Sports Med 2003; 33 (5): 323-345

REVIEW ARTICLE 0112-1642/03/0005-0323/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Glutamine Supplementation In Vitro

and In Vivo, in Exercise and
in Immunodepression
Linda M. Castell
Nuffield Department of Anaesthetics, University of Oxford, Oxford, England

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
1. The Role of Glutamine in Immune Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
2. Muscle Glutamine Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
3. Plasma Glutamine in Clinical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
4. Plasma Glutamine in Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
5. The Relationship Between Plasma Glutamine and Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
6. The Incidence of Illness After Endurance Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
6.1 Upper Respiratory Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
6.2 Gastrointestinal Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
6.2.1 Intestinal Function and Glutamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
7. Immune Cell Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
8. Transient Immunodepression in Prolonged, Strenuous Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
8.1 Circulating Cell Numbers in Endurance Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
8.2 Cell Function in Endurance Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
9. Glutamine Availability and Uptake by Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
10. Glutamine Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
10.1 Glutamine Feeding in Clinical Situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
10.2 Glutamine Feeding in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
10.2.1 After Prolonged, Exhaustive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
10.2.2 In Body Building . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
11. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
11.1 So, How Does Glutamine Work? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
11.1.1 Via Glutathione? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
11.1.2 Via Gastrointestinal Function? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
11.1.3 In Neutrophils? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
12. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

Abstract In situations of stress, such as clinical trauma, starvation or prolonged, strenu-

ous exercise, the concentration of glutamine in the blood is decreased, often
substantially. In endurance athletes this decrease occurs concomitantly with
relatively transient immunodepression. Glutamine is used as a fuel by some cells
of the immune system. Provision of glutamine or a glutamine precursor, such as
branched chain amino acids, has been seen to have a beneficial effect on gut
function, on morbidity and mortality, and on some aspects of immune cell
function in clinical studies. It has also been seen to decrease the self-reported
324 Castell

incidence of illness in endurance athletes. So far, there is no firm evidence as to

precisely which aspect of the immune system is affected by glutamine feeding
during the transient immunodepression that occurs after prolonged, strenuous
exercise. However, there is increasing evidence that neutrophils may be implicat-
ed. Other aspects of glutamine and glutamine supplementation are also addressed.

1. The Role of Glutamine in concentration in culture medium below that normal-

Immune Cells
In the early 1980s glutamine was identified as
being an important fuel for some specific cells of the
immune system, namely lymphocytes and macro-
phages.[1] These cells were originally thought to
obtain most of their energy from the oxidation of
glucose.[2] However, it was established by Ardawi
and Newsholme[1] that freshly isolated lymphocytes
and macrophages utilise glutamine at a rate which is
either similar to, or greater than, that of glucose.
Further evidence is provided by the fact that there is
a high maximal catalytic activity of glutaminase in
these cells, which is the key enzyme in the gluta-
mine utilisation pathway.[1,3-5]
High rates of glutaminolysis and glycolysis (the
partial oxidation of glutamine and glucose, respect-
ively) provide energy for these cells. Glutamine also
provides nitrogen for the synthesis of purine and
pyrimidine nucleotides. The nucleotides are needed
for the synthesis of new DNA and RNA during
proliferation of lymphocytes, and for mRNA syn-
thesis and DNA repair in macrophages. The rate of
glutaminolysis in lymphocytes is considerably in
excess of the rates of synthesis of these compounds.
Newsholme et al.[6] proposed, as an explanation for
this phenomenon, that the synthetic pathways for de
novo nucleotide synthesis require specific and pre-
cise increases in the rate of synthesis of these nucle-
otides during the proliferative process. Glutamine is
used at a high rate by some cells of the immune
system; even when they are not stimulated these
cells would be primed to respond to an invasion by a
foreign organism.[6] This would require glutamine to
be available at a reasonably constant level in the
bloodstream.
Evidence to support this hypothesis was provided
by in vitro studies.[7] A decrease in the glutamine
ly present in human plasma (600 μmol/L) not only
decreased the maximum rate of proliferation in re-
sponse to mitogenic stimulation in peripheral blood
lymphocytes but also slowed down the response
time of the cells. These effects occurred despite the
fact that the culture medium contained sufficient
amounts of all other nutrients and growth factors,
including carbohydrate in the form of glucose. In the
same studies, a decrease in the phagocytic ability of
macrophages was observed in response to a decrease
in culture medium glutamine concentration.[7]
Glutamine was originally classified as a non-
essential amino acid.[8] However, more recently
there is evidence that glutamine is ‘conditionally
essential’.[5,9] After clinical trauma such as major
surgery or burns there is a marked decrease in the
concentration of blood glutamine which is often
maintained for several days (see also section
3).[7,10,11] It is worth noting that a similar drop in
blood glucose levels would bring about symptoms
of hypoglycaemia. Thus, exogenous provision of
glutamine may be ‘essential’ in these conditions.
Eagle et al.[12] established in 1955 that adding
glutamine to a final concentration of 2 mmol/L was
the ideal culture medium for HeLa cells. Since then
it has become traditional to grow a variety of cells in
a medium containing 2 mmol/L glutamine. The
work undertaken by Parry-Billings et al.[7] on human
lymphocytes and macrophages isolated from fresh
blood samples, provided a careful demonstration of
this principle. Further evidence that cells function
optimally in culture medium containing 1 mmol/L
glutamine has come from a study on rat spleen
lymphocytes.[13] Nevertheless, the present author
has undertaken many in vitro studies using gluta-
mine-free culture medium (without foetal calf se-
rum) to dilute whole blood samples prior to incuba-

© Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression
tion. This was done on the premise that, in circum-
stances where glutamine availability in vivo to some
immune cells might be compromised, putting them
back after isolation into an optimal glutamine con-
centration might distort the picture.[14] The level of
glutamine that occurs in the individual’s plasma at
the time of taking the blood sample has therefore
routinely been used in these lymphocyte prolifera-
tion studies, albeit with a 1 in 10 dilution. However,
after mitogenic stimulation, labelling with 3H
thymidine and measuring the change in cell numbers
as counts per minute, this protocol can lead to lower
lymphocyte numbers compared with data from stud-
ies using 2 mmol/L glutamine. Nevertheless, clearly
measurable changes can be seen and, in the author’s
opinion, this protocol provides a good reflection of
individual depression of the proliferative ability of
lymphocytes due to different types of stress.
Two recent in vitro studies investigated the ef-
fects of altering glutamine concentrations in culture
medium. Yaqoob and Calder[15] studied human
peripheral blood mononuclear cells, i.e. a combina-
tion of lymphocytes and monocytes isolated from
fresh blood. They observed that T cells (stimulated
with the mitogen concanavalin-A) and monocytes
(stimulated with lipopolysaccharide) functioned ad-
equately in terms of cytokine production in 100
μmol/L glutamine. Interestingly, Liu et al.[16] using
rat lymph node lymphocytes, found that lympho-
cytes exposed to endotoxin apparently required a
lower level of glutamine to function maximally than
the control samples in terms of proliferative ability.
There is increasing evidence that glutamine may
be important to neutrophils. In in vitro studies, the
depressed bactericidal ability of neutrophils in sam-
ples from burns patients was not only restored but
enhanced by the addition of glutamine to the culture
medium.[17] A similar effect has been reported more
recently.[18] Using a novel chemiluminescence as-
say, Vance et al.[19] observed an increase in oxida-
tive burst in human neutrophils stimulated with both
f-Met-Leu-Phe and phorbol myristate acetate when
glutamine was added to the culture medium.
© Adis Data Information BV 2003. All rights reserved.
325
2. Muscle Glutamine Release
Glutamine is the main amino acid released from
skeletal muscle during short-term starvation such as
an overnight fast. In humans, the muscle concentra-
tion of glutamine is 20 mmol/L,[20] compared with
0.6 mmol/L in plasma.
In severe cachexia, the muscle glutamine concen-
tration can be substantially reduced: Roth et al.[21]
observed decreases as high as 80% in patients with
severe abdominal sepsis.
During stress such as exercise, an increase in the
concentration of cortisol in the blood leads to prote-
olysis of muscle proteins and increased release of
glutamine. Several tissues including liver, muscle,
adipose and lung can synthesise and release gluta-
mine into the bloodstream. However, skeletal mus-
cle is quantitatively the most important, since it both
synthesises and stores glutamine, which is taken up
by the intestine, liver and kidney and by some cells
of the immune system. About 8–9g of glutamine per
day is released from the entire human muscula-
ture.[22] The rate of release of glutamine across the
plasma membrane, which occurs via a specific
transporter, may be controlled not only by the hor-
monal milieu but by chemical messengers such as
cytokines. It is suggested that these may be released
from different cells of the immune system and com-
municate with skeletal muscle.[23] There is support
for this notion from the work of Horig et al.[24] who
observed that, at certain stages of the cell cycle, the
secretion of cytokines and cell surface activation
markers was glutamine-dependent. The effects of
glutamine supplementation in vitro and in vivo on
some cytokines is discussed in sections 10.1 and
10.2.
3. Plasma Glutamine in
Clinical Conditions
The plasma concentration of glutamine (p[Gln])
is decreased in clinical situations such as major
surgery, burns, starvation and sepsis.[7,11,21,25-28]
There is also evidence that immune function is im-
paired during such clinical trauma.[29,30] There is a
strong likelihood that the requirement for glutamine
is increased in these conditions, since there will be
Sports Med 2003; 33 (5)
326
an increased number of cells which use glutamine as
a fuel involved in proliferation and repair.[4]
4. Plasma Glutamine in Exercise
Hiscock and Mackinnon[31] compared the resting,
fasting p[Gln] in athletes participating in different
types of sport, and found a considerable variation.
For example, cyclists had a markedly higher resting
p[Gln] than all other sports studied: the lowest con-
centration was seen in powerlifters. Somewhat sur-
prisingly, these authors observed an inverse correla-
tion between p[Gln] and dietary protein relative to
body mass, an observation also made by Matthews
and Campbell[32] in a healthy control group at rest.
Resting, fasting p[Gln] has been seen to be de-
creased in overtrained athletes;[10] more recently,
Rowbottom et al.[33] provided further evidence of a
decrease in p[Gln] related to overtraining in athletes
from a variety of sports. The term ‘overtraining’ has
recently been redefined as ‘unexplained un-
derperformance syndrome’.[34] In elite athletes, after
a sojourn in a training camp at moderate altitude
(1640m), Bailey et al.[35] observed a decrease in
p[Gln], which was more marked in those with the
most severe infections.
The p[Gln] is increased in athletes after short-
term exercise.[10,36,37] For events such as a 30km race
or a 15-mile training run[14,38] the plasma concentra-
tion of glutamine does not appear to change. How-
ever, in athletes after prolonged, exhaustive exercise
such as running a full marathon, p[Gln] can be
decreased by as much as 25%.[10,39-41] This biphasic
response of p[Gln] to exercise was first reported in
separate studies by Poortmans et al.[36] and Decom-
baz et al.[39] It was subsequently confirmed in a
single study in athletes who exercised on a treadmill
for 3.75 hours at 50% maximal oxygen uptake
(V̇O2max) that p[Gln] first increased during exercise
but then decreased by 17% below pre-exercise le-
vels after 3.75 hours.[42] In the author’s experience
of undertaking several studies on more than 350
marathon runners, p[Gln] is usually reduced by
about 10% in samples taken immediately after or
within 15 minutes after the marathon, and decreases
by a further 10–15% within the next hour (e.g. 669 ±
© Adis Data Information BV 2003. All rights reserved.
Castell
25 to 533 ± 29 μmol/L, n = 18). Walsh et al.[43]
observed a decrease in p[Gln] 5 hours after repeated
1-hour bouts of cycling. Rohde et al.[44] observed a
marked decrease in p[Gln] in triathletes at 2 hours
after prolonged exercise and found that this was
paralleled by changes in lymphokine activated killer
(LAK) cell activities. The post-exercise decrease in
p[Gln] often tends to be concomitant with a decrease
in circulating lymphocyte numbers, after the tran-
sient initial increase, which is part of the well-
known leucocytosis observed after exhaustive exer-
cise (see section 8.1).
Lehmann et al.[45] saw no change in p[Gln] after a
24-hour ultramarathon. The present author also saw
no change in p[Gln] in ultramarathon runners who
had just participated in a 95-mile (153km) race.[14]
During this race, runners stopped routinely for 15
minutes (as required by the rules), and ingested
drink and snacks ad lib.
The decrease in p[Gln] observed after running a
full marathon is relatively transient, lasting perhaps
for 6–9 hours. The question arises whether muscle,
together with other tissues, can always respond suf-
ficiently to release enough glutamine to maintain the
normal blood concentration. This would be particu-
larly important in the event of muscle damage dur-
ing excessive exercise. Muscle damage presents an
area of tissue, which may be large, to which immune
cells migrate. For example, MacIntyre et al.[46] com-
pared exercised muscle with non-exercised muscle
in females using eccentric repetitions of the right
quadriceps. They observed a significantly greater
number of radiolabelled white blood cells in the
right quadriceps within a 24-hour period after ex-
haustive eccentric exercise than in the non-exercised
muscle.
As the number of migrating cells increases, activ-
ity increases and/or proliferation of some cells
which, in turn, increases the local demand for gluta-
mine. Thus, it is reasonable to suggest that it might
be important for extra glutamine to be provided after
exhaustive exercise. This would be expected, in
addition to enhancing immune function, to have a
positive effect on nitrogen balance, and to have a
sparing effect on muscle release via the provision of
Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression
an adequate supply for enterocytes and other rapid-
ly-dividing cells in the intestine. Similarly, the
branched chain amino acids, which are precursors
for glutamine, might also be expected to maintain
blood glutamine levels[47] and nitrogen balance.[48]
It is important to be aware that different gluta-
mine assays can produce very different data. Thus, it
is unwise to compare the absolute values of one
research group with another unless they have used
identical assays. For the enzymatic assays, using
either asparaginase[49] or glutaminase[50] to start the
reaction, the ‘normal’ value (given that there is a
good deal of individual variation) is about 600
μmol/L. Other assays, such as Keast et al.’s bioas-
say[51] or, in some studies, high performance liquid
chromatography, have produced much higher values
for normal samples.
5. The Relationship Between Plasma
Glutamine and Glutamate
Smith and Norris[52] have recently made the inter-
esting suggestion that the plasma concentration ratio
of glutamine to glutamate (p[Gln/Glu]) might act as
a marker of training tolerance in athletes undergoing
heavy training. They observed a low p[Gln/Glu]
ratio of <3.58 in athletes whom they classified as
being overtrained/underperforming. This was in
contrast to well-trained, fit athletes, whose p[Gln/
Glu] ratio was >5.88. Thus, it is interesting that
clinical studies in 1951[53] and 1976[54] demonstrated
a high plasma glutamate which appeared to correlate
with disease severity (cachexia, i.e. muscle wast-
ing). Droge et al.[55,56] observed a correlation be-
tween high glutamate levels and impaired immune
function. Ollenschlager et al.[57] subsequently evalu-
ated whether a decrease in the p[Gln/Glu] ratio
might serve as a prognosticator of increased cachex-
ia. Glutamate, like alanine (figure 1) is a by-product
of glutamine metabolism, and thus it is not unrea-
sonable to expect an increase in the plasma gluta-
mate which is concomitant with increased glutamine
utilisation during stress such as disease cachexia or
endurance exercise. Indeed, the present author made
such observations during the analysis of samples
from cardiopulmonary bypass patients[11] and geriat-
© Adis Data Information BV 2003. All rights reserved.
327
ric patients undergoing restorative surgery.[14] In the
cardiopulmonary bypass patients glutamate in-
creased concomitantly with the decrease in p[Gln]
after surgery, except at one time point where both
decreased simultaneously. However, the changes in
the p[Gln/Glu] ratio were more inconsistent in the
geriatric study: in general, after either elective or
non-elective surgery, both glutamine and glutamate
decreased at the same time points. Ollenschlager et
al.[57] concluded that “valid information with respect
to the progress of an individual [patient] cannot be
obtained by the determination of plasma glutamate”
and, accordingly, the p[Gln/Glu] ratio. Hack et al.[58]
observed a decrease in plasma glutamine and an
increase in plasma glutamate (p[Glu]) after 8 weeks
anaerobic training. The present author saw no
change in p[Glu] in marathon runners after, com-
pared with before a race (table I), although there was
a strongly significant decrease in p[Gln]. Thus, in
Span of
TCA cycle
3
Glutamine
1
NH3 Malate
2-Oxoglutarate Glutamate
2
4
Aspartate Oxaloacetate
6
5
Phosphoenolpyruvate
7
Pyruvate
8
9
Alanine Lactate
Fig. 1. The proposed pathway of glutamine metabolism in cells of
the immune system. The reactions are as follows: 1 = glutaminase;
2 = aspartate aminotransferase; 3 = enzymes of the Krebs cycle
converting 2-oxoglutarate to malate; 4 = malate dehydrogenase
(NAD+-linked); 5 = malic enzyme [NADP+-linked]; 6 = phosphoe-
nolpyruvate carboxykinase; 7 = pyruvate kinase; 8 = lactate
dehydrogenase; 9 = alanine aminotransferase (this figure first ap-
peared in its present form in The Biochemist, 2002; 20 (3): 28-33.
Reprinted with permission from The Biochemical Society. © 2002
The Biochemical Society[59]). NAD = nicotinamide adenine dinucle-
otide; NADP = nicotinamide adenine dinucleotide phosphate; TCA
cycle = tricarboxylic acid (Krebs) cycle.
Sports Med 2003; 33 (5)
328
Table I. Plasma concentration (μmol/L) of glutamine and glutamate
in samples before and after a marathon (modified from Castell et
al.,[60] with permission)a
Glutamine Glutamate
Pre-exercise 571 62
15 min post- 462* 62
exercise
1h post-exercise 421* 55
16h post-exercise 555 63 8.81
a Assays were carried out enzymatically (for glutamine,
Windmueller and Spaeth;[49] for glutamate, Bernt and
Bergmeyer[61]).
* p < 0.001 vs pre-exercise mean.
this study, the ratio was dependent on p[Gln]. It is
possible that inconsistent data might make this ratio
a marker which may not always be reliable.
6. The Incidence of Illness After
Endurance Exercise
As has been well documented, there is a higher
incidence of illness in athletes after prolonged, ex-
haustive exercise. Symptoms are more prevalent in
these individuals, for example, after a marathon,
than in athletes undertaking moderate exercise, or in
athletes training for but not competing in endurance
events.[41,62-68] Most reported incidences are due to
upper respiratory tract infections (URTIs). In ul-
tramarathon runners, the highest incidence of URTI
occurred in those who finished in the fastest time
(figure 2). It has been suggested that moderate,
regular exercise helps to reduce the level of infec-
tion in sedentary individuals[69] whereas, in individ-
uals who undertake excessive exercise, the inci-
dence of illness appears to increase marked-
ly.[65,68,70] This suggests that immunodepression may
occur in some athletes during the stress of pro-
longed, exhaustive exercise and/or competition.
There is also a high incidence of minor infections in
athletes with unexplained underperformance syn-
drome, or overtraining.[71]
6.1 Upper Respiratory Tract Infections
Approximately 40% of URTI in adults are caused
by rhinoviruses which occur all year round.[64,72]
However, a 50% increase in the number of respirato-
© Adis Data Information BV 2003. All rights reserved.
Castell
ry infections attributable to adenoviruses has been
observed in military personnel in winter compared
Glutamine/ with that observed during summer. Exposure to
glutamate adenoviruses in crowded dormitories, classrooms
9.21 and gymnasiums might account for the higher inci-
7.45 dence of colds in some individuals during winter.[64]
It is therefore a debatable point whether cold expo-
7.65
sure per se is actually responsible for the increase in
infections in the cooler months. The author has
undertaken several marathon studies at different
times of the year. During these studies the lowest
incidence of self-reported URTI occurred during the
week after a marathon which took place on a day in
April when the ambient temperature was unseasona-
bly high (70°F). In fact, it was several degrees
higher on the day of the marathon than runners had
experienced during 2–3 weeks training prior to the
race. The day was characterised by the sight of
runners lying sunbathing whilst recovering from the
race. In addition, it was interesting that many par-
ticipants failed to achieve a personal best time,
presumably due to the unexpected heat stress.
Although rhinoviruses are most likely to be trans-
mitted via aerosol routes,[73] they can also be spread
by hand-to-hand transmission, for example, by play-
ing contact sports or handling contaminated sports
equipment. Eleven out of 15 recipients (73%) of a
‘rhinovirus contaminated hand-shake’ were infected
via direct hand-to-hand contact.[74] The athlete’s
life-style and attention to hygiene are therefore im-
portant factors likely to affect his/her susceptibility
to infections. Mast and Goodman[75] have suggested
40 Infected
Non-infected
35
Number of runners
30
25
20
15
10 42%
32%
5 47%
27%
19%
0
<4 4–4.5 4.5–5 5–5.5 5.5–6
Race time (h)
Fig. 2. The incidence of upper respiratory tract infections after ultra-
marathon running (reproduced from Noakes,[71] with permission;
data from Peters and Bateman[62]).
Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression
measures to prevent the transmission of infectious
disease in competitive sports. It is also of considera-
ble interest that Ryan et al.[76] undertook a large-
scale study on a simple programme of hand-washing
among young military recruits: they saw a 45%
decrease in outpatient visits for respiratory illness as
a result of implementation of this programme.
Some risk factors which might render athletes
more vulnerable to opportunistic viruses or bacterial
agents are:
• a higher training mileage;[63,77]
• additional stress (the mental stress of competition
more than doubled the risk of getting an upper
respiratory tract infection);[78]
• a low body mass;[77]
• bypassing the nasal filter mechanism (during
strenuous exercise athletes breathe through the
mouth rather than through the nose, thus impair-
ing the protective effects of mucosal secre-
tions);[79,80]
• a decrease in temperature;[72,81]
• greater[64] exposure to others incubating infec-
tions.
6.2 Gastrointestinal Problems
Athletes undertaking prolonged, exhaustive exer-
cise can also experience abdominal pains, abnormal
defecation, vomiting and nausea.[82] Dehydration,
decreased blood flow and tissue hypoxia frequently
lead to problems with the lower intestinal tract.
Damage to the intestine could lead to failure to
absorb in the small intestine, and thus to undigested
food entering the large intestine, leading to fermen-
tation and diarrhoea. The absorption of glucose and
amino acids may be impaired, leading to an energy
deficit, possible cell damage and enhanced secretion
of some gastroenteral and pancreatic hormones.[82] It
has been suggested[83] that the gut might be respon-
sible for triggering the exercise-induced inflam-
matory response.
6.2.1 Intestinal Function and Glutamine
Intestinal enterocytes are avid consumers of glu-
tamine; 50–60% of dietary glutamine is taken up by
these cells.[49] In animals and man, glutamine plays
© Adis Data Information BV 2003. All rights reserved.
329
an important role in protecting the intestine (table
II)[84-86] and has been seen to be particularly effec-
tive in alleviating problems due to radiation dam-
age.[87-89] Van der Hulst et al.[90] observed that gluta-
mine had a beneficial effect on the increased bowel
permeability observed in patients fed intravenously.
Permeability was greatly reduced by glutamine
feeding in post-operative patients in whom it had
markedly increased.[91]
7. Immune Cell Function
Cells of the immune system are normally present
as circulating cells in the blood and lymph. When an
infectious agent attacks, in the first instance the
inflammatory response acts together with the innate
immune response; this is accompanied by the adap-
tive immune response, involving T- (thymus-de-
rived) and B- (derived from bone marrow) lympho-
cytes. The specificity of immune responses is due to
the lymphocytes, which are the only cells in the
body intrinsically capable of specifically recognis-
ing and distinguishing different antigenic determi-
nants. On average, lymphocytes remain in the blood
stream for only about 30 minutes each time they
pass through: this means that the pool of circulating
lymphocytes is exchanged about 48 times per day.
In man, approximately 5 × 1011 lymphocytes leave
the blood every day[93] out of a total number in the
body of approximately 2 × 1012 and circulate
through different tissues.
Table II. Some effects of glutamine supplementation on gut func-
tion (reproduced from Stehle and Furst,[92] with permission)
Experimental studies
Mucosal thickness and protein/DNA content Increased
Bacterial translocation after radiation Reduced
Mucosal cellularity/intestinal atrophy Maintained
Jejunal atrophy Reduced
Mucosal hyperplasia after small bowel resection Enhanced
Adverse effects of enterocolitis Weakened
Clinical studies
Intestinal function after bone marrow transplant Maintained
Intestinal permeability Improved
Intestinal absorption capacity during parenteral Maintained
nutrition
Sports Med 2003; 33 (5)
330
Given the complexity of the whole immune sys-
tem and the different areas that can be studied, it is
an immense task to establish precisely which aspects
might be affected, and how. In other words, how
might some aspects of immune function be affected
(i) by intensive exercise, and (ii) in terms of the
focus of this review, by the provision of exogenous
glutamine, particularly in a situation where it is
required to restore physiological levels? For exam-
ple, more than 160 clusters of differentiation (i.e.
groups of monoclonal antibodies that identify the
same cell-surface molecule, known as CDs) are
already established. The list of CDs, cytokines and
chemokines continues to grow, and includes many
whose functions or target cells or receptors are not
yet known. Thus, an important issue in this field is
what has not yet been addressed, rather than dis-
counting an effect of glutamine on the whole
immune system per se, via only some specific as-
pects.
8. Transient Immunodepression in
Prolonged, Strenuous Exercise
Two questions have always been of particular
interest to the present author: (i) do endurance ath-
letes make a good model for the acute phase re-
sponse (i.e. the inflammatory response to an
immune challenge)?; (ii) how important in the long
term is the transient immunodepression which oc-
curs after exhaustive exercise?
8.1 Circulating Cell Numbers in
Endurance Exercise
The first question was asked by Weight et al.[94]
in 1991, who concluded that they probably do not.
This was largely based on the observation that circu-
lating numbers of cells such as lymphocytes and
neutrophils return to baseline levels within about 24
hours after running a marathon. However, natural
killer (NK) cell numbers are still markedly reduced
at 16 hours after a marathon.[60]
The numbers of circulating white blood cells
increase markedly as a result of both acute and
prolonged, exhaustive exercise. This phenomenon,
known as leucocytosis, was first observed by Larra-
© Adis Data Information BV 2003. All rights reserved.
Castell
bee[95] who deduced that it was mainly due to a large
increase in circulating neutrophils. Garrey and Bry-
an[96] described it as a shift of cells from the margi-
nal to the circulating pool. It has now been estab-
lished that, in samples taken immediately after a
marathon or intensive training, there is also a tran-
sient increase in circulating lymphocyte numbers at
the start of the recovery period. However, numbers
of lymphocytes subsequently decrease below pre-
exercise levels within 30 minutes after strenuous
exercise, and possibly as rapidly as within 15 min-
utes.[60]
The marked leucocytosis which occurs in the
circulation after endurance events may be affected
by dehydration, i.e. the cell numbers may be more
concentrated in a lower plasma volume which would
be reflected by an increase in haematocrit. However,
in several studies it has been concluded that less than
10% of this leucocytosis could be attributed to dehy-
dration, on the basis of little or no change in
haematocrit levels.[97-102]
In 1985, Noakes[71] suggested that the body’s
immune system, and with it the athlete’s resistance
to infection, is impaired by heavy training and com-
petition. Parry-Billings et al.[28] expanded on this in
their review of exercise-induced immunodepres-
sion. They proposed that the decrease in plasma
glutamine also observed for a few hours after a bout
of exhaustive exercise, such as a marathon, might
account for the decrease in cell numbers and func-
tion. The exercise-induced period of immunodepres-
sion was subsequently dubbed the ‘open window’
by Pedersen and Ullum.[103] More recently, Nieman
and Pedersen[68] have suggested that this may last as
long as 72 hours, depending on which parameter is
being measured. At 72 hours, the majority of aspects
of immune function investigated to date would al-
ready have been activated if the athlete had become
infected. In this context it is worth bearing in mind
that, although the cycle time of B lymphocytes post-
antigen can be about 6 hours, on average B and T
lymphocytes have a turnover time of about 15–24
hours (i.e. they replicate in approximately 15–24
hours).
Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression
Lymphocyte apoptosis (programmed cell death,
as opposed to senescence) is increased by treadmill
exercise to exhaustion.[104] Apoptosis occurred in
63% of lymphocytes immediately after exercise and
in 86.2% 24 hours after. It has been suggested that
glutamine deficiency makes human monocytes
more vulnerable to some specific triggers of apopto-
sis.[105]
Neutrophils, together with macrophages, are re-
sponsible for ingesting invading organisms by phag-
ocytosis. They are the first cells to respond to such
an invasion. The oxidative burst process employed
by these cells to phagocytose bacteria, by releasing
toxic oxygen products, is over in a matter of min-
utes. When fully mature, the marginal pool of neu-
trophils can remain primed to respond to an immune
challenge for a long time. Neutrophils are released
from the pool soon after the start of exercise. As well
as acute mobilisation of mature neutrophils during
exercise, it has been suggested that there is an in-
creased release of immature neutrophils from bone
marrow[106] in response to strenuous exercise and the
consequent more vigorous circulation of the blood.
8.2 Cell Function in Endurance Exercise
Adverse effects on several different aspects of
immune function occur after endurance
events.[60,65,66,70,99,107-112] These include:
• decreased neutrophil activity;
• impaired antibody synthesis;
• decreased immunoglobulin levels in blood and
saliva;
• decreased cytolytic activity of NK cells;
• lower circulating numbers of T lymphocytes for
3–4 hours after exercise;
• decrease in the proliferative ability of lympho-
a in T cell proliferation in rats immediately after 4
cytes;
• a decreased ratio of CD4+ to CD8+ cells.
One of the earliest studies showed a marked
depression in lymphocyte responsiveness to
mitogenic stimulants in runners after a marathon,
compared with moderate exercise. The lymphocytes
were functioning normally again within 24 hours of
recovery.[113] In general, the immunodepression ob-
served to date in various studies appears to be most-
© Adis Data Information BV 2003. All rights reserved.
331
ly transient (e.g. not lasting longer than a few hours).
However, some parameters may remain affected for
as much as 24 hours after prolonged, exhaustive
exercise. For example, after a transient initial surge,
NK cell activity is decreased within 30 minutes after
prolonged exercise and remains so for at least 16
hours. Thus, undertaking intensive exercise sessions
within two days of running a marathon, for example,
may give insufficient time for the immune system to
‘recover’ sufficiently to function normally. There is
evidence for this from studies on repeated bouts of
exercise.[114]
In another early study on immune cell response to
endurance exercise, Gmunder et al.[99] observed a
substantial decrease in the responsiveness of lym-
phocytes to the mitogen concanavalin-A in blood
samples from seven athletes taken after a marathon
compared with those taken before, together with
marked changes in cell populations which are neatly
described in figure 3.
More recently, Castell[14] observed a significant
decrease (p < 0.001) in lymphocyte proliferative
ability in 37 runners 2 hours after a marathon com-
pared with immediately after; this reduction re-
turned to normal the next morning (16 hours after
the race).
In studies on lymphocyte subsets, a decreased
ratio of T-helper to T-cytotoxic (CD4 : CD8) cells
in athletes after acute exhaustive exercise observed
by Berk et al. in 1986,[115] has also been confirmed
by Lewicki et al.[116] and Haq et al.[101] It has been
suggested that a ratio of CD4 : CD8 cells below 1.5
is subnormal, and may be a cause of, and an indica-
tor of, immunodepression.[69,107,117]
Koyama et al.[118] observed a significant decrease
weeks of treadmill exercise, compared with a seden-
tary control group. The reduced proliferation did not
return to normal within 24 hours of recovery. p[Gln]
was also significantly decreased immediately after
the exercise.
Neutrophil activity, as measured both by an oxi-
dative burst technique[119] and elastase release, was
decreased 1 hour after cycling to exhaustion (mean
duration 40 minutes) at 80% V̇O2max, and 2.5 hours
Sports Med 2003; 33 (5)
332 Castell

2.0 3.0 2.5 1.6

Suppressor/cytotoxic T cells (109/L)

Lymphocyte responsivenss (RPI)

1.8 1.4

Helper/inducer T cells (109/L)

2.5 2.0
1.6
1.2

Pan T cells (109/L)

1.4
2.0
1.2 1.5 1.0

1.0 1.5 0.8

0.8 1.0 0.6
1.0
0.6
0.4
0.4 0.5
0.5
0.2 0.2

0.0 0.0 0.0 0.0

1 2 3 1 2 3 1 2 3 1 2 3

0.6 25 5 1400

0.5 1200

Lymphocyte counts (109/L)

20 4
Leukocyte counts (109/L)

Hydrocortisone (nmol/L)
1000
0.4
B cells (109/L)

15 3 800
0.3
10 2 600
0.2
400
5 1
0.1 200

0.0 0 0 0
1 2 3 1 2 3 1 2 3 1 2 3

1800 1
800
1600 2
700
1400 3
Norepinephrine (pg/L)

600 4
Epinephrine (pg/L)

1200
500 5
1000
400 6
800
7
300
600
200 400
100 200
0 0
1 2 3 1 2 3
Fig. 3. Effect of marathon running in seven athletes on lymphocyte responsiveness (expressed as the relative proliferation index), numbers
of pan T cells, helper/inducer and suppressor/cytotoxic subsets, B cells, leucocyte and lymphocyte counts, and blood levels of cortisol,
epinephrine and norepinephrine. The numbers on each x-axis are: sample 1 (2 days prior); sample 2 (immediately after); and sample 3 (2
days after the marathon); respectively (reproduced from Gmunder et al.,[99] with permission from Aviation Space and Environmental
Medicine). RPI = Relative Proliferation Index.

after cycling at 55% V̇O2max for 3 hours.[120] After a Despite the fact that prolonged, exhaustive exer-
100km race, the percentage of neutrophils incorpo- cise causes some pro-inflammatory cytokines, such
rating bacteria (the phagocytic rate) was unchanged as IL-6, to reach similar levels to those observed in
but the phagocytic activity (the amount of bacteria critically ill patients (e.g. the 45-fold increase ob-
incorporated per cell) decreased by 34%.[121] Fukat- served by Castell et al.[60]) the levels return to nor-
su et al.[122] found that neutrophil bactericidal activi- mal relatively rapidly, i.e. within 3 hours after exer-
ty decreased after a 50-mile (80km) walking race: cise. Ostrowski et al.[123] referred to a trauma-like
they deduced that this was due to an increase in elevation of the plasma cytokines (IL-1 [18-fold]
cortisol and ketone bodies. and IL-6 [26-fold]) in response to treadmill running

© Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression 333

p[Gln]
for 2.5 hours at 75% V̇O2max. In a subsequent field PBMC[Gln]
study on marathon runners, they observed an even
800 35
higher elevation of IL-6 (128-fold) immediately af-
700 30
ter the race. Recently, the suggestion came from †

PBMC[Gln] μM • 103
600 25
Pedersen’s group that IL-6 should be regarded as an

inflammatory responsive cytokine with an anti-in-
flammatory role, rather than a pro-inflammatory
cytokine.[124]
9. Glutamine Availability and Uptake
by Cells
Parry-Billings et al.[28] suggested that the vulner-
ability of athletes to opportunistic infections for
several hours after prolonged, exhaustive exercise,
may be partly due to a decreased availability of
blood glutamine at a time when some key immune
cells are being challenged. The fact that regular low-
intensity exercise appears to be beneficial for the
immune system[66,69,70] may perhaps be because
p[Gln] remains unaltered at that level of exercise.
It therefore seems reasonable to speculate that the
timing of such a situation may be quite specific and,
moreover, may affect certain cells in quite a specific
way. If it is supposed that one of the reasons for a
decrease in the p[Gln] is that glutamine is taken up
by certain cells soon after the immune system is
challenged, then the availability of glutamine might
only start to become a problem when the rate of
release of glutamine from muscle slows down.
In a collaborative study with the author’s labora-
tory,[125] intracellular glutamine was measured in
peripheral blood mononucleocyte samples taken
from nine cyclists exercising at normoxia in the
Hypoxia Research Unit, University of Glamorgan,
Wales. There was a significant decrease (19%) in
p[Gln] immediately after exercise (p = 0.014).[125]
Thirty minutes after exercise there was a 109%
increase in the intracellular glutamine concentration
of peripheral blood mononucleocytes per cell, com-
pared with immediately after exercise (p = 0.003)
and with baseline levels (p = 0.022) [figure 4]. This
suggests that the disappearance of glutamine from
the circulation might be due to its uptake into cells
that use it as a fuel. The return of p[Gln] to baseline
levels 30 minutes after exercise indicates that there
p[Gln] μmol/L
500 ††
* 20
400
15
300
10
200
100 5
0 0
Pre Post 0 Post 30 Post 120
Time (min)
Fig. 4. Comparison of p[Gln] and PBMC[Gln] in response to
120-minute cycling ergometry at 50% V̇O2max (mean ± SEM) in
nine cyclists. PBMC[Gln] was adjusted for changes in PBMC count
(reproduced from Hiscock et al.,[125] with permission from the Physi-
ological Society). PBMC[Gln] = intracellular glutamine concentra-
tion of peripheral blood mononucleocytes; p[Gln] = plasma concen-
tration of glutamine; Pre = before exercise; Post0 = immediately
after exercise; Post = minutes post-exercise; † indicates a signifi-
cant difference in p[Gln] from Pre to Post0 (p = 0.014); †† indicates
a significant difference in PBMC[Gln] from Post 0 to Post 30 (p =
0.003); * indicates a significant difference in PBMC[Gln] from Pre to
Post 30 (p = 0.022).
was subsequently less requirement for glutamine by
the cells. More frequent samples would give a more
detailed picture of the fate of the blood glutamine in
these circumstances.
10. Glutamine Supplementation
10.1 Glutamine Feeding in Clinical Situations
The first recorded instance of glutamine feeding
in humans was by Welbourne et al.[126] who looked
at the effect of glutamine administration on urinary
ammonia excretion in both healthy controls and
patients with renal disease. They found that oral
glutamine increased p[Gln] in both controls and
patients during alkalosis.
Evidence that both parenteral (intravenous) and
enteral (oral) glutamine feeding can have beneficial
effects on gut function (see section 8.2) and/or the
immune system in both humans and animals, comes
from several clinical studies (table III and table IV).
Beneficial effects in human studies include a
decreased incidence of infections and increased T

© Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (5)
334 Castell

Table III. Some beneficial effects of feeding glutamine or a glutamine precursor in humans, including specific effects on the immune
system[14,41,47,127-141]
Recipients Condition (n) Method of feeding Beneficial effects
Patients Bone marrow transplant (45) TPN (L-glutamine) Decreased number of positive microbial cultures and
clinical infections;[130] enhanced recovery of circulating
lymphocytes, total T lymphocytes, CD4 helper, CD8
suppressor;[130] shorter stay in hospital;[130,134,137] improved
mood[139]
Patients Colorectal cancer (20) TPN (glycyl-glutamine Enhanced post-operative T lymphocyte DNA
dipeptide) synthesis[132,135]
Patients Severe, acute pancreatitis (13) TPN Enhanced T cell response, decreased IL-8 production[133]
Patients Intensive care (84) TPN Reduced mortality, shorter stay in hospital, reduced
incidence of infections[131]
Patients Severe burns (26) IV Reduced incidence of Gram-negative bacteraemia[136]
Patients Multiple trauma (60) Enteral Decreased sepsis and bacteraemia[140]
Patients Abdominal surgery (28) TPN Improved lymphocyte recovery, shorter hospital stay[141]
Patients Intensive care (12) Enteral Increased lymphocyte proliferation, concomitantly with
increased IL-2[138]
Neonates Very low birthweigh (68) Enteral 2-Fold lower incidence of hospital-acquired sepsis; blunted
increase in NK cells and HLA-DR+ cells[127]
Volunteers Healthy (9) Enteral Decreased IL-6 and IL-8 production both in vivo and in
vitro[128]
Athletes Marathon runners (151) Oral (after race) Decreased incidence of self-reported infections (43%)[41]
Athletes Marathon runners (10) Oral (after race) Decreased IL-8 production; return to normal levels of
neutrophils 16h after race[14]
Athletes Marathon runners (97) Oral (daily for 1mo prior to Decreased incidence of self-reported infections (18%)
competition)a decreased IL-8 production[129]
Athletes Triathletes (12) Oral (daily for 3 wks prior to Decreased incidence of self-reported infections (34%)
competition)a increased IL-1, IL-2, TNFα, IFNγ[47]
a Two studies in which branched chain amino acids were given as glutamine precursors.
IFN = interferon; IL = interleukin; IV = intravenous; NK cells = natural killer cells; TNF = tumour necrosis factor; TPN = total parenteral
nutrition.

cell recovery in bone marrow transplant patients;
enhanced T cell response in patients undergoing
surgery or experiencing acute pancreatitis; and a
favourable effect on red cell nicotinamide adenine
dinucleotide (NAD) redox potential in patients with
sickle cell anaemia.[151] Studies on animals include
findings of increased alveolar macrophage phagocy-
tosis, reversal of biliary immunoglobulin (Ig) A
suppression, and increased numbers and function of
lymphocytes during sepsis.
Clinical studies have also reported that the provi-
sion of large daily quantities of glutamine appears to
help to prevent a further decrease in muscle gluta-
mine in patients in a catabolic condition, or to re-
store muscle glutamine to physiological levels.
Ziegler et al.[130] observed a reduction in infec-
tions and an increase in numbers and function of
lymphocytes in bone marrow transplant patients
given glutamine-enriched parenteral nutrition (total
parenteral nutrition [TPN] with L-glutamine). In a
3-year study, Griffiths et al.[131] fed 42 critically ill
patients in intensive care with glutamine-enriched
TPN and 42 with standard TPN. They studied them
during their stay in intensive care and at 6 months
after starting the study. At 6 months, 67% of the
standard TPN group had died, whereas only 43%
died in the glutamine-enriched group. The patients
were carefully matched in every aspect. Further
analysis of the data[152] has shown that the incidence
of infections was reduced in the glutamine group
compared with the placebo group. In 1996, O’Ri-
ordain et al.[132] saw an increase in lymphocyte
proliferative ability and a decrease in the
chemokine, IL-8, in patients with acute pancreatitis

© Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression 335

Table IV. Some beneficial effects of glutamine feeding in animals including specific effects upon the immune system[142-150]
Recipients Condition Method of feeding Beneficial effects
Rats Healthy – suppressed biliary TPN (L-glutamine) Increased biliary concentration of IgA normally
IgA suppressed by TPN[144]
Rats Tumour bearing TPN (alanyl-glutamine Increased phagocytic activity of alveolar
dipeptide) macrophages[146]
Rats Tumour bearing Oral Increased mitogenic response in splenocytes,
increased NK cell numbers in spleen but not
activity[147]
Rats Sepsis TPN (alanyl-glutamine Increased rate of lymphocyte proliferation and
dipeptide) increased number of lymphocytes[150]
Rats Chemotherapy Oral Decreased sepsis defined as decreased white
blood cell count plus decreased positive blood
cultures[145]
Rats Septic shock IV Attenuation of TNFα and IL-1β; decreased
mortality[149]
Rats Healthy Oral Reduced IL-10 production by mesenteric
mononuclear cells[143]
Mice Healthy Oral Increased TNF, IL-1β, IL-6 production by
macrophages[148]
Mice Endotoxaemic Oral Prevented lymphocyte and GSH depletion of
Peyer’s patches[142]
GSH = glutathione; Ig = immunoglobulin; IL = interleukin; IV = intravenous; NK cells = natural killer cells; TPN = total parenteral nutrition.

who received glutamine-enriched TPN. This finding supplied may have provided sufficient for the neu-
agreed with the author’s observation of a similar trophils’ requirements and reduced the need for
decrease in IL-8 production in vitro in a group of chemical signals to attract more neutrophils to the
endurance athletes receiving oral glutamine after a site of injury. Evidence for this comes from in vitro
marathon.[14] Since then, further studies carried out and ex vivo studies[17,18,153] and, as discussed in the
in the author’s laboratory have provided additional paragraph above, from in vivo glutamine feeding
evidence that glutamine feeding reduces IL-8 pro- studies.[14,132] To date, the presence of glutaminase,
duction (table V). the major enzyme in the degradation pathway of
glutamine, has only been reported in rat neutro-
It is suggested that the reason for this is that
phils.[154] However, recent work from the author’s
human neutrophils utilise glutamine. Thus, it is
laboratory has now provided evidence that
tempting to speculate that the exogenous glutamine
glutaminase is present in human neutrophils and that
Table V. The effects of glutamine versus placebo on cell in- glutamine therefore has a role in neutrophil func-
terleukin-8 production (pg/L) in endurance athletes after strenuous tion.[19]
exercise
Female rowers Marathon runners 1h after a
after a 2km marathon
10.2 Glutamine Feeding in Athletes
ergotest
spring winter
10.2.1 After Prolonged, Exhaustive Exercise
Placebo 535 ± 112a 609 ± 104a 1387 ± 229b
(n = 5) (n = 8) (n = 4)
Having confirmed the observations of Parry Bill-
Glutamine 122 ± 78** 174 ± 62*** 1063 ± 262*
ings,[38] viz., that the plasma concentration of gluta-
(n = 5) (n = 6) (n = 7) mine can be decreased by as much as 25% in endur-
a R&D Systems ELISA. ance runners after a marathon, a series of studies
b BenderMed ELISA. was undertaken by the author in which supplementa-
ELISA = enzyme-linked immunosorbent assay; * p < 0.13; ** p < ry glutamine was administered at rest or after exer-
0.02; *** p < 0.01 vs placebo.
cise. As discussed earlier, about 50% of dietary

© Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (5)
336
glutamine is utilised by the intestine.[49] Neverthe-
less, the provision of 0.1 g/kg (approximately 7g for
most individuals) of glutamine as a drink after an
overnight fast, resulted on average in a 2-fold in-
crease in the p[Gln] within 30 minutes in eight
healthy humans.[155] This level returned to almost
baseline levels after approximately 2 hours. A simi-
lar, but slightly smaller, increase was observed in
response to a dose of 5g. Investigation of diurnal
variation indicated that p[Gln] increased 2 hours
after a mixed meal.[156] The author also observed
that consumption of a wheatmeal bread sandwich
containing tuna fish led to an increase in p[Gln] of
150 μmol/L but this increase was not observed until
2 hours after ingestion. Thus, the first study estab-
lished an appropriate glutamine dose and timing of
administration for the subsequent studies. These
double-blind studies were undertaken in marathon
runners who were given drinks containing either
glutamine or a placebo after competition.[41,60,155]
At the same time points when p[Gln] was seen to
decrease, increases were observed in acute phase
response markers such as the cytokine IL-6 and
complement C5a. The plasma concentration of C-
reactive protein was markedly increased 16 hours
after the race: this reflects muscle damage due to
strenuous exercise.
There was a 30% decrease in total circulating
lymphocytes within 15 minutes after the race. How-
ever, numbers of circulating leucocytes were re-
stored to baseline levels the next morning in the
glutamine group, compared with the placebo group.
At the same time point, numbers of circulating neu-
trophils had returned to baseline in the glutamine
group, compared with the placebo group, in whom
they were still slightly elevated.[102] In another mara-
thon study, the decrease in the CD4 : CD8 ratio 2
hours after the marathon was less (p < 0.02) in
runners who took glutamine as opposed to place-
bo.[155]
The marathon runners who participated in the
glutamine feeding study also completed question-
naires for 7 days after the marathon (n = 151).
Overall, the percentage of participants in the gluta-
mine group who reported being free of infections
© Adis Data Information BV 2003. All rights reserved.
Castell
was significantly greater (81%) than in the placebo
group (49%).[41] The analysis of these question-
naires included, in both the placebo and the gluta-
mine groups, a small number of athletes who report-
ed a sore throat for one day after the marathon.
However, this did not affect the overall statistical
significance.
Bassit et al.[47] observed a similar magnitude of
decrease in the incidence of infections in triathletes;
this decrease was in a group supplemented for 1
month with branched chain amino acids (BCAA)
compared with a placebo group. They demonstrated
that, as precursors for glutamine, the BCAA main-
tained the p[Gln] levels. They considered that the
maintenance of p[Gln] enabled an increased produc-
tion of IL-1, IL-2, tumour necrosis factor (TNF)α
and IFN-γ. In a similar study[157] on runners after a
30km run, the same group observed a decrease in
IL-4 in the BCAA group which they concluded
modified the T helper-1 type immune response.
More recently they concluded[158] that carbohydrate
supplementation in cyclists positively affected the
immune response by minimising changes in p[Gln].
In a recent study in the author’s laboratory[129] mara-
thon runners (n = 97) took BCAA (0.1 g/kg body
mass) for 1 month before competition. Those in the
BCAA group had an 18% lower incidence of self-
reported illness in the week after the race, and a
decrease in IL-8 production in samples taken one
hour after the race.
Thus, it may be that the provision of glutamine,
or a glutamine precursor, after prolonged, exhaus-
tive exercise might increase its availability for some
cells of the immune system at a critical period when
athletes may be vulnerable to opportunistic infec-
tions.
In the many published reports on glutamine feed-
ing studies, no problems of toxicity have been ob-
served. It is important to bear in mind, however, that
glutamine is unstable in solution and should not be
kept in that form for more than a few hours at room
temperature, nor added to hot drinks. As with all
supplements, it is better to take moderate
amounts.[159] A survey on the safety of glutamine
and other amino acids has been made by Garlick.[160]
Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression
10.2.2 In Body Building
The terms ‘volumisation’ and ‘anti-catabolic’ are
popular parlance in the supplementation industry.
Welbourne[161] observed an increase in the plasma
concentration of growth hormone, bicarbonate and
glutamine in humans after 2g glutamine was in-
gested orally. Nevertheless, despite its popularity in
body building,[162,163] there is little published evi-
dence to show that glutamine is effective in this
sport. In a study in patients with short-bowel syn-
drome, Scolapio et al.[164] observed that the adminis-
tration of glutamine plus growth hormone to these
patients resulted in increased bodyweight and a de-
crease in percentage body fat. However, the increase
in body mass was subsequently attributed to fluid
retention since the patients also developed periph-
eral oedema as a result of the treatment. Colker et
al.[165] observed an increase in fat-free mass in ath-
letes being provided with whey protein, glutamine
and branched chain amino acids, compared with
those taking only whey protein. Both groups under-
took resistance training over the 10 weeks of the
study. Unfortunately the authors did not include a
group taking only glutamine in addition to the whey,
thus it is not possible to establish which amino acid
supplementation might have been responsible for
the improved body composition and performance
observed. Candow et al.[166] observed no significant
effect of high-dose glutamine supplementation (45
g/day) on muscular performance, body composition
or muscle protein degradation in a study on 31
young, healthy adults undergoing resistance train-
ing.
The muscle glutamine concentration in humans is
20 mmol/L,[20] which is substantially higher than the
blood glutamine concentration (0.6 mmol/L). At
rest, the ingestion of 5g glutamine increases the
p[Gln] approximately 2.5-fold for about 2 hours.[155]
Given that 50–60% of dietary glutamine is used by
intestinal cells,[49] unacceptably high amounts of
glutamine would have to be consumed orally to have
an effect on muscle levels in athletes. Thus, it seems
unlikely that glutamine supplementation per se
would have a direct effect on bodybuilding in terms
of muscle mass increase. It seems much more likely
that exogenous glutamine would only have a direct
© Adis Data Information BV 2003. All rights reserved.
337
effect on muscle glutamine in conditions of severe
muscle wasting, such as in critically ill patients.
High doses of intravenous glutamine in dipepetide
form, given to markedly catabolic patients, have
been effective in preventing the substantial de-
creases in muscle glutamine that occur due to severe
muscle wasting.[167,168]
11. Discussion
There is increasing evidence, particularly from in
vitro and from clinical studies that glutamine has an
important role in enhancing some aspects of
immune cell function. However, to date there is little
published evidence of which specific aspects of
immune function glutamine might enhance during
the transient immunodepression observed after pro-
longed, exhaustive exercise, or for its apparent con-
sequences.
The majority of studies that have found no effect
of glutamine on some specific aspects of the
immune system in exercise (see table VI) are the
carefully designed ones from Professor B.K. Peder-
sen’s group. In in vitro studies, Rohde et al.[169]
observed that the addition of glutamine to culture
medium produced a dose-dependent increase in the
proliferative response and lymphocyte activated
killer (LAK) cell activity of peripheral blood mono-
nuclear cells from healthy individuals at rest. How-
ever, they were not able to repeat this result in
samples taken from either healthy controls or pa-
tients with HIV after concentric exercise. In 1996,
Rohde et al.[44] observed that the decrease in serum
glutamine concentrations from 468 to 318 μmol/L
after a triathlon correlated most appropriately with a
decrease in LAK activity. They subsequently inves-
tigated the effects of glutamine supplementation on
LAK activity after a marathon.[170] The placebo
group p[Gln] decreased from 647 to 470 μmol/L and
the glutamine group p[Gln] was maintained; they
observed that the decrease in p[Gln] after exercise
did not appear to be responsible for the exercise-
induced decrease in LAK activity. Similarly, in a
study where repeated bouts of bicycle ergometer
exercise were undertaken, glutamine supplementa-
tion did not influence the decrease in LAK cell
Sports Med 2003; 33 (5)
338 Castell

Table VI. Some glutamine feeding studies in exercise which have shown no, or limited, beneficial effects upon the immune system[170-172]
Recipients Type of exercise (n) Method of feeding Effects on immune system Reference
Athletes Cyclists (8) Oral No effect on: LAK cell activity; PHA stimulated lymphocytes; 171
lymphocyte numbers
Athletes Marathon runners Oral, post-exercise No effect on: LAK cell activity; proliferation; numbers of 170
(16) leucocyte subsets studied
Athletes Cyclists (11) Oral, during No effect on salivary IgA 172
exercise
Athletes Cyclists (10) Oral, during No effect on: CD3 T cell receptors; NK cells; CD8, CD4 173
exercise with/without CD28 and 95 surface receptors
Neutrocytosis less in glutamine group than placebo group
Athletes Cyclists (7) Oral No effect on: leucocytosis; plasma elastase release from 174
LPS-stimulated neutrophils
Ig = immunoglobulin; LAK = lymphokine activated killer cells; LPS = lipopolysaccharide; NK cells = natural killer cells; PHA =
phytohaemagglutinin.

activity, circulating lymphocyte numbers, or of glutamine on neutrophils when neutrophilia was

phytohaemagglutinin-stimulated lymphocyte proli-
feration.[171] In this study, arterial, rather than ve-
nous, glutamine was measured; it was decreased in
the placebo group from 508 to 402 μmol/L, com-
pared with the glutamine group where levels were
maintained. In a study on cardiopulmonary bypass
patients, the present author compared venous and
arterial samples and found no significant differences
in the concentration of glutamine taken at the same
time points.[11] It is worth noting that the amount of
glutamine ingested in the study by Rohde et al.[171]
was very high (0.9 g/kg bodyweight; compare with
Candow et al.[166] in section 10.2.2).
Recently Krzywkowski et al.[172] studied the ef-
fect of glutamine on salivary IgA after 2 hours
exercise on a cycle ergometer on three successive
days. The post-exercise decrease in salivary IgA
was not abolished by either glutamine or protein
supplements. In another lab-based study, this group
investigated the effects of glutamine supplementa-
tion on lymphocytes in much greater detail.[173] They
measured, among others, CD3 T cell receptors, NK
cells, CD8 and CD4 T cells with/without CD28 and
CD95 surface receptors. They observed that gluta-
mine supplementation had no effect on these param-
eters in samples taken after exercise.
The only positive observation made in the gluta-
mine group was that neutrocytosis was less pro-
nounced than in the placebo group.[173] This agrees
with the present author’s observations on the effects
attenuated in the glutamine group the morning after
a marathon.[155] In addition, the author has observed
a decrease in the chemokine IL-8, after glutamine
feeding, in at least three different exhaustive exer-
cise studies (table VI). O’Riordain et al.[132] made a
similar observation in parenterally fed patients with
acute pancreatitis.
Thus, it remains to be established precisely how
glutamine supplementation affects the incidence of
infections in field studies. In this context, there are
some important issues:
1. Do measurements of the numbers and activities of
the small proportion of peripheral blood leucocytes
properly reflect the performance of immune cell
function in the whole body? In human studies, they
are the only measurable link we have with the much
larger number of cells in the whole immune system.
2. Is it reasonable to expect to see a rapid effect of
glutamine feeding upon the cell parameters studied?
For example, the time course between the release of
immature neutrophils and their degranulation is
about 24 hours. The turnover time of lymphocytes
(i.e. between their first appearance and mitosis is a
minimum of 6 hours, and in most cases will be
around 24 hours (see section 8.1).
3. Why does supplementation (short- and long-term)
with glutamine or a glutamine precursor, appear to
reduce infectious episodes in both patients[127,130,152]
and athletes?[19,41,47,129] At the time of writing the
author is not aware of any other published reports on

© Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (5)
Glutamine Supplementation in Exercise and Immunodepression
glutamine feeding and the incidence of illness/infec-
tion in humans in exercise.
11.1 So, How Does Glutamine Work?
11.1.1 Via Glutathione?
Glutamine is an important component in the me-
tabolism of glutathione (GSH). GSH metabolism
responds rapidly to exercise, and is a consistent
marker of exercise-induced oxidative stress.[175-177]
Tissue GSH metabolism reflects the level of train-
ing.[178,179] Intracellular GSH in lymphocytes and
monocytes increased to an optimal concentration
after 8 weeks aerobic training, compared with anaer-
obic. In the same study p[Gln] was decreased after
anaerobic training but maintained with aerobic
training.[58] Glutamine is a precursor for GSH,
which is a tripeptide consisting of glycine, gluta-
mate and cysteine. The gut is a major producer of
GSH and, in a study on rats, Cao et al.[180] observed a
3-fold increase in GSH fractional release in the gut
after oral glutamine supplementation. GSH appears
to play an important antioxidant role in blood during
intensive exercise.[181,182] Glutamine administration
has resulted in maintenance of GSH levels in the
liver, following hepatic injury.[183] It has also en-
hanced GSH concentration in tumour-bearing
rats[89] and suppressed prostaglandin E2 synthesis in
breast cancer via increased GSH production.[184] The
relationship between glutamine, oxidative stress and
apoptosis has been extensively reviewed by Mates et
al.[185] Manhart et al.[142] observed increased lym-
phocyte production by Peyer’s patches in endotoxic
mice, possibly via GSH. Thus, there is a link be-
tween glutamine, GSH and immune cells.
It has been suggested[186] that the reduced form of
nicotinamide adenine dinucleotide phosphate
(NADPH) may be the factor that links the effects of
glutamine in different cells. NADPH is important
for free radical production in the formation of nitric
oxide and superoxide and also for DNA and RNA.
Glutamine can generate the NADPH required via a
catabolic metabolism involving NADP+-dependent
malate dehydrogenase [glutamine → glutamate →
2-oxoglutarate → malate → pyruvate]. Studies by
Garcia et al.[187] and Furukawa et al.[188] have found
© Adis Data Information BV 2003. All rights reserved.
339
that glutamine provision has a beneficial effect on
superoxide generation in neutrophils.
11.1.2 Via Gastrointestinal Function?
Marshall[83] suggested that the gut might be re-
sponsible for triggering an exercise-induced inflam-
matory response. It is possible that strenuous exer-
cise could decrease glutamine synthesis in the gut,
possibly via inhibition of glutamine
synthetase.[189,190] This would therefore reduce the
availability of glutamine which would be likely to
lead to increased gut atrophy[84] and possible in-
creased bacterial translocation via increased perme-
ability. This would be similar to the situation in
long-term intravenous feeding in critical illness, and
could clearly also lead to a decrease in the availabili-
ty of glutamine for rapidly-dividing intestinal cells
such as enterocytes and lymphocytes. A recent study
by Clarke et al.[191] observed that glutamine was
essential as an enterocyte fuel substrate for the pres-
ervation of a functional barrier to micro-organisms.
It has been previously speculated that glutamine
supplementation might not only enhance the func-
tional ability of some cells of the immune system,
but might also improve the digestive and defence
mechanisms of the intestine.[192,193] More recently,
Coeffier et al.[128] observed a modulatory effect of
enteral glutamine on pro-inflammatory cytokine
production by human intestinal mucosa; interleukin
(IL)-6 and IL-8 were decreased in both in vivo and in
vitro studies. Wischmeyer et al.[194] have observed a
protective effect of glutamine on intestinal epithelial
cells in vitro by means of heat shock proteins.
11.1.3 In Neutrophils?
One aspect of immune function which merits
further investigation is neutrophil activity. As men-
tioned in section 10.1, recent studies in the author’s
laboratory have established the presence of
glutaminase in human neutrophils.[19] This has pro-
vided support for the observation that increased
oxidative burst occurs following the addition of
glutamine to human neutrophils in vitro. Despite the
considerable increase in circulating numbers of neu-
trophils after strenuous exercise, decreased neutro-
phil function has been observed in both runners and
cyclists. It should be borne in mind that more imma-
Sports Med 2003; 33 (5)
340
ture neutrophils will be recruited in such a situation,
which will not function as well as the mature ones. It
is also of interest that glutamine feeding in athletes
has led to a decrease of IL-8, the chemoattractant for
neutrophils, compared with the placebo group (table
V). A similar observation was made in patients with
acute pancreatitis (see table III).
12. Conclusions
Feeding of single amino acids may cause imbal-
ance of others.[195] Indeed, commonsense dictates
that a sensible proportion of mixed ingredients con-
stitutes the best type of nutrition. Nevertheless, there
is a powerful biochemical argument in favour of the
repletion of some nutrients, certainly during long-
term depletion, and often during transient depletion,
in a variety of situations.
The word ‘supplement’ is defined as “something
added to supply a deficiency” (Oxford English Dic-
tionary, 2001). Supplementation can therefore be
described as supplying that which is wanting. How-
ever, the interpretation of supplementation by some
frequently implies that beneficial effects can be de-
rived by taking additional amounts of a compound
without the knowledge that it actually becomes defi-
cient, or (more worryingly) when it is in fact already
present in abundance. In the latter case, taking what
is in effect an overdose might actually cause delete-
rious effects.[159] Glutamine supplementation may
be most effective when given to restore glutamine to
physiological levels at a time of depletion due to
stress, for example, after prolonged exercise. The
provision of glutamine at a time when the level is
not decreased, or is elevated (as in the early stages of
exercise) might even give rise to an inhibitory action
which affects the production of cytokines and/or the
ability of cells to function maximally. Timing of
both supplementation and samples to monitor plas-
ma concentration is clearly important. Achieving the
correct balance may be another key factor. For ex-
ample, some of the bactericidal agents produced by
neutrophils are also toxic to host cells, and thus
phagocytosis can cause damage to tissues during an
infection. An excessive consumption of glutamine
(or indeed any relevant nutraceutical) might pro-
© Adis Data Information BV 2003. All rights reserved.
Castell
mote too much phagocytosis and thus have harmful,
rather than beneficial, effects.
Clinical studies have clearly indicated that gluta-
mine feeding contributes to the alleviation of infec-
tions and improved gastrointestinal function. A re-
duction in the incidence of infections in endurance
athletes has been attributed to supplementary feed-
ing with glutamine or glutamine precursors. Howev-
er, the situation is not clear with regard to the precise
effect of glutamine on the immune system after
prolonged, exhaustive exercise. It may be that the
transient nature of the immunodepression observed
in this situation is sufficiently short term for the
body to recover rapidly and effectively with ade-
quate nutrition. Nevertheless, undertaking repeated
bouts of exhausting exercise, particularly in close
succession, may lead to a more chronic immu-
nodepression for which glutamine repletion would
prove beneficial.
It is worth remembering that glutamine is the
most abundant and versatile amino acid in the body,
and that in vitro studies have established its role as a
fuel for some important cells of the immune system.
In relation to exercise-induced immunodepression,
there may well be some hitherto unconsidered as-
pect of immune function for which rapid replenish-
ment of glutamine may be essential. In this context,
more detailed research is required into different
aspects of immune function, especially for several
days after an endurance event.
Acknowledgements
There are no conflicts of interest in relation to this review,
and the preparation of it was not funded. The author is
grateful to Professor Philip Calder for reading the manuscript.
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Correspondence and offprints: Linda M. Castell, Nuffield
Department of Anaesthetics, University of Oxford, Rad-
cliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK.
E-mail: lindy.castell@nda.ox.ac.uk
Sports Med 2003; 33 (5)