Probiotics and nutritional supplements: Do they really "boost" the immune system? (Proceedings)

Considering the large impact of immunology on companion animal practice (e.g. vaccines, allergies, infectious and immune-mediated diseases), it's natural to wonder what role nutrition plays. Commercial diets, supplements, special foods, home recipes, nutraceuticals – is there any scientific evidence behind the promotional claims that they "strengthen" or "boost" immunity or ''modulate the immune system"? Many studies have been done looking at the immune system in people and laboratory animals, but there is far less research available in dogs and cats. The following overview will attempt to sort out what we know and don't know about nutrition and immunology.

Lifespan

One of the oldest scientific pursuits is how to extend lifespan, and postpone aging as long as possible. As the immune system plays a major (but not exclusive) role in this process, research has looked into how to measure changes in immunity over time and whether diet can help. The concept of "immunosenescence", which is a decreased immune response to internal and external stress (e.g. cancer, infections, degeneration) is believed to be a factor in aging and death. Certain measures of immune function do change over time, but the significance is often unknown.

The best study to date is a longitudinal (lifelong) research project involving Labrador Retrievers, who were housed, fed, and managed at the Nestlé Purina Pet Care Center (Gray Summit, Missouri) from birth until natural death (1987-2001). A number of investigations were done on 48 dogs who were pair-matched into well-fed and caloric restricted groups (25% less food intake than controls). Blood samples were taken three times a year from ages 4-11 for evaluation of the status of the immune system (total leukocytes and lymphocytes, lymphocyte proliferation, natural killer cell activity, and neutrophil phagocytosis).

Some tests of immune status declined or remained the same in both the control and calorie-restricted groups. Other effects were positive in the restricted group, with significant differences in age-related declines in cell numbers and lymphoproliferative responses. The study's conclusion was that calorie-restriction retarded (or postponed) immunosenescence as well as enhanced several immune markers predictive of survival. Overall, calorie restriction to 75% of control dogs' diets extended the median life span by 15% (from 11.2 years to 13 years).

These findings are not as dramatic as those seen in laboratory rodents. However, in many species studied to date, calorie restriction appears to be a major factor in prolonging life span. Cats have not yet been studied in this manner. Whether this effect is due to slowing or modifying immunosenescence is an attractive hypothesis but more research is needed. The practical relevance of this lifelong study, which practitioners may communicate to their clients, is that feeding dogs less (fewer calories) will likely improve immunity and promote a longer, healthier life.

Probiotics

Probiotics are live bacteria administered orally that may result in a health benefit. Live microbial food supplements have been investigated in lab animals, livestock, and humans for improving microbial balance and modulating the immune system. Few scientific studies have been conducted in dogs and cats. Some strains have effects on nonspecific immune responses (increased phagocytic and natural killer cell activity) as well as humoral and cell-mediated immunity (increased antibody and cytokine levels).

Some of the medical conditions that have been studied using probiotics include allergies and asthma, inflammatory bowel disease, diabetes, cancer, rheumatoid arthritis, and gastrointestinal viral infections. Different types of probiotics (yogurt, powdered supplements, different strains and doses) used in various studies makes interpretation of studies difficult.

Products marketed for veterinary use in dogs and cats include FortiFlora (Nestlé Purina), Prostora Max Iams), and Proviable (Nutramax). Many other companies produce various types of probiotics for animals and humans. Probiotics are not regulated by the FDA and the quality of commercial products varies widely. One study of products sold for human use found that 8 out of 26 contained 1% or less of the amount of live bacteria claimed on the labels. An evaluation by consumerlab.com found that 5 of 13 human probiotics did not contain an adequate amount of organisms and 2 of 3 products marketed for pets did not contain enough organisms (and one was contaminated with mold). Commercial pet diets claiming to contain probiotics were recently evaluated. Of 19 products, only 10 contained at least one of the live bacteria claimed on the label. No growth was present in 5 diets, and no product contained all the listed organisms. The conclusion was that the diet contents were not accurately represented by the labels.

One study compared the responses to FVRCP vaccination in 18 kittens, where half were given E. faecium and half were controls. A positive effect was seen at certain time intervals where IgA and IgG antibody levels were higher in the treated group. The overall immune modulating effects were not significantly different, however. In puppies, an enhanced response to distemper vaccine was seen when E. faecium was given. Another study using laboratory mice showed a significant reduction in Giardia shedding and increased intestinal IgA with E. faecium. However, in a kennel of Beagles with chronic giardiasis, E. faecium had no benefit.

Probiotics appear to be safe when given to dogs and cats, and practitioners may wish to use them for gastrointestinal disorders or other conditions when "immune system enhancement" is desired. Medical claims for probiotics cannot be made by manufacturers, as the FDA would then consider them to be unapproved drugs. Before selecting products to recommend to clients, ask if there is proof of stability (are the organisms alive in stable form? can they be recovered from the GI tract?), safety (any side effects or problems with unbalancing the GI normal flora?), and efficacy (studies in healthy animals or those with disease where a product benefit was seen). Keep in mind that concurrent antibiotic therapy may destroy probiotic organisms in the GI tract.

Antioxidants

Some pet food companies add various antioxidants to commercial diets. The health claims accompanying certain of these foods include statements such as: "a wellness food protocol that fights free radicals", "help them age healthier", "the power of antioxidants – older dogs act younger", "powerful antioxidant package to help support your pet's immune system and reduce free radicals", and "enriched with antioxidants" (collected from websites of three premium pet food companies). Many of these diets contain more than one ingredient that can be considered an antioxidant, so evaluation of the benefits can be difficult. The "cocktail" approach may be more effective than single-ingredient antioxidants, but the contributions of the various components as well as interactions (positive or negative) are largely unknown. The overall goal of antioxidant supplementation seems to be to reduce (but not eliminate) oxidative stress. Oxidative stress may lead to illness or in the long term decreased longevity or quality of life, but these concepts are only hypothetical, not proven.

One study using 36 young and old dogs (Labradors and Fox Terriers) looked at β-carotene-supplemented diets and the effect on the immune system. β-Carotene is a naturally occurring plant pigment with provitamin A and antioxidant activity. The results showed evidence of immunosenescence in older dogs that were positively influenced in the treated group. Various measures of the immune system status improved that were dose-responsive. The conclusion was that β-carotene may be a useful additive to dog diets.

Another study using lutein, a carotenoid, in 56 Beagles demonstrated enhanced cell-mediated and humoral immune responses. Antibody response to vaccination was greater in lutein-supplemented dogs. A study using four antioxidants (vitamin E, vitamin C, β-carotene, and selenium) in a growth diet showed improved immune response in puppies vaccinated for distemper but not parvo. One conclusion was that AAFCO-recommended dietary vitamin E levels for growth may be insufficient. In kittens supplemented with an antioxidant cocktail (vitamin E, β-carotene, lutein, and others) higher antibody levels 1, 2, and 4 weeks after vaccination were observed compared to controls.

In a recent study, vitamins C (0-60 mg) and E (60 mg) were supplemented in healthy dogs. No effects were seen on several immune system assays (serum IgA and IgG concentrations, lymphocyte population, mononuclear cell proliferation). Antioxidative measurements were not improved with supplementation. A prospective study of dogs newly diagnosed with lymphoma showed differences in certain antioxidant biomarkers compared with healthy dogs. Further studies are needed to evaluate clinical or therapeutic relevance. Critically ill dogs were recently shown to have decreased erythrocyte glutathione concentrations compared with healthy controls, and critically ill cats had higher ascorbate (vitamin C) serum concentrations.

Research into longevity in cats was begun in 2000. 90 healthy cats were assigned to one of 3 diets – a basal or maintenance diet, basal diet with added vitamin E and β-carotene, or basal diet with other added antioxidants including vitamins, fatty acids, and prebiotics. Results to date suggest that cats eating the 3rd diet with antioxidants live about 1 year longer than cats eating the first two diets.

One study compared the effects of antioxidants in a group of healthy cats with another group diagnosed with inflammatory bowel disease (IBD). Either a control diet or an antioxidant-supplemented diet (vitamin E, vitamin C, and β-carotene) was fed. Results were inconclusive in terms of efficacy of diet, but markers of inflammation (lymphocyte proliferative activity, higher Th cells) were increased in IBD cats. Another study of cats with renal insufficiency showed reduced DNA damage when those antioxidants were fed. The clinical relevance is unknown at this time.

One antioxidant, lipoic acid, is sometimes recommended for dogs and cats but a challenge study using acetaminophen in cats showed that lipoic acid enhanced oxidation instead of protecting against it. Dogs tend to show improved memory and behavior with supplementation of alpha-lipoic acid and acetyl-L-carnitine. A new nutraceutical product is being marketed with similar claims that contains a cocktail of antioxidants such as ginkgo biloba, vitamin E, and other ingredients (Senilife, Ceva).

One precaution in using antioxidants in both humans and animals is that some have the potential of acting as pro-oxidants, especially at high levels. Therefore, clients should not be advised to freely give antioxidant or other supplements to their pets without guidance. A meta-analysis of human studies showed that supplementation with β-carotene, vitamin A, and vitamin E may increase all-cause mortality (death for any reason). Vitamin C and selenium does not seem to have an effect but there are no clear benefits in increasing longevity or reducing all-cause mortality.

Fatty Acids

Polyunsaturated fatty acids (PUFA), which are found in commercial pet diets as additives or as part of food ingredients, include omega-6 (linoleic, gamma linolenic, and arachidonic) and omega-3 (alpha-linolenic, eicosapentaenoic, and docosahexaenoic) acids. Current nutritional requirements only list linoleic acid (LA) as essential for dogs and cats, and arachidonic acid (AA) as essential for cats (dogs can synthesize AA from LA but cats cannot). Omega-3 fatty acids are most likely "conditionally essential" in pets for vision and neural development, but appropriate types and amounts are not yet defined.

Many pet foods have been supplemented or "enriched" with PUFA with the goal of preventing or treating various health conditions, including immune system modulation. Research in lab animals and humans has demonstrated that omega-3 fatty acids are useful in reducing arrhythmias and mortality in coronary disease due to antiinflammatory and antithrombotic effects. As dogs and cats rarely suffer from coronary heart disease, this benefit is not directly applicable. Also in humans, high doses of omega-3s help decrease joint pain and swelling in rheumatoid arthritis. Less is known about effects on degenerative joint disease (non-rheumatoid DJD) in people, but the antiinflammatory properties of omega-3s have shown benefit in dogs with DJD.

Several commercial diets are now available that contain high levels of omega-3 fatty acids that are intended to help manage osteoarthritis (OA) in dogs. The proposed mechanism is that omega-3s replace AA found in cell membranes and compete with AA for cyclooxygenase-2 conversion, resulting in less-inflammatory eicosanoid production. Also, matrix metalloproteinase activation, which leads to synovial inflammation, is decreased. Several studies in dogs have indicated improvement in signs of OA with prescription diets with high omega-3 concentrations (JM, Nestlé Purina; j/d, Hill's; Mobility Support JS 21, Royal Canin).

Another use of PUFAs is maintaining healthy skin and decreasing inflammation and pruritus associated with atopic dermatitis. Many studies in lab animals, dogs, and cats have investigated effects of various fatty acids (FA), either in food or as additives (capsules, oils). Research studies describing effects of supplements are difficult to interpret because the base diets fed are often not described or analyzed for PUFA content, other fats, or fat-soluble vitamins such as vitamin E. Antiinflammatory and anti-pruritic effects are likely due to incorporation of omega-3s into cell membranes as noted above. The amount of fat in typical diets far exceeds the amount found in supplements, so any effects (or lack of effects) observed are more likely a result of the diet rather than the additive. Recently, some pet diets have been formulated to take into account both the amounts and types of fats and oils, with the goal of helping manage some types of dermatologic conditions. As many factors are involved in skin disease, it is unlikely that diet alone will "cure" allergies, pruritus, or other disorders, and novel protein diets are needed to diagnose and manage true food allergy. However, it is reasonable to do a trial with commercial diets enriched with omega-3s and monitor for response (examples include Skin Support SS 21, Royal Canin; d/d, Hill's; Response, Iams; DRM, Nestlé Purina; or one of the diets for OA management listed above).

A complete discussion of fatty acids is beyond the scope of this presentation, and research is ongoing to evaluate potential benefits for other conditions including cancer, inflammatory diseases such as glomerulonephritis, hypertension and hyperlipidemia, cognition and learning, etc.

References for this article and all Clinical Immunology proceedings are available on request from the author

Craig Datz, DVM, MS, DABVP (Canine/Feline, Feline)

University of Missouri-Columbia

900 East Campus Drive

Columbia, Missouri 65211

573-882-7821

datzc@missouri.edu