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David NiemanNorth Carolina Research Campus and Appalachian State University, Boone

IntroductionPhysical activity infl uences immune function and risk of certain types of infection such as upper respiratory tract infections (URTI). In contrast to moderate physical activity, prolonged and inten-sive exertion by endurance athletes causes numerous changes in immunity in multiple body compartments and an increased risk of URTI. Elite endurance athletes must train intensively to compete at the highest levels and are prime candidates for immunonutrition support to bolster immune system function in the face of physiological stress.

Infl uence of Heavy Exertion On ImmunityEach acute bout of heavy exertion leads to physiological stress and transient but clinically signifi cant changes in immunity and host pathogen defense. Beginning in the mid-1980s, my research team has repeatedly shown that the immune system refl ects the physiologic stress the endurance athlete’s body is experiencing as cortisol, epinephrine, and pro- and anti-infl ammatory cytokines rise to high levels (1). Natural killer cell activity, various measures of T and B cell function, upper airway neutrophil function, salivary IgA concentration, granulocyte oxidative burst activity, skin delayed-type hypersensitivity response, and major histocompatibility complex (MHC) II expression in macrophages are sup-pressed for at least several hours during recovery from prolonged, intense endurance exercise. These immune changes occur in several compartments of the immune system and body (e.g., the skin, upper respiratory tract mucosal tissue, lung, blood, muscle, and peritoneal cavity).

Infection Risk in AthletesDuring the “open window” of impaired immunity (which may last between three and 72 hours, depending on the immune measure), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. My research team has conducted several epidemiological studies showing that athletes engaging in marathon and ultramarathon race events and/or very heavy training are at increased risk of URTI (2). Together, these epidemiological and exercise immunology studies support the viewpoint that heavy exercise workloads increase URTI risk through altered immune function.

Immunonutrition Support for AthletesVarious nutritional agents have been tested for their capacity to attenuate immune changes following intensive exercise and thus lower the magnitude of physiologic stress and URTI risk. This strategy is similar to the immu-nonutrition support provided to patients recovering from trauma and surgery, and to the frail elderly. Supple-ments studied thus far in human athletes include zinc, N-3 polyunsaturated fatty acids (N-3 PUFAs), plant sterols, antioxidants (e.g., vitamins C and E, beta-carotene, N-acetylcysteine, and butylated hydroxyanisole), glutamine, bovine colostrum, and carbohydrate. Immunonutrition support for athletes has been a major focus of my re-search efforts during the past 15 years. Except for carbohydrate, results have been disappointing (see Table 1), and we have shifted focus to a new class of “advanced supplements” such as quercetin, isoquercetin, epigallocatechin 3-gallate (EGCG), β-glucan, and other plant polyphenols (3).

Immunonutrition support for Athletes

David Nieman

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Physical activity infl uences immune function and risk of certain types of infection such as upper respiratory tract infections (URTI). In contrast to moderate physical activity, prolonged and inten-

research team has repeatedly shown that the immune system refl ects the physiologic stress the endurance athlete’s body is experiencing as cortisol, epinephrine, and pro- and anti-infl ammatory cytokines rise to high levels (1). Natural killer cell activity, various measures of T and B cell function, upper

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Table 1 Summary of rationale and fi ndings for selected immunonutrition supplements.

Immunonutrition Supplement Proposed Rationale Recommendation based on current Evidence

N-3 PUFAs Exerts anti-infl ammatory effects post-exercise

Not recommended; no different from placebo

Vitamin E Quenches exercise-induced reactive oxygen species (ROS) and augments immunity

Not recommended; may be pro-oxidative with heavy exertion.

Vitamin C Quenches ROS and augments immu-nity

Not recommended; no different from placebo

Glutamine Important immune cell energy subst-rate that is lowered with long exercise

Not recommended; body stores exceed exercise-lowering effects

Carbohydrdate Maintains blood glucose during exer-cise, lowers stress hormones, and thus counters immune dysfunction

Recommended, but 60 g/hr of heavy exertion helps dampen immune infl ammatory responses, but not immune dysfunction.

β-glucan Receptors found on immune cells, and animal data show supplementation improves innate immunity and redu-ces infection rates.

Not recommended; human study with athletes showed no benefi ts.

Quercetin In vitro studies show strong anti-infl ammatory, anti-oxidative, and anti-pathogenic effects. Animal data indicate increase in mitochondrial bio-genesis and endurance performance.

Recommended; human studies show strong reduction in illness rates during heavy training and mild stimulation of mitochondrial bioge-nesis and endurance performance in untrained subjects.

Quercetin with EGCG Flavonoid mixture promotes anti-in-fl ammatory and anti-oxidative effects, and immune function improvement, above just quercetin alone.

Recommended; human study showed strong anti-infl ammatory effect, with modest anti-oxidative effect and improvement in innate immunity.

Carbohydrate: A Partial CountermeasureIn a series of studies dating back to the mid-1990s, my research team has shown that carbohydrate beverage ingestion during prolonged exercise (about one liter/hour of a 6% carbohydrate beverage) attenuates increa-ses in blood neutrophil and monocyte counts, stress hormones, and infl ammatory cytokines such as IL-6, IL-10, and IL-1ra, but has little effect on decrements in salivary IgA output and T cell and natural killer cell function (4). Thus carbohydrate ingestion during heavy exercise has emerged as an effective but partial countermeasure to immune dysfunction, with favorable effects on measures related to stress hormones and infl ammation, but not downturns in innate or adaptive immunity.

Advanced Nutritional SupplementsIn vitro/cell culture and animal research indicate that advanced supplements such as β-glucan, curcumin, quercetin, isoquercetin, EGCG, and other plant polyphenols warrant human investigations to determine if they

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are effective countermeasures to exercise-induced immune dysfunction and risk of URTI. Our evolving hypothesis is that the immune system is so diverse that a cocktail of these advanced supplements within a carbohydrate beverage will probably perform better than any one alone. Recent data from my research team affi rm this approach (5). We also have decided that the primary immune target should be the nonspecifi c, innate arm of the immune system to enhance immunosurveillance against a wide variety of pathogens.

β-Glucan: Impressive Data in Mice But Not Humansβ-Glucans are polysaccharides found in the bran of oat and barley cereal grains, the cell wall of baker‘s yeast, certain types of fungi, and many kinds of mushrooms. Evidence from studies conducted with rodents, fi sh, poultry, and swine indicates that oral β-glucan ingestion stimulates innate immune defenses and antitumor responses, and increases resistance to a wide variety of infections. Rodent studies indicate that oat β-glucan supplements offset the increased risk of infection associated with exercise stress through augmentation of macrophage and neutrophil function. My research team was impressed with the animal data, and conducted a doubled-blinded, placebo controlled study with cyclists who received 5.6 grams/day of oat β-glucan or placebo beverage supplements for two weeks prior to, during, and one day after a 3-d period in which subjects cycled for 3 h/day at ~57% Wattsmax. The oat β-glucan supplement did not alter chronic resting or exercise-induced changes in immune function, or URTI incidence in the cyclists during the 2-week period following intensifi ed exercise (6). This study reminded us that nutritional supplements that work in mice often do not confer similar benefi ts in human subjects.

QuercetinThe physiologic effects of dietary fl avonols such as quercetin are of great current interest due to their antioxi-dative, anti-infl ammatory, anti-pathogenic, cardioprotective, and anticarcinogenic activities. The richest food sources of quercetin are onions, apples, blueberries, curly kale, hot peppers, tea, and broccoli. Total fl avonol intake (with quercetin representing about 75%) varies from 13 to 64 mg/day depending on the study sample and the population studied. Human subjects can absorb signifi cant amounts of quercetin from food or supplements, and elimination is quite slow, with a reported half-life ranging from 11-28 hours. Animal studies indicate that 7-days quercetin feeding augments muscle and brain mitochondrial biogenesis, endurance performance, and survival from infl uenza virus innoculation. A double-blind, placebo controlled study with 40 cyclists showed that 1,000 mg/day quercetin for three weeks signifi cantly increased plasma quercetin levels and reduced URTI incidence during the 2-week period following 3-days of exhaustive exercise (7). (Figure 1). Immune dysfunction, infl ammation, and oxidative stress, however, were not altered suggesting that quercetin exerted direct anti-viral effects, at least within the context of the stu-dy design. Mitochondrial biogenesis was not increased following the 3-week period of quercetin supplementa-tion in the trained cyclists. However, a follow-up study with untrained subjects showed a signifi cant increase in endurance performance and an increase in mtDNA, but not nearly to the extent seen in mice following quercetin feeding.

There is increasing support for coingestion of quercetin with other fl avonoids and food components to improve and extend quercetin’s bioavailability and bioactive effects. These include the fl avonoid EGCG from tea, iso-quercetin which is the glycosylated form of quercetin in onions and other foods, N3-polyunsaturated fatty acids (N3-PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the nutrients vitamin C and folate. In a study with 39 trained cyclists, a quercetin supplement combined with EGCG, isoquercetin, and N3-PUFAs was more effective than quercetin alone in partially countering exercise-induced infl ammation and

-Glucans are polysaccharides found in the bran of oat and barley cereal grains, the cell wall of baker‘s

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oxidative stress (5). These data add to a growing literature support for the concept that quercetin’s anti-in-fl ammatory and anti-oxidative effects are amplifi ed when combined in supplement form with other fl avonoids, food components, and micronutrients.

Summary RemarksEndurance athletes must train hard for competition and are interested in strategies to keep their immune sys-tems robust and to avoid illness despite the physiologic stress they experience. The ultimate goal is to provide athletes with a sports drink containing carbohydrate and a cocktail of advanced supplements that will lower infection risk, exert signifi cant and measurable infl uences on their innate immune systems, and attenuate exercise-induced oxidative stress and infl ammation. The athlete can combine this strategy with other approa-ches that help maintain immunity and health including: • Keep other life stresses to a minimum (mental stress in and of itself has been linked to increased URTI risk).• Eat a well-balanced diet to keep vitamin and mineral pools in the body at optimal levels.• Avoid overtraining and chronic fatigue.• Obtain adequate sleep on a regular schedule (disruption has been linked to suppressed immunity).• Avoid rapid weight loss (has been related to adverse immune changes).• Avoid putting the hands to the eyes and nose (a major route of viral self-innoculation). • Before important race events, avoid sick people and large crowds when possible.• Receive the infl uenza vaccination each year.

Figure LegendFigure 1 Plasma quercetin levels (P<0.001) and upper respiratory tract infection (URTI) infection rates (P=0.004) in cyclists during a two-week period following a 3-day period of overtraining and ingestion of quercetin (1,000 mg/day) or placebo (7).

References1. Nieman DC. Immune response to heavy exertion. J Appl Physiol 82:1385-1394, 1997.2. Nieman DC. Is infection risk linked to exercise workload? Med Sci Sports Exerc 32 (suppl 7):S406-S411, 2000.3. Nieman DC. Immunonutrition support for athletes. Nutr Rev 66(6):310-320, 2008.4. Nieman DC, Bishop NC. Nutritional strategies to counter stress to the immune system in athletes, with special reference to football. J Sports Sci 24:763-772, 2006.5. Nieman DC, Henson DA, Maxwell K, Williams A, McAnulty SR, Jin F, Shanely A, Lines T. Infl uence of supplemental quercetin and epigallocatechin 3-gallate on exercise performance, mitochondrial biogenesis, immunity, infl ammation, and oxida- tive stress. Med Sci Sports Exerc (in press).6. Nieman DC, Henson DA, McMahon M, Wrieden JL, Davis JM, Murphy EA, Gross SJ, McAnulty LS, Dumke CL. Effects of β-glucan on immune function and upper respiratory tract infections in endurance athletes. Med Sci Sports Exerc 40:1463-1471, 2008.7. Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, Carmichael MD, Dumke CL, Utter AC, McAnulty SR, McAnulty LS, Mayer EP. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc 39:1561-1569, 2007.

Nutritional strategies to counter stress to the immune system in athletes, with special reference to

Infl uence of supplemental quercetin and epigallocatechin 3-gallate on exercise performance, mitochondrial biogenesis, immunity, infl ammation, and oxida-