrointestinal Diseases
Danilo Pagliari,1 Ciriaco A. Piccirillo,2 Anis Larbi,3 and Rossella Cianci1
1Department of Medical Sciences, Catholic University of Rome, Largo A. Gemelli 8, 00168 Rome, Italy
2Department of Microbiology & Immunology and Medicine, Montreal General Hospital,
McGill University and Research Institute of McGill University Health Centre (MUHC), Montreal, QC, Canada
3Singapore Immunology Network (SIgN), Singapore
Correspondence should be addressed to Rossella Cianci; rossellacianci@gmail.com
Received 5 January 2015; Accepted 5 January 2015
Copyright © 2015 Danilo Pagliari et al.This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The gut microbiota refers to the collection of microbial
populations that reside in the gastrointestinal tract. It is
characterized by an interplay between different cell types and
their defense systems, food particles, molecules derived from
digestion, and the vast array of residingmicrobial specieswith
their secretory products. These microorganisms present in
the gut lumen, which can be classified as probiotics, commen-
sals, or pathogens, form the microbiota, which exerts several
physiological functions, that is, the absorption and digestion
processes, tolerance to non-self-food antigens, and defense
from pathogens.The humanmicrobiota can weigh up to 2 kg
in total and contains tens of trillions of microorganisms, a
number 10 to 20 times greater than the total number of cells in
the human body, and includes at least 1000 different bacterial
species [1]. This rich gut microbial community has coevolved
in a symbiotic relationship with the human intestinal mucosa
in such a way that the indigenous microbiota is essential for
gut homeostasis. This ecosystem acts as a functional unit;
thus, microbiota is considered a “superorganism” and is an
integral part of the gastrointestinal tract [2].
The human intestine has the dual function of nutrient
absorption and protection against intestinal pathogens.These
two tasks have conflicting demands in the body. Optimal
absorption requires a large surface area and selective perme-
ability to nutrients through a thin epithelial layer. However,
a large surface area increases exposure to luminal bacteria,
and the thinness of epithelium increases the possibility of
bacterial invasion. The intestinal immune system acts in
order to avoid bacterial invasion of the epithelial layer.
At the same time, it must not initiate inappropriate immune
responses towards the commensal bacteria that reside in the
intestinal lumen, as these responses may result in inflamma-
tory diseases, such as Inflammatory Bowel Diseases (IBD),
Celiac Disease (CD), and Diverticular Disease. Accordingly,
it is important for the intestinal immune system to maintain
an appropriate balance of pro- and anti-inflammatorymecha-
nisms to ensure tolerance to commensal and dietary antigens
and intestinal homeostasis [3].
The relationship between gut flora and humans is not
merely commensal but rather a symbiotic one. This rela-
tionship is constantly challenged by many factors, such as
the rapid turnover of the gastrointestinal epithelium and
mucus, the exposure to the peristaltic activity, the presence
of molecules resulting from digestion, the pancreatic and
biliary secretions, the host defense, the presence of drugs
or medications, the changes in pH and redox potential,
and the exposure to transient organisms from the oral
cavity and esophagus. Alternatively, numerous beneficial
functions are ascribed to the microbiota in the human gut
such as fermenting unused energy substrates, educating the
immune system, preventing growth of harmful, pathogenic
bacteria, regulating gut development, producing vitamins
for the host, such as biotin and vitamin K, and producing
hormones to direct the host to store fats [4]. Furthermore,
the gut microbial community is akin to a safeguard of
our health because the microbiota competes for space and
nutrients with potential pathogens and induces the secretion
of antimicrobial peptides through interaction with intestinal
Hindawi Publishing Corporation
Journal of Immunology Research
Volume 2015, Article ID 898297, 3 pages
http://dx.doi.org/10.1155/2015/898297
2 Journal of Immunology Research
epithelial cells [1]. The gut microbiota can also stimulate
the differentiation and proliferation of epithelial cells, which
regulate intestinal homeostasis [5].
According to the beneficial functions of gut microbiota
mentioned above, it is clear that several bacteria that form
microbiota confer a health benefit on the host. These bac-
teria have been mentioned as “probiotics.” Thus, in recent
years, experimental and clinical researchers have identi-
fied probiotics as a potential therapeutic target for several
gastrointestinal diseases, as reported in the review by G.
Giorgetti et al. Quali-quantitative changes in bacterial strains
suggest that gut microbiota may be a therapeutic target based
on probiotics and on probiotic-driven metabolic products,
called “postbiotics.” New therapeutic approaches based on
probiotics are now available, and further treatments based on
postbiotics will come in the future.
A principal function of the microbiota is to protect
the intestine against colonization by exogenous pathogens
and potentially harmful indigenous microorganisms. The
specific mechanisms by which commensal bacteria achieve
this function remain poorly understood, but there is evidence
to indicate that both direct and indirectmechanismsmight be
involved. These mechanisms include the direct competition
for limited nutrients, the promotion of mucosal barrier
function, the modulation of innate immunity to pathogens
and infections, the promotion of adaptive immunity, and
even the protective role of the commensal microbiota against
systemic infection [1]. However, in certain conditions, some
species of bacteria are thought to cause disease by producing
infection or increasing the risk of cancer in the host. In
fact, particular bacterial populations that are typically found
in very low abundance can acquire pathogenic properties.
These conditions include inherent immune defects as well
as changes in diet and/or acute inflammation and can
result in the disruption of the normal balanced state of
the gut microbiota, a condition referred to as dysbiosis [6].
Dysbiosis involves the abnormal accumulation or increased
virulence of certain commensal populations of bacteria,
thereby transforming former symbionts into “pathobionts.”
Pathobionts are typically colitogenic in that they can trigger
intestinal inflammation [1]. Hence, the breakdown of the
normal microbial community contributes to increase of
the risk of pathogen infection, the overgrowth of harmful
pathobionts, and inflammatory disease. Thus, understanding
the interaction of themicrobiota with pathogens and the host
might provide new insights into the pathogenesis of disease,
as well as novel avenues for preventing and treating intestinal
and systemic disorders [1].
A prototype to understand the breakdown of the normal
gut microbial community leading to dysbiosis is Clostridium
difficile infection (CDI). In this special issue, S. Bibbò et al.
describe the epidemiological and clinical characteristics of
CDI and discuss how the intestinal microbiota modifications
and the modulation of innate immune response can promote
and exacerbate CDI. In this infection, the alteration of intesti-
nal homeostasis promotes the development of an ecological
niche that allows the growth of Clostridium difficile. More-
over, intestinal dysbiosis can promote a proinflammatory
environment, whereas Clostridium difficile itself modulates
the innate immunity through both toxin-dependent and
toxin-independent mechanisms.
CDI causes intestinal inflammation leading to a sub-
sequent reduction of intestinal microbiota diversity. The
proportion between Clostridium difficile and the other gut
bacteria has been related to the severity of inflammation.The
work of C. Vincent et al. demonstrates how fecal excretion
of abundant quantities of human DNA is associated with
intestinal inflammation and with incipient CDI; thus, fecal
excretion of host DNA should be investigated as a potential
clinical marker of intestinal inflammation and CDI risk.
The specific composition of the microbiota is influenced
by immune cells as well as external environmental factors,
especially the use of antibiotics and diet [7]. For the preserva-
tion of gastrointestinal homeostasis, the intestine maintains
control over the microflora, discriminating between patho-
genetic and nonpathogenetic organisms by means of local
innate immunity [1].
Initiation of innate immune responses in the intestine is
triggered by pathogen-recognition receptors (PRRs) which
serve as sensors of pathogen-associated molecular patterns
(PAMPs) from the intestinal lumen. The most studied PRRs
are the Toll-like receptors (TLRs) [8]. In this special issue, two
reviews illustrate the major role of TLRs in the interaction
between microbiota and immune system. In particular, M.
Valentini et al. focus the attention on the possibility that
microbiota acts through TLRs expressed by adaptive T cells
providing regulatory signals. S. Frosali et al. discuss the role
of TLRs polymorphism in human gastrointestinal pathology
and the role of TLRs and their interactions with human
microbiota in the pathogenesis of Inflammatory Bowel Dis-
eases.
TLRs may be involved in the pathogenesis and clinical
course of the diverticular disease. In the paper by R. Cianci
et al., it has been demonstrated that variations before and
after the antibiotic therapywith Rifaximin exist.This suggests
that TLRs are modified by the presence of pathogenic flora in
UDD.The role of pathogenic flora is supported by the finding
that Rifaximin acts in the gutmucosa homeostasis by limiting
the activation of TLRs. Furthermore, Rifaximin may also
have a luminal anti-inflammatory function modulating the
adaptive immune response in an inhibitory sense. Rifaximin
keeps under control TLRs expression in peripheral blood
suggesting that, in addition to its activity in gut mucosa, it
may also have a systemic action on immune system.
The intestinal barrier regulates intestinal homeostasis
throughout innate and adaptive immune responses. Unfortu-
nately, in some cases, the innate immune system’s attempt to
protect the host fails and chronic inflammation and intestinal
autoimmunity occur, such as in the case of IBD and Celiac
Disease (CD). In this special issue, in the paper of D. Pagliari
et al. it is clarified how CD may be considered as a model
to explain the pathogenesis of several other autoimmune
diseases. In fact, during this disease, the steady state condition
homeostasis due to the complete balance between pro- and
anti-inflammatory factors is altered. The breakdown of the
interaction among microbiota, innate immunity, and genetic
and dietary factors leads to the disruption of homeostasis
leading to inflammation and tissue damage. Thus, focusing
Journal of Immunology Research 3
the attention on this interaction and its breakdownmay allow
a better understanding of the CD pathogenesis and finally get
novel translational avenues for preventing and treating this
widespread disease.
The contributions of the gut microbiota to the devel-
opment of the immune system have been extensively char-
acterized. There is a coordinated cross talk between the
gut microbiota and the immune system allowing the host
to tolerate the large amount of antigens present in the
gut. Hence, recent data have demonstrated that microbiota
plays a pivotal role in orchestrating the immune response
in gut mucosa and in regulating the balance between pro-
and anti-inflammation factors. Gut flora has a continuous
and dynamic effect on the host’s gut and systemic immune
systems. Bacteria are key in promoting the early development
of the gut’s mucosal immune system. The immune system
recognizes and fights harmful bacteria, but, throughout the
mechanism of tolerance induction within the first days of
life, permits the colonization and growth of helpful species
of bacteria. On the other hand, the immune-gastrointestinal
flora interface plays a pivotal role in maintaining gut home-
ostasis with resident microbial communities, thus ensuring
that the symbiotic nature of the host-microbial relationship
is maintained [2].
According to what has been described so far, the interac-
tion between human gut microbiota and intestinal immune
system can be considered as the pivotal axis that contributes
to the maintenance of intestinal homeostasis and allows
proper defense to infections. As the intestinal immune system
is influenced by many factors, including dietary components
and commensal bacteria, strategies that restore a healthy gut
microbial community by affecting themicrobial composition
are being developed as new therapeutic approaches to treat
several gastrointestinal diseases.
We hope that this special issue will contribute to a better
understanding of the strong interactions between innate
immunity and microbiota in developing gastrointestinal dis-
eases. These new acquisitions will be fundamental to finding
new therapeutical strategies.
Danilo Pagliari
Ciriaco A. Piccirillo
Anis Larbi
Rossella Cianci
References
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Editorial The Interactions between Innate Immunity and Microbiota in Gastrointestinal Diseases

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Editorial The Interactions between Innate Immunity and Microbiota in Gastrointestinal Diseases

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