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Medicine 18
B acteria
Introduction
Inflammatory bowel disease (IBD)
is the term applied to a group of
poorly understood enteropathies
that are characterized by the infil
tration of the gastrointestinal
mucosa by inflammatory cells. The
cellular infiltrate is composed of
variable populations of lymphocytes,
plasma cells, eosinophils neutro
phils and macrophages, and is often distributed
throughout the gastrointestinal tract. The infiltrate
is variably accompanied by changes in the mucosal
architecture such as villous atrophy, fusion, fibrosis and
lymphangiectasia. IBD is likely the leading diagnosis in
dogs and cats presented for the investigation of chronic
gastrointestinal causes of vomiting, diarrhea, weight loss
and anorexia. However, little is known about its etiology,
and treatment is usually based on empirical combinations
of diet, antimicrobials and immunosuppression. This
presentation will focus on the role of bacteria in canine
and feline inflammatory bowel disease.
Evidence to support a role for intestinal bacteria in IBD
Recent research on the immunological environment in
the gastrointestinal tract reveals a complex interplay
between luminal constituents (e.g. dietary, bacterial
microflora), the epithelium, immune effector cells (e.g.
lymphocytes and macrophages) and soluble mediators
such as chemokines and cytokines. In health, this system
functions to avoid active inflammation by antigen
exclusion and the induction of immune tolerance and
the cytokine profile is dominated by the production of
the immunomodulatory cytokines (cytokines are soluble
mediators of inflammation) TGF- and IL-10.
In people with inflammatory bowel disease there is a
failure to suppress the inflammatory response, with
pro-inflammatory cytokines such as TNFa, IL-1 and
IFNproduced in excess. Mechanistic studies in rodents
with engineered genetic susceptibility to IBD, e.g. -/-IL-10,
-/IL-2 mice and HLA-B27 transgenic rats, indicate that
the enteric microflora is required for inflammation,
with inflammation observed in conventionally housed
but not germ-free conditions. In these models, bacterial
species regarded as part of the normal intestinal flora,
such as Bacteroides and Enterobacteriaceae, particularly
E. coli, have been associated with inflammation. Hence,
it has been proposed that IBD is a consequence of an
overly aggressive immune or inflammatory response to
a subset of commensal enteric bacteria in genetically
predisposed individuals.
Evidence implicating the resident enteric microflora
in the pathogenesis of spontaneous IBD in people is
provided by the clinical responses of Crohns disease
(CD) to fecal stream diversion and antimicrobials,
the increased circulating and intraluminal humoral,
T cell responses to enteric commensal bacteria, and
imbalances in the ratio of beneficial to harmful bacteria
(termed dysbiosis) observed in CD. Complementing
this is the discovery of mutations in genes regulating
microflora sensing ability (NOD2/CARD15 and TLR-4) of
patients with CD. This provides mechanisms to explain
individual susceptibility to the resident microflora
that, in the presence of the enteric microflora and
appropriate triggers, may lead to up-regulated mucosal
cytokine production, delayed bacterial clearance and
increased bacterial translocation, thereby promoting and
perpetuating intestinal inflammation.
A diverse spectrum of pathogenic bacteria, including
Listeria, Streptococcus, Enterococcus, Enterobacteriaceae,
Bacteroides, Clostridium, Yersinia and Mycobacterium
avium paratuberculosis (MAP), have been implicated in
the development of inflammation, but no single agent
has emerged as a consistent cause. In the absence of a
defined cause, therapy is symptomatic and supportive,
and achieves remission rather than cure.
Recent advances in molecular microbiology have led to
a new awareness of the diversity and complexity of the
enteric flora. Culture-independent analyses of bacterial
16S rDNA libraries reveal that only 30% of the fecal flora
appears cultivable, and there is significant variation
in the flora in different gastrointestinal segments
and luminal contents versus the mucosa of healthy
individuals. Analysis of 16S rDNA libraries constructed
from endoscopic biopsies of the ileum from patients
with Crohns ileitis (a disease phenotype that occurs in
approximately 70% of individuals with CD), demonstrates
selective enrichment of ileal mucosa in E. coli and
relative depletion in Clostridiales compared to both
patients with CD restricted to the colon, and to healthy
individuals. PCR of ileal DNA yielded no evidence of MAP,
Listeria or Shigella, and confirmed the increase in E. coli.
Similarly, 16S rDNA library-based evaluation of surgically
resected CD ileum shows an increase in Proteobacteria
(this phylum includes Enterobacteriaceae), decrease in
Firmicutes (this phylum contains Clostridiales), and the
absence of DNA from MAP in CD mucosa. Microscopy
with a probe restricted to E. coli/Shigella reveals that the
ileal mucosa of CD patients harbors significantly more
E. coli than normal ileum, and mucosally invasive E. coli are
Proceedings of the 33rd World Small Animal Veterinary Congress 2008 - Dublin, Ireland
WSAVA / FECAVA Programme 2008 | 427
21-07-2008 11:21:37
18 Medicine
Proceedings of the 33rd World Small Animal Veterinary Congress 2008 - Dublin, Ireland
428 | WSAVA / FECAVA Programme 2008
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