Use of probiotics in small animal veterinary medicine

Maria C. Jugan Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Adam J. Rudinsky Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Valerie J. Parker Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Chen Gilor Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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The environment of the GIT is composed of a diverse microbiome. On the basis of environmental, dietary, and genetic factors, the GIT environment develops from a sterile environment to one consisting primarily of anaerobes.1 During development of the microbiome and after the microbiome is stabilized, commensal and pathogenic microorganisms, along with their interactions, impact the overall microenvironment. The resultant steady-state microenvironment or alternations in steady state attributable to microbial organisms and their products (eg, pH or fatty acid production) interact with the host through the local immune system and enteroendocrine signaling. These local effects, which are influenced by diet composition and intermicrobial interactions, affect the primary GIT microorganism population and impact GIT motility, permeability, and nutrient absorption, thereby affecting the health status of the GIT.2 Furthermore, extraintestinal factors (alterations in the systemic immune system [eg, IgA deficiency] or endocrine hormone influences) are capable of altering the GIT microbiome, thereby impacting GIT motility, permeability, and nutrient absorption.1,3,4

The normal microbiome in adult dogs and cats is primarily composed of organisms from the phyla Actinobacteria, Bacteroides, Bifidobacteria, Firmicutes, Fusobacteria, and Proteobacteria; phyla proportions differ along the length of the GIT.5–10 Although the major phyla are relatively conserved among microbiomes, substantial intraindividual and interindividual variability in phyla proportions occurs over time, with less interindividual variability observed in cats.7,11 Despite similarity in phyla, major differences exist in the microorganism population at the genus and species levels; the importance of these differences in relation to GIT health and disease has not been fully clarified.11 It is proposed that alterations in the normal microbiome composition contribute to acute and chronic enteropathies and affect the host both locally and outside the GIT, in part as a result of alternations in microbial by-product formation (eg, increased serum d-lactate concentrations in cats with GIT disease).6,12–16

Probiotics are live microorganisms that, when consumed in adequate amounts, have the potential to confer a beneficial health effect.17 Proposed mechanisms for the effects of probiotics include displacement of pathogenic microorganisms,18–20 production of antimicrobial by-products,21 improvement in GIT epithelial barrier function,22 improvement in micronutrient absorption,19 and modulation of the enteric and innate immune responses.19,21,22 It is important to note that even minor alterations (eg, change in microorganism strain) can determine whether these benefits are realized.23 The investigation of microorganisms and their applications in health and disease conditions in veterinary medicine is an ongoing process.

General considerations

Information is accumulating regarding probiotics and their effects; thus, it is important to understand some practical aspects regarding formulation and labeling of probiotics that make it challenging to provide direct comparisons and interpret results of studies. Regulation of commercial veterinary and human probiotics differ on the basis of location (eg, United States vs European Union) and a product's labeled use (eg, supplement-type product, food, or biological [ie, products intended to improve health or function]), which has led to common labeling inconsistencies.17,24–28 Products containing live organisms inherently pose challenges (stability during the manufacturing process, contamination, and long-term storage), which leads to actual microorganism concentrations that range from 0.008% to 215% of the labeled concentrations.28 All 8 veterinary products evaluated in 1 study29 contained concentrations for individual microorganisms that were < 2% of label claims; such products also contained unlisted, potentially pathogenic genera (eg, Staphylococcus spp and Pediococcus spp).29 More recent studies30,31 on veterinary probiotic content have provided similar findings. Importantly, lack of growth of some microorganisms may be related to their fastidious nature, rather than to an actual lack of inclusion in a product or effects during manufacturing.28,31

It is important to remember when comparing results of studies conducted to evaluate commercial probiotic products that manufacturing processes can affect the ability of bacteria to express desirable traits. Therefore, 2 probiotics that contain the same microorganism strain and concentration could have different effects on the GIT microbiome because the manufacturing processes differed. For example, in 1 study,32 probiotic culture media and microorganism viability of various Lactobacillus spp impacted probiotic efficacy for pathogen exclusion. Growth characteristics of Lactobacillus acidophilus and Bifidobacterium spp are affected by coculture with oligosaccharides33; extrusion and drying can negatively impact viability of Bacillus spp spores.34 These interactions among microorganism species are crucial when considering combination probiotic products formulated with multiple microorganisms or when assessing synbiotics (ie, products that are a combination of a prebiotic and probiotic). Prebiotics are substrates for microorganism fermentation, which can be tailored to a specific microorganism's growth needs.35 Inclusion of a prebiotic may select for enhanced activity of the probiotic microorganism as well as naturally occurring bacteria within the GIT. Therefore, effects of synbiotic products may be attributable to prebiotic influence on commensal GIT bacteria, prebiotic influence on supplemented probiotic species, or a combination of interactions; their impact cannot be extrapolated to effects of the probiotic bacteria alone.

The ability of enteric pathogens to cause clinical disease depends, in part, on their ability to penetrate the GIT biofilm and adhere to intestinal mucosa.36 Penetration and adherence are important for biological effects of many probiotic bacteria. Interactions with mucosal immune cells as well as interference with adherence and proliferation of pathogenic bacteria can be important. For example, several species express mucous-binding proteins or fimbriae, which allow direct adhesion. However, many host-microbial interactions rely on GIT recognition of microorganism-associated molecular patterns and interaction with GIT dendritic cells. Effects include upregulated cytokine expression and mucous secretion, which lead to changes in GIT function.19,37 Probiotic effects may be further altered by the ability of probiotic microorganisms to adhere to GIT mucosa and to tolerate the GIT environment (eg, bile concentration or acidity). Probiotic microorganisms that are able to adhere may have improved pathogen exclusion or displacement, compared with effects for those that only alter cytokine profiles or GIT secretions. Standard laboratory test criteria (eg, incubation in solutions of differing acidities and bile concentrations, bile salt hydrolase activity, and in vitro mucosal adherence) can be used to evaluate microorganisms and probiotic products for adherence properties and ability to survive in the GIT environment.26,38

Goals for probiotic administration differ, but some measures of clinical effect include improvement in fecal score, decreased duration and severity of clinical signs, decreased fecal counts of pathogenic microorganisms, and decreased concentrations of systemic inflammatory markers (eg, inflammatory cytokines). Probiotic bacteria have been evaluated in various in vitro studies. In vitro studies are useful for generating hypotheses for in vivo studies, but their clinical applicability is extremely limited because of an inability to evaluate the impact of microbial by-product formation, microorganism interaction, and cellular signaling and environmental influences.

Importantly, the effect of a probiotic in a specific clinical context is likely unique to that context. For example, one cannot extrapolate the effect of a probiotic in dogs with a specific disease from results of studies on healthy dogs or on dogs with another disease. Because the clinical context is important, studies on the use of probiotics should ideally define the study population clearly (including diet, diet history, and microbiome before probiotic administration) and fully describe the probiotic (including the exact strain, dose, and dosage regimen). It should be mentioned that most studies have limitations, including the number of subjects, extent of population characterization, appropriate characterization of underlying disease, control of potential confounders (diets and other environmental effects), and comprehensive examination of potential outcome measures. Also, many studies are uncontrolled or use inappropriate or incomplete control groups. Therefore, it is impossible to draw conclusions about probiotic efficacy on the basis of the current literature.

Evidence for use of probiotics in healthy dogs and cats

In vivo studies have been conducted on the use of probiotics in healthy dogs and cats. These studies have described the impact of oral administration of probiotics on the GIT microbiota population, GIT metabolome, systemic and GIT immune response, and biomarkers of GIT function. Although studies of healthy dogs and cats frequently provide apparently positive effects of probiotics, the implication for disease states is unknown. For healthy animals, there are many potential benefits of probiotics that could be evaluated. These range from improving fecal consistency and fecal odor to augmenting immunity against future infections and modulating the immune system to prevent immune-mediated diseases. Most of these applications have not been explored. Importantly, no study has found major negative effects of probiotics administered to healthy animals, which suggests their relative safety and allows further investigation.

Studies on probiotic administration to healthy animals are often used to assess the ability of a microorganism to survive transit in the GIT and persist after cessation of administration. For the present report, effective transit is defined as identification of probiotic microorganism species in fecal material, as determined by results of bacterial culture or PCR assay. It is important to mention that identification of DNA with a PCR assay does not imply viability; rather, it implies that a microorganism was present in the probiotic and recognizable DNA sequences survived GIT passage. The importance of persistence of an identifiable microorganism is unclear because there also could be an effect that persists after the probiotic microorganism can no longer be detected. Investigators of 1 study39 of dogs found altered Lactobacillus spp strain diversity (as assessed by use of denaturing gradient gel electrophoresis) after cessation of probiotic administration. The fact that altered strain diversity was evident when the probiotic bacteria could no longer be detected implies a continued effect. Decreased microbial diversity has been documented for disease states (eg, IBD) and after antimicrobial treatment.40–42 Some authors have also presumed that decreased microbial diversity is a benefit of probiotic administration and evidence of restoration of a healthy or stable bacterial population.43 However, this appears to be an opinion held by only a minority of researchers and clinicians. Also, the importance of shifts in microbiota populations in healthy animals and the clinical impact (if any) are unknown.

Many studies of healthy dogs and cats have reported changes in bacteria that are typically considered pathogens; thus, it is important to acknowledge that these microorganisms are present in healthy animals. Therefore, the presence of these presumed pathogenic organisms might not necessarily cause clinical disease, and any attempt to treat animals because of them might be ill-advised. Maintenance of a healthy bacterial end-product metabolome, which could be identical despite variations in microbiota, might be of more importance than maintenance of the microbiota.

Although most studies of healthy animals document viability of microorganism species in probiotic product and in feces, in vitro studies have revealed effects of nonviable organisms that, in some circumstance, may be greater than effects of viable organisms.44 Therefore, lack of viability or persistence does not imply lack of effect, especially when extrapolating data from healthy patients to a clinical population.

Evidence for probiotic use in dogs and cats with GIT illness

Probiotics have been administered to dogs and cats with acute and chronic enteropathies.

Acute enteropathy

Studies have been conducted on sled dogs with exercise-induced diarrhea. In 1 study,45 dogs in routine training that were administered a synbiotic (Enterococcus faecium SF68, Bacillus coagulans, L acidophilus, fructooligosaccharides, mannanoligosaccharides, and B vitamins) had decreased biodiversity of the fecal microbiota, with no change in fecal SCFA composition. Fatty acid composition of fecal material is evaluated as a marker of colonic health because SCFAs (eg, butyrate) are an important energy source for colonic epithelium.46–48 Furthermore, fecal scores (scales denoting fecal consistency as a surrogate of moisture content) improved relative to baseline values, and dogs administered probiotics had diarrhea for fewer days, compared with results for control dogs that received a placebo (microcrystalline cellulose).45 Although results of that study45 indicated a positive effect of the probiotic product, no conclusion can be drawn regarding an independent role of the probiotic component.

Furthermore, importance of changes in biodiversity of the GIT microbiota in the absence of metabolome changes is unknown. Investigators compared effects of E faecium SF68a and effects of a placebo in training sled dogs; the dogs that received the probiotic had a more rapid clinical improvement, fewer diarrhea episodes, and resolution of clinical signs by day 5 of administration, whereas diarrhea did not resolve in the placebo group during the 7-day study period.b Unfortunately, the investigators did not evaluate the microbiome or perform fecal biochemical analysis (eg, fecal SCFA content).

Administration of E faecium SF68a to cats in a shelter setting resulted in a lower percentage of cats with diarrhea for > 2 days, compared with the percentage of cats administered a placebo.49 A similar comparison could not be made for administration of the probiotic to dogs in the shelter because too few in the probiotic and placebo groups had diarrhea for > 2 days. That study was also limited because the clinical outcome was determined for a dynamic population (duration of administration of the probiotic or placebo differed, depending on the amount of time animals remained in the shelter), and the results were confounded by the presence of GIT parasites (15% of cats and 17% of dogs).49 Another studyc (performed by the manufacturer of the same E faecium SF68 producta) on shelter dogs compared the effect of metronidazole or metronidazole in combination with the same probiotic product.a Dogs that received the probiotic and metronidazole had a more rapid improvement in fecal scores (2.8 days vs 4.4 days for the metronidazoleonly dogs), but fecal score at study completion did not differ between the treatment groups. A synergistic effect between the probiotic and antimicrobial could not be excluded in that studyc because there was no group that received only the probiotic. Taken together, these studies do not provide evidence for use of this probiotic in dogs in a shelter setting and provide only weak evidence for use in cats in a shelter setting. It should be mentioned that some studies on the effects of E faecium SF68 have not been published in peer-reviewed journals or proceedings, which precludes a full evaluation of their results.

Dogs that received Bifidobacterim animalisd (canine isolate AHC7) before and during housing in a kennel had fewer episodes of stress-induced diarrhea, improved fecal scores, and increased numbers of Bifidobacteria spp (in cultures of fecal samples), compared with results for control dogs.50 These effects were dose dependent. Fecal Clostridium perfringens culture counts were unchanged. Although dogs originated from different environments, an attempt was made to decrease variability by use of a 2-week acclimation period and feeding of a standard diet. No fecal microbiome analysis was performed to allow comparison of results between dogs that were under the stress of being housed in a kennel and dogs during an at-home supplementation period.50 Administration of the same B animalis isolated at a higher dose twice daily in cocoa butter treats resulted in a shorter duration of clinical signs in dogs with acute idiopathic diarrhea (3.9 days vs 6.6 days for control dogs).51 Dogs were enrolled if they developed diarrhea during a 3-month period. With regard to a probiotic effect, it is important to mention that dogs (number unknown) received metronidazole at the veterinarian's discretion. Fewer dogs that received the probiotic also received metronidazole (38.5% vs 50% for the placebo group)51; however, metronidazole was usually given when multiple dogs in the same area had an outbreak of diarrhea, and the addition of metronidazole was a subjective decision. These limitations prevent a meaningful comparison because it is unknown whether baseline illness severity was equivalent between groups.51

A commercial combination producte (Lactobacillus farciminis [porcine isolate], Pediococcus acidiliactici, Bacillus subtilis [soil isolate], Bacillus licheniformis [soil isolate], and L acidophilus MA 64/4E [human isolate]) has been evaluated for dogs with acute diarrhea attributable to various causes.52 Compared with administration of a placebo, administration of the commercial product at twice the recommended dose 3 times/d resulted in a shorter duration of acute diarrhea (1.3 days vs 2.2 days for the placebo dogs), with no impact on vomiting duration or combined clinical signs. Results of that study52 are confounded by differences in the admitting complaint and severity of disease and potentially by concurrent unstandardized manipulation of the diet, which make it impossible to assess whether the difference between groups was truly a result of probiotic administration.

For dogs with antimicrobial-induced diarrhea, administration of the yeast Saccharomyces boulardii (1,000 mg/d) after diarrhea onset was associated with shorter duration of clinical signs (2.9 days vs 6.5 days for control dogs) and a more rapid return of fecal SCFA concentrations to baseline values.53 Dogs that received the probiotic concurrently with antimicrobials did not develop diarrhea and had no change in fecal SCFA concentrations. There was no difference in results between groups and time points (before diarrhea, at onset of diarrhea, at resolution of diarrhea, and 1 week after resolution) for culture of Escherichia coli, Shigella spp, Salmonella spp, and Campylobacter spp or for direct examination of fecal smears to detect C perfringens spores and Clostridium difficle toxin; no toxins or pathogens were isolated at any point.53

Overall, studies of dogs and cats with acute diarrhea provide weak evidence for the exclusive use of probiotics, yet provide substantial evidence for preventable stress-induced diarrhea (attributable to housing in shelters and kennels, extreme physical exercise, or antimicrobial administration). Evidence for use of probiotics in dogs and cats with naturally occurring acute diarrhea is lacking.

Chronic enteropathy

Evidence for efficacy of probiotics in dogs with chronic infection attributable to Giardia spp is limited. A subset of shelter dogs with Giardia-induced diarrhea of at least 2 days' duration that received E faecium SF68 in combination with metronidazole (25 mg/kg [11.4 mg/lb], PO, q 12 h) had normal fecal consistency by study completion, compared with only 43% of Giardia-positive dogs treated with metronidazole alone.c Severity of clinical signs related to giardial infection versus comorbidities was unknown, and the number of dogs with giardial infection was small. The independent effect of the probiotic could not be assessed in that study because of the lack of a probiotic-only group (without metronidazole). In a study54 of dogs with chronic infection attributable to Giardia spp (diagnosed by direct fecal immunofluorescence assay), administration of E faecium SF68 over a 6-week period had no advantage over administration of a placebo powder in terms of clinical response, improvement in shedding of Giardia spp in the feces, or change in immune indicators (fecal IgA content or blood leukocyte phagocytic activity). The fecal microbiome was not evaluated in that study.54

Several studies have been conducted to evaluate dogs with food-responsive enteropathies. In 2 studies,55,56 addition of a probiotic combinationf (an L acidophilus NCC2628/NCC2766–Lactobacillus johnsonii NCC2767 combination, E faecium, fructosoligosaccharides, and gum arabic) to a standardized elimination diet resulted in similar improvement in clinical signs, compared with results for use of a standardized elimination diet alone. Both groups had a similar decrease in Enterobacteria spp counts (determined by culture of a fecal sample)55 and a similar change in histopathologic markers of inflammation (interleukin-1β and interleukin-18).56 The authors concluded that there was a large impact of the standardized elimination diet. In contrast, dogs with idiopathic IBD had a similar, although slower, response (10.6 days) to administration of a probioticg (Lactobacillus spp, Bifidobacteria spp, and Streptococcus spp), compared with the response (4.8 days) for dogs that received metronidazole (20 mg/kg [9.1 mg/lb], PO, q 12 h) and prednisone (1 mg/kg [0.45 mg/lb], PO, q 24 h).57 However, baseline clinical scores in that study57 were lower (which suggested milder disease) in the group that received the probiotic. Mucosal concentrations of transforming growth factor-β increased in both groups, with a greater increase for dogs receiving the probiotic. The number of mucosal CD3+ T cells decreased and the number of FoxP3+ regulatory T cells increased in dogs receiving the probiotic. A quantitative PCR assay targeting Faecalibacterium spp and Turicibacter spp in feces revealed lower numbers of these bacteria in the probiotic group at baseline, compared with the numbers for healthy control dogs; however, the number of Faecalibacterium spp increased in the probiotic group, which suggests a positive modulation of the microbiome.57 In that study,57 investigators used the PCR assay to narrow assessment of the entire fecal microbiota to these 2 genera. A broader assessment of the microbiome, which might have revealed other (and potentially negative) effects, was not conducted.

Differences in histopathologic findings between dogs with food-responsive and idiopathic enteropathies in the aforementioned studies could reflect differences in response to probiotic administration or differences in underlying disease mechanisms. Although these results are encouraging for dogs with IBD, it is important to emphasize that the probiotic combination in these studies contained probiotics and prebiotics and that the isolated effect of either was not examined. Overall, there currently is no definitive evidence that probiotics are effective for dogs with chronic diarrhea, especially not dogs with more severe IBD. However, the fact that probiotics can affect both the host and GIT microbiota of dogs with IBD suggests that further investigation is warranted.

Six German Shorthair Pointers with chronically poor fecal scores were allowed a 12-week period of diet acclimation and then received L acidophilus (DSM 13241).58 This regimen reduced frequency of defecation and improved fecal consistency during and for 4 weeks after cessation of probiotic administration. Fecal dry matter (ie, water-free percentage of fecal material [an objective measure of fecal consistency]) was increased only during probiotic administration. Fecal samples were assessed for C perfringens, Escherichia spp, lactobacilli, and Bifidobacteria spp and by use of fluorescent in situ hybridization; results indicated no significant changes in baseline microorganism populations.58 There were no significant changes in the numbers of Lactobacilli spp and Bifidobacteria spp, but there were decreased numbers of C perfringens and Escherichia spp in dogs during probiotic administration and a more constant microbiome population (as assessed by use of fluorescent in situ hybridization), which led the authors to suggest that probiotic administration led to stabilization in the GIT populations of C perfringens and Escherichia spp.58 However, analysis of the fecal microbiota by use of fluorescent in situ hybridization limited the assessment of the microbiota to only a few species. Broader investigation of the entire microbiota with large-scale DNA sequencing was not conducted. In addition, that study58 involved only a small number of dogs, and further investigation will be needed to elucidate the importance of these apparent positive benefits.

For client-owned cats with undefined chronic (> 3 weeks' duration) diarrhea, fecal firmness increased in 72% of cats that received a synbiotic59 (E faecium NCIMB 30183, Bifidobacteria bifidum NCIMB 30179, Enterococcus thermophiles NCIMB 30189, Lactobacillus delbrueckii NCIMB 30186, Lactobacillus casei NCIMB 30188, Lactobacillus plantarum NCIMB 30187, L acidophilus NCIMB 30184, fructooligosaccharides, and arabinogalactans) when a capsule of the synbiotic was opened and the contents were mixed in food. However, that was an uncontrolled study60 in which cats received other treatments and had other diet changes, and response to treatment was subjectively evaluated by owners. In a controlled study,61 cats with undefined chronic diarrhea had a decrease in frequency of severe diarrhea when fed an E faecium SF68 probiotic.

Overall, limited comparisons can be made regarding probiotics and their use in animals with acute and chronic GIT illness. In most studies, underlying disease processes were unknown, which precluded specific therapeutic targets and the use of directed evaluation markers. Furthermore, studies of sick pets often focus on resolution of clinical signs and lack evaluation of the baseline GIT microbiome and how it changes with administration of probiotics, synbiotics, or treatments, which potentially overlooks subtle but important changes. For any given disease, only 1 or 2 probiotic microorganism species (when defined) were evaluated, and most studies were underpowered or confounded by response to traditional treatments. Similar to results for healthy animals, no adverse effects were reported with probiotic administration, and additional studies are warranted.

Evidence for use of probiotics in puppies and kittens

The impact of probiotic administration on GIT microbiota, health, immunity, and clinical signs in puppies and kittens has been evaluated in a few studies. In 1 study,i increased numbers of fecal Bifidobacteria spp and Lactobacillus spp (typically considered beneficial GIT bacteria) were detected in puppies receiving E faecium SF68a (administered in food) from 3 weeks to 1 year of age. However, there was no difference between puppies fed or not fed the E faecium SF68a with regard to numbers of fecal E coli, Campylobacter spp, or Salmonella spp, and no clinical benefit was detected.h In contrast, E faecium SF68 was inconsistently detected via bacterial culture and subsequent PCR assay in the feces of pathogen-free kittens receiving the same commercial producta from 7 to 27 weeks of age62; there was no difference in fecal quality and detection of fecal Clostridium enterotoxin (as determined with an ELISA) between kittens receiving and not receiving the probiotic.62 Another E faecium producti had positive effects when administered to healthy research puppies from 2 to 5 days of age.63 Administration was associated with improved nutrient digestibility (determined on the basis of fecal analysis) in large-breed puppies and improved daily weight gain in small-breed puppies, compared with results for control dogs.63 In contrast, E faecium SF68a had no effect on weight gain in kittens.62 Puppies61 and kittens62 receiving this commercial producta from 8 to 52 weeks of age and 7 to 27 weeks of age, respectively, had enhanced immune responses to vaccination (vaccinations were administered at weeks 1 and 4 of the study). Although there was a slight increase in fecal IgA content (specific to SF68) in puppies, samples were cross-reactive against commensal organisms in control dogs. The IgA content is of interest, particularly the IgA content in the feces, because it is the major antibody component of the GIT mucosa and therefore a surrogate marker for the local immune system. An increase in IgA content could be interpreted as a marker of enhanced protection against pathogens. However, increased IgA concentrations might represent a response to increased antigenic stimulation without enhanced immunity or to the body's protective mechanism against a harmful stimulus. Only challenge exposure with a pathogen can prove that increased IgA concentrations represent enhanced protection. The authors suggested that these changes represented no harm to GIT commensals on the basis of a lack of clinical difference between dogs receiving the probiotic and control dogs receiving a liver digest vehicle.64 Lack of clinical signs does not rule out major impacts on the baseline GIT microbiome or long-term implications of an upregulated immune response. Kittens receiving the probiotic had higher serum and salivary concentrations of IgA against FHV-1, but there were no significant differences in concentrations of IgG against FHV-1 and feline coronavirus, total IgA, or total IgG. In contrast to puppies, kittens receiving the probiotic had increased numbers of peripheral CD4+ lymphocytes, compared with results for control kittens.64 These results in kittens suggest upregulation of the immune system, but without clinical context, the risks or benefits of this response is unknown.

Healthy 7- to 8-month-old research puppies that received B subtilis (strain C-3102; added to a commercial diet at 0.01% of diet) had improved fecal scores, higher dry-matter content, and lower ammonia concentrations, compared with results for control puppies.65 However, no difference in fecal output was noted, and fecal scores were ideal in both groups.65

In 1- to 6-month-old puppies with parvovirus enteritis (diagnosed by use of an ELISA) treated by use of standard supportive care, adjunctive administration of the probiotic combinationg of Lactobacillus spp, Bifidobacterium spp, and Streptococcus spp was associated with reduced clinical signs, increased lymphocyte counts, and improved survival rates, compared with results for control puppies.66 No fecal microbiome evaluations were performed, and although puppies were randomly assigned to groups, the method of randomization was not described. Three puppies that received only standard supportive care died within the first 3 days, compared with only 1 puppy that received standard supportive care and the adjunctive probiotic and died during that same time period, which could suggest unequal disease severity at baseline. It is possible that the difference in outcome was the result of selection bias or absence of optimal care by the owner and not to disease management.

During an acute diarrhea outbreak in kittens, only 9.5% of kittens that received E faecium SF68 required other medical interventions, compared with 60% of control kittens that did not receive the probiotic67; however, the use of other treatments was subjectively determined. Kittens that received the probiotic had a more rapid resolution of clinical signs, compared with kittens that did not receive the probiotic (18 days vs 45 days), and had increased numbers of fecal Bifidobacteria spp, decreased numbers of fecal C perfringens, and increased serum IgA concentrations.67

Studies of puppies and kittens have limitations similar to those for studies of adult dogs and cats, including small numbers of subjects, limited evaluations for disease states, and limited control populations for direct comparison. One important feature, which is highlighted when puppies and kittens are concurrently evaluated, is that important species differences in response to probiotics exist; therefore, evidence from one species cannot automatically be extrapolated to another species. Probiotics are also likely to have different effects in immature animals than in adult animals because the GIT microorganism population transitions to the adult microorganism population during development in immature animals.1

Evidence for use of probiotics in dogs and cats with non-GIT illness

Probiotics have been evaluated for use in several non-GIT illnesses because of their potential effects on the immune system and systemic inflammation.68–78

Atopic dermatitis

Several studies79–81 were conducted to evaluate research dogs sensitized to Dermatophagoides farinae. One breeding pair was mated to produce 2 litters. The first litter served as control puppies, with the breeding pair receiving Lactobacillus rhamnosus GGk prior to birth of the second litter. Puppies in the second litter received the probiotic from 3 weeks to 6 months of age. All puppies were sensitized to D farinae and subsequently underwent intradermal allergen testing. Although the puppies that received the probiotic had reduced reactions for intradermal skin tests and lower IgE titers, clinical signs after allergen exposure were not different, compared with results for the first litter, and evaluation of skin biopsy specimens revealed no difference in filaggrin expression (a protein that is decreased in animals with atopic dermatitis).79,81 At 3 to 4 years of age, dogs that received the probiotic had reduced severity of clinical signs (eg, dermal erythema or excoriations) on the basis of results for a standardized scoring system after allergen exposure,80 compared with results for the first litter.80 That study80 had multiple limitations, including a small population of nonatopic Beagles (n = 10) used for generation of cytokine reference ranges, lack of a placebo group, and lack of fecal microbiome analysis. Comparisons among puppies were also performed on different litters, which could have had differences in regard to maternal-derived immunity and environmental antigenic exposure.

Genitourinary tract infection

In women with recurrent urinary tract infections, oral administration of a probiotic helps to restore normal vaginal microbiota by increasing vaginal numbers of LAPB.82 On the basis of that finding, a study83 was performed to determine whether oral administration of a probiotic would increase vaginal numbers of LABP in dogs. Investigators found that LAPB are uncommonly isolated from the vaginal vault of healthy spayed female dogs (approx 20% of dogs) and that oral administration of a commercial synbioticl (Lactobacillus spp, Bifidobacterium spp, Bacillus spp, yeast, enzymes, and prebiotics) did not increase vaginal populations of LAPB in these client-owned dogs. However, in dogs with a history of recurrent urinary tract infections, LAPB were even less common (< 10% of dogs).84 However, the effect of probiotic administration on LAPB was not evaluated in dogs with chronic urinary tract infections. It is possible that although there is no effect in healthy dogs, female dogs with reduced numbers of LAPB and a history of recurrent urinary tract infections might benefit from probiotic administration.

Administration of a synbiotic productl (Streptococcus thermophiles, L acidophilus, Bifidobacterium longum, and psyllium husk) had no effect on azotemia (ie, no significant percentage change in BUN or creatinine concentration) in cats with stable chronic kidney disease in a double-blinded, controlled (prebiotic only), randomized clinical trial.85 This result was in contrast to the manufacturer's claim. Albumin content was assessed in that study84 as a surrogate for hydration status, and it too remained within reference limits and was unaffected by probiotic administration. However, the probiotic was not administered as formulated (an enteric-coated capsule); instead, capsule contents were sprinkled on the food. In an earlier study,86 an improvement in BUN and creatinine concentration was reported for a group of 7 cats with chronic kidney disease receiving that product.l However, there were multiple flaws in the methods of that study86; it was an uncontrolled, nonblinded study in which the diagnosis of chronic kidney disease was based on palpation of small kidneys in cats with persistently elevated BUN and creatinine concentrations, with no determination of urine specific gravity and no control for hydration status. Also, cats recruited for that study86 were fed a variety of diets and received other concurrent medications. Therefore, there currently are no indications for administration of probiotics to cats with chronic kidney disease. Importantly, investigators of these studies evaluated the effect of the probiotic on azotemia as a marker for improved glomerular filtration rate and renal function. However, probiotics might influence urea processing in the GIT such that serum BUN concentration is decreased via reduced amino acid fermentation in the GIT or via ion trapping of ammonium from luminal acidification without any effect on renal function and glomerular filtration rate.87 In addition, changes in creatinine concentrations can be a result of changes in muscle mass. Taken together, the effect of probiotics on renal function in these studies is questionable.

Respiratory tract disease

Administration of E faecium SF68a to FHV-1–infected research cats did not have a significant impact on viral DNA expression or viral shedding. To account for the potential effect of stress, cats were housed in groups for 28 days, housed individually for 28 days, and then housed in groups for an additional 84 days. It should be mentioned that none of the cats had positive results when tested for FHV-1 DNA by use of a fluorogenic PCR assay; thus, the effect of SF68 administration on the amount of FHV-1 shedding could not be determined. All cats had elevated anti–FHV-1 antibody concentrations (measured with an ELISA), and those did not change over time. Although cats had fewer episodes of conjunctivitis when receiving the probiotic, compared with results for cats receiving a placebo, some cats had received topical antivirals, which introduced a confounding factor. A potential benefit to administration of the probiotic was observed in that decreased fecal microbiota biodiversity (as determined with temporal temperature gradient electrophoresis and PCR assay) was detected in cats receiving the placebo, but biodiversity was maintained in the cats receiving the probiotic.43 No attempt was made to examine the mechanism of decreased biodiversity in cats receiving the placebo.

Overall, evidence for probiotic use in non-GIT illness is limited to a few studies with limited numbers of animals. Populations often had loosely defined diseases or were not naturally affected by the proposed disease target. These studies included limited microbiome assessment, which prevents a full understanding of the interaction between the GIT and affected body systems.

Clinical Summary

A clear role for administration of probiotics to dogs and cats is not evident on the basis of the current literature. Evidence in healthy dogs, as well as dogs with GIT and non-GIT illness, suggests some effect of probiotics on the GIT microbial population, metabolic status (eg, fecal SCFA concentrations), and immune system as well as systemic effects (eg, changes in serum biochemical variables), but there are no clear clinical benefits. Similar but weaker evidence is available for cats, but with fewer controlled studies.

Although general conclusions can be drawn for a specific study population, results were variable among studies, and some studies indicated no effect of probiotics. Undetected differences may have resulted from inclusion of small numbers of animals and low statistical power; however, discrepancies in results among studies may have been secondary to differences in study design or lack of specific product efficacy, representing real conflicting differences. Unfortunately, it is difficult, if not impossible, to make direct comparisons among studies. There are no standards for probiotic formulations and doses, administration duration, or timing of clinical evaluation and study end points. In many studies, investigators attempted to document persistence, colonization, and duration of effects, but methods differed among studies, including use of bacterial counts, PCR assays, and fecal qualities. Alterations in variables among healthy animals are not fully understood.

Many investigators considered changes in presumably pathogenic or beneficial bacteria as important outcomes but did not fully speciate microorganisms (eg, pathogenic vs commensal clostridial organisms) and did not take into account interactions among bacteria. Metabolomics of the GIT are rarely studied in veterinary medicine, which limits conclusions that can be drawn about the effects of probiotic administration on beneficial versus pathogenic species.

Currently, evidence suggests that administration of probiotics may play a role in animals with acute GIT disease, especially stress-induced diarrhea, mainly for decreasing the time until resolution of clinical signs when compared with outcomes for standard treatments. Results for studies of dogs with chronic enteropathies are more difficult to interpret because they are typically confounded by administration of concurrent treatments. No substantial adverse effects were noted after probiotic administration in any of these studies, which suggests relative safety over a short period for the microbial populations evaluated.

On the basis of examination of the current data, no specific product can be recommended for use. Effective probiotic species are likely disease- and individual-specific microorganisms. Because of questions regarding accuracy of product labeling, products should be evaluated by outside laboratories.88 Long-term outcomes and administration periods require evaluation for both safety and efficacy.

Future studies should focus on clear definitions of disease, standardized study populations, and inclusion of both healthy and placebo (or at least standard treatment) control animals to enable direct comparison of the effects of probiotic administration in a population. Consistent microbiome and metabolome assessment will help more clearly define mechanisms of response and GIT influences in GIT and non-GIT diseases. Ultimately, the most appropriate approach to specific disease processes can be developed.

ABBREVIATIONS

FHV-1

Feline herpes virus-1

GIT

Gastrointestinal tract

IBD

Inflammatory bowel disease

LAPB

Lactic acid–producing bacteria

SCFA

Short-chain fatty acid

Footnotes

a.

Fortiflora, Nestle Purina PetCare, St Louis, Mo.

b.

Gore AM, Reynolds A. Effects of Enterococcus faecium SF68 on stress diarrhea (abstr), in Proceedings. Am Coll Vet Intern Med Forum 2012;543.

c.

Fenimore A, Groshong L, Scorza V, et al. Effect of the probiotic Enterococcus faecium SF68 supplementation with metronidazole for the treatment of nonspecific diarrhea in dogs housed in animal shelters (abstr), in Proceedings. Am Coll Vet Intern Med Forum 2012;793.

d.

IAMS Prostora, Procter & Gamble Pet Care, Mason, Ohio.

e.

ZooLac Propaste, Chem Vet A/S, Silkeborg, Denmark.

f.

Synbiotic D-C, Protexin Ltd, Somerset, England.

g.

VSL#3, VSL Pharmaceuticals Inc, Gaithersburg, Md.

h.

Paciflor, Prodeta, Vannes, France.

i.

Fermactiv, C. Richter Gesmbh Co KG, Wels, Austria.

j.

Culturelle HS, Amerifit Brands/Culturelle, Cromwell, Conn.

k.

Y+ Powder, Rayne Clinical Nutrition, Kansas City, Mo.

l.

Azodyl, Vetoquinol, Fort Worth, Tex.

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