Antibiotic Responsive Diarrhoea

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Also known as: Small Intestinal Bacterial Overgrowth — SIBO — ARD

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. Idiopathic ARD is particularly common in German shepherd dogs and much of the current research relates to this breed.

  • 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[1]. 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 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 '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 (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.

  • 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[2]. 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 [3] and another indicating that this was the case [4]. Since German shepherd dogs were found to have normal numbers of IgA positive plasma cells in the GALT[5], 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 [6]. 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.
  • 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[7][8]. 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[9]. 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[7], 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.

Research continues to attempt to describe the immunological and microbiological features of the disease.

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
    • Exocrine Pancreatic Insufficiency results in an inability to digest fat, protein and carbohydrate, leaving these substrates in the intestinal lumen. This is thought to be the major cause of secondary ARD
    • Lymphangiectasia leads to increased luminal concentrations of fat and protein.
    • 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, allowing leakage of substrates into the intestinal lumen.
  • 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, of which the most clinically significant is 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. As stated above, animals which apparently fulfill the microbiological criteria for ARD may not show any clinical signs of the syndrome. 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:

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 to 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 [1][10] 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 [10]. Folate is absorbed in the jejunum and severe jejunal disease (such as 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 [10].

Fermentation by some species of bacteria leads to the production of hydrogen. The gas is absorbed into the blood and excreted via the lungs on exhalation. Breath hydrogen levels can therefore be measured and the level should rise before a test meal would be expected to reach the colon, when hydrogen is produced normally after large intestinal bacterial fermentation. Increased breath hydrogen may also be found with lactose intolerance and conditions that cause an decreased intestinal transit time, delivering substrates to the colonic bacteria sooner than would normally be expected.

Treatment

As suggested by its name, the major treatment option for ARD is antimicrobial therapy.

Idiopathic Antibiotic Responsive Diarrhoea

Antimicrobial therapy should be instituted for an initial period of 4-6 weeks and the patient should then be reassessed to determine whether further treatment is necessary. Some dogs will improve spontaneously after this initial course, either because bacterial population dynamics have returned to a more stable form or because of maturation of the mucosal immune system. Animals that do not respond or which relapse after initial treatment may require long-term or permanent treatment.

Suitable drugs include oxytetracycline, tylosin and metronidazole. Oxytetracycline is sometimes preferred for the management of idiopathic ARD because it is cheap, easy to administer and can be used long-term. It does not cause reliable reductions in bacterial numbers in the small intestine and it may have immunomodulatory actions (as may tylosin and metronidazole). However, bacterial resistance develops quickly to oxytetracycline.

Many clinicians provide an anthelmintic (such as fenbendazole) concurrently to rule out infection with helminths and Giardia duodenalis.

Secondary Antibiotic Responsive Diarrhoea

The underlying cause of the disease should be treated and the ARD should then resolve.

Dietary modification

A highly digestible diet with high quality protein, low fibre content and low fat content should be used limit the availability of excess substrate for bacterial growth. Fructo-oligosaccharides may be added to the diet as 'pre-biotics' to encourgae the growth of only normal host flora and, in one study of their use in German shepherd dogs, they produced a reduction in bacterial numbers on duodenal juice culture [11].

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.


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References

  1. 1.0 1.1 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 7.0 7.1 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.
  8. 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.
  9. 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.
  10. 10.0 10.1 10.2 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.
  11. Willard MD, Simpson RB, Delles EK, Cohen ND, Fossum TW, Kolp D, Reinhart G. Effects of dietary supplementation of fructo-oligosaccharides on small intestinal bacterial overgrowth in dogs. Am J Vet Res. 1994 May;55(5):654-9.
  • 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.




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