How can nutraceuticals assist in acute and chronic enteropathy therapy?

The microbiome in all species is affected by age, is unstable and changeable in disease states, tends to cluster in households, and is significantly influenced by diet

The microbiome in all species is affected by age, is unstable and changeable in disease states, tends to cluster in households, and is significantly influenced by diet. A change or imbalance in the composition of the microbiome is called ‘dysbiosis.’ Photo ©BigStockPhoto.com
The microbiome in all species is affected by age, is unstable and changeable in disease states, tends to cluster in households, and is significantly influenced by diet. A change or imbalance in the composition of the microbiome is called ‘dysbiosis.’

An explosion of microbiome data and information about its impact on health is linked with advances in genetic sequencing techniques, and comparison to huge databases, to determine species and specific strains of organisms completely unique to each host.1

The microbiome is defined as organisms (such as bacteria, viruses, protozoa), bacteriophages (viruses that infect bacteria), and archaea (single cell organisms that form a separate domain from bacteria) and their collective genetic material found on and within the body.1,2

In both cats and dogs, the main types of bacteria present include firmicutes, fusobacteria, bacteroidetes, proteobacteria, and actinobacteria. The microbiome in all species is affected by age, is unstable and changeable in disease states, tends to cluster in households, and is significantly influenced by diet. Adult microbiota is achieved by 30 weeks of age in the cat and approximately 20 weeks in the dog. A change or imbalance in the composition of the microbiome is called dysbiosis.3

Diagnosis of dysbiosis

Alterations in serum cobalamin and folate have historically been used to diagnose dysbiosis. However, the uptake of these molecules is complex and not specific for dysbiosis.19 Increased utilization of cobalamin by increased numbers of bacteria in the small intestine may lead to reduced serum levels, but severe inflammation within the ileal wall can do the same.

Bacteria accumulating in the proximal small intestinal tract may produce folate and increase serum levels; however, dietary folate in increased amounts may also produce the same result, therefore, the sensitivity of these serum levels for diagnosing dysbiosis is not optimal and may not diagnose some patients.19,20

Fecal cultures and polymerase chain reaction (PCR) panels are most useful for identifying specific enteropathogens, such as Campylobacter jejuni or Salmonella. PCR panels can also detect toxin genes or toxin production as noted with Clostridiodes perfringens and Clostridiodes difficile. However, other important anaerobic bacteria in the canine and feline microbiome are not easily cultured, thus limiting the use of culture for looking at larger groups of important organisms. Also, PCR and culture panels interpretation is limited by the fact some dogs and cats without clinical signs can carry these enteropathogens.21

FISH (fluorescent in situ hybridization) is a technique used on formalin fixed tissues that typically targets 16S ribosomal rDNA of various bacteria, and specifically adherent and invasive E. coli in the diagnosis of granulomatous colitis in boxer dogs and French bulldogs. This technique is performed on colonic biopsies from affected dogs, together with histopathologic evaluation, looking for large numbers of macrophages staining positively for periodic acid- Schiff (PAS).22,23

A quantitative PCR assay, called the fecal dysbiosis index (DI), is available through the Texas A&M gastrointestinal laboratory. This index was created using a mathematical model and evaluation of feces from cohorts of both healthy dogs and dogs with chronic enteropathy diagnosed with histopathology.

Healthy dogs generally have a DI less than zero, between zero and two is equivocal, and a DI above two is consistent with dysbiosis. Highest numbers equate to a greater deviation from normal and more severe change. Fecal DI in dogs is not affected by age, body weight, or gender. This index may be useful in diagnosing and tracking dysbiosis following therapeutic intervention and clinical improvement.19,24

A diagnosis of dysbiosis, while not equating to a specific disease, allows decisions targeting these microbiome changes and avoiding noncritical antimicrobial use. This moves the veterinary profession forward in the quest for improved antimicrobial stewardship in animals.

Causes of dysbiosis in dogs and cats and associated therapies

There are multiple dysbiosis patterns in disease, and many overlap in the same patient, especially in chronic enteropathy.5 These include:

  • undigested nutrients or medications (e.g. drugs such as mycophenolate), which create metabolites that cause secretory diarrhea;
  • loss of beneficial bacteria such as Clostridium hiranonis (e.g. antimicrobial use), which reduces conversion of primary to secondary bile acids, resulting in pathogenic bacteria invasion;
  • increased bacterial numbers in the small intestine (e.g. exocrine pancreatic insufficiency, decreased gastric acid due to acid suppressing drugs), which increases the inflammatory immune response and secretory diarrhea; and
  • increased adherent or invasive bacteria, such as E.coli (e.g. granulomatous colitis in boxers and French bulldogs), which causes increased inflammatory immune response.5,25

It is unclear whether dysbiosis is a direct cause of inflammation, or a secondary consequence of the disease process. Although there are many disease states that may be linked with dysbiosis, the following are common syndromes practitioners are faced with on a regular basis.

Acute enteropathy

Acute diarrhea of less than 14 days is a common complaint in veterinary practice. Chaitman et al have documented significant changes in fecal microbiota, increased DI, and alterations in the bile acid environment.26,27 Dogs with acute diarrhea show more profound changes in the microbiome versus more chronic enteropathy.

AHDS

Acute hemorrhagic diarrhea syndrome (AHDS, formerly referred to as ‘acute hemorrhagic diarrhea’) has been associated with increased C. perfringens type A and associated enterotoxin NetF presence in the feces.28,29 However, some affected dogs have no detectable toxin production, and healthy dogs may carry various C. perfringens strains.

Research is ongoing to define whether AHDS is caused by a single infectious agent and toxin, or multiple products of several infectious agents. Diagnosis and treatment are based on clinical signs, including dehydration, hypovolemic shock, and an elevated PCV.30

The presence of bacteremia appears to be low in dogs with AHDS, and use of antimicrobials does not appear to alter the outcome or survival. Because antimicrobials can disrupt protective intestinal microbiota and cause long-term dysbiosis, their use should be restricted to febrile patients or those showing other signs of sepsis.30 Use of a probiotic has been associated with a more rapid normalization of the fecal microbiome and lower abundance of C. perfringens enterotoxin.28

Parvo

Canine parvoviral enteritis is an important viral intestinal disease of puppies. Recent study of the viral-bacterial interaction in control and affected dogs showed significant differences in fecal bacterial communities and diversity between the groups.31

Use of a probiotic has been shown to improve both clinical scores and leukocyte counts in young dogs with parvoviral enteritis versus controls.32 Further, fecal microbiota transplantation (FMT), in addition to standard supportive therapy, has been associated with faster resolution of diarrhea and shorter hospitalization times.33

Antimicrobial therapy

Antimicrobial therapy, especially the use of metronidazole or tylosin, is commonly used for acute diarrhea in dogs and cats. Both drugs lead to prolonged effects on the composition and diversity of gut microbiota and amounts of important bile acids needed for gut health.4,34

Moreover, metronidazole (versus placebo) does not result in faster resolution of acute diarrhea of less than seven days, even when Clostridium perfringens is detected in feces.35

Use of antibiotics, such as amoxicillin-clavulanate, for acute diarrhea show no benefit versus administration of a placebo, and may result in drug-resistant fecal E. coli for weeks following therapy.36

When amoxicillin-clavulanate was used in cats to induce gastrointestinal signs, administration of a probiotic improved diarrhea scores.37 A synbiotic has been shown to reduce hyporexia associated with enrofloxacin-metronidazole administration, with reduction of negative gastrointestinal signs lasting for weeks after antimicrobial drugs are discontinued.37   

Chronic enteropathy

Chronic enteropathy (CE) appears to differ in dysbiosis patterns from more acute diarrhea diseases.3 Bacterial groups commonly decreased in CE are important short-chain fatty acid (SCFA) producers. These fatty acids are important end-products of bacterial carbohydrate fermentation; they support gut motility and exert immunomodulatory and anti-diarrheal effects.39 Dogs with CE, including inflammatory bowel disease (IBD), have been shown to have altered SCFA concentration and lower gut bacterial diversity similar to that shown in humans with IBD.3,25,39

In veterinary medicine, CE with intestinal inflammation is often divided into subgroups based on response to therapy, including food, steroid, and antimicrobial-responsive enteropathies. IBD is a subgroup of enteropathy that results in persistent gastrointestinal inflammation due to an unknown cause.25 Dogs with food-responsive enteropathy comprise the largest group in CE diagnoses.40

In humans, remission of CE induced by a hydrolyzed diet resulted in an improved microbiota presence, an expansion of bile-acid producing clostridia, and increased levels of beneficial secondary bile acids.41 In dogs, studies have focused on assessing food-response CE and use of probiotics or synbiotics in addition to diet with variable results.

Dogs showed beneficial changes in microbiota linked with administration of probiotics (Lactobacillus acidophilus or cocktails of multiple Lactobacillus strains) during a diet trial, in addition to improvements in fecal score and frequency.42-43

In another study, dogs with CE rapidly responded clinically to a diet trial without additional apparent clinical or cytokine expression benefit from administration of Enterococcus faecium NCIMB 10415 E1707.44

A study of 12 dogs on a hydrolyzed diet following diagnosed food-responsive enteropathy assessed placebo versus a synbiotic (Enterococcus faecium NCIMB 10415 4b1707 and fructooligosaccharides).45 Synbiotic use increased richness and diversity of fecal microbial communities in both control diet and food responsive groups. Finally, feeding raw diets is an approach used by some clients in diet trials designed to diagnose food responsive enteropathy.

A comparison of normal dogs consuming a variety of commercial wet and dry diets with a group consuming various raw diets found significant differences in the fecal microbial communities.46 Higher amounts of fecal E. coli, C. perfringens, and a significantly higher DI were noted in the raw-fed group. The significance of these findings in food-responsive enteropathy dogs is unknown, but should be a consideration, especially if the DI is used for monitoring of disease response.

Studies on steroid responsive enteropathy have generally focused on dogs diagnosed with IBD.47-49 A longitudinal assessment of dogs with steroid-responsive enteropathy confirmed abnormal fecal unconjugated bile acid (fUBA) metabolism at baseline, and improvement of both bile acids and DI following steroid administration.47

Dogs diagnosed with IBD and treated with either a probiotic or prednisone and metronidazole both clinically improved.48 However, the probiotic group was associated with enhancement of regulatory T-cell markers and normalization of dysbiosis. Dogs with IBD treated with diet and prednisone and either a placebo or probiotic showed clinical improvement and increased numbers of bacterial communities in both groups. The probiotic group was associated with additional changes that suggested improvement in epithelial barrier function.49

Despite responsivity of CE to antimicrobials in many small animal patients, dogs with antibiotic- responsive diarrhea (versus response to food or steroids) have a higher diarrhea relapse rate long-term (six to 12 months).40 Due to the negative impact on microbial community diversity and bile acid populations, it is recommended even short-term antimicrobial therapy be avoided unless specifically indicated by the presence of adherent or invasive bacteria such as E. coli in granulomatous colitis diagnoses.

Metagenomics milestones: A timeline of advances in microbial communities. (Escobar A, Vera-Ponce de Leon A, Sanchez- Flores A. [2015]. The Road to Metagenomics: From Microbiology to DNA Sequencing Technologies and Bioinformatics. Front Genet. 6[348]: 1-15.) Image courtesy Escobar et al.
Metagenomics milestones: A timeline of advances in microbial communities. (Escobar A, Vera-Ponce de Leon A, Sanchez- Flores A. [2015]. The Road to Metagenomics: From Microbiology to DNA Sequencing Technologies and Bioinformatics. Front Genet. 6[348]: 1-15.)
Image courtesy Escobar et al.

Without use of traditional antimicrobial therapy

Prebiotics

Prebiotics are non-digestible fibre compounds, such as mannan-oligosaccharides (MOS), fructo-oligosaccharides (FOS), and beta-glucans, which are shown to have beneficial effects on bacteria and gut health. They provide energy sources to support the health of bacteria such as bifidobacterium and lactobacilli and their associated production of SCFA.5

MOS enhances immune function and may produce greater Lactobacillus populations than FOS.50 Psyllium is a soluble fibre which is fermented by colonic bacteria and forms a gel in water. These properties allow production of beneficial SCFA and improved fecal score. This may be beneficial in many types of enteropathies, including large bowel (colitis) diarrhea.51

Probiotics

Probiotics are products with appropriate numbers of live bacteria that confer a health benefit to the patient. Benefits include immune modulation, improved intestinal barrier function, and immune modulation.52 Not all probiotics are equal with respect to type, number of live bacteria, or manufacturing processes and quality control.53

Although the number of live bacteria in most products equals at least 1×108 per gram, the optimal strain, number of strains in a product, or numbers of bacteria have not been established in veterinary medicine. If a specific probiotic was associated with a positive effect in a study, this may not apply to another probiotic product.52 Further, a probiotic’s effect may be dose-dependent and the beneficial effect may vary within an individual. 

Synbiotics

Synbiotics are products that combine a prebiotic and probiotic with potential synergistic effects in the patient. Multiple products exist in the Canadian market—consideration of peer-reviewed literature, limited and/or hydrolyzed protein ingredients when using in a chronic enteropathy patient, Health Canada approval, and a veterinary label are all useful guidelines when choosing a product. 

FMT

Fecal microbial transplantation (FMT) is the transfer of feces from a healthy donor into the gastrointestinal tract of a diseased patient as a therapeutic tool. The beneficial effect is thought to be not only due to the transferred bacteria, but also archae, protozoa, viruses, and their metabolites.54,55

FMT is the standard therapy in humans for Clostrioides difficile infections where the cure rate is 92 to 98 per cent with either fresh or frozen feces.55,56 A small number of clinical studies in veterinary medicine have shown a therapeutic benefit.33,56

Acute diarrhea syndromes are expected to respond better to a single FMT treatment compared to chronic enteropathies.56 Information about donor screening and infusion protocols are available to practitioners.55,56 Freeze-dried donor feces in capsules are also available for veterinary practitioners (animalbiome.com). To date, no peer-reviewed publications are available that evaluate the benefit of oral administration of freeze-dried feces in dogs and cats.

THE ROLE OF THE MICROBIOME IN BODY SYSTEMS

The microbiome has roles in energy and nutrient production (such as short chain fatty acids, which are beneficial to colonic health), gut motility, protection against colonization of the gut with pathogens, immune modulation, and metabolic consequences, such as deconjugation of bile acids to secondary bile acids.1

Dysbiosis has been associated with many body systems and disease states in both humans and companion animals:

  • Dysbiosis and gastrointestinal disease has been studied in humans and companion animals, with varying outcomes and associations of these changes in many different diseases.4-7
  • Association of the microbiome and diseases such as asthma, diabetes mellitus, and metabolic syndrome and obesity in humans, mice, and dogs have been published.1,8,9
  • Dysbiosis has been associated with increasing severity of myxomatous mitral valve disease in dogs.10
  • Decreased microbiome diversity is associated with chronic kidney disease in cats.11
  • Changes in gut microbiota are associated with age-related sarcopenia in aging humans.12
  • Dysbiosis has been linked to alterations in the immune system in canine chronic enteropathy, respiratory disease, and atopic dermatitis.13
  • Dysbiosis is linked to many central nervous system diseases in humans, including epilepsy and autism spectrum disorders.14 Gastrointestinal inflammatory disease has been associated with abnormal behaviour (fly biting, excessive licking, and pica) in dogs and cats, though not specifically dysbiosis.15-17 A more recent study comparing the microbiome between diagnosed aggressive, phobic, or normal dogs found the aggressive group had a very different gut environment versus the phobic and normal dogs.18

Susan Kilborn, DVM, DVSc., DACVIM (SAIM), received her DVM from the Western College of Veterinary Medicine at the University of Saskatchewan before completing a post-graduate degree at the Ontario Veterinary College. She became board-certified in the American College of Veterinary Internal Medicine in 1995. Dr. Kilborn currently sees referral internal medicine cases at Orleans Veterinary Hospital in Ottawa and consults (internal medicine and nutrition) for Antech Diagnostic Laboratories. She has been Ottawa region and One Health director for Community Veterinary Outreach since 2008. Community Veterinary Outreach is a Canadian-registered charity that provides pro bono veterinary care to pets of homeless, street-involved, and vulnerably housed adults and youth, while providing health and social services for the clients. For more information, please visit vetoutreach.org. Kilborn was the recipient of the Canadian Veterinary Medical Association Small Animal Practitioner Award in 2015.

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