Chronic inflammatory enteropathy is a collective term that typifies disorders of the gastrointestinal tract (small intestinal and/or large intestinal) distinguished by recurrent or persistent gastrointestinal signs (defined as longer than 3 weeks' duration) and histopathological evidence of primary intestinal mucosal inflammation. Clinical signs such as hyporexia, nausea, weight loss, abdominal pain, vomiting and diarrhoea result from uncontrolled inflammation that may be constant or periodic in nature. Inflammatory enteropathies have been found in up to 70% of dogs with chronic diarrhoea (Volkmann et al, 2017), and are deemed to be the most common cause of gastrointestinal disease.
Classifications of chronic inflammatory enteropathy have historically been described in accordance with the clinical response to various therapies involving dietary manipulation (food-responsive enteropathy), empiric treatment with antibiotics (antibiotic-responsive enteropathy) and immunomodulatory therapies (immunosuppression-responsive enteropathy). Although the use of antimicrobials in chronic inflammatory enteropathy is considered out-dated to modern advancements in veterinary practice and has largely been replaced by an attempt to manipulate bacterial populations in small intestinal dysbiosis. A subset of dogs with immunosuppression-responsive enteropathy that respond to prednisolone are aptly categorised as a separate phenotype of chronic inflammatory enteropathy, known as steroid-responsive enteropathy. By the same token, non-responsive or refractory chronic idiopathic enteropathy consists of patients that fail these therapies (Figure 1).
As a result of documented adverse antibiotic-induced gastrointestinal signs, including diarrhoea, reduced faecal quality, bile acid dysmetabolism, reductions in commensal anaerobic bacteria and derangements in the faecal microbiome, the appropriateness of antibiotic prescription and administration should be evaluated on a case-by-case basis. Similarly, several reports have detailed the outcome of antibiotic-induced dysbiosis through use of broad-spectrum antibiotics (Honneffer et al, 2014; Bottero et al, 2022). On account of these well-known consequences of antibiotic usage, there is renewed interest in the role of probiotics, prebiotics and synbiotics for use in chronic inflammatory enteropathy. For this reason, pre/probiotics and synbiotics are favoured to preferentially support the bacterial ecosystem of the intestine, which can lead to normalisation of the intestinal microbiota (Pilla and Suchodolski, 2020). Accordingly, commonly used treatments to induce clinical remission in chronic inflammatory enteropathy include specifically formulated diets, pre/probiotics, synbiotics and immunosuppressive medications (Makielski et al, 2019).
Canine chronic enteropathy activity index
The development of canine chronic enteropathy clinical activity indices extrapolated from human medicine offer a quantifiable and repeatable measure of monitoring response to treatment. The most commonly used scoring system is the canine IBD activity index (CIDAI), which includes a summation of scoring for six different clinical signs (stool consistency, stool frequency, appetite, weight loss, vomiting and activity/attitude) that can be easily assessed by owners. The canine chronic enteropathy clinical activity index (CCECAI) embraces the original CIBDAI frame-work, with supplementary scoring of peripheral oedema and ascites, serum albumin concentration and the severity of pruritus, which are used to predict prognostic outcome and provide an improved estimation of possible therapeutic success (Allenspach et al, 2007) (Table 1).
Table 1. The canine chronic enteropathy activity index
| Category | Description | Score | Total |
|---|---|---|---|
| Attitude/activity | Normal | 0 | |
| Slightly decreased | 1 | ||
| Moderately decreased | 2 | ||
| Severely decreased | 3 | ||
| Appetite | Normal | 0 | |
| Slightly decreased | 1 | ||
| Moderately decreased | 2 | ||
| Severely decreased | 3 | ||
| Vomiting | Normal | 0 | |
| Mild (1x/wk) | 1 | ||
| Moderate (2x/wk to 3x/wk) | 2 | ||
| Severe (>3x/wk) | 3 | ||
| Stool consistency | Normal | 0 | |
| Slightly soft faeces | 1 | ||
| Very soft faeces | 2 | ||
| Watery diarrhoea | 3 | ||
| Stool frequency | Normal | 0 | |
| Slightly increased (2x/d to 3x/d) or blood/mucus/both | 1 | ||
| Moderately increased (4x/d to 5x/d) | 2 | ||
| Severely increased (>5x/d) | 3 | ||
| Weight loss | None | 0 | |
| Mild (<5%) | 1 | ||
| Moderate (5–10%) | 2 | ||
| Severe (>10%) | 3 | ||
| Albumin levels | Albumin >20 g/litre | 0 | |
| Albumin 15–19.9 g/litre | 1 | ||
| Albumin 12–14.9 g/litre | 2 | ||
| Albumin <12 g/litre | 3 | ||
| Ascites/peripheral oedema | None | 0 | |
| Mild ascites/peripheral oedema | 1 | ||
| Moderate ascites/peripheral oedema | 2 | ||
| Severe ascites/peripheral oedema | 3 | ||
| Pruritus | No pruritus | 0 | |
| Occasional itching | 1 | ||
| Regular itching, but stops when asleep | 2 | ||
| Regularly wakes up due to itching | 3 | ||
| Total score | |||
| Allenspach, 2007 | |||
Diagnosis of chronic inflammatory enteropathy
In spite of extensive research within the human analogues of gastrointestinal disease, the aetiology of chronic inflammatory enteropathy remains undetermined. Equally, the exact pathogenesis of chronic inflammatory enteropathy is poorly understood, although proposed clinicopathological factors suggest a complex interplay of host genetic susceptibility, impaired immune system regulation, microbial dysbiosis and environmental influences such as diet (Isidori et al, 2022). Current concepts refer to the interactions between food components, environmental factors and the intestinal microbiota, which then cause inflammation in a genetically predisposed patient.
A diagnosis of chronic inflammatory enteropathy centres on the exclusion of extra-intestinal disorders (pancreatic, renal or hepatic disease, hypercalcaemia and hypoadrenocorticism), metabolic, infectious, neoplastic and parasitic disease, as well as intestinal disease of other aetiologies (primary enteropathies). Endoscopy, in conjunction with biopsy sampling of the gastrointestinal tract, helps with the diagnosis by allowing assessment of morphological and architectural changes in the intestinal mucosa, confirming the presence, severity and type of intestinal inflammation and omitting diffuse intestinal tumours such as lymphoma. As such, multifocal lesions seen in chronic inflammatory enteropathy support endoscopic examination and sampling of different regions along the gastrointestinal tract to ensure that specimens can be obtained that are affected by the pathological process. In turn, a definitive diagnosis of chronic inflammatory enteropathy is often attained in response to a stepwise diagnostic work-up involving therapeutic interventions (historically antimicrobials), diet trials, probiotics, synbiotics, anti-inflammatory or immunosuppressive drugs, and histopathological evaluation of intestinal mucosal biopsy specimens.
Dietary management
Dietary management is the mainstay of treatment for dogs with chronic inflammatory enteropathy, as removal of antigenic sources offered by a single-source, novel protein and hydrolysed protein diet consecutively reduces the enteric inflammatory response (Dandrieux and Mansfield, 2019). In view of failed or an inadequate clinical response to elimination diet trials, adjunctive treatments such as antimicrobials and immunosuppressive drugs are used. The current recommendations for the diet to feed in dogs with chronic inflammatory enteropathy incorporates low fat, highly digestible, fibre-enriched, hydrolysed, novel protein diets or exclusively home-made food preparations (Tolbert et al, 2022).
Case reports have corroborated that assessing the response to an elimination diet is the most effective method for diagnosis and treatment of food-responsive enteropathy (Kennis, 2006; Hall and German, 2010). For dogs with mild signs of small intestinal disease, a diet trial using a low residue therapeutic gastrointestinal diet is often considered as the first-line dietetic therapy (Kathrani, 2021). To reduce poor dietary compliance among owners and improve success during the performance of a stringent diet trial, owners should be notified of the expected time frame for observation of a clinical response, ranging from within the first few days up to 14 days (Marks et al, 2002; Allenspach et al, 2016).
There is a scarcity of research and available data comparing the efficacy of a novel protein (or limited protein) and hydrolysed protein diet in the treatment of dogs with chronic inflammatory enteropathy. Thus, a prospective validation study is warranted to affirm the advantages of feeding hydrolysed or novel single-source protein diets in modulating gastrointestinal signs and achieving clinical remission in dogs with chronic inflammatory enteropathy. However, it should be noted that choice of diet is often highly dependent upon acceptance. Before concluding that chronic inflammatory enteropathy is non-food responsive, multiple diet trials should be performed in an attempt to distinguish the presence of an ingredient- or nutrient-specific disease.
Intestinal microbiota
The gastrointestinal tract of dogs is colonised by a vast population of microorganisms, known as the intestinal microbiota, which is composed of viruses, fungi, archaea, bacteria and protozoa that play a crucial role in host physiology by providing multiple benefits to the host. These include stimulation of gastrointestinal motility, immune system regulation, defence against enteropathogens and the provision of nutritional support for enterocytes (Suchodolski, 2022).
Syndromes of chronic inflammatory enteropathy often present with consistent changes to the microbiome. Numerous factors such as disease, diet and medical interventions can lead to adverse alterations to the intestinal microbiota. Disruption to the canine microbiota and changes in composition of the intestinal microbiota leads to impaired barrier protection that allows opportunistic pathogenic agents to colonise the intestinal lumen, inducing pathological reactions (Tuniyazi et al, 2022). The effects of several complementary therapies, including prebiotics and probiotics, on intestinal barrier function to decrease mucosal inflammation and ameliorate microbial dysbiosis have been studied. Dysbiosis can be further considered as a pathophysiological element in chronic intestinal inflammation that indicates changes in the gut bacterial microbiome (Huang et al, 2020). During both acute and chronic diarrhoea the gut microbiota is altered, producing a negative dysbiotic effect. A dysbiotic microbiome may result in deleterious functional or immunological impacts on the host (Groves, 2020). Therefore, as alterations in the intestinal microbiota have been correlated with acute and chronic gastrointestinal disease in dogs, measures to optimise and repopulate healthy bacterial communities within the host and promote normobiosis are of interest therapeutically.
Faecal microbiota transplantation
Faecal microbiota transplantation is a novel medical therapy that entails the administration of an infusion of faecal matter (via collection of naturally eliminated stools from a healthy donor) and subsequent deposition into the intestinal tract of a diseased recipient, with the aim of increasing microbiota diversity and restoration of the recipient's native microbiome (Salavati Schmitz, 2022). In human medicine, faecal microbiota transplantation is a preferred treatment for refractory Clostridiodes difficile infection that has successful clinical outcomes. Correspondingly, there is emerging interest in the role of the gastrointestinal microbiota and intestinal dysbiosis in acute and chronic canine gastrointestinal disorders, with contemporary research evaluating the efficacy of faecal microbiota transplantation for the management of chronic enteropathies in animals. There is a paucity of literature exploring the utility of faecal microbiota transplantation in veterinary species, although preliminary reports have shown promise in improving the composition of gut microbial communities, in addition to improvement in clinical signs in dogs with gastrointestinal dysfunction (Sugita et al, 2019; Chaitman et al, 2020; Wen et al, 2022).
Gal et al (2021) demonstrated the clinical applicability of faecal microbiota transplantation in dogs, with a single faecal microbiota transplantation procedure resulting in a significant change in the faecal microbiome of recipient dogs up to 1 month post-faecal microbiota transplantation, characterised by increased enrichment of short-chain fatty acid producing bacteria. Short-chain fatty acids are end products derived from carbohydrate fermentation that offer a multitude of beneficial effects to host physiology, including anti-diarrhoeic effects, regulatory effects on gastrointestinal motility and immunomodulatory effects which serve to suppress and regulate gastrointestinal inflammation (Minamoto et al, 2019).
In addition, several case reports have documented shorter hospitalisation times and a rapid resolution of diarrhoea in puppies with parvoviral enteritis that received faecal microbiota transplantation (Pereira et al, 2018), in addition to improved clinical scoring indices and faecal consistency of dogs with chronic enteropathy, as well as in dogs with inflammatory bowel disease considered refractory to other therapeutic interventions when faecal microbiota transplantation was used to treat dysbiosis assumed to contribute towards disease pathogenesis (Bottero et al, 2017; Niina et al, 2019). A case report by Berlanda et al (2021) found two consecutive treatments with faecal microbiota transplantation markedly reduced CCECAI scores and adequately controlled symptoms of chronic inflammatory enteropathy. It should be borne in mind that decreased mortality rates, reduced average recovery times and a shorter duration of hospitalisation offered by the practical application of faecal microbiota transplantation may reduce the risk of hospital-acquired infections.
On the other hand, addition of faecal microbiota transplantation to standard therapy (including a hypoallergenic diet and corticosteroids) for the treatment of IBD in 13 client-owned dogs provided no significant differences between the CCECAI of the placebo and faecal microbiota transplantation group at each time point (Collier et al, 2022). Ultimately, documentation of single case reports using faecal microbiota transplantation may limit its use by clinicians as a rational alternative to standard treatments, and prospective longitudinal studies to evaluate the longer term effect on microbial diversity, clinical signs and other outcomes are desirable.
How to perform faecal microbiota transplantation
Before faecal microbiota transplantation, confirmation of vaccination, deworming and gastrointestinal history of the donor dog is advisable, accompanied by evidence of negative faecal parasitology testing, infectious disease and enteropathogenic bacteria polymerase chain reaction sampling, a normal complete blood cell count and serum biochemistry profile. Adherence to a strict donor screening process including physical and biological examinations should be implemented when intending use of faecal microbiota transplantation, combined with providing detailed explanations of potential risks which are conferred to the owner of the recipient dog (transmission of multi-drug resistant bacteria, pathogens or other adverse events including bloat, constipation or diarrhoea). To the author's knowledge, no moderate or severe complications of faecal microbiota transplantation in dogs have been documented thus far.
Case studies have described administration of faecal microbiota transplantation via colonoscopy, descending endoscopy, or by indigestion of peroral capsules and oral gavage (Figure 2). However, rectal enema is the most commonly used route of administration of faecal microbiota. Preparation of faecal microbiota transplantation aliquots includes collection of faecal samples via spontaneous defecation or digital rectal examination from a healthy donor and processing within 6–12 hours, or freezing if required to preserve viability (Chaitman and Gaschen, 2021). Alternatively, in human studies, Staley et al (2017) found that frozen stool samples were just as effective as fresh faecal material; for this reason, the availability of pre-screened faecal material provides both a cost and time-effective approach to implementing faecal microbiota transplantation in canine clinical practice.
If freezing is required, donor stools are thawed to room temperature and blended with sterile saline at a ratio of 1 part faeces to 4–5 parts 0.9% sterile saline (4–5x the quantity of faeces (g)), as proposed by Takáčová et al (2022). The ensuing faecal suspension is then filtered through a sterilised sieve to remove large particulate matter until appropriate consistency for use. The faecal microbiota preparation can be administered by a retention enema into the proximal portion of the rectum via enema, colonoscopy or via a urethral catheter, often facilitated by insertion of gauze into the rectum (Figure 3).
To help with the deposition and diffusion of faecal material by gravity, the recipient's pelvis can be raised and the animal maintained in lateral recumbency. There are numerous protocols for preparation of faecal microbiota transplantation solution, although there are no published reports of standardised dosage or optimum treatment intervals. The disparity among authors includes a range of faecal microbiota transplantation dosages, such as 5 ml/kg advocated by Gaschen (2018) compared to 10 ml/kg as recommended by Niina et al (2019).
Future research
There is a surfeit of research relating to the application of faecal microbiota transplantation in gastrointestinal disease in humans, but very little in the veterinary literature. Research evaluating the efficacy of faecal microbiota transplantation in a large cohort of small animals would be helpful in providing results that are applicable to a wider population. At present, there is limited evidence, but some studies support the clinical utility of faecal transplant therapy in restoring the microbial balance of a dysbiotic gut resulting from disease associated with disruption to the normal intestinal flora. Thus, faecal microbiota transplantation infusions may be a helpful adjunctive option for non-responsive chronic inflammatory enteropathy and may provide conceivable benefits in relation to an increased proportion of short-chain fatty acids and short-chain fatty acid-producing bacteria and resolution of dysbiosis. To provide evidence as to the efficacy of faecal microbiota transplantation, evaluating the longer-term impact in dogs with chronic inflammatory enteropathy is warranted.
Conclusions
Chronic inflammatory enteropathies can be considered on a sliding scale of disease that is defined by response to medical treatment. Conventional therapeutic approaches using diet trials and pharmacological treatment (antimicrobials, pre and probiotics, and immunosuppressive medications) remain the principal tool to differentiate between the different phenotypes of chronic inflammatory enteropathy, with dietary manipulation performed in the first instance.
The canine gut microbiome is an immensely diverse microbial community that can be likened to an intricate biological ecosystem which provides essential benefits to the host's health. Faecal microbiota transplantation is a newly adapted, practical, economical approach to treating a variety of gastrointestinal disorders in dogs with the view of restoring a healthy microbiota in a dysbiotic patient.
Faecal microbiota transplantation is an emerging non-pharmacological treatment for chronic inflammatory enteropathy in dogs which seems to have a good safety profile. The main challenge to implementation is a lack of standardisation which currently presents a barrier to its use by clinicians as an alternative to standard treatments.
KEY POINTS
- Chronic inflammatory enteropathy can be broadly categorised into: food-responsive, immunosuppression-responsive or small intestinal dysbiosis.
- The gastrointestinal tract of dogs is colonised by a vast population of microorganisms, known as the intestinal microbiota that plays a crucial role in host physiology.
- Faecal microbiota transplantation is a novel medical therapy that entails the administration of a faecal matter infusion into the intestinal tract of a diseased recipient, with the aim of increasing microbiota diversity.
- Limited evidence supports the clinical utility of faecal microbiota transplantation in restoring the microbial balance of a dysbiotic gut.
- Veterinary literature supports the notion that faecal microbiota transplantation is an emerging non-pharmacological treatment for chronic inflammatory enteropathy which seems to have a good safety profile.