Chronic Enteropathies: Current Thinking and Understanding of the Pathogenesis.
Douglas, DVM, DACVIM
Chronic enteropathies are common clinical condition in small animal internal medicine.
Loosely speaking, it is defined as chronic gastrointestinal signs characterized by
vomiting, diarrhea, weight loss, changes in appetite (increased or decreased),
borborygmus and/or changes in stool volume. These conditions may or may not be
inflammatory nature. Inflammatory bowel disease is a clinical syndrome associated with
chronic clinical signs (chronic enteropathy), compatible histopathologic findings,
absence of response to antibiotics or dietary changes in the lack of a definable etiologic
cause. What a theory regarding the underlying mechanisms of disease have been
proposed. Recently, characterization of several features have been brought to the
forefront regarding pathophysiology of this condition.
It is important to note that inflammatory bowel disease in people is different than that in
small animals. While IBD in people may share similar pathophysiologic mechanisms,
there may be significant species differences between humans and between dogs and
cats. In people, IBD is represented into major conditions; ulcerative colitis and Crohn’s
disease. Histologically, Crohn’s disease represents granulomatous inflammation,
atypical of our inflammatory bowel disease patients. Ulcerative colitis may represent
similarities to inflammatory colitis in dogs and cats but appears to be the minority of the
disease in animals. In dogs and cats, inflammatory bowel disease is generally
associated with small intestinal signs. While idiopathic inflammatory colitis definitely
represent suspect from disease, in my experience, this is less frequent. Therefore,
comparison between species must be interpreted loosely.
Currently, IBD in animals is thought to be associated with changes in local luminal
factors (bacterial populations, dietary triggers), changes in mucosal wall (alter structural
changes), genetics fluctuations and down regulation of T regulator cells. While not
proven, it is suspected that acute insults to the gastrointestinal tract may result in
inflammation that leads to factors contributing to chronic, progressive, ongoing
inflammatory disease within the bowel.
Recently, a great deal of emphasis has been on bacterial flora and the interactions with
the intestine, both locally and systemically. Microbes commonly express microbe
associated molecular patterns (MAMP) which are recognized by pattern recognition
receptors on the surfaces of cells (PRR). One of these pattern recognition receptors
are toll -like receptors (TLR). These toll -like receptors are group of receptors
recognizing and interacting with bacteria and viruses. The interaction of TLR’s with
these what your patterns results in up regulation of the inflammatory cascade through
altered cytokine expression. Recently, alterations in TLR4 and TLR5, have been
documented within German Shepherd dogs and is thought to potentially be associated
with predisposition towards inflammatory bowel disease. Additionally, TLR2 has been
shown to be upregulated in non-German Shepherd breeds. Other genetic factors
including specific DLA II haplotypes may be present in some breeds. Finally, alterations
in NOD 2 (a common genetic mutation in people) have been appreciated in dogs.
Therefore, it is very possible to see that changes in expression of toll -like receptors
could result in both increased cytokine expression or decreased cytokine expression,
leading to expression of disease or protection from disease. One, recently well
described condition (Enteroinvasive E. coli) has been documented in Boxer dogs with
mutated neutrophil cytosolic factor 2, emphasizing the importance of genetics and the
expression of disease, both inflammatory and infectious. Little work has been done in
cats regarding genetic alterations.
The changes in sensitivity to pathogens and nonpathogenic bacteria/viruses is only
compounded by the so-called, dysbiosis that has been described in inflammatory bowel
disease. Dysbiosis, represents an alteration in bacterial flora. This alteration may be
characterized by changes in general phylum, increase in percentage of potential
pathogens and/or narrowing or widening of bacterial diversity. It is important to note
that the gastrointestinal flora (microbiome), functions together to aid in digestion, local
gastrointestinal health and more recently systemic health. There is a great deal of
plasticity within the system, whereby fluctuations in bacterial flora do not alter function of
the gut. However, in a susceptible individual, this dysbiosis may contribute to the
expression of inflammatory disease. It should be noted that complex techniques to
characterize the bacterial flora have recently been employed, documenting both
changes in feline and canine microbiota with chronic enteropathies. As different people
can have different phylogenetic proportions within their gastrointestinal tract, the same
has been documented within animals and clear alterations within microbiota have not
been defined yet. It is more than likely that changes in flora result in functional
changes, , rather than a discrete change within the flora.
Another frequently cited, poorly documented phenomenon is the association of diet
hypersensitivity in inflammatory bowel disease. The clinical definition of IBD in animals
is defined by the lack of response to food (as compared to FRD; food responsive
disease). Therefore, what role does food really play? It is suspected that inflammatory
bowel diseases associated with changes in mucosal permeability through alterations in
epithelial glycocalyx and/or changes in epithelial tight junction function. Is thought that
luminal proteins thereby gain access through a normally protected barrier to the
submucosal lymphatic tissue (gastrointestinal associated lymphoid tissue; GALT). This
exposure sensitizes inflammatory cells to proteins, carbohydrates and other dietary
substrates, thereby contributing to hypersensitivity reactions and perpetuation of
inflammatory disease. It has been long stated that sensitization to diets in the setting of
inflammatory disease is possible, introducing the concept of “sacrificial proteins” in
management of IBD. Additionally, diet does affect inflammatory bowel disease in many
ways. The digestibility and simplicity of the diet may aid in absorption of the diet across
a dysfunctional surface. Additionally, dysfunctional intestinal absorption may result in
malabsorption of the diet and resultant substrates contributing to osmotic forces.
One additional factor documented in dogs with inflammatory bowel disease is the
expression of P glycoprotein (a transmembrane eflux pump). It has been shown that
expression is increased in naïve enterocytes and lymphocytes. Additionally, it is up
regulation is documented in those exposed to corticosteroids. It has been suggested
that therapeutic compounds may be selectively excreted from mucosal surfaces/targets,
reducing the efficacy and increasing refractory nature of the disease.
Several pathways have recently been studied as potential contributing pathways to the
pathophysiology of disease. Recently, NFkB has been shown to be intimately
associated with chronic enteropathies (both food responsive and steroid
responsive/IBD). This highlights potential therapeutic avenues in the future for blocking
the inflammatory cascade. Whether or not this upregulation represents a downstream
signaling pathway or a primary alteration in NFkB expression/activity remains to be
seen. Either way, therapeutic targeting of this pathway seems appropriate in the future.
One potential cause for activation of NFkB and/or other inflammatory signals is the
down regulation of soluble RAGE and/or up regulation of tissue bound RAGE. RAGE
is a pattern recognition receptor that has been associated with vascular recruitment of
inflammatory cells and activation of NFkB. Therefore, it is up regulation in inflammatory
bowel disease can promote progressive inflammation. Additionally, soluble RAGE has
been shown to be decreased. This soluble factor acts as a decoy normally to reduce
contact with membrane-bound RAGE. Therefore, it is down regulation and/or relative
proportions between surface bound and soluble RAGE seem to be associated with the
pathogenesis in dogs. Furthermore, endogenous ligands (most notably S
100A120)have been documented and shown to be increased in inflammatory bowel
disease.
Another confusing factor in inflammatory bowel disease is the type of inflammatory
infiltrates. In some cases, documentation of increased inflammation is not possible
despite steroid responsiveness. Therefore, terminology has shifted away from IBD and
towards chronic enteropathies with characterization based on responsiveness to
therapy (FRD; food responsive disease, SRD; steroid responsive disease). Additionally,
characterization of the inflammation present in these cases is complicated, may not be
the same in every patient, may not be the same within different locations (colonic, small
bowel), may differ with clinical diagnosis (FRD, SRD) disease, and between species.
Furthermore, objective agreement amongst pathologists regarding degree of
inflammation, making comparisons between diseases is oftentimes difficult.
Additionally, alterations in cell counts/histology do not appear to be influenced by
therapy. Therefore, the emphasis in the future will be on qualitative changes within the
gastrointestinal tract so that a further understanding can be made regarding
characterization of chronic inflammation. In other words, it is not enough nowadays to
say that lymphocytes are increased or decreased, correlation with cytokine profiles,
mRNA expression, surface markers (to further define subpopulation of lymphocytes),
etc. will help in the future. Until that point, inflammation is readily documented in dogs
and cats with inflammatory bowel disease and is still considered relevant to the
underlying pathophysiology. Work has been done evaluating cytokine profiles in dogs
and cats with inflammatory bowel disease. Conflicting information exists between
studies depending on how they are individually evaluated (mRNA, protein expression)
without consistent results between studies. However, future work subcategorizing
populations may aid in novel therapies targeting cytokines (i.e. TNF blockers in people).
Tumor necrosis factor has been shown to be increased in some studies within dogs and
cats, suggesting a potential application of this therapeutic arm.
Recently, the focus is shifted from “lymphocytes” to specific cell populations. Dendritic
cells in dogs have been shown to be reduced within the mucosal lining (CD 11c +),
theorized to be important in reducing mucosal tolerance. Additionally, further
characterization of T regulatory cells may suggest a role for down regulation in
inflammatory bowel disease. This down regulation of regulatory T cells may result in
this regulated mucosal immunology and failed oral tolerance to commensal
bacteria/food proteins. Further study evaluating cytokine profiles consistent with TH 17
responses (shown to be associated with down regulation of regulatory T cells) and
evaluating mucosal/peripheral T regulatory cells by documenting expression of Fox P3,
CD4, CD 23 positive cells (typical surface protein expression molecules for T regulatory
cells) is necessary before we potentially can understand their particular role and what
potential therapeutic targets we may have.
Soluble factors secreted from the mucosal surface have been suggested at times to be
contributory to inflammatory enteropathies. Most notably, IGA expression has been
cited. Recent publication in dogs documented reduced IGA levels both in fecal,
duodenal samples and circulation. This finding was only documented in dogs with
inflammatory bowel disease, suggesting that decreased mucosal tolerance may
contribute to the disease process.
One additional factor that may be contributory to progression of inflammatory changes
within diseased individuals includes alterations in apoptosis. Reduced apoptosis may
result in perpetuation of auto reactive cells. This is been shown in dogs with
inflammatory disease.
Cellular infiltration into tissues is mediated by so adhesion molecules. Up regulation of
adhesion molecules has been documented in people with inflammatory bowel disease
and most recently in dogs. Monoclonal antibodies have been used in management of
these conditions within people. Is possible that blockade of cellular infiltration to bowel
could become a therapeutic target in dogs.
Response to tissue injury documented by up regulation of GH, IGF-I, IGF-2 expression
has been documented in animals with chronic enteropathies. It is unknown but possible
that sustained increases in these hormones may be pathologic in inflammatory bowel
disease as, recently, therapeutic interventions have not resulted in changes in this
presumptive reparative process. Another factor potentially contributing to tissue injury
rather than tissue repair is the expression of matrix metalloproteinases (MM2, MM9).
These endopeptidases may be involved in breakdown of extracellular matrix and could
potentially be contributory to tissue injury. They have been shown to be upregulated in
dogs. Further work is needed in both these areas to determine whether or not these
findings represent a response to tissue injury or are intrinsically related to the
pathogenesis or contributing to the pathogenesis of the disease.
Other factors and areas of potential investigation that are ongoing include alterations in
intestinal motility and changes in enteric nervous system.
Therefore, in short our understanding of inflammatory bowel disease in dogs and even
more so in cats is poor. A boom of information regarding inappropriate responses to
bacterial flora through genetic factors contributing to hyperresponsiveness of the gut
appear to be most relevant. While this is one factor that appears to be associated with
the expression of disease, additional factors are clearly being evaluated. It is hoped
that further characterization of the inflammatory cell populations, there cytokine
expression profiles, mRNA expression, etc. may be helpful in the future to provide a
rational basis for therapeutic investigation.