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Probiotics are defined as live microorganisms that confer health benefits on the host when administered in adequate amounts.1 Although most probiotics are bacteria, yeast species may also meet these criteria. Increasingly, probiotic quantity, intestinal epithelium adhesion capability, antimicrobial activity, and antioxidant potential have been recognized as important for probiotic efficacy.2 Prebiotics, nondigestible substrates that selectively promote growth of beneficial microbes, often are combined with probiotics in synbiotic formulations. Prebiotics selected for use in synbiotics might enhance activity of included probiotics, those of native microorganisms, or both. Pro- and synbiotics exert their effects by shifting the host’s microbiome and its metabolome to influence local gut function and systemic physiology.3 They support intestinal colonization, crowd out pathogenic bacteria, and enhance host immune function and digestive health.2 Their use in veterinary medicine has expanded rapidly in recent years. Both are used increasingly to manage gastrointestinal (GI) and extra-GI issues.4-8 This could be due to increasing client demand for natural or alternative modalities, intolerance of conventional management’s side effects, and/or failure of said management options to optimize patient outcomes. There is an expanding body of evidence supporting their use in the management of acute diarrhea, chronic enteropathy, and antibiotic-associated GI signs.

Common gastrointestinal applications

Stress and self-limiting gastroenteritis

Research does not show universal support for probiotics in managing stress-related GI signs. In adequately powered studies, pro/synbiotics decreased feline and canine diarrhea in shelter environments.9,10 In contrast, probiotics have not been shown to reduce diarrhea in weanling kittens,11 working dogs under quarantine,12 or racing Alaskan sled dogs, except during a weeklong contagious outbreak.13

The impact on self-limiting gastroenteritis has been more consistently positive. Probiotics have been shown to decrease the duration of self-limiting diarrhea, whether accompanied by vomiting or not, in dogs by 32% to 41% compared with controls in multiple randomized trials.14-17 Probiotics also have been found to significantly decrease hyporexia and vomiting,18 the use of rescue antibiotics,15 and withdrawal from research studies for "rescue" therapy such as antiemetics and antibiotics.16 Finally, resolution of acute diarrhea significantly correlated with probiotic administration and dietary modification but not antibiotics in a large observational study.8 Synbiotic administration also can help maintain microbiome stability and normalize the dysbiosis index (DI), whereas metronidazole causes severe disruptions in the microbiome and metabolome.19,20

Infectious gastroenteritis

Probiotics reduce the severity of clinical signs of some types of infectious gastroenteritis, although adequately powered study results are limited. In one study, dogs with naturally occurring parvovirus enteritis were administered conventional therapy alone or in combination with a high-dose, multistrain probiotic cocktail. Clinical illness scores, determined using objective criteria, were significantly lower on days 3 and 5 for dogs administered the probiotic than for dogs receiving standard supportive care alone.21 Mortality was also lower, though this difference was not statistically significant. Positive results were also identified for dogs with distemper virus-related diarrhea in a lower-quality trial.22

Although clinical illness scores differed significantly from baseline 1 day earlier in dogs with acute hemorrhagic diarrhea syndrome (AHDS) given probiotics vs placebo, scores were not statistically compared between groups; scores were clinically equivalent between groups at each time point, and all dogs responded well to management.23 There also were no significant differences in clinical recovery time, appetite, or stool consistency in dogs with AHDS administered probiotics vs fecal microbiota transplantation in a subsequent study,24 with rapid clinical improvement noted in both groups. Because there was no placebo group in the second study, it is unclear whether these findings indicate that the treatments had equivalent efficacy or no impact on outcomes. Further study with adequate controls is warranted to determine the value of probiotics for management of AHDS.

Non–food-responsive chronic enteropathy

Cats with idiopathic chronic enteropathy (CE) administered a multistrain synbiotic (Proviable®-DC) had significantly improved fecal scores in an open-label trial.25 Similarly, 9 of 10 cats with idiopathic constipation/megacolon administered a high-dose probiotic in an uncontrolled trial had clinical resolution of signs, with clinically and statistically significant histologic improvement.26

Clinical activity scores similarly improved in dogs with large-bowel dysmotility administered probiotics and a hydrolyzed, high-fiber diet.27,28 Clinical activity scores, defecation frequency, and fecal consistency also were significantly improved in dogs with CE administered Saccharomyces boulardii vs placebo in addition to conventional management,29 as well as in dogs with CE or colonic polyps given a high-dose multistrain bacterial probiotic.30 In another randomized controlled trial, clinical and histologic response rates did not differ for dogs treated with prednisone/metronidazole vs the same probiotic cocktail, with enhanced T regulatory cell function and dysbiosis normalization only in the probiotic group.31 A follow-up randomized controlled study found no difference between dogs administered diet and prednisone alone compared with the probiotic,32 suggesting probiotic effects may be blunted by prednisone coadministration. Finally, dogs with CE administered a synbiotic combined with immunoglobulin Y (IgY) in a randomized, double-blind, placebo-controlled study had significantly improved clinical activity scores, inflammatory markers, and beneficial shifts in mucosal microbiota.33

Chemotherapy-induced adverse gastrointestinal signs

One small, randomized controlled trial evaluated the impact of probiotics on chemotherapy-induced GI signs in dogs receiving CHOP chemotherapy for multicentric lymphoma.34 Dogs administered probiotics had no episodes of diarrhea, whereas 4 of 5 dogs in the control group developed diarrhea. Similarly, vomiting was noted in 1 in 5 dogs administered probiotics vs 4 in 5 dogs in the placebo group. However, differences between groups were not statistically significant. No dog administered probiotics developed secondary sepsis, even though 4 of 5 dogs developed chemotherapy-induced neutropenia (grade 1, 2 dogs; grade 3 and 4, 1 dog each).

Antibiotic-associated gastrointestinal signs (AAGS)

Probiotic administration significantly decreased the duration of lincomycin-induced diarrhea in healthy dogs, and diarrhea did not develop when administered concurrently with antibiotics.35 Oral probiotic administration also prevented antibiotic-induced dysbiosis in dogs administered cefovecin following surgery, whereas bacterial diversity significantly decreased in dogs administered cefovecin alone.36 These results suggest positive effects of probiotics in animals receiving injectable antibiotics, although further study is warranted prior to making widespread recommendations.

Results for preventing of AAGS due to oral antibiotics are more mixed. Administration of a probiotic 2 hours prior to administration of amoxicillin/clavulanate did not significantly decrease AAGS in cats in one study.37 In another study, coadministration of a synbiotic with clindamycin also did not decrease diarrhea in cats38; however, vomiting occurred less frequently in the synbiotic group.32 In a follow-up crossover study, administration of a higher-dose synbiotic (Proviable®-Forte) 1 hour after clindamycin was associated with significantly increased food intake and decreased vomiting in cats, and cats receiving the synbiotic were more likely to complete the initial phase of the study.1 Significant differences also were identified for food intake between the initial treatment period and after a 6-week washout, a phenomenon known as period effects. Period effects indicate the washout time between treatments was inadequate to prevent carryover effects from the initial treatment received. In this case, food intake required to maintain weight was significantly higher at the start of period 2 for cats initially in the placebo group, consistent with the development of antibiotic-induced CE. Several other cats from the placebo group had persistent diarrhea at the end of the washout period, although period effects were not statistically confirmed. Differences in successful completion of the treatment period between the first and second phases of the study suggest that the beneficial effects of synbiotics persisted for at least 6 weeks after administration.

Similarly, in a crossover study with an 8-week washout, derangements in food intake were significantly lower for dogs administered a bacterial/yeast synbiotic combination (Proviable®-Forte with Mycequin®) 1 hour after receiving enrofloxacin/metronidazole compared with placebo.39 Although vomiting and diarrhea did not statistically differ between groups, both were less severe during the second phase of the study. Because AAGS worsen with repeated exposure, the presence of less severe signs during or after synbiotic administration suggests a protective effect of the synbiotic combination against future AAGS. Significant differences in the microbiome and metabolome between groups also were found in several studies.3,38,40 Based on these results, administration of a synbiotic 1 to 2 hours after oral antibiotic administration has the highest likelihood of minimizing AAGS in cats and dogs.

Choosing a probiotic: Selection considerations

Neither prebiotics nor probiotics are regulated as drugs in the United States. In one study, less than one-third of evaluated probiotics labeled for animal use met or exceeded the type and quantity of viable organisms listed on their labels.41 For this reason, only probiotics that undergo regular evaluations for content and viability by their manufacturers should be used.

The most important criterion in product selection is demonstrated efficacy in relevant peer-reviewed literature. Standardized evaluation criteria relating to microbiota composition, SCFA production capability, and clinical indices also are being developed to improve assessment consistency across studies in dogs and cats.2

Product species, microbial strains, and total microorganisms (colony-forming units) should be considered when scientific data are lacking. Commercial probiotics contain between 1 and 20 or more microorganism species or strains. More potent products (those containing more colony-forming units and microbial strains) are recommended for the management of metabolic and GI disorders based on correlations between dose and efficacy in humans.42-44 Yeast probiotics might be preferable for immunocompetent patients receiving antibiotics, because they will not be inactivated if administered concurrently. Products containing prebiotics and probiotics (i.e., synbiotics) often are preferred for GI disorders because they act synergistically to support colonocyte health, prevent binding of pathogenic bacteria, and enhance probiotic growth.2 Other considerations when selecting a product include administration details (such as ability to mix in food), storage requirements, and the inclusion of animal proteins as flavorants, which could adversely impact patients with food sensitivity.

The future of probiotics

Probiotics rarely have adverse effects when appropriately administered, but an evidence-based approach to product selection and dosing is essential for maximal efficacy. Only products that undergo regular testing for content and viability should be used. Limited but moderate- to high-quality evidence supports probiotic or synbiotic administration for management of shelter-induced diarrhea, self-limiting gastroenteritis, parvovirus, intestinal dysmotility, chemotherapy-associated GI signs, and CE in cats and dogs. Randomized, blinded placebo-controlled studies support the use of Proviable®-Forte administered alone or in combination with Mycequin® to mitigate AAGS in patients receiving antibiotics. Evidence also supports the use of probiotics for some extra-gastrointestinal disorders such as chronic kidney disease.5 Benefits of probiotics in the management of canine anxiety have been reported in abstract form,45 but the abstract lacked the detail required to determine the clinical effect. Until study results are published in a peer-reviewed format, an evidence-based recommendation cannot be made regarding the use of probiotics for anxiety. Results for other disorders such as canine atopy are mixed,4,6,7,46 with positive results found primarily in studies using probiotics with higher colony-forming units.4,6,7 This emphasizes the importance of careful product selection, dosing, and attention to details of published research.

References

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