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Antibiotic Responsive Diarrhoea (view source)
Revision as of 14:42, 21 July 2010
, 14:42, 21 July 2010no edit summary
===Idiopathic Antibiotic Responsive Diarrhoea===
===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.
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. 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.
*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 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.
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.'''
*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 name="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 name="one">nothing</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.
*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.
*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 name="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 name="one">nothing</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.
Research continues to attempt to describe the immunological and microbiological features of the disease.
===Secondary Antibiotic Responsive Diarrhoea===
===Secondary Antibiotic Responsive Diarrhoea===
In cases of secondary ARD, there is usually an underlying intestinal disorder, of which the most common are:
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
**[[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.
**[[Lymphangiectasia]] leads to increased luminal concentrations of fat and protein.
**[[Villous atrophy with intact/hypertrophic crypt glands|Villous atrophy]] leads to the loss of digestive enzymes on the brush borders of enterocytes.
**[[Villous 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.
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.
*Disturbances in mucosal permeability.
*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.
*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.
*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).
*Use of substrates that would normally be absorbed by the host, of which the most clinically significant is vitamin B12 (cyanocobalamin).
==Signalment==
==Signalment==
==Diagnosis==
==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.
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.
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:
*Chronic small intestinal diarrhoea
*Chronic '''small intestinal diarrhoea'''
*Weight loss
*Weight loss
*Failure to thrive
*Failure to thrive
===Trial Therapy===
===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:
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.
*Antiparasitic treatment to rule out helminths and protozoa (particularly ''[[Giardia duodenalis]]''. [[Anthelmintic Drugs|Fenbendazole]] is often used for this purpose.
*Antibacterial treatment with tylosin or metronidazole, continued for one month.
*Antibacterial treatment with [[Macrolides and Lincosamides|tylosin]] or [[Nitroimidazoles|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.
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.
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 <ref name="two">nothing</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. 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 ~65% 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.
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==
==Treatment==
As suggested by its name, the major treatment option for ARD is antimicrobial therapy.
===Idiopathic ARD===
===Idiopathic ARD===
*Antimicrobial for an initial period of 4 weeks
*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.
**A longer course may be required if the clinical signs relapse.
**Suitable drugs include [[Tetracyclines|oxytetracycline]], [[Macrolides and Lincosamides|tylosin]], [[Nitroimidazoles|metronidazole]]. [[Tetracyclines|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 [[Tetracyclines|oxytetracycline]]. [[Macrolides and Lincosamides|Tylosin]] and [[Nitroimidazoles|metronidazole]] may be more appropriate at targeting bacteria that are likely to be present in secondary ARD.
**Suitable drugs include [[Tetracyclines|oxytetracycline]], [[Macrolides and Lincosamides|tylosin]], [[Nitroimidazoles|metronidazole]]. [[Tetracyclines|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 [[Tetracyclines|oxytetracycline]]. [[Macrolides and Lincosamides|Tylosin]] and [[Nitroimidazoles|metronidazole]] may be more appropriate at targeting bacteria that are likely to be present in secondary ARD.
===Secondary ARD===
===Secondary ARD===
The underlying cause of the disease should be treated and the ARD should then resolve.
===Dietary modification===
===Dietary modification===
A highly digestible and fat restriction diet, with added prebiotics is recommended. This may be useful in both idiopathic and secondary ARD.
A highly digestible and fat restriction diet, with added prebiotics is recommended. Fructo-oligosaccharides. This may be useful in both idiopathic and secondary ARD.