Managing IBD and diarrhea in adult cats (Proceedings)

Inflammatory bowel disease overview

Feline inflammatory bowel disease (IBD) is the term applied to a collection of feline enteropathies that are characterized by the infiltration of the gastrointestinal mucosa by inflammatory cells. The cellular infiltrate is composed of variable populations of lymphocytes, plasma cells, eosinophils and neutrophils that may be distributed throughout the GI tract. In severely affected cats, the infiltrate may be accompanied by changes in the mucosal architecture such as villus atrophy, fusion, fibrosis and lymphangiaectasia.  Despite the fact that this condition appears to be a very common clinical problem, little is known about the etiology and pathogenesis, or the local and systemic consequences of IBD such as development of lymphoma or nutritional deficiencies.  Further, the nature of the inflammation is just beginning to be characterized beyond the visible changes in gross histopathology (e.g. what happens to cytokines and other mediators of inflammation, what is the role of the bacterial flora is either cause or progression, etc).  This paper will review what is known, and especially focus on the role of commensal and pathogenic intestinal bacteria and diet in the diagnosis and management of feline IBD.

Inflammatory bowel disease (IBD) in cats is a commonly diagnosed condition of adult cats that is characterized by persistent clinical signs consistent with GI disease (vomiting, anorexia, weight loss or diarrhea) that occur concurrently with histologic evidence of mucosal inflammation.  The median age for cats presenting with IBD is around seven years and most cats are presented with a history of these signs occurring intermittently for weeks to years. Purebred cats such as Siamese and Abyssinian cats may be over-represented, but definitive breed predilections are not reported. There is no reported predilection based on sex. Because these clinical signs can be associated with a wide variety both primary GI and extra-GI diseases, it is important consider broad groups of differentials and obtain a minimum data base (CBC, biochemistry panel and urinalysis) until you have enough information in your data collection to narrow the list.  There are a number of possible causes of intestinal inflammation that must be considered in the diagnostic process.  IBD is a diagnosis of exclusion, so infectious, food sensitivity/intolerance, endocrinopathies such as hyperthyroidism, parasitic, or neoplastic diseases of the intestinal tract must all be considered.  These should be investigated thoroughly prior to settling on the diagnosis of idiopathic IBD and instituting a treatment plan that includes chronic immunosuppressive therapy. Food sensitivity or intolerances can be particularly difficult to distinguish from IBD or other intestinal disorders and will cause identical clinical signs and histopathologic changes in the bowel.  Thus, appropriate food trials are an extremely important component of both diagnosis and therapy of cats with GI disease or suspected IBD. The problem is that there is no specific approach to selection of diets for a food trial, other attempting to make a determination whether or not a true food allergy or food intolerance (the more common situation) is occurring. In addition to food trials, the diagnostic plan for a cat with chronic diarrhea should include multiple fecal examinations or therapeutic deworming trials with broad spectrum agents such as fenbendazole, assessment of thyroid and FeLV/FIV status, and GI functional assessment (PLI, TLI, cobalamin and folate measurement).  Many cats with IBD have concurrent inflammation in their liver and pancreas – a phenomenon called triaditis.  Because chronic pancreatitis causes few distinguishing signs and can be quite difficult to diagnose with laboratory tests alone, a degree of clinical suspicion is necessary to carefully assess these cats for this possibility.  Serum cobalamin levels in cats commonly decrease with severe bowel disease or pancreatitis, so it is very important to assess cobalamin status in all cats with GI disease.  Further, in cats with hypocobalaminemia, the diarrhea will not resolve until replacement therapy is instituted.  Cobalamin therapy in some cats may be lifelong, while in others, once the clinical disease resolves the supplementation can be discontinued.  In older cats with concurrent chronic pancreatitis, decreases in production of pancreatic enzymes (detected by measuring TLI) can also result in reduced digestion of foods, development of bacterial dysbiosis, and subsequent weight loss and diarrhea.  Thus, measurement of TLI in cats with chronic diarrhea is an important tool for assessment. In addition to laboratory evaluation of cats with possible IBD, radiographs and ultrasound are important in the overall assessment.   Abdominal radiographs and ultrasound will not prove that a cat has IBD, but they are essential for ruling out other problems (i.e. intestinal foreign bodies, intussusception, finding masses, assessing other organs – especially liver and pancreas).  Many cats with intestinal inflammation will have thickened loops of bowel, changes in bowel layering or evidence of mesenteric lymphadenopathy.  These changes are not indicative of a specific cause, but are further confirmation of intestinal disease that requires further assessment.  One important piece of information that can be obtained via abdominal ultrasound is the location or severity of the lesions, thus suggesting whether or not endoscopy or possibly abdominal exploratory would be the better diagnostic next step.  Because intestinal biopsies, either obtained endoscopically or at an exploratory surgery are still essential to confirm the presence of inflammatory infiltrates, this step can be an important part of the process.  That being said, there are a number of problems with using the histopathologic changes to diagnose IBD.  First, there are well documented problems with correlation of a pathologist's interpretation of inflammation in the GI biopsy with the actual disease – in other words, the presence of lymphocytes and plasma cells in the wall of the gut does not mean the problem is idiopathic, it does not necessarily correlate with the cytokine expression or degree of clinical disease, and it does not mean that you can accurately differentiate IBD from lymphoma.   As a result, standards for histopathologic interpretation of biopsies have been recommended to help increase the utility and consistency of interpreting GI histopath among pathologists.  The interested reader is referred to the WSAVA Guidelines for GI Histopathology for more information.  However, because small cell (lymphocytic, low grade) lymphoma is can be extremely difficult to distinguish from IBD, the disease can be focal (only in the jejunum or ileum), or can be found only in the deeper layers of the intestinal wall (submucosa or muscularis), endoscopic biopsies (if not taken from appropriate sites or in adequate depth) will miss these lesions.  In cats that are not responding to appropriate therapy, or were responding to therapy, but are now losing weight or having a recurrence of diarrhea despite therapy, the possibility of lymphoma should be reconsidered.  The interested reader is referred to several recent reviews on this subject for more details specific to GI lymphoma and its management. 

Inflammation and bacteria

The basis of the immunological response in feline IBD is unknown, and it remains to be determined if the inflammatory response is due to the presence of undefined pathogens or an inappropriate response to dietary antigens or intra-luminal commensal bacteria. Determining the cytokine and immune cell population in IBD is important from both a pathological and a therapeutic standpoint as treatment of IBD in cats is non-specific and is based on dietary modification, antibiotics, and suppression of the immune system. Recent studies in people and experimental animals have resulted in the development of drugs and the identification of bacteria e.g. Lactobacillus spp that modulate inflammation, some of which are now in clinical trials e.g. infliximab, etanercept and probiotics for the treatment of human Crohn's disease. Simpson and coworkers are one group of investigators seeking to determine the effect of mucosal bacteria and relationship to cytokine responses in inflammation in the bowel.  In their recent work, intestinal biopsies were collected from 17 cats undergoing diagnostic investigation of signs of gastrointestinal disease, and 10 healthy controls. Subjective duodenal histopathology ranged from normal (10), through mild (6), moderate (8), and severe (3) inflammatory bowel disease. The number and spatial distribution of mucosal bacteria was determined by fluorescent in situ hybridization (FISH) with probes to 16s rDNA. The mucosal response was evaluated by objective histopathology and cytokine mRNA levels in duodenal biopsies. The number of mucosa-associated Enterobacteriaceae was higher in cats with signs of gastrointestinal disease than healthy cats. Total numbers of mucosal bacteria were strongly associated with changes in mucosal architecture and the density of cellular infiltrates, particularly macrophages. Enterobacteriaceae spp, E. Coli, and Clostridium spp. were associated with significant changes in mucosal architecture (principally atrophy and fusion), upregulation of cytokines (particularly IL-8), and the number of clinical signs exhibited by the affected cats.

These findings indicate that an abnormal mucosa-associated flora is associated with the presence and severity of duodenal inflammation and clinical disease activity in cats. They provide a rationale basis for future investigations to address the potential causal involvement of mucosa-associated bacteria. These observations of Simpson's group are perhaps most consistent with a model proposed for the mucosal response to gram negative bacteria, whereby proinflammatory cytokines (e.g. IL-8, IL1), produced by epithelial cells in response to stimuli such as gram negative bacteria, are modulated by the production of IL-10 by macrophages. Support for this concept in the canine gastrointestinal tract is provided by studies in the small intestines of Beagle dogs, where expression of IL-10 and IFN-mRNA by lamina propria cells and the intestinal epithelium was observed in the face of a luminal bacterial flora that was more numerous than that of control dogs.  To add further to the evidence that bacteria are a key component of development of IBD in cats, Inness and coworkers characterized the gut microflora of both healthy cats and cats with colonic IBD using fluorescence in situ hybridization (FISH).  In their study cats with IBD were found to have significantly higher populations of bacteria in the Desulfovibrio spp. (a group of bacteria that produce toxic sulfides) compared to the normal cats, who had higher populations of bifidobacteria and bacteroides (normal flora).  They proposed that modulation of the intestinal flora with probiotics and dietary intervention (to decrease the production of pathogenic bacteria) were likely very important in treatment of these cats.  Finally, another study by Nguyen et al. found that the expression of cytokines in intestinal biopsies of cats with IBD, the group found that cats with IBD had more transcription of genes encoding IL-6, IL10, IL-12, TNFα, and TGFβ than cats with normal intestines.  These results also suggested that in cats with IBD both pro-inflammatory and immune dysregulation features were present. In humans, recent studies indicate a strong association of development of IBD with a breakdown of normal tolerance mechanisms, host susceptibility and the enteric microflora. 

It is quite likely that these same factors are important in feline IBD.  It is clear that modulation of the enteric microenvironment in humans with IBD has been shown to reduce proinflammatory cytokines in the mucosa and thus, decreases the inflammation. In human IBD therapy, has included use of antibiotics with immune modulating capacity, prebiotics, probiotics, immunosuppression and other drugs that modify cytokine release.  Unfortunately, studies in cats with IBD assessing modulation of the enteric flora (using probiotics, prebiotics, or other specific therapy for cytokines) are only in the early stages of study.  At this time, therapy of IBD in cats continues to include inflammatory suppression and antibiotic therapy.  The most effective therapies for IBD include steroids (prednisolone or methylprednisolone 1-2 mg/kg po q12h po) or other drugs that interrupt the pro-inflammatory pathways that are active in the gut.  In cats that are intolerant of steroids, budesonide therapy may be a reasonable choice.  Alternatively, in those cats in which steroids are no longer effective or are causing morbidity (e.g. diabetics), immunosuppressive therapy may be necessary, and is often effective.  The two drugs that most commonly recommended and effective drugs for cats in this setting are cyclosporine and chlorambucil.  Antibiotic therapy with metronidazole (5-10 mg/kg po q12h) has been effectively used for a number of years and continues to be recommended for initial therapy of IBD.  There is also a widely held belief that metronidazole is effective, not only because of its antibacterial properties, but because of concurrent immune modulation properties.  There is some data to support these ideas, however the specific role of metronidazole in therapy of IBD is still not completely known.  Because metronidazole may be poorly tolerated, and due to side effects or the potential for serious adverse effects, metronidazole should not should not be given indefinitely.   Another antibiotic that may be useful in cats with presumed IBD is tylosin (10-20 mg/kg po q12h); however, less is known about the effects of tylosin on cats when used long term. Finally, there is increasing data in human IBD that probiotics and anti-oxidant, prebiotic nutraceuticals may be important components of therapy. 

At this time, it is difficult to make specific recommendations concerning the specific probiotic or nutraceutical therapy with the greatest benefit. However, probiotics that provide an immune modulating effect or that increase the numbers of beneficial species while competing against pathogens might be expected to be helpful. Further, while probiotic therapy alone would not be expected to produce a clinical remission, cats that are undergoing long term therapy for IBD may benefit from the addition of probiotics to their treatment regimen. 

Inflammation and food 

The use of diet to assist in the management of GI disease is not a new concept.  Nevertheless, the type of diet used to help manage the problem has become an increasingly complex issue.  In many, if not most cases of mild IBD, especially those cases without significant infiltrate of inflammatory cells (mild to moderate infiltrate) or without significant weight loss or other morbidity, the best approach is to feed a highly digestible diet or change the diet to one with fewer additives, flavorings, or other substances than may be associated with food intolerance.  This term is not defined in a regulatory sense, but generally indicates a product with protein digestibility of > 87% (typical diets are 78-81%), and the digestibility of fat and CHO should be greater than 90% (typical diets are 77-85% and 69-79%, respectively). 

These types of diets are designed to provide food that is easy to digest (moderate to low fat, moderate to increased in protein, moderate to decreased carbohydrate), may have additives to improve intestinal health (soluble fibers, omega 3 fatty acids, increased anti-oxidant vitamins, etc), and contain no gluten, lactose, food coloring, preservatives, etc.  There are many different brands available that fall under the category “highly digestible”, but, the key is to remember that they are not all alike.  In particular, the protein digestibility, protein source, and protein quality of the diet chosen are some of the key factors they may determine the success of the diet.  This information can be difficult to access, but in general, meat source proteins are more digestible than plant source (e.g. wheat gluten or other plant protein sources added to foods), animal proteins are more digestible than meat by products.  Meat meals are a good source of protein and are frequently used in dry diets, but they may not be ideal in all situations where GI disturbances are occurring you are attempting to identify food sources.  Also, to increase digestibility of foods in cats, selection of diets with only highly digestible carbohydrate sources present in a lower quantity in the food – e.g. a single source carbohydrate food is better than foods with many different sources, a single highly digestible carb source (such as rice or potato) is better than complex plant source carbs which require higher level digestive processes and may be more likely to result in maldigestion.  Thus, when one diet from this category not accepted or is ineffective, or seems to make the diarrhea worse, you cannot assume that all diets in this category will be ineffective. 

The highly digestible diets from different pet food manufacturers have a wide variety of different formulations: different protein and carbohydrate sources, different levels of fat, and a variety of additives designed to promote intestinal health (FOS, MOS, omega 3 fatty acids, antioxidant vitamins, soluble fiber, etc).  If one type of highly digestible diet has been fed for at least 2 weeks with minimal response, then is it entirely reasonable to either try another diet from a different source, or try an entirely different dietary strategy (e.g. high protein/low carb, novel antigen, hydrolyzed, etc).  Another consideration is that the diarrhea may be due to carbohydrate intolerance or bacterial changes resulting from diet changes.  Thus, addition of probiotics or prebiotics to help influence the microflora are also reasonable therapeutic options as well as addition of either metronidazole or tylosin (as described above).

Novel antigen or elimination diets

Food sensitivity and food intolerance are the most common adverse reactions to food in cats. Food allergy or hypersensitivity is an adverse reaction to a food or food additive with a proven immunologic basis. Conversely, food intolerance is a nonimmunologic, abnormal physiologic response to a food or food additive. Food poisoning, food idiosyncrasy, and pharmacologic reactions to foods also fall under this category of adverse reactions to food. The specific food allergens that cause problems in cats have been poorly documented, with only 10 studies describing the clinical lesions associated with adverse food reactions. In these reports, more than 80% of the reported cases were attributed to beef, dairy products, or fish in cats. The incidence of food allergy in cats is unknown but in most studies is estimated to be only 15-20% of all food related causes of diarrhea. However, food intolerance is believed to contribute to 60-65% of feline diarrhea cases – which was supported in two separate studies where a majority of cats responded to dietary therapy with a highly digestible diet. 

The causes of dietary intolerance that need to be considered in feline diets are primarily protein and carbohydrates – both sources and amounts.  The diagnosis of both food sensitivity and intolerance is based upon a dietary elimination trial.  The major difference between these two types of adverse food reactions is the length of time on the diet that is required to achieve a response (cats with food sensitivity will require 6-12 weeks on the elimination diet before an improvement will be seen).  There are a variety of commercially available and homemade elimination diets, as well as diets formulated with hydrolyzed proteins, that may be used in cats with suspected food sensitivity or intolerance.  The key is to select a diet that has a novel protein source (based on a careful dietary history), that is balanced and nutritionally adequate (commercial diets are best for this), however, homemade elimination diets may be needed to find an appropriate test diet.  If a homemade diet must be used for long term therapy, a complete and balanced diet containing the necessary protein sources should be formulated by a nutritionist.  In most cats with food sensitivity, avoiding the offending food is the most effective therapy and will result in complete resolution of signs.  However, short term steroid therapy can be used to decrease the concurrent intestinal inflammation until the appropriate food sources can be identified. 

Gastrointestinal disease may decrease the availability of a number of micronutrients, such as vitamins and minerals, with important consequences for the pathogenesis, diagnosis and treatment of gastrointestinal disease. The diagnostic utility of measuring the serum concentrations of cobalamin and folate in cats with suspected intestinal disease has recently been established, and although the impact of deficiencies in cobalamin and folate are not completely known, the role of cobalamin in normal function of the GI tract and in many other aspects of metabolism is well documented.  Further, because cats are obligate carnivores that consume much higher amounts of protein in their diet, the importance of cobalamin and other B vitamin in maintenance of protein metabolism cannot be overstated.  Thus, evaluation of all cats with GI disease, not just cats with IBD, is an important part not only of the diagnostic process, but in the management of these diseases as well.  While other vitamin or mineral deficiencies may occur with long standing or severe IBD, they are less likely (due to storage of fat soluble vitamins and some minerals) and supplementation without documentation of a deficiency can be dangerous.  Thus, supplementation of fat soluble vitamins is not generally recommended unless signs of deficiency are occurring (bleeding due to vitamin K deficiency, etc) or tissue or blood levels of the vitamin are determined.

References

Dennis JS, et al.  Lymphocytic plasmacytic gastroenteritis in cats: 14 cases (1985-1990). JAVMA 200: 1712-1718, 1992.

Jergens AE, et al. Idiopathic inflammatory bowel disease in dogs and cats: 84 cases (1987-1990).  JAVMA 200: 1603-1608, 1992.

Hart JR, et al.  Lymphocytic plasmacytic enterocolitis in cats: 60 cases (1988-1990).  JAAHA 30: 505-514, 1994.

Weiss DJ et al.  Relationship between inflammatory hepatic disease and inflammatory bowel disease, pancreatitis and nephritis in cats.  JAVMA 209: 114-116, 1996.

Ritchie L.  Molecular characterization of intestinal bacteria in healthy cats and cats with IBD.  MS dissertation. TAMU, 2008.

Day M et al.  Histopathological standards for the diagnosis of gastrointestinal inflammation in endoscopic biopsy samples of the dog and cat: a report from the World Small Animal Veterinary Association Gastrointestinal Standardization Group, J Comp Path 138: 1-43, 2008.

Guilford WG, et al.  Food sensitivity in cats with chronic idiopathic gastrointestinal problems.  J Vet Int Med 15: 7-13, 2001.

Janeczko S, et al. The relationship of mucosal bacteria to duodenal histopathology, cytokine mRNA, and clinical disease activity in cats with inflammatory bowel disease.  Vet Microbiol 128: 178-193, 2008.

Van Nguyen N, et al.  Measurement of cytokine mRNA expression in intestinal biopsies of cats with inflammatory enteropathy using quantitative real-time RT-PCR. Vet Immuno Innumopath 113: 404-414, 2006.

Waly N, et al.  Immune cell populations in the duodenal mucosa of cats with inflammatory bowel disease.  J Vet Int Med. 18: 113-122, 2004.

Inness VL, et al.  Molecular characterization of the gut microflora of healthy and inflammatory bowel disease cats using fluorescenece in situ hybridization with special reference to Desulfovibrio spp.  J An Phys An Nutr 91: 48-53, 2006.