Genetic Research Of Inflammatory Bowel Disease May Lead To New Treatments

When a German Shepherd Dog experiences idiopathic diarrhea and vomiting, veterinarians generally suspect canine inflammatory bowel disease (IBD). This is because the breed is predisposed to the chronic gastrointestinal condition. A disease that occurs more commonly in middle-aged large-breed dogs, IBD cannot be cured. Veterinarians manage the condition using medications to address the signs.

Efforts to learn more about IBD in German Shepherd Dogs led to the recent discovery of polymorphisms in the TLR4 and TLR5 genes. The research was supported by the Morris Animal Foundation and the American German Shepherd Dog Charitable Foundation (AGSDCF).

Lead investigator Karin Allenspach,, Ph.D., head of the Clinical Investigation Center at The Royal Vet­erinary College of the University of London, says, "It appears German Shep­herd Dogs with chronic enteropathies have a distinctly different microbiome from healthy dogs, as well as from other breeds with IBD. This includes overrepresentation of certain traditionally labeled 'beneficial' bacteria in the duodenum, specifically sequences of the order of Lactobacilalles.

"We've made great progress to identify genetic predispositions underlying IBD in German Shepherd Dogs. We continue to analyze whether the mutation of an immune system protein is linked to the intestinal inflammation associated with IBD. If so, new treatments potentially could be developed. We also have identified antibodies specific for E. coli flagellin in dogs with IBD that are not present in unaffected dogs. This could lead to the development of a noninvasive diagnostic test for IBD."

An AKC Canine Health Foundation study supported by AGSDCF aims to determine whether a high-potency, multi-strain probiotic, known as VSL#3, reduces gastrointestinal inflammation associated with IBD. Primary investigator Albert E. Jergens, D.V.M., Ph.D., professor of veterinary clinical sciences at Iowa State University in Ames, says, "We are studying the clinical, microbiologic and anti-inflammatory effects of this probiotic in the treatment of IBD. Current treatments for IBD include anti-inflammatory drugs, some of which have serious side effects and do not address the underlying basis for disease, the altered microbial composition.

"Probiotics offer an attractive physiologic and nontoxic alternative that effectively protects against and treats IBD. VSL#3 has shown efficacy in the treatment of colitis in several rodent models of intestinal inflammation and in humans with ulcerative colitis and pouchitis. Unfortunately, there is limited clinical data defining treatment of canine IBD with any probiotic preparation."

The need for consistencies diagnosing and determining the severity of gastrointestinal diseases sparked the formation of the World Small Animal Veterinary Association (WSAVA) International GI Standardization Group in 2004. Ultimately, the group developed standards to be used by veterinarians when diagnosing IBD and other gastro­intestinal-related diseases.

Among the findings, the WASAVA standardization group determined that although the underlying cause of IBD remains unknown, accumulating evidence suggests that intestinal inflammation results from altered interaction between gut microbes and the mucosal immune system. Aggressive host immune responses directed against bacteria or their products likely play a central role in the pathogenesis of chronic mucosal inflammation.1

Diagnosing & Treating IBD

While diarrhea and vomiting are the most common signs of IBD, the disorder also may cause anorexia or loss of appetite, weight loss, and blood or mucous in the stool. With loss of appetite, a dog becomes lethargic and loses condition and coat. Signs are persistent, and by the time a veterinarian examines a dog with IBD, overall health condition may be poor.

"The clinician faced with a potential case of IBD usually performs an extensive workup to exclude extra gastrointestinal causes as well as treatable disorders, such as pancreatic diseases, chronic parasitic or bacterial infections, and tumors," Allenspach says.

An accurate diagnosis may require an endoscopic biopsy of the GI tract, although the WASAVA standardization group concluded that an endoscopy is not appropriate for every dog with chronic GI disease.1 A veterinarian looks for lesions caused by lymphoplasma cellular inflammation in the mucous layer of the GI tract. These can be seen in about half of cases.

"The intestinal lining is composed of cells with proteins on the surface," says Allenspach. "Some of the proteins are receptors that recognize microbes. If that protein is not functioning properly, it will tell the immune system to develop inflammation against the normal bacteria in the intestines, causing the diarrhea and vomiting that are characteristic of the disease."

After a tentative diagnosis of IBD is determined, the gold standard approach to treatment is a food trial with an elimination diet containing a novel or hydrolyzed protein. This is based on theories that IBD is caused by an allergic reaction or hypersensitivity to dietary antigens. If a food trial does not reduce signs of IBD, antibiotic treatment is tried for several weeks, followed by immunosuppressant and anti-inflammatory treatments.

Lymphocytic plasmacytic IBD, the type which German Shepherd Dogs are prone, is the most common. This type sometimes responds well to a four- to five-week course of antibiotics, such as metronidazole or tylosin. "These anti­biotics probably are effective because they change the gut microflora," Allenspach explains.

If antibiotics fail, the next step is anti-inflammatories, such as steroids, and immunosuppressants, which help eliminate intestinal inflammation. "Steroids can have significant side effects," says Allenspach, who is researching alternative medications. Cyclosporine, a drug used in humans to prevent organ transplant rejection, has shown excellent results without the side effects associated with steroid use, excessive thirst, urination and gastrointestinal ulcers, she says.

A Recurring Condition

Treating a dog with IBD often involves dealing with signs of disease that wax and wane. In late 2010, Ginny Altman of Shoreview, Minn., who breeds under the Rivaden prefix, took her 9-year-old male, CH Rivaden's Gunther Nibelung ("Gunther"), to the veterinarian for treatment of diarrhea and poor appetite.

"The veterinarian prescribed an antibiotic, metronidazole, which stopped the diarrhea," says Altman, the German Shepherd Dog Club of America recording secretary, health liaison, health award of merit certificate chair, and past president, and vice president of the American German Shepherd Dog Charitable Foundation. "When the diarrhea returned, I noticed lots of mucous and bright red blood in the stool."

Analysis of a fecal sample showed clostridia bacteria, which is common in dogs with IBD. Blood testing detected an elevated white blood cell count, indicating inflammation. The veterinarian prescribed an antibiotic, ciprofloxacin, and a probiotic. Though Gunther did not have much of an appetite, Altman continued feeding a lamb and rice diet. Initially, he responded but then relapsed again.

"We gave him more ciprofloxacin, but he didn't tolerate it well and stopped eating altogether," says Altman. "The veterinarian then switched Gunther to the antibiotic Tylan Powder, which he tolerated better. The diarrhea improved, and Gunther's appetite returned somewhat. Managing the consistency of Gunther's stools became our focus. If mucous returned, blood soon followed and Gunther had to go back on Tylan.

"A course of Tylan was followed by probiotics to normalize the intestinal bacteria. After several weeks, the stools were somewhat normal but soft and uniform. I have a background in health care, and I made the decision to test a method of control that works for some people with chronic colitis. I added psyllium fiber to Gunther's diet." That proved to be the key for Gunther. The addition of soluble fiber, such as psyllium, may help manage dogs that suffer from large-bowel diarrhea, while a low-fiber diet may be best for those with small-intestine diarrhea.

"The fiber I use should be given two hours before or after medications, such as antibiotics and probiotics, as they may interfere with its effectiveness," Altman says.

The protocol that works for Gunther is giving psyllium in the morning, pro­biotics in the evening and antibiotics when a recurrence occurs. Altman gives Gunther Purina Veterinary Diets Fortiflora brand canine nutritional supplement, containing Enterococcus faecium SF68, a live beneficial probiotic, sprinkled on his food each day. "In two years, since the initial episode, Gunther has had three relapses," says Altman. "When the last one occurred, he quickly responded to a 10-day course of antibiotics and then resumed the psyllium/probiotic protocol."

Understanding Breeding Implications

As breeders try to understand whether they should breed dogs with IBD, veterinary experts also grapple with the question. "It is too early to say that dogs with the mutation should be excluded from the breeding pool," Allenspach says. "It is probable that many dogs carry the mutation, but not all of them will get IBD. It is unlikely that one mutation is the single cause of the disease. There are environmental factors and probably other genetic factors that we haven't found yet."

In most breeds, the cause of IBD is likely not strictly genetic or environmental, Allenspach says. Affected dogs within a breed probably share one or more genetic mutations, but the presence of the mutation alone does not mean the dog will develop IBD.

"If the environmental triggers were known, they could be avoided so possibly a dog carrying the mutation would never develop the disease," says Allenspach. "This is an area needing to be studied. At this point, we really don't know."

Meanwhile, Allenspach advises breeders not to link every dog or every breed in the same category. "My belief is that there are different triggers in different breeds and thus different responses to treatment among the breeds as well as among different dogs," she says.

Purina appreciates the support of the German Shepherd Dog Club of America Inc. and particularly Ginny Altman, the GSDCA recording secretary, health liaison, health award of merit chair, and past president, 2004-2005, and vice president of the American German Shepherd Dog Charitable Founda­tion, in helping to identify topics for the Purina Pro Club German Shepherd Dog Update newsletter.

1 Washabau RJ, Day MJ, Willard MD, Hall EJ, Jergens AE, Mansell J, Minami T, Bilzer TW. Endoscopic, Biopsy, and Histopathologic Guide­lines for the Evaluation of Gastrointestinal Inflammation in Companion Animals. J Vet Intern Med. 2010;24:10-26.