Immune-Stimulating Properties of Probiotics

Microbial organisms make up approx­imately 90% of the body’s cells, so it should come as no surprise that their composition can greatly influence host immunity. Many disease processes, including diarrhea, atopy, and upper respiratory disease, are caused in part by immune disturbances due to microbial imbalances.¹ Therefore, investigative studies on the use of probiotics, or live nonpathogenic organisms, in human and animal medicine have increased signifi­cantly in recent years.

At the 2018 Western Veterinary Conference in Las Vegas, Nevada, Michael Lappin, DVM, PhD, DACVIM, discussed the potential immunologic benefits of probi­otics in veterinary medicine. Dr. Lappin, director of the Center for Companion Animal Studies at the College of Veterinary Medicine and Biomedical Sciences at Colorado State University (CSU), cited results from studies conducted worldwide to explain the current understanding of nonspecific and targeted uses of probiotics in veterinary medicine.

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Choose Probiotics Wisely

As the popularity of probiotics has boomed, so has the overwhelming diversity of available products. “Not all probiotics are created equally,” Dr. Lappin noted. A particular probiotic’s reported effect may not carry over across different microbial species or even subspe­cies. Just as important, different probiotics may have immune-modulating effects that range from immune stimulation to immune dampening.

When choosing probiotics for veterinary use, Dr. Lappin advised picking products that consistently meet the label’s claim and for which the manufacturer can provide stability data to prove the product’s shelf life and number of organisms. “Some companies,” he cautioned, “cannot produce this information.” In a study that examined small animal diets claiming to contain probiotics, 26% (5/19) of the examined diets lacked relevant growth of any beneficial bacteria, and none of the products contained all of the organisms listed on the label.² The key takeaway from this infor­mation, Dr. Lappin said, is that veterinarians “should purchase probiotics from reputable companies with excellent quality control that support research on their product’s efficacy.”

Enhanced Immune Function in Young Animals

Dr. Lappin mentioned that while several probiotics have been studied in clinical trials, the majority of his research work has been with the Enterococcus faecium strain SF68, which is the probiotic in the dietary supplement FortiFlora (ProPlan Veterinary Diets, Purina).

A 2003 study discussed the use of E faecium SF68 in dogs and evaluated the effect of feeding the probi­otic on specific and nonspecific immune function in puppies.³ After receiving a canine distemper virus (CDV) vaccine, puppies were fed either a regular diet or one supplemented with SF68 probiotic from wean­ing until 1 year of age.³ The data revealed that fecal immunoglobulin (Ig) A, as well as circulating IgA and IgG specific for the CDV vaccine, were all signifi­cantly higher in dogs that received the probiotic-sup­plemented diet. Also, there was evidence that SF68 probiotic enhanced B-lymphocyte production, because puppies fed the probiotic diet had a greater proportion of circulating mature B cells than did control dogs.³ One drawback to the study, Dr. Lappin noted, was that the investigators be-gan recording data after 10 weeks of probiotic use. Therefore, the ques­tion remained whether significant immune enhancement could occur in even less time.

In response, Dr. Lappin designed a study to examine the effect of E faecium SF68 supplementation on immune function in apparently healthy young adult beagles. In this experiment, the dogs were evaluated before and after 4, 8, and 12 weeks of supplementation, with the postsupplementation results compared with baseline values. The data, which were presented as a research abstract at the American College of Veterinary Internal Medicine meeting in 2017, demonstrated evidence of immune modulation of both T and B lymphocytes within 4 weeks of probiotic use.

Adjunct Therapy For Chronic Diseases

This work in beagles and a previous study published by Dr. Lappin’s group in healthy cats suggested that E faecium SF68 could be an immune-enhancing probi­otic. His research group then considered what clinical trials or experimental models could be used to prove that the effects seen in healthy animals could have utility in clinical situations.

Feline Herpesvirus

Feline herpesvirus 1 (FHV-1) is an extremely common pathogen in shelter environments. In 1 study, Dr. Lappin’s group at CSU screened humane society cats exhibiting upper respiratory signs for several patho­gens, including FHV-1, Mycoplasma spp, Bordetella bronchiseptica, Chlamydophila felis, Pasteurella, and Moraxella.⁴ By far the most prevalent pathogen, FHV-1 was detected in 98% (51/52) of sampled cats. Although most lifelong carriers of FHV-1 do not experience significant issues from the disease, recurrent ocular and respiratory signs can occur, especially during periods of stress.

Dr. Lappin’s group then performed a randomized, blinded study examining kittens with chronic FHV-1 infection.⁵ Each of the 12 cats was administered either oral E faecium SF68 probiotic or a placebo fed with food and monitored for signs of FHV-1. After an initial 14-day equilibration period, cats were exposed to 3 consecutive “stress periods”: group housing for 28 days; individual cage housing for 28 days; and, finally, group housing for 84 days with surgical sterilization. The treated group received probiotic for a total of 140 days. Throughout the study, FHV-1 shed­ding and intestinal microbiome diversity were exam­ined using fecal samples, and herpesvirus-specific humoral and cell-mediated immune responses were measured in serum samples.

Cats that were fed E faecium SF68 had significantly greater fecal microbial diversity compared with control cats. Conjunctivitis, a common clinical sign of FHV-1 infection, was observed in less than 5% of cats supplemented with SF68 compared with about 30% of cats receiving the placebo diet, a statistically signifi­cant difference. These results suggested that immune enhancement by the probiotic lessened clinical signs of FHV-1 in periods of stress. However, Dr. Lappin cautioned that the positive effect may not be recog­nized in all cats.

Based on these results, Dr. Lappin stated that he feels comfortable with a 1-month trial of feed­ing E faecium SF68 to cats with low-grade signs consistent with FHV-1 to see if the clinical signs are perceived by the owner to be improved. However, he cautioned that E faecium SF68 should not be used alone in cats with severe FHV-1 signs, such as ocular keratitis. For these patients, he recommended oral famcyclovir therapy dosed at 40 to 90 mg/kg every 8 to 12 hours.

Inflammatory Bowel Disease

Another study recently evaluated the potential use of probiotics for treatment of canine idiopathic inflam­matory bowel disease, a condition believed to be asso­ciated with abnormal immune responses to antigens.⁶ The investigators compared response to treatment in dogs administered either a combination of metro­nidazole and prednisone or oral probiotic VSL#3 (SIVOY, VSL Pharmaceuticals, Inc.), which contains multiple strains of Lactobacillus, Bifidobacterium, and beneficial Streptococcus. Fecal samples and histologic sections of intestine were examined.

Dogs that received VSL#3 rather than metronidazole or prednisone had evidence of immune modulation, including decreased CD3+ T-cell infiltra­tion and enhancement of certain regulatory T-cell markers. Probiotic admin­istration also correlated with significantly lower disease severity scores, as well as signs of dysbiosis normalization.

Giardiasis

Although studies have produced variable results, there is some evidence that probiotics may benefit patients with giardiasis. One study demon­strated that administering E faecium SF68 to mice for 7 days before inoc­ulation with Giardia resulted in increased intestinal Giardia-specific IgA antibody, as well as upregulation of CD4+ T-helper cells in the spleen and intestinal Peyer patches.⁷ Also, Giardia antigen shedding was lower in mice that received probiotic compared with control mice.

In a more recent study, E faecium SF68 was fed to apparently healthy dogs with chronic Giardia. A clinical effect could not be assessed because diarrhea was not present, but alterations in immune response or decreases in fecal cyst or antigen shedding were not associated with probiotic use.⁸ However, in a recent study of shelter dogs with diarrhea assessing the use of metronidazole with or without E faecium SF68 supplementation, potential positive effects were detected.⁹ The statistical power was too low to make definitive conclusions, however, so a new clinical trial is ongoing at CSU to further assess the effect of this probiotic on clinical signs of giardiasis.

Dermatologic Disorders

Multiple studies have evaluated probiotic use for dermatologic issues in canine and human human medicine, Dr. Lappin noted.^10,11 Most of the work has been with atopy. Although no probiotic available in the United States is known to immune modulate atopic dermatitis, new research is forthcoming.

Canine demodicosis, a multifaceted condition with a genetic predispo­sition, is overrepresented in certain breeds.¹² Humoral and cell-mediated immunity are both important considerations in controlling the disease, Dr. Lappin explained, and Demodex overgrowth seen with juvenile-onset gener­alized demodicosis (JOGD) is believed to be associated with exhaustion of T cells. Acaricidal treatments function by decreasing the antigen load to effectively reverse T-cell exhaustion.¹³

In a study currently in review for publication, Dr. Lappin’s team managed a group of American pitbull terriers or crosses with a standardized Demodex treatment protocol. The dogs were then randomized into an E faecium SF68 group and a placebo group, and immunologic effects, mite counts, and clin­ical responses were monitored. Although there were no statistical differ­ences between groups, dogs in the probiotic group had a number of clinical findings suggesting a potential immune enhanced effect. A larger study will be needed to further detail differences between groups.

The Future of Probiotics in Veterinary Medicine

Results from recent studies demonstrate the potential immune-stimulating and immune-modulating properties of certain probiotics. In addition, some probiotics may serve as effective adjunct therapies for specific diseases, such as FHV-1 and canine demodicosis. Studies investigating the use of probiotics for management of additional health issues, including atopy, anxiety, feline stomatitis, and chronic kidney disease, are ongoing.

Ultimately, it is important to remember that probiotic effects are not universal but are typically limited to a particular bacterial strain. Furthermore, a wide variation in probiotic quality exists. Therefore, prod­ucts should be purchased from reputable veterinary companies that support research and enforce rigid standards for quality assurance and control.

Dr. Stilwell is a medical writer and aquatic animal veterinarian in Athens, Georgia. After receiving her DVM from Auburn University, she completed an MS degree in Fisheries and Aquatic Sciences, followed by a PhD degree in Veterinary Medical Sciences, at the University of Florida.

References

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• Weese JS, Arroyo L. Bacteriological evaluation of dog and cat diets that claim to contain probiotics. Can Vet J. 2003;44(3):212-216.
• Benycoub J, Czanecki-Maulden GL, Cavadini C, et al. Supplementation of food with Enterococcus faecium (SF68) stimulates immune functions in young dogs. J Nutr. 2003;133(4):1158-1162. doi: 10.1093/jn/133.4.1158.
• Veir JK, Ruch-Gallie R, Spindel ME, Lappin MR. Prevalence of selected infectious organisms and comparison of two anatomic sampling sites in shelter cats with upper respiratory tract disease. J Feline Med Surg. 2008;10(6):551-557. doi: 10.1016/j.jfms.2008.04.002.
• Lappin MR, Veir JK, Satyaraj E, Czarnecki-Maulden G. Pilot study to evaluate the effect of oral supplementation of Enterococcus faecium SF68 on cats with latent feline herpesvirus 1. J Feline Med Surg. 2009;11(8):650-654. doi: 10.1016/j.jfms.2008.12.006.
• Rossi G, Pengo G, Caldin M, et al. Comparison of microbiological, histological, and immunomodulatory parameters in response to treatment with either combination therapy with prednisone and metronidazole or probiotic VSL#3 strains in dogs with idiopathic inflammatory bowel disease. PLoS One. 2014;9(4):e94699. doi: 10.1371/journal.pone.0094699.
• Benyacoub J, Perez PF, Rochat F, et al. Enterococcus faecium SF68 enhances the immune response to Giardia intestinalis in mice. J Nutr. 2005;135(5):1171-1176. doi: 10.1093/jn/135.5.1171.
• Simpson KW, Rishniw M, Bellosa M, et al. Influence of Enterococcus faecium SF68 probiotic on giardiasis in dogs. J Vet Intern Med. 2009;23(3):476-481. doi: 10.1111/j.1939-1676.2009.0283.x.
• Fenimore A, Martin L, Lappin MR. Evaluation of metronidazole with and without Enterococcus faecium SF68 in shelter dogs with diarrhea. Top Companion Anim Med. 2017;32:100-103. doi: 10.1053/j.tcam.2017.11.001.
• Baquerizo Nole KI, Yim E, Keri J. Probiotics and prebiotics in dermatology. J Am Acad Dermatol. 2014;71(4):814-821. doi: 10.1016/j.jaad.2014.04.050.
• Fuchs-Tarlovsky V, Marquez-Barba MF, Sriram K. Probiotics in dermatologic practice. Nutrition. 2016;32(3):289-295. doi: 10.1016/j.nut.2015.09.001.
• Ferrer L, Ravera I, Silbermayr K. Immunology and pathogenesis of canine demodicosis. Vet Dermatol. 2014;25(5):427-e65. doi: 10.1111/vde.12136.
• Arsenovik M, Pezo L, Vasic N, Ciric R, Stefanovic M. The main factors influencing canine demodicosis treatment outcome and determination of optimal therapy. Parasitol Res. 2015;114(7):2415-2426. doi: 10.1007/s00436-015-4543-7.