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microenvironment and outcompete other microbes.
For example, possible CRC 'drivers' are specific strains
of E. coli producing genotoxins such as colibactin and
cytolethal distending toxin (CDT). Recent study shows
that CRC patients with micro-satellite instability have
markedly increased colibactin-producing E. coli.65,66
Colibactin triggers CRC development through the
induction of DNA damage and cellular senescence.40,67
Also, mono-colonisation with E. coli NC101, a mouse
commensal with genotoxic capabilities, promotes invasive carcinoma in azoxymethane (AOM)-treated IL10-/mice.40 Significantly, some probiotic strains such as
E. coli Nissle 1917 harbour genotoxicity islands which
are also necessary for their probiotic functions.68
A possible 'passenger' strain, frequently isolated
from colorectal adenoma or carcinoma patients, is
F. nucleatum:69 an invasive anaerobe that has previously been linked to periodontitis and appendicitis
and, in CRC patients, is associated with shorter survival times.70 Kostic et al.69 showed that F. nucleatum
promotes intestinal tumorigenesis in the ApcMin/þ
mouse model.
The role of depleted bacterial strains, such as
Lactobacilli or Bifidobacteria, in CRC pathogenesis is
less well studied. However, it is possible that the depletion of commensals reduces colonisation resistance and
enables the outgrowth of genotoxic strains. Also, the
decreased production of SCFA by commensals may
play a key role in tumorigenesis as SCFA have been
shown to have anti-inflammatory, antitumorigenic and
antimicrobial effects.71
To conclude, gut microbiota and their metabolites
are key players in CRC pathogenesis. Future preventative, diagnostic and therapeutic strategies must be
based on knowledge of the microbiome and its interactions with the tumour's environment. The manipulation of the gut microbiome by dietary changes,
prebiotics, probiotics, specific antibiotics, or faecal
microbiota transplant (FMT) will become an indispensable tool in CRC management.

Microbiota and coeliac disease
Coeliac disease is a lifelong, immunologically mediated
disease induced in genetically predisposed individuals
by gluten in food. This disease is the most common
form of immune-mediated food intolerance, affecting
about 1% of the European population. It is characterised by mucosal atrophy and increased cellularity
of the small intestine which can lead to malabsorption.
The autoimmune nature of this disease is documented
by the presence of autoimmune mechanisms directed
against several autoantigens, including the most
important diagnostic autoantigen, that is, tissue
transglutaminase.

Laboratory Animals 53(3)
Compared to healthy subjects, the presence of
changes in intestinal microbiota composition (intestinal
dysbiosis) was described both in patients with active
coeliac disease and patients treated by following a
gluten-free diet.72-74 Most studies have consistently
reported low levels of Lactobacilli and Bifidobacteria,
and increased levels of Proteobacteria in both children
and adults with active coeliac disease.75,76 Interestingly,
the increased abundance of Proteobacteria correlated
with disease activity. Other studies have reported also
increases in the abundance of Bacteroides and E. coli.72
A recent study in infants with familial risk of coeliac
disease demonstrates that gut microbiota changes, such
as loss of diversity, a decreased abundance of
Bifidobacterium longum, or increase in Enterococcus
spp., precede the onset of disease.9
In contrast to IBD where numerous mouse and rat
models have been described and often used, good
experimental models of coeliac disease had been lacking
for a long time.77 To analyse the complex mechanisms
involved in the pathogenesis of coeliac disease, animal
models have recently been developed, with some of
them being used to determine the role played by gut
microbiota in disease development.78,79 Gut microbiota
in rat and mouse models of coeliac disease can be
manipulated by gnotobiotic technology, changing the
diet, antibiotic treatment and by the administration of
pathogenic or beneficial (probiotic) microorganisms.
The gnotobiotic model of coeliac disease in germ-free
rats in which gluten enteropathy (flattening and
increased cellularity of the mucosa) was induced by
the administration of gliadin soon after birth was developed in our lab. The role of intraepithelial lymphocytes
in this model was analysed and has been established.80
How the composition of gut microbiota affects intestinal barrier function was tested using intestinal loops
of germ-free rats in the presence of various intestinal
bacteria, gliadin and interferon gamma. Translocation
through the gut mucosa of only small amounts of gliadin was found in the presence of Bifidobacterium bifidum. In contrast, in the presence of Shigella, increased
amounts of translocating gliadin and the impairment of
mucosal tight junctions were detected.81
HLA transgenic mice, that is, mice expressing
human DQ8, one of two DQ alleles associated with
coeliac disease were used to study the effect of microbiota.82 Germ-free non-obese diabetic DQ8 mice developed severe gluten-induced enteropathy compared to
colonised mice. These results suggest that intestinal
microbiota could reduce the pro-inflammatory effects
of gluten after ingestion.83,84 The decisive role of gut
microbiota composition in gluten-degradation patterns
was demonstrated by colonisation of germ-free C57BL/
6 mice with bacteria isolated from the small intestines
of coeliac disease patients or healthy controls.



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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