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Consensus Statement: Immunonutrition and Exercise

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In this consensus statement on immunonutrition and exercise, a panel of knowledgeable contributors from across the globe provides a consensus of updated science, including the background, the aspects for which a consensus actually exists, the controversies and, when possible, suggested directions for future research.
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8 • Immunonutrition and Exercise
EIR 23 2017
Key words: Aging; Biomarkers; Exercise; Immune system;
Inflammation; Nutrition; Obesity
Acknowledgements
The co-editors (SB and LC) are very grateful to the authors
for the time they have spent not only on providing appropriate
articles for the series but also (together with the EIR Board)
offering helpful critiques of the full document. The Interna-
tional Association of Athletics Federations (IAAF) is grateful-
ly acknowledged for supporting the editing costs. The help of
Anna Carlqvist in dealing with the references is warmly
appreciated.
CONSENSUS STATEMENT
The first indexed scientific publication about immunonutri-
tion is almost 70 years old (103). Since 1947, more than
10,000 scientific articles have been published in that field rep-
resenting a consistent body of knowledge. Within this field,
exercise (acute or chronic) modalities are of recent interest,
and only approximately 400 publications exist so far. One
third of them has been published during the last three years
showing that immunonutrition and exercise is a fast develop-
ing area of research. This can be explained on the one hand by
the considerable development of the global sports nutrition
market. On the other hand, it is also due to high levels of
expectation from both elite athletes and those who are keen on
the concept of “Exercise is Medicine”. High level athletes are
very frequently exposed to high intensity or exhausting train-
ing programmes, travel, sleep disturbances, psycho-social and
environmental stressors. All these factors are potential
immune disruptors sometimes leading to immunodepression
and increased likelihood of illness.
In order to minimise these phenomena and to optimise recov-
ery, nutritional interventions are often considered by athletes
and their entourages as possible countermeasures to the train-
ing-related immunodepression. However, among the numer-
Consensus Statement
Immunonutrition and Exercise
Stéphane Bermon1, Lindy M Castell2, Philip C Calder3, Nicolette C Bishop4, Eva Blomstrand5, Frank C Mooren6,
Karsten Krüger6, Andreas N Kavazis7, John C Quindry8, David S Senchina9, David C Nieman10, Michael Gleeson11,
David B Pyne12, Cecilia M Kitic13, Graeme L Close14, D Enette Larson-Meyer15, Ascension Marcos16,
Simin N Meydani17, Dayong Wu17, Neil P Walsh18, Ryochi Nagatomi19.
1Monaco Institute of Sports Medicine and Surgery, Monaco, and University Côte d’Azur, LAMHESS, Nice, France
2Green Templeton College, University of Oxford, Oxford, UK.
3Human Development & Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
4School of Sport, Exercise and Health Sciences, Loughborough University, Leics, UK.
5Swedish School of Sport and Health Sciences, Stockholm, Sweden
6Department of Sports Medicine, Justus-Liebig University, Giessen, Germany
7School of Kinesiology, Auburn University, Auburn, AL, USA;
8Health and Human Performance, University of Montana, Missoula, MT, USA
9Kinesiology Program, Biology Department, Drake University, Des Moines, IA, USA
10Appalachian State University, Human Performance Laboratory, North Carolina Research Campus, Kannapolis,
North Carolina, USA
11 School of Sport, Exercise and Health Sciences, Loughborough University, Leics, UK.
12Australian Institute of Sport, Australia
13Sport Performance Optimisation Research Team, School of Health Sciences, University of Tasmania, Launceston,
Tasmania, Australia
14 Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK
15 Nutrition & Exercise Laboratory, Department of Family and Consumer Sciences, University of Wyoming, Laramie,
WY, USA
16 Institute of Food Science, Technology and Nutrition (ICTAN), Spanish National Research Council (CSIC), Madrid, Spain
17 Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
18 School of Sport, Health and Exercise Sciences, Bangor University, Bangor, United Kingdom
19 Laboratory of Health & Sports Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan
Address for Correspondence:
Stéphane Bermon, Monaco Institute for Sports Medicine and
Surgery (IM2S), 11 avenue d’Ostende, 98000, Monaco
Phone: +377 99991000, Email: bermon@unice.fr
Immunonutrition and Exercise • 9
EIR 23 2017
ous nutrients available, only a few of them have so far shown
any positive effects in maintaining athlete immune health.
Moreover, elderly and overweight/obese individuals who
demonstrate increased inflammatory status and immune dys-
function are often prescribed physical training programmes as
a countermeasure. In such circumstances, nutrition appears as
a possible valuable additional support to these populations. As
significant biotechnological progress has been achieved dur-
ing the last fifteen years, it is of critical importance, when
designing an experiment in the field of immunonutrition and
exercise, to select adequate biomarkers which fit best to the
research aim and the experimental design.
In this consensus statement on immunonutrition and exercise,
a panel of knowledgeable contributors from across the globe
provides a consensus of updated science, including the back-
ground, the aspects for which a consensus actually exists, the
controversies and, when possible, suggested directions for
future research.
This consensus statement series includes an introduction sec-
tion (Stephane Bermon and Philip Calder) followed by sec-
tions on: carbohydrates (Nicolette Bishop); fatty acids (Philip
Calder); branched chain amino acids (Eva Blomstrand); gluta-
mine (Lindy Castell); polyphenols (David Nieman) and herbal
supplements (David Senchina); antioxidants (Andreas
Kavazis and John Quindry); minerals (Frank Mooren and
Karsten Krüger); probiotics and prebiotics (Michael Gleeson
and David Pyne); vitamin D (Graeme Close and Enette Lar-
son-Meyer) and bovine colostrum (Cecilia Kitic). It also con-
tains some specific sections on: immunonutrition in competi-
tive athletes and military personnel (Neil Walsh), exercising
obese and overweight (Ascension Marcos, and elderly (Simin
Meydani and Dayong Wu) individuals; biomarkers used in
immunonutrition, and exercise science (Neil Walsh, Simin
Meydani, Dayong Wu, and Ryochi Nagatomi).
Carbohydrates are fuel for the immune cells. As far as
immune functions are concerned, carbohydrates appear to be
more effective when ingested during exercise rather than
increasing their relative content in the daily diet. Carbohy-
drates have been shown to minimise some of the immune per-
turbations that are associated with strenuous or lasting physi-
cal exercise and can be considered as a partial countermeasure
for exercise-induced immunodepression. However, carbohy-
drates have failed so far to demonstrate any reduction in the
incidence of upper respiratory tract illness (URTI) after pro-
longed exercise.
There is evidence from in vitro, animal and epidemiological
studies that several saturated fatty acids promote inflammato-
ry processes through the omega-6 (n-6) polyunsaturated fatty
acids (PUFA) and arachidonic acid pathway. n-6 PUFAs have
also shown some immunodepressive effects. These phenome-
na occur whatever the origin of arachidonic acid: meat, eggs
or plants. In untrained individuals, eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) appear to decrease
the exercise-induced inflammation and muscle soreness.
However, most of the studies on fatty acids and immune func-
tions and inflammation in the context of exercise have provid-
ed data which is difficult to interpret.
Similar to recommendations in sports nutrition, there is no
scientific ground for an athlete to consume an excessive
amount of proteins (more than 2 g/kg body weight per day) in
order to boost his or her immune system or limit an exercise-
induced inflammation. Despite a good rationale for glutamine
(Gln) supplementation based on sound biochemical investiga-
tion, laboratory-based exercise studies have proved mainly
negative in terms of providing any direct enhancement of
immune function due to Gln feeding. More studies need to
investigate the apparent link between glutamine and the
decreased incidence of self-reported URTI. During prolonged
exercise branched chain amino acids (BCAA; leucine,
isoleucine, valine) are oxidized as substrates and their plasma
concentration decreases. An increase in BCAA plasma con-
centration can help to prevent a decrease in the plasma Gln
concentration, and might therefore have the capacity to influ-
ence the immune response indirectly. However, the evidence
for such an effect is weak.
Zinc (Zn), magnesium (Mg) and iron (Fe) are important min-
erals for immune function. As these minerals often show
reduced concentration or availability during exercise or train-
ing, it is important to check that the athlete’s diet contains suf-
ficient quantity of these elements. However, there is no evi-
dence showing that supplementing non-deficient athletes
might boost the immune system or prevent exercise-induced
immunodepression. Selenium (Se) and manganese (Mn) can-
not be classified as immunonutrients for exercise.
Prolonged, exhaustive exercise and immune system activation
are associated with an increased production of reactive oxy-
gen species (ROS), leading to a potential increase in oxidative
stress. However, there is no data to support links between
exercise-induced oxidative stress and immune dysfunction or
the postulated benefits of dietary antioxidant supplementation
in preventing immune dysfunction during exercise, or in
reducing the risk of respiratory illness in athletes. Emerging
evidence indicating that antioxidant supplementation miti-
gates important exercise-induced adaptations (including the
immune system) contributes to the debate for and against
antioxidant supplementation in athletes.
Herbal supplements are widely used by athletes either to
improve their performance or to boost their immune system.
However, few human in vivo studies focusing on specific
immune parameters are available and most of the available
studies use ex vivo or in vitro conditions. Results from these
studies are conflicting and are often not in full agreement with
the purported immunomodulatory claims from the food sup-
plement industry. For example, as therapeutic immunomodu-
lators for athletes, there is some evidence that echinacea may
be efficacious whereas the evidence for ginseng is poor.
Polyphenols, including flavonoids are mostly found in tea,
coffee, fruits and wine. They exhibit strong anti-inflammato-
ry, antioxidant, anti-pathogenic, and immuno-regulatory prop-
erties in vitro. Epidemiological data in general support that
polyphenol-rich plant extracts and unique polyphenol-nutrient
mixtures have small but significant effects in increasing anti-
oxidant capacity, with inconsistent, short-term effects on miti-
gating exercise-induced oxidative stress, inflammation, and
immune dysfunction. Quercetin consumed at high doses (500
10 • Immunonutrition and Exercise
EIR 23 2017
to 1,000 mg/day) has been linked to reduced incidence of self-
reported URTI in athletes.
Probiotics are interesting immunonutrients since they demon-
strate immunomodulation properties on both local and sys-
temic (some aspects of both innate and acquired immune
responses) immunity. In non-athletic populations, a recent
systematic review concluded that probiotic use resulted in a
lower incidence of URTI, reduced numbers of illness days,
and fewer days of absence from day care/school/work.
Despite a lower number of studies, the same benefits seem to
exist in athletic populations. Although a daily dose of ~1010
live bacteria is widely promoted, there is still some debate
about the optimal duration of supplementation and the poten-
tial benefits of selecting and mixing specific bacterial strains
with or without prebiotics.
Bovine colostrum exhibits antibacterial, anti-inflammatory and
anti-viral properties. Several investigations have reported a
reduction (not always statistically significant) in self-reported
URTI incidence in athletes following a period greater than four
weeks of bovine colostrum supplementation. However, the
effect of bovine colostrum on illness duration is less conclusive.
A large number of different immune cells and functions are
influenced by vitamin D. These effects are mainly mediated
through modulation of the expression of several genes. Opti-
mal circulating 25-hydroxy vitamin D concentration is possi-
bly beyond 75 nmol/l as individuals with such a vitamin D
concentration demonstrated a lower incidence of URTI than
those with an actually recommended vitamin D concentration
(of around 50 nmol/l). Optimal vitamin D concentrations for
immune cells require further study before they can be recom-
mended to athletes who would like to maintain their immune
function at the highest level without compromising their
health.
As long as the diet meets the energy demands and provides
sufficient macro- and micro- nutrients to support the immune
system, there is probably no need for consumption of
“immune boosting” supplements. However, there are specific
scenarios when elite athletes or military personnel might ben-
efit from nutritional supplements to bolster immunity. More
randomized controlled trials in these individuals with suffi-
cient participant numbers and rigorous designs are required
to investigate whether the nutritional practices adopted by
elite athletes impair immunity and increase infection; and,
whether purported “immune boosting” supplements benefit
immune health without blunting the desired training adapta-
tions.
Obesity is related to immune dysfunction and chronic low
grade inflammation. There is a consistent body of biological
evidence attesting to the anti-inflammatory effects of regular
physical training in obese or overweight individuals. Indeed,
regular physical activity decreases toll-like receptor (TLR)-4
expression and induces shift from M1-type macrophages to
M-2 type macrophages; both of these phenomenon promoting
anti-inflammatory patterns. The anti-inflammatory effects of
regular exercise are also partly mediated through interleukin
(IL)-6 production at the muscle level. IL-6 triggers an anti-
inflammatory cascade via the induction of the anti-inflamma-
tory cytokines interleukin-1 receptor antagonist (IL-1ra) and
IL-10, and also inhibits tumour necrosis factor (TNF)-α and
its associated insulin resistance pattern. IL-6 also promotes fat
oxidation which is beneficial to obese individuals. These
immunological changes associated with training have been
proven to be clinically relevant in many studies including
obese adults and adolescents.
A decrease in cell-mediated immune function in the elderly
(immunosenescence) contributes to higher morbidity and
mortality. Nevertheless, aging appears to be linked with an
increased inflammatory response. Given the focus on exer-
cise-induced immunodepression in this series and the journal,
it seems likely that extreme exercise will exacerbate immune
system impairment in aging. Moderate regular exercise, how-
ever, may even enhance immune function in the elderly. For
example, calisthenic exercise increases the function of natural
killer (NK) cells and T-cells in older women. It is not known
whether the exercising elderly have specific nutritional needs,
although many appear deficient in micronutrients essential for
immune function. In addition, increased inflammation, oxida-
tive stress and muscle damage suggest that exercising older
adults might require nutrients with immune enhancing and/or
anti-inflammatory properties. In terms of energy provision,
total calorie intake should be adjusted to avoid conversion of
excess caloric intake to body fat. Moreover, glucose tolerance
and insulin sensitivity decrease with aging.
Currently, a single marker able to predict the effect of a
dietary and/or exercise intervention on different aspects of
immune function does not exist. The range of available bio-
markers is quite wide from in vitro tests to clinical symp-
toms. However, each biomarker should be carefully chosen
according to its intrinsic characteristics (links with causal
pathway and clinical endpoint, biological sensitivity and
specificity, feasibility, practicality, and cost) as well as the
designed study’s aim and primary outcome. Mechanistic
studies or studies aiming at testing hypotheses at molecular,
cellular or immune function levels should rather consider in
vitro or ex vivo biomarkers. Whereas in vivo biomarkers or
biomarkers relying on patient symptoms should be preferred
in experiments describing integrated response or clinical
studies.
INTRODUCTION: IMMUNONUTRITION,
INFLAMMATION AND EXERCISE
Physical exercise (chronic or acute) influences the immune
system and its functions. All immune components or func-
tions, systemic, local or mucosal, innate or adaptive, cellular
or cytokine-related are positively or negatively linked with
exercise regimens (406). This body of knowledge represents
the interdisciplinary field of Exercise Immunology.
Similarly, the diet (macro and micronutrients, as well as non-
nutritive components) is known to influence the immune sys-
tem and its functions. Quantitative aspects (from protein-ener-
gy malnutrition to unbalanced Western diets) as well as quali-
tative aspects (oligo elements, vitamins, mineral, anti-oxi-
Immunonutrition and Exercise • 11
EIR 23 2017
dants, plant-derived immunomodulators, probiotics, amino
acids, and fatty acids) can either stimulate or inhibit selective
immune functions or inflammation. For instance, consump-
tion of dietary fibres reduces chronic inflammation by
decreasing lipid oxidation (124). Fibres also interact with the
gut microbiota via short-chain fatty acids produced during
colonic fermentation (251). Fibres from oats or barley smooth
the rate of appearance of glucose in the blood, reducing the
glycaemic index and glycaemic load, and as a consequence
production of nitric oxide, superoxide and peroxynitrite which
are powerful pro-oxidant and pro-inflammatory molecules
(80). Whole-grain foods also exert anti-inflammatory proper-
ties, such as free radical scavenging, antioxidant enzyme acti-
vation, or modification of the redox status of tissues and cells
(124). These close interactions between diet and the immune
system are the genesis of the term “Immunonutrition” which
represents another new interdisciplinary field of basic and
applied research.
As the immune system and inflammation, one of its major
effectors, are regulated by both exercise and nutrition, it is of
particular interest to address how nutrients can affect immuni-
ty in an exercise perspective. However, when nutrition is con-
cerned, it appears that the commitment and the goals to
achieve are very different when comparing a sedentary over-
weight individual to a high-level athlete. Indeed, as inappro-
priate exercise regimens or training programmes may alter
some immune functions and promote illnesses (306), elite ath-
letes are always considering diet and nutrition plans as possi-
ble countermeasures to the so-called exercise-induced
immunodepression. This latter term is more appropriate than
the traditionally used term “immunosuppression” which
means specific manipulation of the immune system, e.g. via
cyclosporin.
However, among the numerous nutrients and foods promoted
for their purported immuno-modulating effects, only a very
limited number has proved to be effective in maintaining or
restoring some immune functions or preventing illnesses. This
consensus statement series addresses the issue of macronutri-
ents, probiotics, vitamin D, antioxidants and plant-derived
immunomodulators, minerals and some promising dietary
compounds as immune support for exercising humans. It also
deals with immunonutrition in exercising overweight or elder-
ly individuals and explores the relevance of selected
immune/inflammation markers commonly used when design-
ing a nutrition study in exercise immunology.
When the diet is inappropriate (more likely excessive high
glycaemic index foods and/or caloric intakes), a part of the
innate immune system is overreacting to the excessive amount
of visceral fat leading to a chronic, low grade inflammation
and potential subsequent inflammation-related diseases. Here,
regular exercise is considered as a potential countermeasure to
the inflammatory-driven morbidities such as cardiovascular
diseases, chronic obstructive pulmonary diseases, colon and
breast cancers, insulin resistance, type II diabetes, and some
neurodegenerative diseases (307,326).
The anti-inflammatory effects of exercise are achieved
through several possible pathways (143). The reduction in
visceral fat mass associated with a secondary reduced release
of adipokines is one of the main mechanisms. Moreover, fol-
lowing each bout of exercise, the release of high amounts of
cortisol and adrenaline associated with an increased produc-
tion and release of IL 6 and other mediators now often
referred to as “myokines” from working skeletal muscles con-
tribute to the generation of an anti-inflammatory “milieu”. IL-
6 is pleiotropic: it may have different actions in different con-
texts, and thus may not always act in a manner that could be
described as pro-inflammatory.
At the cellular level, a reduced expression of TLR on mono-
cytes and macrophages and a subsequent inhibition of down-
stream pro-inflammatory cytokines production are observed.
Within the adipose tissue quantitative and qualitative changes
in monocytes-macrophages are noted. The number of M1-
type macrophages is decreased as well as their associated pro-
inflammatory cytokines (IL-6 and TNF-α), whereas M2-type
macrophage numbers and their anti-inflammatory cytokines
(IL-10 and adiponectin) are increased (205). Franceschi and
colleagues (133) introduced the concept of ‘inflammaging’ as
part of the spectrum of immunosenescence. Inflammaging is
the chronic low-grade inflammatory state present in aging
individuals and is believed to be a consequence of a remodel-
ling of the innate and acquired immune system. It is character-
ized by increased systemic concentrations of pro-inflammato-
ry cytokines such as IL-1, IL-6, and TNF-α (398) as well as
increased C-reactive protein (CRP) concentration which are
used as clinical markers. Inflammaging increases the risk of
morbidities and age-related diseases, and is also associated
with increased skeletal muscle wasting, strength loss, and
functional impairments. In this particular context, both nutri-
tion (115) and exercise (219) interventions are proposed for
elderly or frail individuals as a countermeasure of the aging
process and its associated inflammation-related diseases. This
provides the rationale for producing the present consensus
statements.
Most athletes, whether recreational or elite, and in all parts of
the world, use sports foods and supplements. The popularity
of certain types of dietary supplements demonstrates that ath-
letes may often be more motivated by an interest in health
benefits rather than, for example, direct ergogenic effects. In
this series of consensus statements on immunonutrition, ath-
letes are therefore strongly advised not only to seek the advice
of a properly qualified nutritionist before embarking on sup-
plementation but also to pay careful attention to the impor-
tance of the recommended daily allowance (RDA). It is a
common misconception among athletes that, if x g of a prod-
uct works, then taking double that amount will be even better!
In fact, this approach is very likely to lead to health problems
rather than to solutions. Readers can find more detailed dis-
cussion on this topic in Castell et al. (78).
CARBOHYDRATES
Background
The role of carbohydrate as an ergogenic aid for performance
has long been recognised. The recommended daily carbohy-
drate intake for athletes who train for one to three hours each
12 • Immunonutrition and Exercise
EIR 23 2017
day is 6–10 g/kg body mass increasing to 8–12 g/kg body
mass for athletes training more than four hours each day, with
additional intake of 30-60 g/h during exercise lasting for 1
hour or more (384). This guidance is principally aimed at
restoring muscle and liver glycogen stores before exercise
and maintaining blood glucose levels during exercise to
ensure sufficient glucose availability for skeletal muscle con-
traction. However, carbohydrate availability also has the
potential to limit the degree of exercise-induced immune dys-
function through direct or indirect actions. Directly, glucose
acts as a fuel substrate for immune cells (12) therefore it
could be argued that post-exercise hypoglycaemia could
endanger immune cell function. However, the significance of
this alone is questionable given that immune cells do not rely
solely on glucose for energy. Conversely, since both cate-
cholamines (adrenaline, noradrenaline) and cortisol are
known to have potent modulatory effects on immune function
(208) increasing carbohydrate availability may more likely
act indirectly by reducing the stress hormone response to the
exercise, thereby limiting exercise-induced immune impair-
ments.
Consensus: carbohydrates, exercise and immune function
Dietary carbohydrates
Performing exercise at around 70% VO2max for at least 1
hour following several days on very low carbohydrate diets
(typically less than 10% of dietary energy intake from carbo-
hydrate) is associated with a greater adrenaline and cortisol
response, higher circulating neutrophil counts and modest
depressions in circulating lymphocyte counts. These effects
are diminished when exercising following a high (typically
more than 70% of energy intake) carbohydrate diet (36,259).
High carbohydrate diets prior to exercise are also associated
with a blunted cytokine response (e.g. IL-6, IL-10 and IL-1ra)
(37), thought to be related to a reduced need for IL-6 to exert
its glucoregulatory actions (309).
In contrast, increasing dietary carbohydrate does not appear
to exert any beneficial effects on either resting or post-exer-
cise immune cell functions. A high or a low carbohydrate
diet for several days was associated with similar levels of
bacterially-stimulated neutrophil degranulation and mitogen-
stimulated lymphocyte proliferation before exercise, and
resulted in a similar magnitude of impairment post-exercise
(36,259).
Carbohydrate supplementation during exercise
Given the established association between cortisol and
immune cell function, nutritional measures that attenuate
exercise-induced elevations in plasma cortisol have been
hypothesized to be effective in minimizing post-exercise
immune impairments. Specifically, carbohydrate (compared
with placebo) ingestion during exercise is suggested to limit
exercise-induced falls in immune function by maintaining
plasma glucose levels, thereby blunting the plasma cortisol
response. While evidence from the literature largely supports
this, there is evidence to suggest that the beneficial effects of
consuming carbohydrate during exercise can also occur in the
absence of any effect on plasma cortisol levels (35,153). Con-
suming around 60 g/h of carbohydrate during prolonged exer-
cise attenuates the rise in plasma cytokines (270), attenuates
the trafficking of most leucocyte subsets, apart from NK cells
(174,285,289), prevents the exercise-induced fall in bacterial-
ly-stimulated neutrophil degranulation (38) and increases neu-
trophil respiratory burst activity (351). In addition, consuming
carbohydrate (compared with placebo) during prolonged exer-
cise prevents the decrease in both number and percentage of
anti-viral Type 1 helper T cells and the suppression of interfer-
on gamma (IFN-γ) production from these cells (224). Con-
suming carbohydrate during exercise also diminishes typical
post-exercise decreases in T lymphocyte proliferation follow-
ing mitogen or antigen (influenza) stimulation (34,174), an
effect that was still evident 24 hours later (34). This may be
partially related to lower T cell apoptosis within stimulated
cell cultures when carbohydrate is consumed during exercise
(153). Migration of immune cells to infected tissue is crucial
to host defence, and carbohydrate ingestion (60 g/h) during
prolonged exercise has been shown to attenuate post-exercise
falls in T-lymphocyte migration into human rhinovirus-infect-
ed airway epithelial tissue (35).
Although carbohydrate feeding during exercise appears to be
effective in minimizing some of the immune perturbations
associated with prolonged strenuous exercise, it has minimal
effect on salivary secretory immunoglobulin A (SIgA) secre-
tion (32,284) or NK cell cytotoxic activity (285) but may
increase NK cell responsiveness to IL-2 (254). Consuming
carbohydrate seems less effective at minimizing more modest
alterations in immune function during intermittent exercise
with regular rest intervals (288), resistance exercise (279) and
exercise to fatigue (33). Furthermore, consuming more than
60 g carbohydrate per hour has negligible additional benefit
(224,350,351) most likely because the maximum rate of
exogenous carbohydrate oxidation is around 1 g/min (i.e. 60
g/h; (400)). Finally, carbohydrate supplementation does not
influence the decrease in in vivo immunity to a novel antigen
seen after 2 hours of moderate intensity exercise in non-fasted
runners (102).
There is insufficient evidence to date to support any beneficial
effect of carbohydrate ingestion on symptoms of upper respi-
ratory illness; one study of 93 runners who consumed placebo
or carbohydrate during a marathon reported that, of the six-
teen runners who reported illness in the fifteen days after the
race, ten had consumed placebo and six had consumed carbo-
hydrate (284).
Conclusion
Carbohydrate ingestion is a partial countermeasure against
exercise-induced immune impairment and is more effective
when consumed as a supplement during exercise than by
increasing dietary content of carbohydrate on a routine basis.
However, evidence that carbohydrate ingestion reduces the
incidence of URTI after prolonged exercise is currently lack-
ing.
FATTY ACIDS AS IMMUNOMODULATORS
Background
Fatty acids are a major component of most human diets and
most fatty acids can be synthesised endogenously in the
human body (54). Individual fatty acids are distinguished by
Immunonutrition and Exercise • 13
EIR 23 2017
the length of their hydrocarbon chain, and by the absence,
presence, number and configuration (cis or trans) of double
bonds within that chain. Saturated and monounsaturated fatty
acids can be synthesised de novo from precursors such as glu-
cose. The simplest polyunsaturated fatty acids (PUFAs),
linoleic acid (18:2n-6) and α-linolenic acid (18:3n-3), cannot
be synthesised in humans, but are synthesised in plants.
Humans can metabolise these two essential fatty acids further,
inserting additional double bonds (desaturation) and extend-
ing the hydrocarbon chain (elongation). Through these
processes, linoleic acid can be converted to arachidonic acid
(20:4n-6) and alpha-linolenic acid to eicosapentaenoic acid
(EPA; 20:5n-3). Further metabolism to longer chain, more
unsaturated derivatives is possible (e.g., of EPA to docosa-
hexaenoic acid (DHA; 22:6n-3)).
The principal roles of fatty acids are as energy sources and
membrane constituents (54). Certain fatty acids have addi-
tional, specific roles, such as serving as precursors for the syn-
thesis of bioactive lipid mediators (e.g. prostaglandins), and
influencing membrane and intracellular signalling processes,
the activation of transcription factors and gene expression
(62). Through these different actions, fatty acids are able to
influence cellular functions and thus physiological responses,
including immune and inflammatory responses (59).
Consensus
There is evidence from in vitro, animal and epidemiological
studies that several saturated fatty acids promote inflammato-
ry processes (334). Lipid mediators, including prostaglandins
and leukotrienes, produced from the omega-6 (n-6) PUFA
arachidonic acid are intimately involved in inflammation and
many widely used anti-inflammatory drugs target arachidonic
acid metabolism (106). Several of the mediators produced
from arachidonic acid also suppress cell-mediated immune
responses by targeting antigen-presenting cell and helper T-
cell activities, acting in part via regulatory T-cells (106).
Arachidonic acid is consumed in the diet from meat, eggs and
organs such as liver, or it can be synthesised from the plant
essential fatty acid linoleic acid. Thus, there is a widely held
view that common n-6 PUFAs of both animal and plant origin
are pro-inflammatory and immunodepressive. However,
strong evidence that variations in dietary intake of linoleic
acid do affect inflammation is lacking (197). Older research
showed that γ-linolenic acid (18:3n-6) and its derivative diho-
mo-γ-linolenic acid (20:3n-6), which are both metabolic inter-
mediates between linoleic and arachidonic acids, exert anti-
inflammatory effects (360). There is limited exploration of the
influence of saturated or n-6 PUFAs on immune function or
inflammation in the context of exercise.
Oily fish and fish oil supplements contain the long-chain
omega-3 (n-3) PUFAs EPA and DHA (60). EPA and DHA are
also found in some algal oils and in krill oil. In each of these
sources both the absolute amounts of EPA and DHA and their
ratio can vary widely. There is substantial evidence from in
vitro, animal, epidemiological and human intervention studies
that the combination of EPA and DHA exerts anti-inflamma-
tory actions (58,61) and may enhance cell-mediated immune
function (59). The effects observed are dose-dependent and
may require an intake of >2 g per day the combination of EPA
and DHA (58,59,61). Both EPA and DHA can independently
exert anti-inflammatory effects (5), and they have been shown
to counter the effects of classic inflammatory stimuli like
endotoxin as well as saturated fatty acids and n-6 PUFAs (61).
EPA and DHA are readily incorporated into cell membranes,
partly replacing arachidonic acid. Thus, they result in
decreased production of pro-inflammatory and immunosup-
pressive omega-6-derived lipid mediators (61). In contrast,
the analogous mediators produced from EPA are often only
weakly bioactive (61). Importantly, both EPA and DHA are
substrates for the biosynthesis of potent mediators which
resolve inflammation and enhance immune function: these are
termed resolvins, protectins and maresins (19). EPA and DHA
act through several other mechanisms to decrease inflammato-
ry responses of neutrophils, macrophages and endothelial cells.
These mechanisms include reducing activation of the pro-
inflammatory transcription factor NFκB and activation of per-
oxisome proliferator activated receptor γ (61). Within antigen-
presenting cells, T-cells and B-cells EPA and DHA act by regu-
lating key signalling events within the cell membrane (184).
Effects of the combination of EPA and DHA, usually as fish
oil, or of DHA alone, on inflammation and immune function
have been explored in a number of studies involving exercise
protocols in both athletes and non-athletes. Several studies
report that supplementation with EPA and DHA decreases the
degree of muscle soreness induced by a bout of exercise in
untrained individuals (201,382,383), although not all studies
saw this (151). This effect also occurred with DHA alone at a
supplemental intake of 3 g/day (91). Furthermore, in
untrained individuals, EPA and DHA have been reported to
diminish the exercise-induced elevation in pro-inflammatory
cytokines including TNF-α and IL-6 (383). Once again this
effect was also seen with DHA alone (108). Thus, the majority
of studies suggest that omega-3 PUFAs decrease the inflam-
matory response induced by exercise in untrained individuals
and that this translates to less muscle damage and soreness. In
contrast, Gray et al. (2012; (152)) and Da Boit et al. (2015;
(99)) both observed no effect of EPA and DHA on the plasma
IL-6 response to an exercise bout, although the production of
IL-2 by mitogen-stimulated blood mononuclear cells and nat-
ural killer cell activity were both enhanced post-exercise with
prior omega-3 PUFA treatment in both of these studies. These
observations suggest that omega-3 PUFAs might enhance
aspects of cell-mediated and innate immunity post-exercise.
Andrade et al. (2007; (10)) reported that elite swimmers who
took EPA and DHA for 45 days showed increased production
of IL-2 and increased T-cell proliferation when peripheral
blood mononuclear cells were stimulated with the mitogen
phytohaemagglutinin, although IFN-γ production was
decreased, making the findings difficult to interpret. There
was no effect of EPA and DHA over 6 weeks on salivary IgA
concentration prior to or after an exercise bout in trained
cyclists (287). There was also no effect on pre-or post-exer-
cise blood leucocyte numbers or the concentrations of C-reac-
tive protein, IL-1β, IL-6 or IL-8 (287). A study of high dose n-
3 PUFAs (3 g/day EPA plus 1.8 g/day DHA) given for 6
weeks to endurance trained males reported no effects on
marathon-induced changes in blood leucocyte numbers or
blood concentrations of TNF-α, IL-1ra, IL-6 or transforming
14 • Immunonutrition and Exercise
EIR 23 2017
growth factor beta (388). Likewise, high dose EPA and DHA
(2.2 g/day of each) for 6 weeks had no effect on treadmill
exercise induced changes in several blood inflammatory
markers in trained males (43). A small study in wheelchair
basketball athletes found that EPA and DHA prevented the
elevation in plasma IL-6, but not other pro-inflammatory
cytokines, induced by an exercise bout, and prevented damage
to neutrophils (244). Capo et al. (66) reported few effects of
EPA and DHA on several plasma cytokines in elite soccer
players undergoing an exercise bout, although there was a
weaker TNF-α and IL-6 response of peripheral blood
mononuclear cells to endotoxin in the n-3 group PUFA after
exercise. This was linked to a lower exercise-induced upregu-
lation of toll-like receptor 4 in the n-3 group (66). Other stud-
ies present results from studies of n-3 PUFAs on immune out-
comes in athletes that are difficult to interpret (105,346).
Controversies and Future Directions
There is limited exploration of the influence of saturated or n-6
PUFAs on immune function or inflammation in the context of
exercise. There are a number of studies of the long chain n-3
PUFAs EPA and DHA, usually in combination, on immune
function or inflammation in the context of exercise in both
untrained and trained individuals. These studies have used
moderate (<1.0 g/day) to high (4 g/day) doses of EPA plus
DHA for a period of one week to several months; some publi-
cations are not sufficiently clear about the n-3 dose used and
many studies have involved a small number of subjects. Few
studies have used the same design and the immune and inflam-
matory outcomes reported are highly variable between studies,
although several report measurement of the same common
plasma inflammatory cytokines. This makes it difficult to draw
firm conclusions. However, EPA and DHA appear to decrease
exercise-induced inflammation and muscle damage and sore-
ness in untrained individuals. It is not yet clear whether EPA
and DHA affect inflammation or immune function in trained
individuals, although some studies suggest they might. Larger
studies of duration of several weeks to months are recom-
mended to explore better the effects of omega-3 PUFAs, and
other fatty acids, on inflammation and immune function in
trained individuals. Immune and inflammatory outcomes to be
measured should be more carefully considered (2,3).
AMINO ACIDS
Amino acids are the building blocks for protein. Twenty
amino acids build up the body proteins, nine of these are con-
sidered essential, that is, they have to be supplied through the
diet; the remaining, non-essential, amino acids can be synthe-
sized by the body. Exercise increases the oxidation of amino
acids, and both synthesis and degradation of muscle protein
are increased after exercise (312). The rate of synthesis can be
elevated for up to 72 hours after exercise (258). Recent con-
sensus indicates that amino acid requirements are increased
with regular exercise training, suggesting that protein intakes
as high as ~150-200% of current recommendations might be
necessary for these individuals (313).
Several amino acids also have other important roles, for
example serving as substrates in the synthesis of neurotrans-
mitters, stimulating protein synthesis or improving immune
function. A list of amino acids involved in immunology and
their roles can be found in a comprehensive review by Li et al.
(2007; (230)). The most studied amino acids in exercise
immunology are Gln, BCAA, alanine and arginine. Gln and
BCAA are the most studied in terms of supplementation
before and after exercise.
Branched chain amino acids
During prolonged, fatiguing exercise the branched chain
amino acids (BCAA) (leucine, isoleucine and valine) are
taken up by the working muscle and their plasma concentra-
tion decreases (41,397). The BCAA are oxidized to provide
energy but, more importantly, the metabolism of BCAA pro-
duces nitrogen for Gln synthesis.
Intake of BCAA rapidly increases their plasma and muscle
concentration (42,154,260), and it is suggested that this will
increase the production of Gln. A fall in the plasma concen-
tration of Gln (p[Gln]) has been observed during/after sus-
tained exercise (104,332), and has been proposed to be linked
with exercise-induced immunodepression ((77,336); see Glu-
tamine chapter). BCAA intake could therefore indirectly
influence the immune response. However, despite the elevat-
ed levels of BCAA in plasma and muscle after intake of these
amino acids, the release of Gln from the exercising muscle
remains unchanged unless large amounts of BCAA are
ingested (42,236,237). In contrast to these findings, chronic
supplementation with BCAA to athletes was able to prevent
the decrease in p[Gln] and immunodepression following a
triathlon or a 30 km race (21). Furthermore, ten weeks of
BCAA supplementation to trained cyclists prevented the
increase in neutrophil number in trained cyclists which was
observed without supplementation (207).
A direct effect of BCAA on cells of the immune system may
also be conceivable since these amino acids, in particularly
leucine, may stimulate protein synthesis and activate cytokine
and antibody production through a direct effect on mTOR sig-
nalling (see (230)). However, there is currently no evidence
for such an effect, and available data indicate that BCAA are
required to maintain the high rate of protein synthesis in these
cells rather than to stimulate the immune function (see
(57,97)).
Consensus
There are some indications that BCAA intake can reduce
exercise-induced immunodepression. However, there is cur-
rently not enough data from controlled studies to recommend
BCAA ingestion in combination with exercise to enhance
immune function.
Glutamine
Background
Glutamine is the most abundant amino acid in the body and
was originally classified as a non-essential amino acid (340).
However, since the 1990s there has been increasing evidence
that Gln becomes “conditionally essential” in specific condi-
tions of stress (73,220).
Immunonutrition and Exercise • 15
EIR 23 2017
Gln is synthesized, stored and released predominantly by
skeletal muscle and, to a lesser extent, by adipocytes, liver
and lung. It is taken up by intestinal cells, such as enterocytes
and colonocytes, by the kidney, liver and immune cells such
as lymphocytes, macrophages and neutrophils. It has been
suggested that Gln supplementation might improve the diges-
tive and defence mechanisms of the intestine (100,410).
Gln is required by rapidly-dividing cells (213), providing
nitrogen for purine and pyrimidine nucleotide synthesis,
enabling synthesis of new DNA and RNA, for mRNA synthe-
sis and DNA repair. Ardawi and Newsholme (1985; (12,13))
observed a high Gln utilisation by human lymphocytes at rest.
Subsequent in vitro work (303) showed that when Gln was
reduced in culture medium a decrease occurred in the prolifer-
ative ability of human lymphocytes. Gln and BCAA (see
Amino acids section) are the most studied amino acids in
terms of supplementation before and after exercise.
The p[Gln] is increased in athletes after short-term exercise
(316). However, after prolonged, exhaustive exercise such as
a marathon, the p[Gln] can be decreased by 20-25% (77,104).
Similar decreases have been observed after repeated bouts of
prolonged exercise (336). In two studies at moderate altitude
(athletes, in summer) and high altitude (military personnel, in
winter) a significant decrease in p[Gln] occurred after inten-
sive training and coincided with a high incidence of URTI
(16,79).
The post-exercise decrease in p[Gln] is often concomitant
with a decrease in circulating lymphocyte numbers which
transiently increase initially as part of the well-known leuco-
cytosis observed after exhaustive exercise. Immune cell
function is also decreased at this stage, for example, in both
lymphocytes and NK cells. Rohde et al. (1996; (336))
observed a marked decrease in p[Gln] in triathletes at 2
hours after prolonged exercise, paralleled by changes in lym-
phokine activated killer (LAK) cell activities. A decrease in
p[Gln] in marathon runners coincided with increases in acute
phase markers such as the cytokine IL-6 and complement
C5a, as well as an increased incidence of self-reported URTI
(76,77).
There is some evidence that Gln, or a Gln precursor (BCAA),
can lessen the incidence of exercise-induced URTI after
marathon running (21,77). However, several studies, mostly
laboratory-based, have shown no effect of maintaining a nor-
mal or high p[Gln] on various aspects of immune function.
These included: LAK cell activity, lymphocyte numbers,
some leucocyte subsets, salivary IgA, CD3 T-cell receptors,
NK cells, leucocytosis, plasma elastase release from
lipopolysaccharide (LPS)-stimulated neutrophils
(216,335,337,403); CD8, CD4 with/without CD28 & 9 sur-
face receptors (215), although the latter study also showed
less neutrocytosis in the Gln group than the placebo group.
In a recent study Caris et al. (2014; (67)) observed a positive
effect of both Gln and carbohydrate in modulating the
Th1/Th2 (helper cells) balance after exercise. The post-exer-
cise ratio of CD4+helper/ CD8+cytotoxic/suppressor cells
has been seen to be higher in athletes provided with Gln rather
than placebo after both marathon running (75) and heavy load
training (373).
It has been suggested that muscle Gln is not markedly
decreased as a result of exercise, although Rennie et al. (1981;
(332)) did see a decrease in muscle Gln in their study, which
also produced a biphasic response of p[Gln] to 3.75 hours of
exercise. The decrease is markedly less than the pathological-
ly low Gln concentrations observed in the muscle of critically
ill patients (341). Current opinion considers that, in general,
the body has sufficient stores of Gln to replenish post-exercise
plasma reductions readily (see (139)). The time frame for this
is not known. Interestingly, Hiscock et al. (2002; (180)) meas-
ured the intracellular content of Gln in peripheral blood
mononucleocytes (PBMC), and found good availability of
Gln for the cells after exercise.
The presence of glutaminase, the major degradation enzyme
of Gln, was established in human neutrophils by Castell et al.
(2004; (74)). There appears to be a link between production of
the major neutrophil chemoattractant, IL-8, and Gln. In in
vitro studies the provision of Gln results in a decrease in IL-8
production in athletes (73), and in clinical studies in patients
with acute pancreatitis (23). Provision of exogenous Gln
might therefore lead to a decrease in the requirement for IL-8
secretion to attract more neutrophils to the site of tissue dam-
age, though this is speculative.
IL-6 is probably the most studied cytokine (myokine) in exer-
cise immunology. The plasma concentration of IL-6 increases
markedly after strenuous and prolonged exercise and this
increase was further enhanced after Gln supplementation
(181). This might prove beneficial if, as has been suggested,
IL-6 acts as an anti-inflammatory cytokine in exercise (311).
In regard to leucocytosis after endurance exercise, Fehren-
bach et al. (1999; (126)) described a possible protective effect
of heat-shock protein (HSP) in athletes. There is substantial
evidence that Gln is important for HSP generation in both in
vitro and in vivo studies (200,423,426). Zuhl et al., 2014 (433)
observed anti-inflammatory effects of Gln via HSP70 on
intestinal permeability and peripheral blood mononuclear
cells. Raizel et al. (2016; (327)) recently showed that treating
rats with oral free L-Gln (with L-alanine or as a dipeptide)
induced cytoprotective effects via HSP70 after resistance
exercise. HSP facilitates neutrophil activity (179,296): given
the presence of glutaminase on the secretory granules of
human neutrophils (74), the effect of Gln on the heat shock
response might induce changes in neutrophil function.
Consensus
Despite a good rationale for Gln supplementation based on
sound biochemical investigation, laboratory-based exercise
studies have proved disappointing in terms of providing any
direct enhancement of immune function due to Gln feeding
(see Controversies). Recently, it has been suggested that there
is sufficient Gln availability in body stores to combat post-
exercise decreases in immune function after endurance
events. Nevertheless, a decrease in p[Gln] may act as a mark-
er for immunodepression and increased incidence of minor ill-
nesses. Thus, a marked decrease in p[Gln] may indicate
16 • Immunonutrition and Exercise
EIR 23 2017
decreased immunocompetence, in particular in the individual
who is vulnerable to opportunistic infections. There are some
indications that provision of Gln or a Gln precursor can lessen
the incidence of exercise-induced URTI.
Controversies
Since p[Gln] decreases by approximately 20-25% after pro-
longed, exhaustive exercise, given its role in some key
immune cells, this might be expected to have ramifications for
immune function in athletes. There was a sound biochemical
and clinical rationale for thinking that Gln provision might be
a simple panacea for minor illnesses and for exercise-induced
immunodepression. Despite the evidence that Gln or a Gln
precursor can lessen the incidence of exercise-induced URTI,
several laboratory-based studies have shown no effect of
maintaining a normal or high p[Gln] on some specific aspects
of immune function.
Future Directions
Data on the effects of supplementation with Gln or Gln pre-
cursors on neutrophil function in exercise have become
increasingly interesting, and further investigation in humans
should prove to be useful. Gln has a role in generating heat
shock protein: this might have a protective effect on immun-
odepression in exercise, and more studies are required. There
may also be other aspects of immune function as yet unstud-
ied, which might respond more effectively to the provision of
Gln before or after prolonged, exhaustive exercise.
MINERALS
Background
Several minerals are known to exert modulatory effects on
immune function, including Zn, Mg, Fe, Se, and Mn. With the
exception of Zn and Fe, isolated deficiencies are rare. Regard-
ing exercise, requirements for some of these minerals are cer-
tainly higher in athletes compared with sedentary people. On
the one hand, exercise has a pronounced effect on mineral
metabolism; on the other hand, exercise increases losses in
sweat and urine. However, excess intakes of some minerals
are known to impair immune function. Earlier reviews have
discussed mineral supplementation comprehensively
(63,138). The present consensus statement considers supple-
mentation of five specific minerals (Zn, Mg, Fe, Se and Mn)
in relation to exercise.
Consensus
Zinc
The essential trace element Zn is an important co-factor of
several enzymes and transcription factors and thereby
involved in various physiological processes during growth,
metabolism, and development. Studies with hereditary dis-
eases of Zn deficiencies such as acrodermatitis enteropathica
have demonstrated the importance of proper Zn levels for
immune function of both adaptive and non-adaptive systems
(187). Severe Zn deficiency in these patients is accompanied
by several symptoms including enhanced susceptibility to
infections. But even mild Zn deficiency occurring in popula-
tions at risk such as elderly people or vegetarians may result
in impairment of NK cell lytic activity and T cell mediated
functions (319). Intracellular Zn levels in T cells seem to be
highly regulated and involved during T cell activation. In
macrophages Zn seems to play a part in important anti-inflam-
matory roles by inhibiting NF-κB signalling. Beside its action
on immune cells Zn seems to have direct anti-viral properties
via Intercellular Adhesion Molecule (ICAM)-1 receptors on
respiratory epithelial cells of the nasal epithelium (186).
The RDA of Zn for men and women in the US is 11 and 8 mg,
respectively; in the EU a gender independent value of 10 mg
is given. Zn can be found in a wide variety of foods like cer-
tain types of sea food such as oysters, crabs and lobsters, red
meat, poultry, beans, nuts and whole grains. In contrast,
bioavailabilty of Zn is impaired by phytates which are present
in whole-grain breads, cereals, and legumes, and by Fe sup-
plementation.
There is considerable mobilization of Zn during exercise into
the blood, which is re-distributed soon after termination of
exercise. Nevertheless losses of Zn via sweat and urine, in
addition to reduced dietary intake, have been identified as
major risk factors for Zn deficiency in athletes. Therefore a
number of studies reported Zn deficiency (serum levels < 70
µg/dl) in elite athletes, especially in endurance athletes (257).
However, the impact of these alterations on athletes’ immune
system/function remains to be shown. Therefore regular sup-
plementation of Zn cannot be recommended. Nevertheless,
there is some evidence from general population studies that
Zn supplementation might be effective in the prevention and
therapy of the common cold, which represents the major dis-
ease form of athletes during transient immunodepression in
the early post-exercise period. A recent study presented weak
evidence for Zn in the prevention of the common cold in chil-
dren (6). In addition, recent meta-analysis including 17 trials
and a total of 2121 participants presented moderate evidence
that oral Zn formulations may shorten the duration of symp-
toms of the common cold (354). It has been suggested that
supplementation should start within 24 hours of the onset of
symptoms (367). Based on these studies, a transient supple-
mentation during periods of intensive exercise bouts together
with psychological stress such as during competition might be
beneficial, especially if a history of recurrent infections exists.
Side effects of Zn supplementation include bad taste and nau-
sea.
Magnesium
Mg is an essential biological element which is predominantly
located in bones (approx. 52%), in muscle cells (28%), and
soft tissue (19%). Serum and red blood cells contain only
0.3% and 0.5%, respectively. In general, Mg is involved as an
important regulator in three main physiological processes; 1)
enzyme activation, e.g. during energy metabolism, 2) stabiliz-
ing membrane function and integrity, 3) cell signalling, e.g. as
a natural antagonist of intracellular calcium signals (263).
With respect to the function of the immune system Mg seems
to be involved in the following steps: cofactor for
immunoglobulin synthesis, immune cell adherence, antibody-
dependent cytolysis, activation of macrophages. Moreover,
Mg deficiency is associated with clinical signs of inflamma-
tion, such as immune cell activation and enhanced levels of
circulating inflammatory mediators (222).
Immunonutrition and Exercise • 17
EIR 23 2017
The concentration of total serum Mg is approximately 0.75-
1.1 mmol/l, which is, however, a rather poor indicator of the
body’s Mg status. Serum acts as a transit pathway between
electrolyte uptake and excretion, bone stores and actively
metabolising tissues. These processes are affected by a num-
ber of hormones such as parathyroid hormone, calcitonin,
vitamin D, insulin, glucagon, antidiuretic hormone, aldos-
terone and sex steroids.
Exercise-induced alterations of serum Mg seem to depend on
exercise intensity and duration. After short-term, high-intensi-
ty exercise the majority of studies indicated an increase of
extracellular Mg; however, after prolonged submaximal exer-
cise most studies reported a hypomagnesaemia (56). It seems
unlikely that sweat Mg losses and/or enhanced renal Mg
excretion alone account for this decrease in serum. Some
authors suggested therefore that, during prolonged exercise, a
shift of Mg into the cellular compartment occurs. Longitudi-
nal and cross-sectional studies demonstrated that intensive
training periods may be followed by Mg depletion and that
athletes are prone to Mg deficiency (348).
Therefore it can be speculated that the exercise-associated
changes in immune function especially in the early post-exer-
cise period might be aggravated in Mg-deficient athletes
(222). In contrast, it has been demonstrated that Mg supple-
mentation did not prevent exercise-induced alterations of
immune parameters in athletes with balanced Mg status (262).
Therefore, Mg supplementation can be recommended only
after diagnosis of Mg deficiency which relies on both clinical
symptoms and laboratory diagnosis (serum Mg < 0.75 mmol/l
is considered to be a useful measurement for severe deficien-
cy). Important food sources of Mg are vegetables, fish, nuts,
and whole grains. Mg formulations include both inorganic
and organic compounds of which the latter seemed to have a
better bioavailability.
Iron
Fe is an essential nutrient which is primarily used as a cofac-
tor for enzymes in the mitochondrial respiratory chain, in the
citric acid cycle and during DNA synthesis, as well as being
the central molecule for binding and transport of oxygen by
haemoglobin and myoglobin (414).
For immunity, Fe is important for lymphocyte proliferation
and differentiation while it interferes with cell mediated
immune effector pathways and cytokine activities (356,414).
Furthermore, Fe exerts multiple effects on macrophage polar-
ization and functionality (269).
Changes in Fe status can thus affect the immune response in
multiple ways, particularly in the context of infection (82).
The RDA is 18 and 8 mg for women and men respectively.
Sources of Fe are flesh foods, vegetables and grains. The
haem Fe, found in meat products, is best absorbed. In general,
male athletes tend to consume at least the RDA for Fe, but
female athletes tend to consume somewhat less (166). If this
under-supply is combined with heavy Fe loss by menstrua-
tion, haemolysis, gastrointestinal bleeding, inflammatory sta-
tus by heavy physical activity or loss by sweat, Fe balance
may be compromised (235,253). Accordingly, Fe deficiencies
have been reported mainly in women competing in running,
field hockey, cross country skiing, basketball and others
(253). In this case, the use of Fe fortified foods and Fe supple-
ments may be considered (51). Therefore, Fe supplementation
in combination with vitamin C should be recommended for
athletes with Fe deficiency anaemia and monitored carefully
for prophylaxis. During infection the supplementation of
some minerals like Fe is not recommended because it is sug-
gested that pathogenic microorganisms might benefit (107).
However, an immunological effect of Fe supplementation in
the context of exercise has not been shown so far.
Selenium and Manganese
Se status may affect the function of cells of both adaptive and
innate immunity. Currently, the recommended amounts for
adequate Se intake of adults range between 25 and 100
μg/day, with an average of 60 μg/day for men and 53 μg/day
for women (328,376). Neither Se deficiencies nor immuno-
logical effects of supplementation in athletes have been
described yet. For Mn, daily intake through dietary sources
provides the necessary amount required for several key physi-
ological processes, including antioxidant defence, energy
metabolism, immune function and others. During exercise,
Mn might play a role as an antioxidant since a superoxide dis-
mutase in the mitochondrial matrix functions with Mn. There
is no evidence for neither deficiency nor supplementation for
Se nor Mn in athletes, thus both minerals cannot be classified
as immunonutrition during exercise (81). An overview about
these minerals, their immune related functions, symptoms of
deficiency, deficiencies in sports and recommendations for
supplementation is given in Table 1.
Future directions
While there is evidence that regular exercise training of high
volume and intensity may be accompanied by deficiencies of
certain minerals such as Zn, Mg and Fe, the impact of these
alterations on the athlete’s immune function needs to be
demonstrated. In vitro experiments could demonstrate the
involvement of these ions in certain immune processes. But it
remains to be shown whether these deficiencies are able to
aggravate exercise-induced immune responses.
ANTIOXIDANTS
Background
Free radicals are reactive molecules with unpaired electron(s)
(158). High levels of free radicals damage cellular compo-
nents. Antioxidants are chemical compounds and enzymes
that exist as a natural means of quenching free radical over-
production. However, moderate levels of radicals and other
oxidants are central to the control of gene expression, cell sig-
nalling pathway regulation, and physiological modulation of
skeletal muscle force production (318). In the context of
inflammation in health and disease, genomic, cellular, and
physiological outcomes are regulated by fluctuations between
free radical species and their antioxidant counterparts. In this
section, we outline oxidants (mainly ROS and reactive nitro-
gen species (RNS)) and antioxidants (with a focus on dietary
sources of antioxidants), their effects on exercise, and the
interface with the immune system (329).
18 • Immunonutrition and Exercise
EIR 23 2017
Relevant to immune system interactions, superoxide is one of
the strongest cellular oxidants, but it is quickly dismutated to
hydrogen peroxide by the enzyme superoxide dismutase.
Hydrogen peroxide is a more stable, non-free radical ROS
that is permeable to cellular membranes. Despite being a
weak oxidizing agent, high local concentrations of hydrogen
peroxide are cytotoxic. Toxicity is typically associated with
oxidizing chain reactions promoted by Fe (Fenton reaction)
centered molecules which produce hydroxyl radicals.
Hydroxyl radicals are strong oxidants, highly reactive and,
when concentrated, can be the most damaging ROS in biolog-
ical systems. Central to inflammation, hypochlorite is another
well-known ROS product (329). Hypochlorite is formed by
the action of the oxidative enzyme myeloperoxidase utilizing
hydrogen peroxide. Hypochlorite is produced by neutrophils
and macrophages (233,432) and, independent of pathogen
defence, can oxidize circulating cholesterol and other humoral
factors with deleterious consequences. Moreover, this oxidant
readily forms hypochlorous acid, subsequently crossing cell
membranes and damaging essentially all cellular constituents
with negative effects (71).
Nitric oxide is held to be the main RNS in inflammatory
processes and is synthesized enzymatically (nitrogen oxide
synthase isoforms) from the amino acid L-arginine. Nitric
oxide is a weak reducing agent, but can react with superoxide
to produce peroxynitrite. As with ROS, RNS promote health
or disease within the context of a dose, duration and the local
biochemical environment. In certain scenarios peroxynitrite is
a strong oxidizing agent that depletes thiol groups, and dam-
ages DNA and proteins (234).
Consensus
Undeniably, participation in acute exercise is associated with
a transient production in the ROS/RNS (317). Moreover,
while the source of ROS/RNS production is largely thought to
be generated within the contracting skeletal muscle (331)
there is ample evidence that the immune system is also
responsible for exercise-generated radical species (325).
The involvement of the immune system in ROS and RNS
production
The rate of oxygen consumption by phagocytes (e.g., neu-
trophils, eosinophils and mononuclear phagocytes) increases
when exposed to certain stimuli (e.g., pathogens, pollutants,
etc.). When this occurs, the phagocytes produce high levels of
superoxide and collectively these events are known as the
"respiratory burst" (14). The purpose of this phenomenon is to
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 % 
 
&
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)-",
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/0()
1
",
2 2
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
"
2 2 2
Table 1: Overview about specific minerals, their immune related functions, symptoms of deficiency, deficiencies in sports and recommendations
for supplementation.
Immunonutrition and Exercise • 19
EIR 23 2017
generate powerful microbiocidal agents by the internal
defence arm of the immune system. Specifically,
macrophages produce NO which plays a critical role in redox-
related functions of the immune response (422).
Interaction of exercise and antioxidant content (potential) of
the immune system
It is well established that prolonged, high intensity training
and competition can result in acute immune impairment in
athletes and usually manifests as an increased susceptibility to
minor illnesses, particularly URTI (see Section 12). Essential
to this understanding is the fact that acute high intensity exer-
cise is associated with upregulation of endogenous antioxi-
dant enzyme transcripts (129). This finding is important and
suggestive of the fact that, as with muscle level adaptations,
the immune system is resilient and ultimately adapts benefi-
cially to exercise.
Controversies
Advocates of antioxidant supplementation argue that exer-
cise-induced oxidant production cannot be adequately
quenched without dietary intervention. While this logic may
seem reasonable at first, several arguments contradict the
notion that athletes and recreational exercisers require dietary
antioxidant supplementation. For example, dietary antioxidant
consumption has been proposed to reduce the risk of respira-
tory illness, but conclusive data to support or oppose this
statement are not available (121). Furthermore, links between
exercise-induced oxidative stress and immune dysfunction
(275), and the postulated benefits of dietary antioxidant sup-
plementation in preventing immune dysfunction during exer-
cise, are not substantiated empirically (276).
In addition, to counteract the proposed need for supplemental
antioxidants, there is no conclusive evidence that exercise-
induced ROS production is detrimental to human health. By
contrast, the fact that exercise elicits both oxidative stress and
numerous adaptive health and athletic performance benefits is
paradoxical to the idea that supplemental antioxidants are
needed. Moreover, regular exercise training promotes fortifi-
cation of endogenous enzymatic and non-enzymatic antioxi-
dants, a fact that extends to circulating immune cells from
exercised individuals (129). The adaptive increase in endoge-
nous antioxidants does not fully quench the ROS/RNS gener-
ated during the exercise, but is clearly sufficient to protect
against deleterious outcomes due to exercise-induced oxida-
tive stress (194).
According to scientific consensus, therefore, athletes who
consume an appropriate energy intake from nutrient-dense
foods do not need antioxidant supplementation. Moreover,
there is no evidence that exercise in extreme environments
necessitates antioxidant supplementation (324). In contrast,
one feasible circumstance in which supplemental dietary
antioxidants may be warranted is in individual cases of nutri-
ent deficiencies (e.g., antioxidant status below the normal
range for good health). This latter instance is a rare exception
to our broader understanding of exercise and oxidative stress:
nevertheless it has been questioned scientifically by investi-
gating the dietary practices of athletes (396). Importantly,
emerging evidence indicates that antioxidant supplementation
mitigates important exercise-induced adaptations which now
appear to extend to the immune system.
Future directions
The debate for and against antioxidant supplementation in
athletes and regular exercisers appears likely to continue
despite comprehensive understanding of immunonutrition and
exercise-induced oxidative stress. Antioxidant supplementa-
tion practices are often driven by business models and con-
sumer biases that seek a convenient means to improve athletic
performance, health, and longevity. Accordingly, there is a
pressing need for additional research to demonstrate when,
and in what context, antioxidant supplementation may be effi-
cacious. Moreover, future work should be mindful of corpo-
rate biases and include points for consumer advocacy when-
ever possible. It is proposed that exercise and nutritional sci-
entists should join with practitioners to educate athletes about
the current scientific understanding regarding antioxidant sup-
plements and exercise-induced oxidative stress and inflamma-
tion. Education efforts should be strategic and ever mindful of
consumer demand for pill-based solutions to complex prob-
lems like performance enhancement, a point that is of particu-
lar importance to exercise and immunonutrition.
PLANT-DERIVED IMMUNOMODULATORS:
HERBAL SUPPLEMENTS
In this article “botanical supplements” (“herbal supplements”)
refers to single- or multi-organ plant extracts in tablet or liq-
uid form containing a diverse array of phytochemicals, in con-
trast to “botanicals” (“herbals”) which refers to isolated plant
compounds or compound groups.
Background
Several plants are used by athletes as dietary/nutritional sup-
plements (Table 2). Quantifying global rates of use is logisti-
cally problematical because athletes and researchers differ in
their definition of “herbal supplement”, and multicomponent
preparations or foodstuffs may contain herbs unbeknownst to
athletes. Usage surveys sometimes neglect herbal supple-
ments or lump different supplements together as one group
(123,211,359). Thus, use is likely to be underestimated.
Athletes consume herbal supplements for both health and per-
formance reasons, and a given supplement often has more
than one presumed use. Many herbal supplements consumed
by athletes have purported immunomodulatory capacities
(Table 2). Presumed immunomodulatory herbal supplements
are diverse in terms of taxonomy, plant organs used, and
bioactive compounds.
Consensus
Empirical evidence for the immunomodulatory capacities of
herbal supplements is often incomplete, equivocal, and/or
weak, whether the studies used athletes/non-athletes or exer-
cise/non-exercise models. Ginseng and echinacea possibly
serve as the best models for examining immunomodulatory
herbal supplements in athletic contexts, because they have
been more robustly researched, and bioavailability studies
suggest these supplements’ bioactive molecules can pass
20 • Immunonutrition and Exercise
EIR 23 2017
through the gut into the bloodstream in physiologically rele-
vant quantities.
Echinacea is primarily taken by athletes for prevention or
treatment of upper respiratory tract infections such as colds or
influenza. Recent reviews and meta-analyses from clinical tri-
als with the general population concur that echinacea supple-
mentation may lessen symptom severity or duration, but are
equivocal in their assessment of its prevention capabilities
(204,349). Results from athlete/exercise studies on echinacea
are similar (Table 3) (27,155,353). Though all three studies
used E. purpurea-based preparations, Table 3 epitomizes the
problems in forming conclusions
about echinacea supplements (or
most herbal supplements for that
matter; e.g., few studies, different
populations, measurements, exer-
cise interventions, and treatment
interventions). One recent review
that examined clinical studies, ex
vivo studies (where blood samples
were drawn pre- and post-exercise,
but lymphocytes were stimulated in
vitro), and in vitro studies conclud-
ed that echinacea supplements may
stimulate both innate and adaptive
immunity (the former more so) and
that alk(yl)amides and caffeic acid
derivatives are the likely bioactive
molecules (358). In terms of
ergogenic potential, echinacea sup-
plementation did not improve
endurance capacity or VO2max in
three studies (22,25,375) but did in
one (417).
Ginseng is primarily taken by ath-
letes as an ergogenic or adaptogenic
aid, either as a standalone supple-
ment or in multicomponent “energy
drinks.” Recent reviews have dis-
counted its utility as an ergogenic
aid (15) and further suggest that any benefits seen in energy
drinks are likely attributable to caffeine or sugars and not gin-
seng (18). Ginsenosides are the presumed immunomodulatory
constituents. A review of the immunomodulatory effects of
ginseng supplements in athletes has been provided elsewhere
(Table 2 in (358)). Though there are more in vivo studies on
ginseng and its potential immunomodulatory effects than
echinacea, outcomes were worryingly inconsistent across
studies and often weak, likely owing to the diverse species,
extract types, and dosing used. The two studies investigating
IL-6 are a good example of this predicament. In one study
(202), trained males consumed heat-treated P. ginseng supple-
ments for seven days before two 45-
minute treadmill runs and demon-
strated reduced IL-6 compared to
controls a couple hours post-exer-
cise but not a day later. In a sepa-
rate study (225), untrained male
subjects consumed P. pseudogin-
seng for three days before 30 min-
utes of treadmill running at 60%
VO2max and demonstrated no dif-
ference in IL-6 levels post-exercise
compared to controls.
Owing to the sparse literature avail-
able, many athletics-associated
claims about herbal supplements
have yet to be scientifically
addressed and recommendations
need be cautious. As therapeutic
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Table 2: Herbal supplement use by 8424 athletes based on 27 published surveys. Data used for
this table were gleaned from a subset of 27 athlete surveys identified by Knapik et al. (211) as con-
taining references to specific herbal supplements (references 9-12, 15, 19, 23, 35, 49, 58, 67, 68,
80, 101, 121, 123, 128, 131, 132, 141, 144, 149, 151-153, 159, and 198 in (211)), but were analyzed
differently here. * = Many herbal supplements were quantified only once and were not tabulated:
alfalfa, chamomile, ciwujia, evening primrose, goldenseal, green tea, guarana, kava kava, kola nut,
peppermint, tea tree oil, and yohimbe. Some surveys also noted “herbal supplements” (4 surveys;
0.9 ± 2.9%) or mixed herbal preparations (4 surveys; 3.5 ± 10.5%). = “Yes” indicates at least
some use among athletes as an immunomodulator, and “no” indicates the supplement is not con-
sumed as an immunomodulator; designations do not connote whether the plant is primarily taken
as an immunomodulator (e.g., echinacea) or only secondarily (e.g., ginseng), or efficacy. ‡ Two
additional studies did not provide usage statistics. §One additional study did not provide usage
statistics.
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Table 3. Representative studies concerning potential immunomodulatory effects of Echinacea
supplementation in athletes. Abbreviations: RA = recreationally-active, TR = trained.
Immunonutrition and Exercise • 21
EIR 23 2017
immunomodulators for athletes, there is some evidence that
echinacea may be efficacious whereas the evidence for gin-
seng is murky. Scant literature exists on the potential
immunomodulatory effects of the other herbal supplements in
Table 2 among athletes or even in the general population, and
reviews may be found elsewhere (78).
Controversies and Future Directions
For some herbal supplements, data are only available from
animal models or in vitro work with human or animal cells.
While valuable, such data may not directly translate to human
clinical outcomes because of bioavailability/pharmacokinetic
reasons or species differences. Potential immunomodulatory
effects of bystander molecules (such as endotoxin [LPS] from
bacteria growing on plant material or incorporated during the
extraction process) are concerns for in vitro studies and may
explain contradictory activities of plant extracts such as dual
cytokine-enhancing and -suppressing properties from a single
extract (387); some experiments proactively addressed such
concerns whereas others did not. Unaccounted “pre-clinical
factors” (especially those during plant growth, harvest, and
processing) and differences in experimental methods con-
found cross-study comparisons (357).
Muddying the waters are issues related to the products them-
selves: herbal supplement labels may not accurately represent
actual supplement contents; there can be lot-to-lot variation
from a single manufacturer; and stark differences can exist
across manufacturers for a single supplement. Supplements
may also inadvertently (or, some allege, covertly) contain
substances considered banned/”doping agents
(92,135,214,297). Many herbal supplements are not regulated
by government agencies.
Thus, one should be cautious in concluding that any given
supplement is consistently efficacious, or that there is a signal
failure due to a lack of consiliency in the published research.
Rather, lack of consiliency represents the Byzantine nature of
herbal supplements in “real world” contexts due to the factors
just described. It also limits the guidance professionals can
provide to athletes concerning herbal supplement efficacy or
safety.
Aforementioned pitfalls can guide future work, which will
need to be transdisciplinary to account for all pre-clinical and
clinical factors that may influence immune outcomes. Few
human in vivo studies have focused on specific immune
parameters such as cell subpopulations or antibody or
cytokine profiles. Such work would help illumine mecha-
nisms and provide the additional benefit of linking clinical
outcomes with findings from ex vivo or in vitro studies.
POLYPHENOLS
Introduction to Polyphenols
The plant kingdom uses nearly 50,000 secondary metabolites
for defence, attraction, and protection (163). These plant
metabolites include approximately 29,000 terpenes, 12,000
alkaloids, and 8,000 phenolics. The 8,000 phenolic com-
pounds or polyphenols are divided into four main classes:
flavonoids (~50% of all polyphenols), phenolic acids, lignans,
and stilbenes. Flavonoids are further classified into six simple
(flavan-3-ols, flavanones, flavones, isoflavones, flavonols,
anthocyanins) and two complex subgroups (condensed tan-
nins or proanthocyanidins, derived tannins) (17) (Table 4). In
foods, flavonoids, lignans, and stilbenes are usually found as
glycosides, and phenolic acids as esters with various polyols,
and structural variations influence absorption and bioavail-
ability (429).
Nutritional assessment of dietary polyphenol and flavonoid
intake has improved with the development of databases from
Phenol Explorer (www. http://phenol-explorer.eu/) and the
U.S. Department of Agriculture (http://www.ars.usda.gov/ser-
vices/docs.htm?docid=24953). Recommendations for dietary
polyphenol and flavonoid intake have not yet been established
but should be forthcoming as improvements in assessment
methods continue. In Europe, the average dietary polyphenol
intake has been estimated at 1,187 mg/day (ranging from
about 1,700 mg/day in Denmark to 660 mg/day in Greece),
with coffee, tea, fruits, and wine as the principal sources
(429). In Europe, only ~100 polyphenols are consumed at lev-
els exceeding 1 mg/day, and flavonoids represent 40% of the
total polyphenols ingested (429). Dietary flavonoid intake
from all foods and beverages among US adults is 251 mg/day,
with tea as the primary source (80% of total flavonoid intake)
(355). Only 29% consume tea on a given day, and when tea is
removed from the analysis, total flavonoid intake falls to
about 50 mg/day, reflecting the low intake of fruits and veg-
etables by US adults (~2 servings/day) (185,355).
Many flavonoids exhibit strong anti-inflammatory, antioxi-
dant, anti-pathogenic, and immuno-regulatory properties
when studied using in vitro procedures (1,128,241,413). Most
flavonoids are poorly absorbed in the human small intestine
and undergo extensive biotransformation after ingestion.
Thus, in vitro data using the original food-based flavonoid
molecule has questionable relevance when evaluating bioac-
tive effects following ingestion. A large proportion of ingested
plant polyphenols reaches the colon, and microbial degrada-
tion transforms the extremely diverse population of dietary
polyphenols into a smaller number of metabolites, including
simple phenols and derivatives of benzoic acid, phenylacetic
acid, mandelic acid, phenylpropionic acid, and cinnamic acid
(116,119,120,345). The bacterial transformation of food
polyphenols in the colon varies widely depending on the
unique gut microbiota composition of the individual as influ-
enced by genotype, diet, lifestyle, and other factors (116). The
metabolites created from bacterial degradation can exert local
health benefits to colon endothelial cells, modulate the com-
position of the microbiota, and hence indirectly influence
their own metabolism and bioavailability (116). The gut-
derived phenolics can be reabsorbed into the portal vein,
undergo phase II biotransformation in the liver, enter the sys-
temic circulation and become a part of the so-called “food
metabolome”, exert a variety of bioactive effects, and then
finally be excreted in the urine (119,120,345) (see Figure 1).
Recent in vitro studies using biotransformed phenolics at
physiologically relevant concentrations indicate that degrada-
tion of flavonoids to simpler phenolics actually increases their
overall anti-inflammatory bioactivity (241,413).
22 • Immunonutrition and Exercise
EIR 23 2017
Epidemiological studies support a strong linkage between
high versus low dietary polyphenol intake and reduced risk
for overall mortality (189) and a wide spectrum of health con-
ditions including neurodegenerative diseases (371), body
weight gain (29), systemic inflammation and oxidative stress
(11,72), diabetes (391), cardiovascular disease (409), and
hypertension (223). A higher intake of flavonoids predicts
increased odds of healthy aging (344). A systematic review
and meta-analysis showed that flavonoid supplementation
(range of 0.2 to 1.2 g/day in 14 selected studies) decreased
URTI incidence by 33% compared with control (372). Many
flavonoids exert anti-viral effects, modulate NK cell activities
and regulatory T (Treg) cell properties, and influence
macrophage inflammatory responses (209). High dietary
intake of flavonoids has been linked in the Framingham Heart
Study Offspring Cohort with decreased systemic inflamma-
tion using a cluster of biomarkers (72).
Countermeasure Effects of Polyphenols to Exercise-Indu-
ced Physiological Stress
Taken together, cell culture and epidemiological data support
the recent focus of investigators on the use of polyphenols as
potential countermeasures to exercise-induced inflammation,
oxidative stress, immune changes, illness, and delayed onset
of muscle soreness (DOMS) (for reviews, see
(268,277,278,379)). Multiple dosing strategies have been
employed including single and combined purified polyphe-
nols (e.g., quercetin, resveratrol), plant extracts (e.g., green
tea, black currant, pomegranates), and increased fruit and veg-
etable food or juice intake (e.g., blueberries, bananas, tart
cherry juice). Most studies incorporate a one to three week
polyphenol loading period prior to an exercise stress interven-
tion. Few papers are available for any particular polyphenol or
plant extract, and research designs vary in regards to the sup-
plementation regimen, form of exercise stress, and outcome
measures (268,277,278,281,282,379). The data in general
support that polyphenol-rich plant extracts and unique
polyphenol-nutrient mixtures (e.g., quercetin with green tea
extract, vitamin C, and fish oil, or freeze-dried blueberry pow-
der with green tea extract) have small but significant effects in
increasing anti-oxidant capacity, with inconsistent, short-term
effects on mitigating exercise-induced oxidative stress,
inflammation, and immune dysfunction. High blueberry and
green tea flavonoid versus placebo intake for 17 days was
linked to reduced ex vivo viral replication in blood samples
collected from athletes after a 3-day overreaching, running
protocol (1). Large-dose intake of
single flavonoids (e.g., 500 to
1,000 mg quercetin) has been
linked to reduced URTI in athletes,
but has not proved to be a useful
alternative to ibuprofen in regards
to countering post-exercise pain,
inflammation, and soreness for the
athlete (277).
Future Directions
Future studies should focus on the
long-term relationship between
increased intake of polyphenols,
gut-derived phenolics, and sys-
temic and post-exercise inflamma-
tion, oxidative stress, anti-viral
defence, and immune function in
athletes using global and targeted
metabolomics (281,282). Intense
and prolonged exertion has been
related to an enhanced transloca-
tion of gut-derived phenolics into
the circulation during a 17-day
period of polyphenol supplementa-
tion (282) (Figure 1). Elevated
blood and tissue gut-derived phe-
nolics from chronic, high polyphe-
nol intake over several months may
result in subtle but important
bioactive effects that translate to
improved recovery and ability to
train intensively, with reduced rates
of illness (1,241,281,282). This is a
complex relationship that demands
a multi-omics, long-term approach.
Research is needed to define opti-
mal dosing regimens and whether
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
Table 4. Polyphenol classes and subclasses, and food sources.
Immunonutrition and Exercise • 23
EIR 23 2017
increased intake of foods high in polyphenols such as berries,
tea, and coffee results in meaningful bioactive effects without
the need for high doses of unique flavonoid mixtures. In the
very least, long-term, high polyphenol intake from plants food
sources is important for the health of all humans, including
and more importantly, in relation to the present series, for ath-
letes.
PROBIOTICS – PREBIOTICS
Background
Probiotic-rich foods and supplements contain non-pathogenic
bacteria that colonise the gut purportedly yielding a variety of
health benefits that include reduced incidence of respiratory
and gastrointestinal illness. There are several possible ways
in which probiotics may reduce the risk of respiratory and
gastrointestinal illness symptoms. By their growth and
metabolism, probiotics help inhibit the growth of other bacte-
ria, antigens, toxins and carcinogens in the gut, and reduce
potentially harmful effects. Probiotics can also influence
immune function via interaction with immune cells associat-
ed with the gut. Prebiotics are non-digestible food ingredients
that promote the growth of beneficial microorganisms in the
intestines. Probiotics are found in several foods, particularly
dairy products such as milk, yoghurt and cheese (134),
although concentrations are relatively low. Consequently,
there is widespread interest in use of dietary supplements
containing probiotics in both the general and sporting com-
munities.
Figure 1
Figure 1 - Cyanidin-3-glucoside (C3G) is a widely consumed dietary anthocyanin, and can be used as a sample polyphenol to show how the
body metabolizes flavonoids. After ingestion, the majority of C3G goes to the colon where bacteria degrade it to multiple, simple phenolics
including hydroxybenzoic acid. Next, hydroxybenzoic acid and other phenolics are absorbed through the colon to the liver via the superior
mesenteric and hepatic portal veins. Prolonged and intensive exercise accelerates the translocation of simple phenolics from the colon to the
liver. In the liver, phase II metabolism adds glycine to convert hydroxybenzoic acid to hippuric acid that is released into the circulation. Hippuric
acid has been linked to multiple bioactive effects, and is ultimately eliminated from the body through the urine. Many other polyphenols go
through a similar biotransformation pathway.
SOURCES: Based on data from references (128) and (281). The contribution of Xiaowei Chen in designing this figure is acknowledged.
24 • Immunonutrition and Exercise
EIR 23 2017
Consensus
In clinical practice, probiotics have been used since the early
1900s to manage common gastrointestinal conditions includ-
ing stomach cramps, irregular bowel movements, excessive
flatulence, diarrhoea, and irritable bowel syndrome. In
research settings, the focus has been on verifying the clinical
benefits of probiotic ingestion and supplementation, and
underlying mechanisms of action. Many studies have been
conducted on the effects of probiotic use on gastrointestinal
problems and URTI in the general population. A recent sys-
tematic review (210) of twenty placebo-controlled trials con-
cluded that probiotic use resulted in lower numbers of illness
days, shorter illness episodes and fewer days absence from
day care/school/work. The most recent Cochrane systematic
review of probiotic benefits for URTI using data from ran-
domised controlled trials involving 3,720 non-athletes from
12 studies concluded that probiotics were better than placebo
in reducing URTI incidence by ~47%, and the average dura-
tion of an acute URTI episode by ~2 days (162).
The most important mechanisms of probiotic action are
thought to be via immunomodulation of local immunity (by
interaction with gut-associated lymphoid tissue and mainte-
nance of gut barrier function) and systemic immunity (by
enhancing some aspects of both innate and acquired immune
responses) (31,227). Probiotic intake can increase NK cell
cytolytic activity (330), enhance phagocytic activity and
microbicidal capacity of granulocytes and monocytes, modify
the production of cytokines and elevate levels of specific IgG,
IgA and IgM (162), with effects that can extend beyond the
gut to distal mucosal sites. Animal studies indicate that regu-
lar probiotic ingestion can influence responses in the respira-
tory tract and improve protection against bacterial and viral
pathogens via modulation of lung macrophage and T-cell
numbers and functions (131,227,245).
Controversies
To date there are few published studies of the effectiveness of
probiotic use in athletes and team sports; a recent comprehen-
sive review (323) identified 15 relevant experimental studies
that investigated immunomodulatory and/or clinical out-
comes. Of the eight studies that recorded self-reported URTI
incidence, five found reduced URTI frequency or fewer days
of illness (94,142,167,415,416), and three reported trivial or
no effects (141,206,386). A randomised, placebo-controlled
trial involving physically active individuals (415) reported
that fewer URTI episodes (relative risk ratio 0.73) were expe-
rienced in those who ingested daily a Bifidobacterium probi-
otic compared with placebo over a 150-day intervention peri-
od. However, a large study of 983 Finnish military recruits
failed to show significant clinical benefits for supplementa-
tion with a combination of Lactobacillus rhamnosus GG
(LGG) and Bifidobacterium animalis ssp. lactis BB12 for 150
days (203). Studies that examined immunomodulatory effects
of probiotics in athletes have reported increased interferon-γ
production in whole blood culture (83) and T-cells (94) and
better maintenance of secretory IgA during intensive training
(142,242). A recent study reported that URTI incidence was
unchanged despite reductions in cytomegalovirus (CMV) and
Epstein-Barr Virus (EBV) antibody titres after 20 weeks of
supplementation with Lactobacillus casei (144).
Most studies have examined probiotic effects in small num-
bers (<50) of recreationally active individuals over periods
lasting <6 months. URTI has typically been established by
self-report questionnaires and not all studies have used a ran-
domised, placebo controlled design. However, there is now
sufficient understanding of the mechanism of action of certain
probiotic strains, and enough evidence from trials with ath-
letes and highly physically active people (in addition to 12
studies cited in The Cochrane review (162) on children and
adults) to signify that there are mostly positive effects. Similar
to other supplements for which health claims are made there is
concern of bias in the literature, with a stronger likelihood of
publication of studies with positive, as opposed to trivial,
equivocal or negative outcomes.
Other potential benefits of probiotics could be reduced risk of
gastrointestinal discomfort symptoms and diarrhoea (e.g. so-
called runner’s trots) during prolonged exercise, reduced
endotoxaemia during exercise in the heat, and reduced inci-
dence of gastrointestinal infections – a particular concern
when travelling abroad. Further large-scale studies are needed
to determine if these potential benefits are real, and to confirm
that taking probiotics can reduce the number of training days
lost to infection and which strains of probiotics are most
effective for athletes. The studies that have shown reduced
URTI incidence in athletes have been mostly limited to Lact-
obacillus and Bifidobacterium species and used daily doses of
~1010 live bacteria. These doses (~1010 live bacteria) showing
efficacy with athletes are comparable to those used in non-
athlete studies (range ~108-1010) although recommended
dosages can be strain-specific. Although probiotic supple-
ments contain similar bacterial species to dairy foods, there is
little consensus on the relative effectiveness of commonly
used species. As for prebiotics, or combinations of prebiotics
and probiotics, there are currently no published studies on
their efficacy in athletes for reducing respiratory or gastroin-
testinal illness symptoms.
Future Directions
Long-term tolerance of probiotic supplementation in highly-
trained athletes over several months to years or the benefits, if
any, of cycling on and off probiotics, are important questions
warranting investigation. The laboratory-based efficacy and
field effectiveness of multi-component formulations combin-
ing several different probiotics species, or probotics and pre-
biotics, need evidence-based studies. Pharmaceutical compa-
nies are already making a wide range of multi-component for-
mulations. No studies have systematically investigated how
the dosage regimens of probiotic supplementation might vary
as a function of sex, age, medical history, dietary practices,
fitness level and/or training background. Health care practi-
tioners are seeking this information to assist them in prescrib-
ing individualised probiotic/prebiotic supplementation pro-
grammes.
BOVINE COLOSTRUM
Background
Bovine colostrum is the fluid produced by the mammary
glands for 24-72 hours following calving. While antibody
Immunonutrition and Exercise • 25
EIR 23 2017
transfer in a human takes place predominantly via the placen-
ta, calves rely on colostrum for the passive transfer of
immunoglobulins (Ig). As such, the concentration of Ig and
other immune factors, in combination with growth factors and
nutrients, is much greater in bovine than human colostrum.
For the calf, bovine colostrum is essential for immune system
establishment and gastrointestinal growth and differentiation.
This has led researchers to explore the potential of bovine
colostrum to modulate immune function in humans, particu-
larly in exercise where immune perturbations are common.
Bovine colostrum is an incredibly complex fluid and under-
standing of its potential molecular function is improving with
advances in technology, such as proteomic analysis (8).
Bioactive components of bovine colostrum include IgG,
lactoferrin, lactoperoxidase, defensins, trypsin inhibitor,
micro RNAs, insulin-like growth factor-1 (IGF-1) and trans-
forming growth factor-β (190,343). Following ingestion,
many of these components have been shown to survive diges-
tion and exert effects at the level of the gut, or systemically. In
cell culture and animal models (porcine, rat and mice) bovine
colostrum exhibits anti-bacterial, anti-inflammatory and anti-
viral properties (425,427). However, the effectiveness of sta-
ble, standardised preparations of non-hyperimmunised bovine
colostrum to modulate the immune system in healthy, exercis-
ing humans is less clear.
Consensus
Exercise is associated with immune perturbations and upper
respiratory symptoms (URS) are commonly reported in elite
athletes (122). Several investigations have reported URS inci-
dence following a period of bovine colostrum supplementa-
tion, with all of them suggesting that bovine colostrum sup-
plementation is associated with a reduction (not always statis-
tically significant) in URS incidence in athletes. A retrospec-
tive analysis of training diaries from investigations with
healthy, active male participants (n=174) reported a signifi-
cantly lower incidence of URS with eight weeks of bovine
colostrum supplementation of 60 g/day (32%) compared to a
whey placebo (48%) [relative risk (RR) of 0.6](49). Similarly,
when compared to a whey or skim milk powder placebo, oth-
ers have reported a trend for a reduction in URS incidence
over 8-12 weeks of lower dose colostrum supplementation (10
to 25 g) in trained cyclists [RR 0.4 (362) and 0.3 (363)], elite
swimmers (weeks 5-10: RR 0.4) (95), active males (RR 0.6)
(198) and marathon runners (mean URS incidence of 0.8 in
colostrum group compared to 1.1 in placebo) (96). The ability
of bovine colostrum to shorten URS duration is less clear,
with some investigations reporting no change (49,198,362)
and some a reduction (95,96,363). While the ability of bovine
colostrum to shorten symptom duration is unclear, bovine
colostrum supplementation (10-60 g) for greater than four
weeks appears to reduce self-reported URS incidence by 30 to
60%.
While changes in salivary SIgA have been related to URS
(137) the mechanism for a reduction in URS following a peri-
od of bovine colostrum supplementation does not appear to
relate specifically to increases in SIgA concentration
(101,199,363). One investigation reported a significant 79%
increase in SIgA concentration after 12 weeks of bovine
colostrum supplementation (26 g/day) (d=4.8) (96), although
the placebo group also reported a large increase over this
timeframe (d=3.0). While some of the increase in SIgA was
attributed to competing in a marathon, colostrum accounted
for 29% of the variation in SIgA (96). In contrast, studies of
similar duration and/or those providing higher doses of bovine
colostrum (~60 g/day) have not reported changes in SIgA
(198,256,362,363). Other proposed mechanisms for the
reduction in URS incidence may be related to minimising the
increase in winter salivary bacterial load (198) or a reduction
in the suppression of receptor-mediated stimulation of neu-
trophil oxidative burst (199). There is also evidence that
bovine colostrum may reduce the post-exercise decrease in
neutrophil function and salivary lysozyme (101), and reduce
immunodepression during a period of intensified training
(362) although these mechanisms are yet to be confirmed. It is
unlikely that bovine colostrum supplementation alters circu-
lating cytokine concentrations following short-term intense
exercise (68,362) in athletes who have not undertaken a peri-
od of intensified training overload.
Controversies
The gastrointestinal tract is the largest immune organ in the
human body and in combination with its intestinal microbiota
it not only provides a physical barrier against commensal and
pathogenic bacteria, but plays a central role in innate and
adaptive immunity (364). In the calf, bovine colostrum is
essential for intestinal development, providing a rationale to
investigate the potential of bovine colostrum to influence gut
health in humans.
Early work in healthy adults demonstrated that bovine
colostrum reduced gastrointestinal permeability when co-
ingested with non-steroidal anti-inflammatory drugs (314)
and reduced systemic endotoxin concentrations in abdominal
surgery patients (44), suggestive of maintenance of the intes-
tinal barrier preventing endotoxin translocation across the gut.
Only two human studies have investigated if bovine
colostrum reduces the increase in intestinal permeability asso-
ciated with exercise (240,264) and their findings are conflict-
ing, possibly attributable to study differences in markers of
intestinal permeability, exercise protocols, colostrum dose and
period of supplementation. While animal studies suggest a
beneficial effect (321), more controlled human studies are
required to determine the impact of bovine colostrum on exer-
cise associated gut permeability and endotoxin translocation.
In combination with influencing gastrointestinal growth, IGF-
1 plays a role in immune and neuroendocrine regulation.
While only one study has reported autonomic alterations fol-
lowing a period of colostrum supplementation (363), contro-
versy exists as to the possibility of absorption of IGF-1 from
bovine colostrum. Only one laboratory has reported increases
in IGF-1 following bovine colostrum supplementation periods
of eight days and of two weeks (255,256) with others report-
ing no change (53,90,228), and athletes ingesting 60 g/day not
returning any positive doping test (for substances banned in
2002) (217). Mero determined that orally administered IGF-1
alone did not appear in the circulation and concluded that
IGF-1 is not absorbed from bovine colostrum (255) although
this is not necessarily correct as bovine colostrum contains
26 • Immunonutrition and Exercise
EIR 23 2017
numerous components that would keep IGF-1 intact during
gastrointestinal transit (315). The IGF-1 content in a 20 g dose
of bovine colostrum (343) is approximately equivalent to that
contained in three glasses of milk. Although not on the World
Anti-Doping Agency’s list of banned substances, this govern-
ing body does not recommend the ingestion of colostrum.
Future Directions
While bovine colostrum appears to reduce the incidence of
URS, the specific mechanism/s for this require further investi-
gation and should include measures of salivary antimicrobial
proteins, in addition to SIgA. Well-designed investigations are
also necessary to elucidate the potential of bovine colostrum
to modulate intestinal permeability and inflammation in exer-
cising humans.
As more is discovered about the minor constituents of bovine
colostrum (8), there is the potential to discover novel bioac-
tive proteins, and enhance understanding of the efficacy of
already known components. Lactoferrin, isolated from bovine
colsotrum, shows particular promise as an immune modulat-
ing glycoprotein. The majority of orally administered bovine
lactoferrin survives gastric transit (392), exerting its effects
through the interaction with gut enterocytes and resident
immune cells. In neonatal animal models lactoferrin stimu-
lates crypt cell proliferation (333), increases serum IgG and
modulates cytokine secretion of stimulated mesenteric lymph
nodes and spleen immune cells (89). Animal and cell culture
models support the anti-viral, anti-bacterial immune modulat-
ing properties of lactoferrin (399) so it is suprising that there
is limited literature investigating the effects of bovine lacto-
ferrin supplementation in healthy humans (266), and no stud-
ies investigating potential effects on exercise-induced
immune modulation. Benefits of lactoferrin for Fe deficiency
anaemia associated with pregnancy (301), and a reported
increase in T cell activation in healthy males (unblinded
study) (266) support the exploration of bovine lactoferrin sup-
plementation to modulate exercise-induced immune perturba-
tions and/or enhance immune surveillance.
VITAMIN D
Introduction
From a sport and exercise science perspective, interest and
research into vitamin D over the last decade has witnessed a
remarkable resurgence (420). The reason for this is partly
attributable to the re-emergence of the entirely preventable
bone disorder rickets (298) but perhaps mainly due to the
emerging evidence to suggest a fundamental role of vitamin D
in many areas pertinent to the athlete. These include: skeletal
muscle function (84), body composition (172), inflammation
(421), muscle regeneration (299), and cardiac structure as
well as aspects of innate and acquired immunity (168).
Vitamin D is unique in that, unlike other vitamins, it is not pri-
marily obtained from dietary sources; rather it is synthesized
via UV irradiation of the skin’s dermis. Once in the circula-
tion, either from diet, supplements or UV irradiation, vitamin
D is transported to the liver bound to vitamin D binding pro-
tein where it is hydroxylated eventually leading to its activa-
tion. The hydroxylated compound 25-(OH) D is the major cir-
culating vitamin D metabolite and is therefore the assay of
choice when it comes to detecting vitamin D deficiencies. A
further hydroxylation step in the kidney (or some tissues
directly) is required to produce the active metabolite 1,25-
(OH)2D and it is this active metabolite that is responsible for
the multiple biological effects via both genomic and non-
genomic mechanisms.
Defining terminology and why deficiencies occur
Although the multiplicity of fundamental biological roles of
vitamin D is now appreciated, it is well documented that
many individuals, including elite athletes, exhibit vitamin D
deficiencies (Figure 2). These deficiencies are clear in athletes
who live in temperate (84) as well as sunny climates and train
predominantly in both indoor (424) and outdoor environments
(84). This worldwide phenomenon of vitamin D deficiencies
is partially attributable to poor dietary intakes, although the
major reason is more likely a direct consequence of modern
sun-shy lifestyles, including the use of appropriately applied
high-factor sunscreen creams (125), which significantly
restrict vitamin D synthesis.
A major area of confusion in the vitamin D literature arises
from a lack of consensus as to what constitutes a genuine vita-
min D deficiency and, more recently, the concept of a poten-
tially “optimal” vitamin D concentration for health and athlet-
ic performance. It is beyond the scope of this article to explore
this debate and therefore an “adequate” concentration will be
classed here as >50 nmol/l as defined by the US Institute of
Medicine. Moreover, it has also been suggested that what may
be optimal for one tissue, such as bone or skeletal muscle,
may not be optimal for another, such as immune function. In
fact, from an exercise immunology perspective recent
research is beginning to indicate that aspects of the immune
system may require higher concentrations of vitamin D than
has previously been defined as “adequate” for bone health
(168).
Vitamin D and the immune system
Emerging research suggests that vitamin D plays a key role in
both innate and acquired immunity, most likely exerting its
function through gene expression modulation (168,183). In
this role 1,25-(OH)2D functions as part of a heterodimer with
its vitamin D receptor (VDR) and the retinoid X receptor
modulating the expression of genes with specific vitamin D
response elements located in the regulatory region (168). In
fact it is estimated that close to 5% of the human genome is
modulated by vitamin D (430), which is required in sufficient
quantities to work effectively in gene expression modulation.
Many cells of the immune system including monocytes,
macrophage, neutrophils and T and B lymphocytes contain
the VDR and also express the enzyme, 1-α hydroxylase,
which is responsible for hydroxylation of 25-(OH) D to its
active 1,25-(OH)2D form. Activation in immune cells appears
to be regulated by circulating concentrations of 25-(OH) D
and induced by activation of the toll-like receptor cascade in
the presence of pathogenic microbiota (30). In the immune
system specifically, vitamin D up-regulates gene expression
of broad-spectrum anti-microbial peptides (AMP), important
regulators in innate immunity (231,408), and exerts an
Immunonutrition and Exercise • 27
EIR 23 2017
immunomodulatory effect on T and B lymphocytes in
acquired immunity (168,431). AMP, including cathelicidin,
are important proteins in the innate immune system (148) and
help defend against acute illness including tuberculosis,
influenza and the common cold (64,65,395). It is further sug-
gested that vitamin D maintains a balance between the inflam-
matory Th1/Th17 cells and the immunosuppressive Th2/Treg
cells to dampen inflammation and tissue damage (178) and to
modulate the acquired immune response. Additional studies
suggest that vitamin D enhances natural killer cell cytolytic
activity (4), and acts to trigger the oxidative burst in activated
macrophages (368). A single dose of vitamin D3 (100,000 IU)
has been shown to enhance the innate immune response and
restrict growth of mycobacteria in vitro (248).
V
ariations in vitamin D concentrations have the potential to
influence immune response. A handful of studies in athletes
(93,168), military personnel (218) and the general population
(28,136,342) have reported negative associations between
vitamin D concentration and incidences of URTI. In one study
in college athletes, vitamin D concentrations over the winter
and spring were negatively associated with documented fre-
quency of acute URTI (157). The breakpoint for contracting
single illness appeared to occur at ~95 nmol/l such that all ath-
letes with circulating concentrations lower than this break-
point had one or more episodes of illness whereas those with
higher concentrations had one or fewer episodes. As has been
shown in Figure 2, many athletes present with vitamin D con-
centrations significantly below this proposed breakpoint. A
similar study in endurance athletes reported that a greater pro-
portion of athletes maintaining circulating 25-(OH) D concen-
tration <30 nmol/l presented with URS with the fewest symp-
toms reported in those with 25-(OH) D concentrations >120
nmol/l (171). Athletes with low vitamin D concentrations also
had more URS days and higher symptom-severity scores.
Randomly-assigned, placebo-controlled studies are needed in
athletic populations to confirm the effectiveness of correcting
low vitamin D concentrations on aspects of immune health
and the prevention of URTI. A recent study in university ath-
letes found evidence that 14-week supplementation with 5000
IU per day of vitamin D3during winter training significance
increased salivary secretion rates of cathelicidin and SIgA
(171).
Consensus
It is now established that many athletes present with deficient
D concentrations, especially during the winter months, which
result in numerous deleterious consequences. The concept of
an “optimal” vitamin D concentration, however, is proving
difficult to establish with emerging evidence suggesting that
“optimal” vitamin D concentrations may in fact be tissue spe-
cific. Recent evidence is suggesting that athletes presenting
with “sufficient” vitamin D concentrations (>50 nmol/l) may
still be at an increased risk of contracting a URTI compared
with athletes presenting with >75 nmol/l (171).
It must be stressed that there is a growing trend for mega dose
supplementation in athletes. This is of concern due to some
evidence which suggests an increase in all-cause mortality in
individuals with high (>140 nmol/l) vitamin D concentrations
(118), although cause and effect data to prove this are still
lacking.
At present, perhaps the best advice for athletes is to monitor
their vitamin D concentration and, in terms of immune health,
aim for a target concentration >75 nmol/l. During the summer
months athletes should aim to obtain sensible sun exposure,
whilst ensuring that they do not suffer from sunburn, and con-
sider a supplement of up to 4000 IU vitamin D3per day during
the winter months if concentrations drop below 75 nmol/l.
Figure 2 Vitamin D concentrations of a variety of athletes tested (at rest) internationally. Pink area represents deficiency (<30 nmol/l), yellow
area insufficiency (<50 nmol/l) and green area adequate (>50 nmol/l) as defined by the US National Institutes of Health Office of Dietary Supple-
ments. (Data redrawn from (84,157,226,421,424)).
28 • Immunonutrition and Exercise
EIR 23 2017
Future directions
Future studies now need to establish if there is in fact an opti-
mum concentration for an athlete’s immune health utilizing a
research design that will allow cause and effect to be estab-
lished rather than reliance on correlative data.
IMMUNONUTRITION AND EXERCISE IN
SPECIFIC POPULATIONS
Competitive athletes and military personnel
Background
A commonly asked question is, ‘do athletes and military per-
sonnel have special nutritional requirements to maintain
immunity; for example, do they need ‘immune-boosting’ sup-
plements?’ A somewhat simplistic answer is ‘no’; so long as
the diet meets the energy demands and provides sufficient
macro- and micro- nutrients to support the immune system
(140,405). The reasoning here is mostly based on the empiri-
cal evidence along with some sound logic: support for
‘immune-boosting’ nutritional supplements largely comes
from studies in those with compromised immunity, such as
the elderly and clinical patients; not, from young, otherwise
healthy, individuals whom, as logic would dictate, might have
little to gain from such supplements (229). To accept this
viewpoint ignores the proviso about matching energy intake
to expenditure and providing sufficient macro- and micro-
nutrients to maintain immunity. Indeed, there are various ath-
lete and military scenarios where energy, macro- and micro-
nutrient intake may be insufficient.
Consensus
In the real world, athletes and warfighters either intentionally
or non-intentionally experience deficits in energy intake (e.g.
weight-loss diets, restricted rations) and macronutrient intake
(e.g. restricted carbohydrate). There is substantial evidence
showing that only a few days on restricted energy intake com-
promises immunity (221,295,401). There may be other times
when athletes or warfighters experience both a down-turn in
host defence and increased exposure to pathogens, e.g. for-
eign travel for training camps, competitions and military oper-
ations. As such, there are specific scenarios when these indi-
viduals might benefit from nutritional supplements to bolster
immunity (Table 5). Thus the current, more reasoned, answer
to the question, ‘do athletes and military personnel have spe-
cial nutritional requirements to maintain immunity?’ is ‘yes,
sometimes.’
Controversies and future directions
Paradoxically, nutritional strategies currently adopted by
endurance athletes, including training with low carbohydrate
(Table 5), may benefit training adaptations and performance at
the expense of immunity; for example, carbohydrate restric-
tion may increase the immunosuppressive stress hormone
response to exercise (86,140,165). Consequently, the rather
modest benefits studies show in terms of training adaptations
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Table 5. Effects of nutritional supplements on the common cold and immunity in athlete and military scenarios
Immunonutrition and Exercise • 29
EIR 23 2017
and performance might, in the long term, be lost if the athlete
gets sick more often; viz. ‘the less sick the more the athlete
trains and the better they perform’ (246,380,407). Studies are
required to investigate whether the nutritional practices adopt-
ed by elite athletes impair immunity and increase infection;
and, whether purported ‘immune-boosting’ supplements bene-
fit immune health without blunting the desired training adap-
tations. Recent Cochrane reviews have noted the low quality
of many studies on nutritional supplements to support
immune health; specifically, small samples, poor controls and
unclear procedures for randomisation and blinding were com-
monplace (162). Clearly, there is a pressing need for random-
ized controlled trials in elite athletes and military personnel
with sufficient participant numbers; rigorous controls and pro-
cedures; appropriate supplementation regimens; and, clinical-
ly meaningful in vivo measures of immunity (see section on
biomarkers)
Overweight and obese exercising humans
Obesity, a state of malnutrition related to excessive intake of
energy has been related to immune dysfunction (175). High
body fat levels are accompanied by changes in white blood
cells, especially an increase in total leucocyte number, with
altered differential counts in neutrophils, monocytes and lym-
phocytes, finding increased values of lymphocytes and neu-
trophils in boys and girls, respectively. However, low T- and
B-cell mitogen-induced proliferation is shown in obesity
(247). Both cell-mediated and humoral immunity are affected
by obesity, with low antibody production after vaccination
(247,361). Moreover, obesity has been characterized as a state
of chronic low-grade inflammation, with an excessive amount
of adipose tissue as the main determinant of this process
(411).
Physical inactivity seems to be a prominent and modifiable
risk factor to develop excess weight and obesity. According to
epidemiological studies and clinical trials there is evidence
addressing the influence of physical activity and fitness on
low-grade inflammation in adulthood (160,302), athletes
(292,390) and, to a lesser extent, in children and adolescents
(412). Regular exercise seems to have proven anti-inflamma-
tory effects in normal subjects (412) but also in overweight
and obese individuals (175,411).
Regular training leads to a reduced TLR4 expression baseline,
accompanied by a lower percentage of circulating
CD14+CD16+ monocytes, which could result in an anti-
inflammatory effect (243,385). In the case of obese subjects,
macrophages are a potential source of inflammatory processes
where the microbiota is also involved leading to lower insulin
sensitivity in several tissues (liver, adipose tissue, hypothala-
mus, muscle) and a state of chronic low-grade inflammation
(393). Studies performed in mice fed a high fat diet showed
that exercise training reduces visceral adipose tissue followed
by a change of M1 macrophage phenotype to M2
macrophages (205).
Cytokines have been shown to play a particular role in the
regulation of the metabolism due to exercise, leading to
immunomodulation within the adaptation mechanisms
involved (272). However, it is important to highlight that the
cytokine response depends on the acute or chronic exercise as
well as its intensity, duration, the mass of muscle recruited,
endurance capacity and idiosyncracy of the person practising
exercise (411). The contracting skeletal muscle is a major
source of circulating IL-6 in response to acute exercise. Dur-
ing heavy exercise, such as a marathon, there can be up to a
120-fold increase in the IL-6 plasma levels with the duration
of the event explaining more than 50% of the variation. The
aforementioned plasma IL-6 increase supports the hypothesis
that post-exercise cytokine production is related to skeletal
muscle and duration of exercise. Nevertheless, IL-6 shows a
markedly lower response to acute exercise in trained subjects.
The health benefits of long-term regular exercise are ascribed
to the anti-inflammatory response elicited by an acute bout of
exercise, which is partly mediated by muscle-derived IL-6.
This IL-6 increase seems to induce an anti-inflammatory
cytokine cascade (IL-1ra and IL-10), and to inhibit the pro-
duction of pro-inflammatory cytokines, such as TNF-α
(305,308). Therefore, the anti-inflammatory effects of exer-
cise may offer protection against TNF-induced insulin resist-
ance.
IL-6 stimulates lipolysis as well as fat oxidation. The increase
of IL-6 after acute exercise is linked to increased CRP levels
(290). In response to regular physical activity, basal as well as
post-exercise plasma levels of IL-6 decrease by mechanisms
that might include increased glycogen content, improved anti-
oxidative capacity and improved insulin sensitivity. The lower
levels of IL-6 in circulation will subsequently result in lower
CRP levels. In untrained subjects, basal plasma IL-6 and CRP
levels are elevated via mechanisms that may involve impaired
insulin sensitivity and/or increased oxidative stress (305,308).
The status of glycogen stores is also an important contributor
to IL-6 production with exercise: the lower the glycogen the
higher the IL-6 production. It is of particular importance in
overweight, obese and diabetic patients especially for those
with particular diets.
Adipose tissue is regarded as an active endocrine organ that
releases a large number of bioactive mediators (pro-inflam-
matory cytokines, leptin, adiponectin, peptide YY, among oth-
ers) modulating not only appetite and metabolism, but also the
immune system involving inflammatory processes (339).
The EVASYON study aimed to develop a comprehensive
intervention including diet and physical activity and to evalu-
ate its efficacy in adolescents with excess weight and obesity.
Some beneficial changes were achieved due to an early reduc-
tion of immunological and metabolic markers including lep-
tin, IL-8 and TNF-α, delivered by adipose tissue and whose
high levels are considered to be linked to an inflammatory
state (339).
In the AFINOS study performed in Spanish adolescents, car-
diorespiratory fitness and muscular fitness were shown to be
inversely associated with adiponectin and leptin levels. Vigor-
ous physical activity levels have also been inversely associat-
ed with leptin (249).
Preliminary evidence from the AFINOS study seemed to indi-
cate that achievement of a healthy weight in this population
30 • Immunonutrition and Exercise
EIR 23 2017
group might be the most effective strategy to prevent chronic
low-grade inflammation and future cardiovascular and meta-
bolic diseases. Indeed, an active lifestyle and a desirable car-
diorespiratory fitness may attenuate these problems.
Therefore, physical exercise has been shown to increase
weight management efficacy, being a potential therapeutic
approach to modulate low-grade inflammation. Particularly,
the encouragement of doing physical activity during adoles-
cence could have important implications for public health, as
a specific strategy to avoid high levels of the well-known
sedentary habits during this crucial life period. Likewise,
other types of physical activity related to muscular fitness
(that is, resistance training) might be taken into consideration
during adolescence because high levels of muscular fitness
have shown negative associations with inflammatory proteins.
Therefore, understanding the interrelationships between phys-
ical activity, fitness and fatness may be the main way to pre-
vent low-grade inflammation, particularly at these ages (250).
The exercising elderly
It is well documented that aging is associated with a decline in
cell-mediated immune function, a phenomenon often called
immunosenescence, which contributes to the higher morbidity
and mortality from infectious diseases in older population. On
the other hand, mounting evidence suggests that aging is asso-
ciated with an increased inflammatory response
(212,347,398). Chronic, low-grade inflammation has been
implicated in the pathogenesis of many common degenerative
and metabolic diseases associated with aging. Several studies
have shown that acute and prolonged or vigorous bouts of
exercise cause immunodepression as well as the related
increase in incidence of URTI symptoms, and may also
induce increased inflammation and oxidative stress
(273,365,406). Therefore, extreme exercise may exacerbate
the age-associated dysregulation of the aging immune system
(286,366,394). However, regular moderate exercise in general
causes no such adverse effect, and might even enhance the
immune function (274), particularly in older individuals
(365,406). Studies showed that calisthenic exercise increased
NK activity and T cell function in elderly women (286); pri-
mary antibody and delayed-type hypersensitivity (DTH)
responses to the novel antigen keyhole limpet haemocyanin
(KLH) were lower in older than in young subjects, but these
in vivo measures of the immune function were improved by
exercise in older but not young subjects (150,370). A possible
reason behind this observation is that, relative to their young
counterparts, the older individuals have a less optimal
immune response which is restored by moderate exercise
(406).
Proper nutrition, i.e., adequate and well balanced intake of
nutrients, is important for normal function of the immune sys-
tem. Currently no information is available as to whether exer-
cising older persons have unique nutritional needs compared
to their young adult counterparts. However, a significant per-
centage of older adults have low consumption of several
micronutrients including the B vitamins, vitamin E and Zn, all
of which are needed for the normal function of the immune
system (239,300). At the same time, both inflammation and
oxidative stress increases with aging suggesting that the older
exercising adults might require higher level of nutrients and
foods with antioxidant and anti-inflammatory properties. In
addition, when conducting the same type of exercise, the older
persons are known to more easily suffer from muscle damage
and require a longer period to recover from it (127). The exer-
cise-induced muscle damage can initiate an inflammatory
response, which could further exacerbate the chronic low-
grade inflammation observed in older adults, further suggest-
ing that exercising older adults might require higher level of
nutrients and other dietary components with immune enhanc-
ing and/or anti-inflammatory properties than non-exercising
older adults or their young counterparts. However, previous
studies which mainly involve younger adults have indicated
that consuming antioxidant supplements, with the possible
exception of quercetin, does not help in terms of improving
exercise-induced immunodepression, inflammatory response,
and URTI (see the antioxidants and polyphenols sections
both in this series). In support of this, studies thus far suggest
that antioxidant micronutrient supplementation may not
afford protection against muscle damage but, rather, it may
interfere with cellular signalling functions of ROS and inter-
rupt training-induced adaptations (50,192). Further studies are
needed to determine whether exercising older adults would
respond in a different manner from young adults, given the
observation that older adults may have higher requirements
for nutrients and food components that possess antioxidant
and anti-inflammatory properties.
Another nutritional consideration for older adults is the
amount of total energy. Since the intensity and duration of
exercise are usually less in older persons compared to young
adults, the total calorie intake should be adjusted accordingly
to avoid conversion of excess calories to body fat. Additional-
ly, the general recommendation to increase calorie intake
from carbohydrates should be exercised with caution for older
persons, due to the fact that glucose tolerance and insulin sen-
sitivity are decreased with aging.
In summary, information on nutritional needs of exercising
older adults whether micro or macro-nutrients is scarce. The
age-associated dysregulation of the immune response (sup-
pression of cell-mediated immunity and increased inflamma-
tion), together with other age associated changes, and low
consumption of nutrient rich foods strongly supports the
necessity of further research in this area so that specific rec-
ommendations can be made.
BIOMARKERS IN IMMUNONUTRITION
Introduction
In this section the strengths and weaknesses of various bio-
markers used in studies by nutritional immunologists are eval-
uated (Table 6). An important consideration is that exercise
immunologists often perform investigative work in the field,
away from the rigorously controlled laboratory environment.
Consequently, the studies are often limited by a lack of exper-
imental control and the choice of measurement tool(s) is often
dictated by convenience, practicality and cost. With this in
mind, areas of uncertainty, gaps in knowledge and opportuni-
ties for continued research development on immune biomark-
Immunonutrition and Exercise • 31
EIR 23 2017
ers are highlighted, particularly research targeted towards the
development of technologies applicable in the field. These
opportunities include rapid, non-invasive measurements of
immunity by portable devices at single time points and even
continuous monitoring by wearable technology (e.g. smart
contact lenses) may be possible in the not too distant future.
Classification of upper respiratory tract illness
Arguably the most illuminating studies on factors influencing
common cold incidence (e.g. psychological stress, sleep) have
quarantined individuals before and for up to 7 days after intra-
nasal inoculation with live common cold viruses (rhinovirus,
respiratory syncytial virus or coronavirus) and assessed the
development of clinical colds (Table 6) (87,88). Although this
represents a strong experimental model to identify the effects
of nutritional interventions on common cold incidence, there
are obvious limitations that have prohibited its adoption by
exercise immunologists. These include ethical considerations,
as well as cost, requirement for medical facilities and support,
together with the fact that athletes are unlikely to participate
in a study where ~40% of individuals develop a common cold
(191). Another limitation is that studies using the common
cold challenge model have not identified whether the
increased development of common cold in those under psy-
chological stress (88) or sleep stress (87) is due to a systemic
immunodepression or local effects at the nasal mucosa. For
these reasons exercise immunologists have relied heavily on
subjective self-report of common cold symptoms using either
unstandardised health logs, standardised symptom question-
naires (e.g. Jackson) or physician assessment of common cold
symptoms (Table 6). In 1958 Jackson et al. reported clinical
features of the common cold after infecting >1,000 individu-
als by nasal instillation of nasal common cold secretions col-
lected from donors (191). In the ~40% of individuals who
developed symptoms of a common cold in the 6-day monitor-
ing period, 8 clinical symptoms were incorporated into the
questionnaire. Symptoms included headache, sneezing, chilli-
ness and sore throat that appeared in the first 48 h and nasal
discharge, nasal obstruction, cough and malaise that appeared
later. The 8 clinical symptoms were scored on a 4-point scale
from 0 (no symptom) to 3 (severe symptom): Jackson’s crite-
ria for a common cold included a total symptom score of ≥14
and a “yes” answer to the dichotomous question, ‘do you
think that you are suffering from a common cold?’ during the
6-day monitoring period (191).
The Wisconsin upper respiratory symptom survey (WURSS;
(20)) has also been used widely by exercise immunologists
(149,283,374), including nutritional intervention studies
(149), as it considers the impact of common cold symptoms
on quality of life measures (Table 6). Studies have raised
questions about the validity of the physician-verified common
cold, highlighting that neither self-reported nor physician-ver-
ified common colds should ubiquitously be referred to as
infectious (93,374). Notwithstanding these limitations, studies
highlight the negative impact of self-reported common cold
symptoms on training volume (246) and medal-winning
prospects in elite athletes (322,380).
Three key recommendations include: 1) standardising the
recording of common cold symptoms in athletes (e.g. incorpo-
rating the Jackson common cold scale or the WURSS into a
training log); 2) recording the impact of common cold symp-
toms on training and performance (e.g. discontinued or
reduced training); and 3) where possible, incorporating identi-
fication of infections from pathological analysis of swabs
(Table 6 see next page). Common cold challenge studies show
that only ~40% of those inoculated develop symptoms associ-
ated with the common cold yet >80% are typically infected
(positive virology/specific antibody response) (87,88,191).
Thus, an important research question for exercise immunolo-
gists is, ‘why do less than half of those infected develop
symptoms of the common cold? Adopting these recommenda-
tions will allow the exercise immunologist to understand more
fully the influence of exercise training and nutritional inter-
ventions on the development of common cold symptoms and
their impact on training and performance in those with and
without confirmed infectious aetiology.
In vivo immunity
Where feasible, exercise immunologists are encouraged to use
in vivo methods for assessing immune responses (3,405,406).
By initiating an integrated and highly coordinated immune
response in the normal tissue environment, in vivo immune
methods provide more clinically relevant information that
extends beyond in vitro assays (Table 6) (87). A weakness of
many in vitro assays is the requirement to separate immune
cells from their normal environment and incubate in artificial
culture. Examples of in vivo immune methods include assess-
ing: the circulating antibody response to influenza vaccination
and hepatitis B vaccination (55); the local skin response to
intradermal antigens using delayed type hypersensitivity
(DTH) (52) and to topically applied antigens using contact
hypersensitivity (CHS) (164). Studies demonstrate that both
acute and chronic exercise can increase influenza vaccination
success (circulating antibody titre) in those with sub-optimal
immunity (e.g. elderly) or where antigen immunogenicity is
low; but little is known about the influence of high-level train-
ing and nutritional interventions on the success of influenza
vaccination in young, healthy athletes. A distinct advantage of
the vaccine model (e.g. influenza) is that athletes may be keen
to participate in a study where the clinical protection afforded
by the vaccine is directly beneficial to them (147,406). Recog-
nised limitations with the vaccine model include that the ex
vivo T cell response to influenza vaccination has been more
strongly related to vaccine protection than the circulating anti-
body titre that is typically measured (304). Also, the incorpo-
ration of repeat antigens in the influenza vaccine elicits a mix-
ture of primary and secondary antibody responses; thus pro-
viding limited mechanistic insight (55,406). Using a novel
antigen in the DTH method (e.g. keyhole limpet haemo-
cyanin) (369); or CHS method (e.g. diphenylcyclopropenone
(DPCP))(109,164) presents the opportunity to assess the
influence of exercise as a stressor, and nutritional interven-
tions on both the primary and secondary immune response.
The DTH and CHS methods (Table 6) also overcome some
other limitations with the vaccine method including: variable
immunogenicity (e.g. hepatitis B (177)); annual changes in
vaccine composition (e.g. influenza (55)); and, difficulty
when comparing the circulating antibody results from differ-
ent studies using in-house enzyme-linked immunosorbent
assays (ELISA) or other technologies (55). Nevertheless,
32 • Immunonutrition and Exercise
EIR 23 2017
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7
7'(+,$7
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3$
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3$$
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7
7#$4
%! 5"
4
Table 6. Classification and ratings of biomarkers used in immunonutrition and exercise experiments
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Immunonutrition and Exercise • 33
EIR 23 2017

0+/!B=1
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
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A
$-&.
7$4
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4$7
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7$
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&.C$4
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7
77
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