Genetic Complexity of Cataracts Hampers Efforts to Identify Causative Mutations

Twenty-seven years later, Sandy Jessop still remembers her Siberian Husky "Dax" battling inflammatory bowel disease. At 18 months of age, Dax, who was Jessop's first Siberian Husky, began having chronic soft stools and losing weight, classic signs of the gastrointestinal disease.

The veterinarian suspected inflammatory bowel disease (IBD), a disorder first recognized in dogs around the time Dax was diagnosed. Resolving the diarrhea and finding an appropriate diet that Dax could tolerate was a long, difficult process.

Inflammatory bowel disease consists of a group of poorly defined gastro­in­testinal disorders that cause chronic intestinal inflammation. The cause is unknown but is likely multifactorial. The disease can affect the small intestine, large intestine or both. It also can involve the stomach.

"It was a process of elimination," says Jessop who formerly bred under the Jax Siberians prefix in Long Island, N.Y., and now breeds in Lenoir City, Tenn. "We tried different foods and different amounts. Since Dax was unable to absorb the nutrients from his food due to intestinal inflammation, he lost quite a bit of weight in the beginning."

Thus began lifelong management of the condition. "Dax stayed on medications for the rest of his life," Jessop says. "Fortunately, Dax led a fairly normal life despite having IBD."

Diarrhea and weight loss are common signs of IBD, but other signs are vomiting and anorexia. The condition affects dogs of all ages but is most commonly seen in dogs older than 2 years of age. The disease can be challenging to diagnose since diarrhea and vomiting can occur with other gastrointestinal diseases.

Though IBD is not highly prevalent in Siberian Huskies, it may be more common than previously thought. A 2006 Siberian Husky Health Foundation survey indicated that 1.2 percent of 3,725 dogs had IBD, of which 1.7 percent were males and 0.7 percent were females. The average age of onset was 2 years.

Among breeds considered at increased risk for IBD are Basenji, Boxer, Chinese Shar-Pei, French Bulldog, German Shepherd Dog, Labrador Retriever and Soft Coated Wheaten Terrier. The higher incidence in particular breeds suggests that IBD may have a genetic predisposition.

"Definitely, there is a genetic component," says Kathleen Stryeski, D.V.M., a trustee of the Siberian Husky Health Foundation. "But other factors, such as diet, parasites and bacterial infections, may be involved as well."

Karin Allenspach, Dr.med.vet., Ph.D., DECVIM-CA, a scientist studying IBD at the University of London Royal Veterinary College, agrees. "It is likely that IBD has genetic and environmental causes," she says.

"The latest research shows that some genetic mutations in German Shepherd Dogs and Boxers predispose them to greater susceptibility for development of IBD. Other factors, such as diet and possibly exposure to infectious agents, could exacerbate disease."

Researchers at Iowa State University College of Veterinary Medicine are investigating the genetic profile of the disease to determine whether they can identify a hereditary component. Meanwhile, breeders and owners must learn to cope with caring for dogs with IBD.

Seeking a Genetic Basis

Investigators at Iowa State Univer­sity are delving into the genetics of inflammatory bowel disease, trying to determine which genes may be involved in the initiation and progression of chronic intestinal inflammation. "There's emerging scientific data that suggest that perhaps some of the breeds at risk have fundamental genetic alterations that make them more susceptible to intestinal inflammation," says Albert Jergens, D.V.M., Ph.D., professor of veterinary clinical sciences.

Jergens and his research team are focusing on intestinal gene profiles associated with intestinal inflammation and altered bacterial composition in dogs with IBD. Their study aims to identify key genetic factors that contribute to IBD and to characterize progression of the disease to help predict a dog's response to specific treatments.

"My group is investigating the gene expression patterns in diseased intestinal tissues to unravel the cause and progression of intestinal inflammation," Jergens says. "We hope to provide a framework for identifying genes that make some breeds more susceptible to IBD."

The study involves looking at differences in gene expression that may help pinpoint potential triggers for disease, as well as the pathways that mediate the inflammatory process. "The value in taking a look at gene profiles is that it will help us hopefully identify pathways of inflammation, maybe distinct gene signatures that are reflective of IBD versus other causes for intestinal inflammation," he says.

Additionally, the research team is analyzing the compositional changes in the intestinal bacteria of dogs with IBD in an effort to better define the complex bacterial populations in a dog's intestines. "We are using a molecular technique called bacterial pyrosequencing that allows us to take DNA isolated from an intestinal biopsy or from feces to decipher which bacteria are present among the numerous and complex species found within the intestinal tract," Jergens says.

Abnormal Immune Response

Inflammatory bowel disease is believed to occur in dogs with an abnormal immune response that affects the gastrointestinal tract, causing intestinal hypersensitivity and poorly regulated immune responses. In normal dogs, mucosa lines the intestines and serves two functions: helping the body absorb nutrients and forming the intestinal mucosal barrier, which prevents bacteria, viruses and toxins from passing through the lining to the walls of the intestine.

That protective function creates mucosal immunity against infections and moderates immune function. Dogs diagnosed with IBD may be abnormally sensitive to an ingredient found in food or to normal intestinal bacteria, resulting in the production of harmful host responses. This sensitivity causes an increased number of white blood cells to accumulate within the intestinal wall, which perpetuates the inflammation.

Though inflammation is a normal immune response to infection or injury, in dogs with IBD, the response is exaggerated. IBD can cause damage to the stomach and intestines, which leads to chronic intestinal inflammation that interferes with digestion and food absorption.

Since signs of IBD are similar to other gastrointestinal conditions, it can be difficult to diagnose. "A diagnosis of IBD is reached after all other causes have been eliminated," Allenspach says. "The signs are vague and unspecific, and it is a common disease. We see approximately five cases per week at the Royal Veterinary College, about 30 percent of our total caseload in internal medicine."

Diagnosis is made through analysis of a dog's history and physical condition. Extensive testing is used to rule out parasite infestation, bacterial and viral infections, pancreatic deficiencies and food sensitivity. Testing may include:

  • Bacterial cultures;
  • Fecal, urine and blood tests including a complete blood count and serum chemistry;
  • Ultrasound and radiography to check for thickening of the intestinal wall; and
  • Biopsy of the intestine by endscopy or exploratory surgery, considered the best tool for definitive diagnosis.

Several forms of IBD occur in dogs. The most common are lymphocytic-plasmacytic IBD and eosinophilic IBD, both named for the type of inflammatory cells involved. Lymphocytic-plasmacytic IBD, which occurs in middle-aged and senior dogs, is diagnosed most often. The second most common form and most severe is eosinophilic IBD. The other forms are regional granulomatous IBD, a rare type, and suppurative or neutrophilic IBD.

Signs vary based on whether IBD affects the upper GI tract, consisting of the stomach and small intestine, or the lower GI tract, the large intestine. Upper GI signs include vomiting, diarrhea, weight loss, dark stools, and gas and loud digestive sounds. Lower GI signs include vomiting, frequent defecation with small volume, straining to defecate, and blood or mucous in the stool.

Managing Signs of Disease

Once inflammatory bowel disease is diagnosed in dogs, the condition is managed, not cured. Medications and diet modification are used to help treat gastrointestinal inflammation.

"Most of my IBD patients are on a special elimination diet and also need long-term immunosuppressive drugs," Stryeski says.

Medications used to treat IBD include immunosuppressive steroids, which decrease inflammation and inhibit the immune system from producing new inflammatory cells. Anti­biotics also may be prescribed to reduce bacteria in the dog's intestines, which may reduce inflammation as well.

Diet is one of the most important factors in managing IBD. "Usually, veterinarians will prescribe an elimination diet — a diet containing a protein that the dog has never eaten before," Allenspach says.

Elimination diets can determine if signs are due to an allergic reaction or sensitivity to something the dog is eating. Finding the right protein is key because the immune system is believed to be most responsive to proteins in the diet.

"Food sensitivities, such as reactions to meat protein, food additives, food preservatives, wheat gluten or milk products, are common," Stryeski says. "Veterinarians usually recommend trying a hypoallergenic dog food to see if a dog responds positively to a novel or hydrolyzed protein. It is important to follow the veterinarian's recommendation to ensure dogs are fed a complete and balanced diet that offers proper caloric intake for an individual animal."

Food trials begin by feeding a single protein and single carbohydrate source that the dog has not been exposed to in the past. The protein source may be duck, rabbit or venison, and the carbohydrate may come from potato if the dog has never eaten these foods in the past. Omega-3 fatty acids from fish oil can be included to control intestinal inflammation. Alternatively, the veterinarian may prescribe a hydrolyzed protein in which the protein is enzymatically broken down to minimize the likelihood of the immune system responding adversely. Fat and gluten intake may be reduced, and additives and preservatives may be eliminated. Fiber may be increased or decreased depending on the dog's sites of intestinal inflammation. For example, a higher fiber diet may be fed when inflammation of the colon is suspected.

Dogs generally are fed several small meals daily. All other food sources, including treats, snacks, table scraps and flavored medications, should be eliminated. Food trials can be time-consuming and require strict adherence and careful monitoring. Often, several diets must be tried before finding the best one.

"Patience is important when you have a dog with this disease," Stryeski says. "Some dogs respond well to a hypoallergenic diet, but most dogs need the diet change plus medications long term to control the problem."

Dax was fortunate. Through Jessop's diligence with his diet and prescribed medications, his signs eventually re-solved. "It was relatively easy to adjust to," Jessop says.

Though Dax spent six years on the supplement and special diet before dying of osteosarcoma at age 7, IBD did not negatively impact his quality of life.

"He had a very good life," Jessop says.

Recognizing Signs of IBD

Inflammatory bowel disease (IBD) can be challenging to diagnose partly because signs of the disease can occur in other gastrointestinal disorders. Among the common signs are:

  • Vomiting
  • Diarrhea
  • Weight loss
  • Anorexia
  • Lack of or increased appetite
  • Blood or mucous in the stool
  • Loose and/or dark stools
  • Frequent defecation with smaller volume
  • Straining to defecate
  • Gas and other loud digestive sounds
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