Antibiotic Responsive Diarrhoea

Description

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.

Idiopathic Antibiotic Responsive Diarrhoea

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.

• 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.

• IgA deficiency of German shepherd dogs - unfinished.

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. 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. 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, 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.

Secondary Antibiotic Responsive Diarrhoea

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
  • Lymphangiectasia leads to increased luminal concentrations of fat and protein.
  • Exocrine Pancreatic Insufficiency results in an inability to digest fat, protein and carbohydrate, leaving these substrates in the intestinal lumen.
  • Villous atrophy leads to the loss of digestive enzymes on the brush borders of enterocytes.
  • 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.
• Altered GI motility causing changes in the population density of enteric microflora
  • Partial intestinal obstruction due to the presence of foreign bodies, neoplastic masses or strangulations.
  • Paralytic ileus
  • Anatomical disorders which may be congenital or acquired (as with surgical removal of the ileo-caeco-colic junction allowing reflux of bacteria from the large to the small intestine.)
• Reduction in the concentration of factors that usually act to limit bacterial population growth
  • Failure to produce gastric acid (achlorhydria) is rare in small animals, even with atrophic gastritis. Gastric acid production may be suppressed by drugs that inhibit secretion, such as ranitidine and omeprazole

Pathophysiology

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.
• Disturbances in mucosal permeability.
• Deconjugation of bile acids which reduces the ease with which they are removed from the circulation by the liver during enterohepatic recirculation. Hepatic bile acid synthesis must therefore increase to compensate. Deconjugated bile acids also irritate the colonic mucosa causing colitis and diarrhoea.
• Hydroxylation of fatty acids, which like deconjugated bile acids, are irritant to the colonic mucosa and cause colitis and diarrhoea.
• Use of substrates that would normally be absorbed by the host, particularly vitamin B12 (cyanocobalamin).

Signalment

Idiopathic ARD is common in young German Shepherd dogs but secondary ARD may occur in any breed or age of dog depending on the underlying cause. ARD is thought to occur in cats but it is not well characterised in this species. It is suggested that the condition is much more common than previously suspected.

Diagnosis

ARD represents a very large diagnostic challenge as the condition is still difficult to define and because no single test offers an acceptable level of sensitivity or specificity. The manifestations of the disease are also extremely heterogenous, with some animals showing some of the recognised diagnostic features but not others. The condition is frequently suspected in animals that are thought to have one of the diseases that leads to secondary ARD but it is rarely confirmed by any meaningful test. This approach is far from ideal as it probably results in the overuse of antibiotics where they may not be necessary.

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

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

• Chronic small intestinal diarrhoea
• Weight loss
• Failure to thrive
• Vomiting
• Variable appetite
• Borborygmi
• Abdominal discomfort

Trial Therapy

Ideally, if the history and clinical signs provide no obvious localisation, a full diagnostic investigation is recommended to define the cause of the condition. This would involve analysis of blood samples, examination of faecal and urine samples, diagnostic imaging and endoscopy and is therefore beyond the reach of most clients. Although less clinically rigorous, it may be justified to begin trial antimicrobial (antibacterial and antiparasitic) therapy at the outset instead to determine whether the condition does respond. This approach may still be appropriate if further diagnostic work is intended as the presence of secondary ARD may impede the diagnosis of any underlying cause. A suitable regime would include:

• Antiparasitic treatment to rule out helminths and protozoa. Fenbendazole is often used for this purpose.
• Antibacterial treatment with tylosin or metronidazole, continued for one month.

If this treatment does not result in any improvement, further investigations would be indicated to detect a primary GI disease. If the clinical signs respond to the therapy but recur when this is withdrawn, a diagnosis of ARD can be made with some confidence.

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 (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.

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

Treatment

Idiopathic ARD

• Antimicrobial for an initial period of 4 weeks
  • A longer course may be required if the clinical signs relapse. This holds true for most cases of ARD.
  • Suitable drugs include oxytetracycline, tylosin, metronidazole. oxytetracycline is the drug of first choice for idiopathic ARD but its use for secondary ARD is controversial. In addition, resistance is fast to develop with oxytetracycline. Tylosin and metronidazole may be more appropriate at targeting bacteria that are likely to be present in secondary ARD.

Secondary ARD

Treat the underlying cause of ARD

Dietary modification

A highly digestible and fat restriction diet, with added prebiotics is recommended. This may be useful in both idiopathic and secondary ARD.

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 a prolonged or life-long treatment. Some cases, however, do resolve and only require a short term treatment.

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.
• 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.