Changes

 

==Description==

==Description==

*When ARD was first recognised, it was thought to resemble human small intestinal bacterial overgrowth which is caused by an absolute increase in the number of intestinal bacteria.  When duodenal juice was cultured however, it was found that there was a large overlap in bacterial numbers between normal dogs and those with ARD, suggesting that the syndrome resulted either from an alteration in the species distribution of the flora or from a change in the host response to intestinal bacteria<ref name="two">Willard MD, Simpson RB, Fossum TW, Cohen ND, Delles EK, Kolp DL, Carey DP, Reinhart GA. '''Characterization of naturally developing small intestinal bacterial overgrowth in 16 German shepherd dogs.''' ''J Am Vet Med Assoc. 1994 Apr 15;204(8):1201-6.''</ref>.  Different samples from the same animal also gave very different results when cultured, even when the samples were apparently collected at the same time and from the same location.  Some animals were found to fulfill the microbiological criteria of SIBO but not to have any clinical signs.  These discrepancies in the traditional view of SIBO in small animals led to a renewed interest in interaction between the bacterial flora and the mucosal immune system, the collective term for the cells and immune structures located in the GI tract.

*When ARD was first recognised, it was thought to resemble human small intestinal bacterial overgrowth which is caused by an absolute increase in the number of intestinal bacteria.  When duodenal juice was cultured however, it was found that there was a large overlap in bacterial numbers between normal dogs and those with ARD, suggesting that the syndrome resulted either from an alteration in the species distribution of the flora or from a change in the host response to intestinal bacteria<ref name="two">Willard MD, Simpson RB, Fossum TW, Cohen ND, Delles EK, Kolp DL, Carey DP, Reinhart GA. '''Characterization of naturally developing small intestinal bacterial overgrowth in 16 German shepherd dogs.''' ''J Am Vet Med Assoc. 1994 Apr 15;204(8):1201-6.''</ref>.  Different samples from the same animal also gave very different results when cultured, even when the samples were apparently collected at the same time and from the same location.  Some animals were found to fulfill the microbiological criteria of SIBO but not to have any clinical signs.  These discrepancies in the traditional view of SIBO in small animals led to a renewed interest in interaction between the bacterial flora and the mucosal immune system, the collective term for the cells and immune structures located in the GI tract.

The major components of the mucosal immune system are the gut-associated lymphoid tissues (GALT), comprising lymphoid aggregates ([[Peyer's Patches - Anatomy & Physiology|Peyer's patches]] in the jejunum and ileum), individual intra-epithelial lymphocytes (IELs) and the mesenteric lymph nodes.  These lymphoid structures are in close contact with specialised 'follicle-associated' epithelium, a tissue that contains microfold (M) cells capable of sampling antigens from the intestinal lumen.  Many other cell types, including nuerones and the enterocytes themselves are able to contribute to immune responses through the production of cytokines and chemokines.  The B cells of the Peyers patches differentiate to produce antibodies of mainly the [[IgA]] isotype which is then transported into the intestinal lumen by a specific transporter.  This antibody is thought to control bacterial growth in the GI tract and also to help to maintain tolerance to benign antigens by complexing with them and reducing their local availability, a phenomenon called '''immune exclusion'''.

The major components of the mucosal immune system are the gut-associated lymphoid tissues (GALT), comprising lymphoid aggregates ([[Peyer's Patches - Anatomy & Physiology|Peyer's patches]] in the jejunum and ileum), individual intra-epithelial lymphocytes (IELs) and the mesenteric lymph nodes.  These lymphoid structures are in close contact with specialised 'follicle-associated' epithelium, a tissue that contains microfold (M) cells capable of sampling antigens from the intestinal lumen.  Many other cell types, including neurones and the enterocytes themselves are able to contribute to immune responses through the production of cytokines and chemokines.  The B cells of the Peyers patches differentiate to produce antibodies of mainly the [[IgA]] isotype which is then transported into the intestinal lumen by a specific transporter.  This antibody is thought to control bacterial growth in the GI tract and also to help to maintain tolerance to benign antigens by complexing with them and reducing their local availability, a phenomenon called '''immune exclusion'''.

The mucosal immune system of the host and the enteric bacterial flora interact constantly in the gastro-intestinal (GI) tract.  The host must remain tolerant of the enteric flora but must still be able to recognise and respond to potentially pathogenic organisms.  These apparently contradictory tasks are resolved by the ability of the immune system to [[Immune Tolerance - WikiBlood|'tolerate']] certain antigens if these are presented to macrophages and dendritic cells in an appropriate manner.  The major factors that enforce tolerance are immunosuppressive [[Cytokines - WikiBlood|cytokines]] (particularly interleukin 10 and transforming growth factor beta) and immunoregulatory clades of T lymphocytes, although the exact mechanisms by which tolerance is actually achieved are the subject of much research and debate.  '''Most of the recent theories regarding ARD suggest that it results from alterations in the interaction between the mucosal immune system and the enteric flora, particularly a loss of immune tolerance to commensal bacteria.'''

The mucosal immune system of the host and the enteric bacterial flora interact constantly in the gastro-intestinal (GI) tract.  The host must remain tolerant of the enteric flora but must still be able to recognise and respond to potentially pathogenic organisms.  These apparently contradictory tasks are resolved by the ability of the [[Immune Tolerance|immune system to 'tolerate']] certain antigens if these are presented to macrophages and dendritic cells in an appropriate manner.  The major factors that enforce tolerance are immunosuppressive [[Cytokines|cytokines]] (particularly interleukin 10 and transforming growth factor beta) and immunoregulatory clades of T lymphocytes, although the exact mechanisms by which tolerance is actually achieved are the subject of much research and debate.  '''Most of the recent theories regarding ARD suggest that it results from alterations in the interaction between the mucosal immune system and the enteric flora, particularly a loss of [[Immune Tolerance|immune tolerance]] to commensal bacteria.'''

*When the serum antibody isotype concentrations were measured in different breeds of dog, normal German shepherd dogs were found to have lower serum concentrations of [[IgA]] than dogs of other breeds<ref>Batt RM, Barnes A, Rutgers HC, Carter SD. '''Relative IgA deficiency and small intestinal bacterial overgrowth in German shepherd dogs.''' ''Res Vet Sci. 1991 Jan;50(1):106-11.''</ref>.  It was suggested that this relative deficiency would prevent affected animals from controlling bacterial population size in the GI tract and lead to SIBO.  Another suggestion is that these animals would be less tolerant of the bacterial flora because the immune exclusion function of [[IgA]] would not be fulfilled.  Several efforts were then made to determine whether there was also a local intestinal deficiency in IgA in normal German shepherd dogs and measurement of faecal concentrations of the isotype produced conflicting results, with one study suggesting that its concentration was not significantly different from that of other breeds <ref>Peters IR, Calvert EL, Hall EJ, Day MJ. '''Measurement of immunoglobulin concentrations in the feces of healthy dogs.''' ''Clin Diagn Lab Immunol. 2004 Sep;11(5):841-8.''</ref> and another indicating that this was the case <ref>Littler RM, Batt RM, Lloyd DH. '''Total and relative deficiency of gut mucosal IgA in German shepherd dogs demonstrated by faecal analysis''' ''Vet Rec. 2006 Mar 11;158(10):334-41.''</ref>.  Since German shepherd dogs were found to have normal numbers of IgA positive plasma cells in the GALT<ref>German AJ, Hall EJ, Day MJ. '''Relative deficiency in IgA production by duodenal explants from German shepherd dogs with small intestinal disease.''' ''Vet Immunol Immunopathol. 2000 Aug 31;76(1-2):25-43.''</ref>, further work was directed at assessing whether the genes encoding the IgA transporter components are expressed correctly in this breed.  By measuring the levels of messenger RNA in intestinal biopsy samples, it was later shown that the transporter and its related genes are expressed normally <ref>Peters IR, Helps CR, Calvert EL, Hall EJ, Day MJ. '''Measurement of messenger RNA encoding the alpha-chain, polymeric immunoglobulin receptor, and J-chain in duodenal mucosa from dogs with and without chronic diarrhea by use of quantitative real-time reverse transcription-polymerase chain reaction assays.''' ''Am J Vet Res. 2005 Jan;66(1):11-6.''</ref>.  The degree to which relative IgA deficiency contributes to ARD in German shepherd dogs is currently unclear and this hypothesis contradicts the next, which suggests that a break in tolerance (partly manifesting as an increase in IgA production) underlies ARD.

*When the serum antibody isotype concentrations were measured in different breeds of dog, normal German shepherd dogs were found to have lower serum concentrations of [[IgA]] than dogs of other breeds<ref>Batt RM, Barnes A, Rutgers HC, Carter SD. '''Relative IgA deficiency and small intestinal bacterial overgrowth in German shepherd dogs.''' ''Res Vet Sci. 1991 Jan;50(1):106-11.''</ref>.  It was suggested that this relative deficiency would prevent affected animals from controlling bacterial population size in the GI tract and lead to SIBO.  Another suggestion is that these animals would be less tolerant of the bacterial flora because the immune exclusion function of [[IgA]] would not be fulfilled.  Several efforts were then made to determine whether there was also a local intestinal deficiency in IgA in normal German shepherd dogs and measurement of faecal concentrations of the isotype produced conflicting results, with one study suggesting that its concentration was not significantly different from that of other breeds <ref>Peters IR, Calvert EL, Hall EJ, Day MJ. '''Measurement of immunoglobulin concentrations in the feces of healthy dogs.''' ''Clin Diagn Lab Immunol. 2004 Sep;11(5):841-8.''</ref> and another indicating that this was the case <ref>Littler RM, Batt RM, Lloyd DH. '''Total and relative deficiency of gut mucosal IgA in German shepherd dogs demonstrated by faecal analysis''' ''Vet Rec. 2006 Mar 11;158(10):334-41.''</ref>.  Since German shepherd dogs were found to have normal numbers of IgA positive plasma cells in the GALT<ref>German AJ, Hall EJ, Day MJ. '''Relative deficiency in IgA production by duodenal explants from German shepherd dogs with small intestinal disease.''' ''Vet Immunol Immunopathol. 2000 Aug 31;76(1-2):25-43.''</ref>, further work was directed at assessing whether the genes encoding the IgA transporter components are expressed correctly in this breed.  By measuring the levels of messenger RNA in intestinal biopsy samples, it was later shown that the transporter and its related genes are expressed normally <ref>Peters IR, Helps CR, Calvert EL, Hall EJ, Day MJ. '''Measurement of messenger RNA encoding the alpha-chain, polymeric immunoglobulin receptor, and J-chain in duodenal mucosa from dogs with and without chronic diarrhea by use of quantitative real-time reverse transcription-polymerase chain reaction assays.''' ''Am J Vet Res. 2005 Jan;66(1):11-6.''</ref>.  The degree to which relative IgA deficiency contributes to ARD in German shepherd dogs is currently unclear and this hypothesis contradicts the next, which suggests that a break in tolerance (partly manifesting as an increase in IgA production) underlies ARD.

**[[Lymphangiectasia]] leads to increased luminal concentrations of fat and protein.

**[[Lymphangiectasia]] leads to increased luminal concentrations of fat and protein.

**[[Villus atrophy with intact/hypertrophic crypt glands|Villous atrophy]] leads to the loss of digestive enzymes on the brush borders of enterocytes.

**[[Villus atrophy with intact/hypertrophic crypt glands|Villous atrophy]] leads to the loss of digestive enzymes on the brush borders of enterocytes.

**[[Biliary Tract - Obstruction|Extrahepatic Biliary Obstruction]] leads to an inability to digest and absorb fat because bile salts do not pass into the intestine.

**[[Biliary Tract Obstruction|Extrahepatic Biliary Obstruction]] leads to an inability to digest and absorb fat because bile salts do not pass into the intestine.

**Congenital deficiencies of brush border enzymes are very rare in animals.

**Congenital deficiencies of brush border enzymes are very rare in animals.

*Altered GI motility causing changes in the population density of enteric microflora

*Altered GI motility causing changes in the population density of enteric microflora

Primary ARD is generally diagnosed where there is a consistent signalment, history and clinical presentation and no other apparent underlying disease.  In secondary ARD, the clinical signs may be difficult to separate from those of the underlying disease, especially in animals with maldigestion/malabsorption.  The underlying disease is usually treated as a priority and the ARD may then resolve or it may require treatment with antibiotics.  

Primary ARD is generally diagnosed where there is a consistent signalment, history and clinical presentation and no other apparent underlying disease.  In secondary ARD, the clinical signs may be difficult to separate from those of the underlying disease, especially in animals with maldigestion/malabsorption.  The underlying disease is usually treated as a priority and the ARD may then resolve or it may require treatment with antibiotics.  

===Clinical Signs===

===Clinical Signs===

German Shepherd dogs with idiopathic ARD may show the following clinical signs:

German Shepherd dogs with idiopathic ARD may show the following clinical signs:

*Weight loss

*Weight loss

*Failure to thrive

*Failure to thrive

*[[Stomach and Abomasum Consequences of Gastric Disease - Pathology|Vomiting]]

*[[Vomiting|Vomiting]]

*Variable appetite

*Variable appetite

*Borborygmi

*Borborygmi

===Laboratory Tests===

===Laboratory Tests===

Ideally, full routine routine haematology, biochemistry, urinalysis, faecal bacteriology and parasitology, diagnostic imaging and gastroduodenoscopy should be performed to identify any underlying disease.  A trypsin-like immunoassay (TLI) can be used diagnose [[Exocrine Pancreatic Insufficiency|exocrine pancreatic insufficiency (EPI)]].   

Ideally, full routine routine haematology, biochemistry, urinalysis, faecal bacteriology and parasitology, diagnostic imaging and gastroduodenoscopy should be performed to identify any underlying disease.  A trypsin-like immunoassay (TLI) can be used to diagnose [[Exocrine Pancreatic Insufficiency|exocrine pancreatic insufficiency (EPI)]].   

Traditionally, the gold standard direct test for diagnosing ARD has been '''culture of duodenal juice''' collected during endoscopy.  Unfortunately, this is an expensive test and it is rarely available.  However the major complaint to be made about duodenal juice culture is that it is currently not possible to define a normal control result in dogs <ref name="two">nothing</ref><ref name="three">German AJ, Day MJ, Ruaux CG, Steiner JM, Williams DA, Hall EJ. '''Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs.''' ''J Vet Intern Med. 2003 Jan-Feb;17(1):33-43.''</ref> and cats.  Traditionally, bacterial numbers greater than 10e5 CFU/ml juice with anaerobes greater than 10e4 CFU/ml were considered to be diagnostic of ARD.

Traditionally, the gold standard direct test for diagnosing ARD has been '''culture of duodenal juice''' collected during endoscopy.  Unfortunately, this is an expensive test and it is rarely available.  However the major complaint to be made about duodenal juice culture is that it is currently not possible to define a normal control result in dogs <ref name="two">nothing</ref><ref name="three">German AJ, Day MJ, Ruaux CG, Steiner JM, Williams DA, Hall EJ. '''Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs.''' ''J Vet Intern Med. 2003 Jan-Feb;17(1):33-43.''</ref> and cats.  Traditionally, bacterial numbers greater than 10e5 CFU/ml juice with anaerobes greater than 10e4 CFU/ml were considered to be diagnostic of ARD.

Indirect tests such as serum '''folate''' and '''cobalamin''' concentrations have been used to give an indication of the bacterial population in small intestine.  Some species of bacteria may increase the level of serum folate concentration or decrease serum cobalamin concentration, or both. The sensitivity of these tests (~65%) is low and therefore their use in the diagnosis of ARD is questionable <ref name="three">nothing</ref>.  Folate is absorbed in the jejunum and severe jejunal disease (such as [[Inflammatory Bowel Disease|inflammatory bowel disease]] may decrease serum folate concentration.  Cobalamin associates with '''Intrinsic Factor''' produced in the stomach and pancreas of dogs and the pancreas of cats and this complex is absorbed in the ileum.  Pancreatic disease may reduce the production of intrinsic factor and ileal disease may reduce the absorption of the complex.  Cobalamin deficiency may cause villous atrophy and, in severe cases, non-regenerative macrocytic anaemia due to a failure of red blood cell nuclear maturation (the equivalent of pernicious anaemia in humans).  An documented deficiency in cobalamin should therefore be treated with B vitamin injections.

Indirect tests such as serum '''folate''' and '''cobalamin''' concentrations have been used to give an indication of the bacterial population in small intestine.  Some species of bacteria may increase the level of serum folate concentration or decrease serum cobalamin concentration, or both. The sensitivity of these tests (~65%) is low and therefore their use in the diagnosis of ARD is questionable <ref name="three">nothing</ref>.  Folate is absorbed in the jejunum and severe jejunal disease (such as [[Inflammatory Bowel Disease|inflammatory bowel disease]]) may decrease serum folate concentration.  Cobalamin associates with '''Intrinsic Factor''' produced in the stomach and pancreas of dogs and the pancreas of cats and this complex is absorbed in the ileum.  Pancreatic disease may reduce the production of intrinsic factor and ileal disease may reduce the absorption of the complex.  Cobalamin deficiency may cause villous atrophy and, in severe cases, non-regenerative macrocytic anaemia due to a failure of red blood cell nuclear maturation (the equivalent of pernicious anaemia in humans).  An documented deficiency in cobalamin should therefore be treated with B vitamin injections.

The concentration of serum '''unconjugated bile acids''' is increased in ~15% of animals with ARD.  Intestinal bacteria deconjugate bile acids and these are then reabsorbed in the ileum to complete the enterohepatic circulation.  Unconjugated bile acids cannot be so easily removed from the portal blood by the liver as conjugated acids and they therefore reach high blood concentrations.  Unconjugated bile acids may also be elevated with other GI diseases and even in animals that have no apparent signs of GI disease <ref name="three">nothing</ref>.

The concentration of serum '''unconjugated bile acids''' is increased in ~15% of animals with ARD.  Intestinal bacteria deconjugate bile acids and these are then reabsorbed in the ileum to complete the enterohepatic circulation.  Unconjugated bile acids cannot be so easily removed from the portal blood by the liver as conjugated acids and they therefore reach high blood concentrations.  Unconjugated bile acids may also be elevated with other GI diseases and even in animals that have no apparent signs of GI disease <ref name="three">nothing</ref>.

==Prognosis==

==Prognosis==

For cases of secondary ARD, the prognosis depends on the underlying cause and success of treatment.  For cases of idiopathic ARD, the prognosis is guarded and many of them are likely to relapse when treatment is stopped, which may require prolonged or life-long treatment.  Some cases, however, do resolve and only require short term treatment.

For cases of secondary ARD, the prognosis depends on the underlying cause and success of treatment.  For cases of idiopathic ARD, the prognosis is guarded and many of them are likely to relapse when treatment is stopped, which may require prolonged or life-long treatment.  Some cases, however, do resolve and only require short term treatment.

==References==

==References==

*Hall, E.J, Simpson, J.W. and Williams, D.A. (2005) '''BSAVA Manual of Canine and Feline Gastroenterology (2nd Edition)''' ''BSAVA''

*Hall, E.J, Simpson, J.W. and Williams, D.A. (2005) '''BSAVA Manual of Canine and Feline Gastroenterology (2nd Edition)''' ''BSAVA''

*Nelson, R.W. and Couto, C.G. (2009) '''Small Animal Internal Medicine (Fourth Edition)''' ''Mosby Elsevier''.

*Nelson, R.W. and Couto, C.G. (2009) '''Small Animal Internal Medicine (Fourth Edition)''' ''Mosby Elsevier''.

[[Category:Intestines,_Small_and_Large_-_Pathology]]

[[Category:Intestines,_Small_and_Large_-_Pathology]]

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[[Category:Intestinal Diseases - Dog]][[Category:Intestinal Diseases - Cat]]

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