Changes

==Description==

==Description==

'''Antibiotic responsive diarrhoea''' (ARD) describes a clinical syndrome which is associated with alterations in the population of enteric bacterial flora and in the response of the host immune system to these bacteria.  It may occur independently of any other apparent pathological process ('''idiopathic''') but it occurs commonly with a number of intestinal diseases ('''secondary''').  The term 'antibiotic responsive diarrhoea' has replaced the previous description of '''small intestinal bacterial overgrowth''' (SIBO) due to uncertainty over the level at which enteric bacteria could be said to be present in excessive numbers and because an increased number of bacteria is not always the cause of the clinical syndrome described.   

'''Antibiotic responsive diarrhoea''' (ARD) describes a clinical syndrome which is caused by alterations in the population of enteric bacterial flora and by changes in the response of the host immune system to these bacteria.  It may occur independently of any other apparent pathological process ('''idiopathic''') but it occurs commonly with a number of intestinal diseases ('''secondary''').  The term 'antibiotic responsive diarrhoea' has replaced the previous description of '''small intestinal bacterial overgrowth''' (SIBO) due to uncertainty over the level at which enteric bacteria could be said to be present in excessive numbers and because an increased number of bacteria is not always the cause of the clinical syndrome described.  The term SIBO is now sometimes taken to mean secondary ARD.   

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 'tolerate' certain antigens if these are presented to macrophages and dendritic cells in an appropriate manner.  A number of hypotheses have been advanced to explain idiopathic ARD that involve some alteration in this host-bacterial flora interaction.

A number of hypotheses have been advanced to explain the aetiology of idiopathic ARD and the balance of opinion has changed over time based on an evolving understanding of the mucosal immune system.

Dogs with idiopathic ARD have higher levels of some cytokines and greater numbers of CD4 T-cells in their intestinal mucosa, suggesting that ARD might occur due to a breakdown in the normal host tolerance of the microflora.

*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.  This led to a renewed interest in the mucosal immune system, the collective term for the cells and immune structures located in the GI tract.

In cases of idiopathic ARD, the only consistent clinical finding is responsiveness to antimicrobial therapy. This is found commonly, but not exclusively, in young [[Canine Breeds - WikiNormals #Pastoral Group|German Shepherd dogs]] and it has been suggested that this is associated with a deficiency in [[IgA]] or with another form of immune dysregulation in this breed.  In cases of secondary ARD, there is usually an underlying intestinal disorder, of which the most common are:

 

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 'tolerate' certain antigens if these are presented to macrophages and dendritic cells in an appropriate manner.  More 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.

 

*According to two studies, dogs with idiopathic ARD have higher levels of expression of some cytokines and greater numbers of IgA plasma cells and CD4 T-cells in their intestinal mucosa, suggesting that ARD might occur due to a breakdown in the normal host tolerance of the bacterial microflora<ref number="one">German AJ, Hall EJ, Day MJ. '''Immune cell populations within the duodenal mucosa of dogs with enteropathies.''' ''J Vet Intern Med. 2001 Jan-Feb;15(1):14-25.''</ref><ref>German AJ, Helps CR, Hall EJ, Day MJ. '''Cytokine mRNA expression in mucosal biopsies from German shepherd dogs with small intestinal enteropathies.''' ''Dig Dis Sci. 2000 Jan;45(1):7-17.''</ref>.  However, a later study using similar methods of reverse transcriptase polymerase chain reaction (PCR) suggested that there was no significant difference in cytokine levels between mucosal biopsy samples from normal dogs and those with SIBO<ref>Peters IR, Helps CR, Calvert EL, Hall EJ, Day MJ. '''Cytokine mRNA quantification in duodenal mucosa from dogs with chronic enteropathies by real-time reverse transcriptase polymerase chain reaction.''' ''J Vet Intern Med. 2005 Sep-Oct;19(5):644-53.''</ref>.  This discrepancy may relate to the nature of the method used to detect cytokine expression, as PCR gives an indication of expression levels at a single point in time and may not reflect the level at which these proteins are actually transcribed by intestinal cells.    The loss of immune tolerance theory is supported by the finding that dogs with ARD had reduced levels of two cytokines (tumour necrosis factor alpha and transforming growth factor beta) after receiving antibacterial treatment<ref number="one"></ref>, even though this therapy did not significantly reduce the number of intestinal bacteria that were present.  This finding could be explained by the fact that many of the antibiotics used in the treatment of ARD (particularly metronidazole and oxytetracycline) have immunomodulatory activity.   

 

In cases of secondary ARD, there is usually an underlying intestinal disorder, of which the most common are:

*Increased concentrations of small intestinal substrates resulting from failure of host digestion or absorption

*Increased concentrations of small intestinal substrates resulting from failure of host digestion or absorption

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

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

**Failure to produce gastric acid (achlorhydria) is rare in small animals, even with atrophic gastritis.  Gastric acid production may be suppressed by [[Gastroprotective Drugs|drugs that inhibit secretion]], such as ranitidine and omeprazole

**Failure to produce gastric acid (achlorhydria) is rare in small animals, even with atrophic gastritis.  Gastric acid production may be suppressed by [[Gastroprotective Drugs|drugs that inhibit secretion]], such as ranitidine and omeprazole

The consequences of ARD are numerous and these are only beginning to be explored fully.  They include:

The consequences of ARD are numerous and these are only beginning to be explored fully.  They include:

*Interference with fluid and nutritional absorption due to dysfunction of the enzymes located at the microvillous brush border.  Depending on the cause of the ARD, this may worsen any concurrent or underlying maldigestion or malabsorption.

*Interference with fluid and nutritional absorption due to dysfunction of the enzymes located at the microvillous brush border.  Depending on the cause of the ARD, this may worsen any concurrent or underlying maldigestion or malabsorption.

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 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 and cats.  The accepted figures for bacterial population density in the canine GI tract are based on extrapolations from similar studies in humans.     

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 and cats.  The accepted figures for bacterial population density in the canine GI tract are based on extrapolations from similar studies in humans.     

Indirect tests such as serum folate and cobalamin concentrations have been used to analyse the bacterial concentrations in small intestines.  Some species of bacteria may increase the level of serum folate concentration or decrease serum cobalamin concentration, or both. The sensitivity and specificity of this test is low and therefore their use in the diagnosis of ARD is questionable.

Indirect tests such as serum '''folate''' and '''cobalamin''' concentrations have been used to analyse the bacterial concentrations in small intestines.  Some species of bacteria may increase the level of serum folate concentration or decrease serum cobalamin concentration, or both. The sensitivity and specificity of this test is low and therefore their use in the diagnosis of ARD is questionable.

Serum unconjugated bile acids

Serum '''unconjugated bile acids'''

==Treatment==

==Treatment==

==References==

==References==

*Ettinger, S.J. and Feldman, E. C. (2000) '''Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat Volume 2''' (Fifth Edition) ''W.B. Saunders Company''.

*Ettinger, S.J. and Feldman, E. C. (2000) '''Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat Volume 2''' (Fifth Edition) ''W.B. Saunders Company''.

*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''