Laboratory Animals - June Issue - 273

Hrncir et al.
the basis of microbiota composition.4 However, a
recent study by Pascal et al.31 shows that the microbiome of CD patients is less diverse and more unstable
than the microbiome of UC patients and that CD
patients have a higher relative abundance of
Fusobacterium and Escherichia and a lower abundance
of Faecalibacterium, Anaerostipes, or Colinsella compared to UC patients.
On a functional level, these compositional alterations have various effects. SCFA including butyrate
and propionate are necessary for the differentiation
and proliferation of regulatory T cells (Tregs), the production of mucin and antimicrobial peptides, and are a
major source of nutrition for intestinal epithelial
cells.32,33 The hydrogen sulphide produced by SRB is
toxic to intestinal epithelial cells and triggers inflammation.25,34 Mucolytic bacteria degrade mucins in the
mucus layer and utilise it as a source of energy.27 The
increase in pro-inflammatory bacteria such as segmented filamentous bacteria (SFB) stimulates the differentiation of T helper 17 (Th17) cells.35 Conversely,
Tregs are induced by selected strains of Clostridia/
Clostridium spp.36 or by the polysaccharide A of
Bacteroides fragilis.37
Mouse models of IBD are often associated with a
typical microbiotic signature. For example, the
increased numbers of Bacteroides distasonis,
Clostridium ramosum, Akkermansia muciniphila, or
Enterobacteriaceae correlate to disease activity in the
dextran sulphate sodium (DSS) model of colitis.38
The trinitrobenzene sulfonic acid (TNBS) colitis,
which is a T cell-mediated, IL-12 driven intestinal
inflammation, is characterised by increased numbers
of Enterobacteriaceae and Bacteroides.39 The colitis in
IL-10À/À mice is associated with increased numbers of
Enterobacteriaceae and adherent-invasive E. coli
(AIEC).40 Nod2-deficient mice, a model for Crohn's
disease, have a diminished capacity to produce antimicrobial peptides by their Paneth cells, resulting in
altered gut microbiota.41 Paneth cell dysfunction has
been associated with Crohn's disease.42 Nod2-/- mice
are unable to regulate the H. hepaticus load in the terminal ileum and develop a granulomatous ileitis,
enlarged Peyer's patches and mesenteric lymph
nodes.43 The TRUC (T-bet-/- Rag-/-) mice, which lack
both adaptive immunity and T-bet-dependent components of innate immunity (ILC1 and NKp46þ ILC3),
develop colitis when colonised by Klebsiella pneumoniae
and Proteus mirabilis, but only in the presence of commensal microbiota.44 It is notable that colitogenic
microbiota can be transplanted to wild-type mice and
will induce colitis.45 To induce colitis in the adoptive Tcell transfer model, specific bacteria including
Helicobacter muridarum, Helicobacter hepaticus or
SFB and the presence of specific pathogen-free (SPF)

273
microbiota are required.46-48 Interestingly, some commensal strains or their components, such as
Parabacteroides distasonis or Lactobacillus casei, were
shown to reduce intestinal inflammation in the DSSinduced colitis model.49,50
To sum up, experimental animal models of IBD,
both chemically induced and genetic, provide strong
evidence for the role of gut microbiota in the pathophysiology of colitis. Since, in most models, germ-free
animals do not develop the disease and the antibiotic
treatment of colitic mice typically reduces intestinal
inflammation.51-54 Frequently, the disease phenotype
could be transplanted to healthy mice along with the
microbiota.

Microbiota and colorectal carcinoma
Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer and the fourth leading cause
of cancer death in the world. In some developed countries, incidence and mortality rates have been gradually
decreasing, possibly due to preventative screening followed by the removal of colonic polyps. However, in
many low- and middle-income countries, CRC incidence and mortality rates are increasing rapidly and
are expected to rise globally to as many as 2.2 million
new cases and 1.1 million deaths annually by 2030.55
The etiological factors contributing to CRC initiation, progression and dissemination include genetic
and environmental factors. But it is increasingly evident
that gut microbiota and its interactions with the host's
immune system play a pivotal role in CRC pathogenesis.56,57 Interestingly, gut microbiota is also a key
factor influencing the efficacy and toxicity of anticancer
therapy.58
CRC patients have, as do IBD patients, compositional alterations of gut microbiota characterised by
a reduced diversity of both mucosa-associated and
faecal microbiota,59,60 a decreased relative abundance
of Firmicutes and an increased relative abundance of
Proteobacteria.61-63 Interestingly, CRC and CD
patients share similar microbiota alterations characterised by increased abundance of F. nucleatum and
E. coli.31
Moreover, IBD patients are more susceptible to later
CRC development which suggests a causal relationship
between microbiota, inflammation and CRC.
Several bacteria including F. nucleatum, genotoxic
E. coli, enterotoxigenic B. fragilis, or Helicobacter
spp. are associated with CRC development, yet it
remains unclear whether these bacteria are CRC drivers
or passengers.64 Driver bacteria induce DNA damage
via genotoxins produced either directly by bacteria or
indirectly by inflamed tissue. Conversely, 'passenger'
bacteria take advantage of the unique tumour



Laboratory Animals - June Issue

Table of Contents for the Digital Edition of Laboratory Animals - June Issue

Contents
Laboratory Animals - June Issue - Cover1
Laboratory Animals - June Issue - Cover2
Laboratory Animals - June Issue - Contents
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