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Department of Pediatrics and Neonatology, University of Florida, Gainesville, FL 32610
2To whom correspondence should be addressed. E-mail: neuj{at}peds.ufl.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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KEY WORDS: • glutamine • intestine • mechanism • placenta • neonate
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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) published his landmark article in
Science. His work demonstrated that the requirement of cells
for growth in culture relied more on glutamine than on any other amino
acid. Since the studies of Eagle in the 1950s, numerous reports have
established the importance of glutamine for a variety of metabolic
processes in the whole organism and suggest that nutritional
supplementation of this amino acid, under certain circumstances, may be
highly beneficial. The goals of this review are to present basic biochemical and metabolic interactions of glutamine, discuss how glutamine relates to fetal physiology, present some of the key aspects of glutamine as a nutritional supplement for very low birth weight infants, and to speculate on mechanisms of action using studies of the intestinal epithelium as a model.
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Overview of glutamine metabolism |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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). Glutamine, via glutamate, is readily converted to 
-ketoglutarate,
an integral component of the citric acid cycle. As seen in this figure,
several important metabolic products are derived from glutamine.
Deamidation of glutamine via glutaminase produces glutamate, a
precursor of 
-amino butyric acid, a neurotransmission inhibitor.
Proline is also produced by the cyclization of glutamate. Proline is an
important amino acid component of collagen and connective tissue. The
transamination and deamidation of glutamine is involved in ammonia
transfer between various tissues. The transfer of amide nitrogen from
glutamine via the amido transferase reaction is also involved in the
biosynthesis of purines and pyrimidines. The amide group derived from
glutamine is important in the production of hexosamines, which are
vital components for maintaining integrity and function of mucosal
surfaces. The antioxidant glutathione, which protects against free
radical damage, is composed of glutamate, cysteine and glycine.
Glutamate is also a component of polyglutamated folic acid, a cofactor
in many enzymatic processes. Glutamine entrance into the citric acid
cycle via -ketoglutarate is also an important pathway for energy
production and anapleurosis.
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Glutamine in the fetus |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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). There was
no umbilical uptake of glutamate in the sheep fetus. In fact, there was
a net flux of glutamate from the fetus into the placenta. This
indicated that glutamate was formed within the fetus. However, of all
the amino acids transferred from the mother and placenta to the fetus,
the concentration of glutamine was the highest. Several subsequent
studies, all of which were performed in the laboratories of Dr.
Giaccomio Meschia and Fred Battaglia (Battaglia 2000
) at
the University of Colorado, support the existence of a
glutamine-glutamate shuttle illustrated in Figure 2
.
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). In this shuttle, glutamine from
the mother travels to the placenta where augmentation by placental
glutamine synthesis significantly increases the concentration of
glutamine reaching the fetus. In the fetus, glutamine is taken up by
the fetal liver. Battaglia (2000
) estimated that for the
130-d sheep fetus, glutamine from the placenta accounts for 
19% of
the fetal nitrogen uptake. It was further demonstrated that the fetal
liver is the primary site for fetal glutamine uptake and glutamate
production, and, as such, determines the glutamate supply to the
placenta (Battaglia 2000
). More recent work has
demonstrated that a significant fraction of the placental glutamate can
also be derived from transamination of the branched-chain amino
acids to their respective keto-acids (Chung et al. 1998
). Thus, the placental supply of glutamate derives from
both its uptake from the fetal circulation and its production in the
placenta associated with branched chain amino acid
transamination. A significant proportion of the remaining glutamine
that is not metabolized to glutamate in the liver and transported to
the placenta is taken up by the fetal carcass for growth. The large
glutamate output from the fetal liver is similar to the large hepatic
glucose output during postnatal life. However, there is no significant
gluconeogenesis or any significant glucose output from the fetal liver
during normal gestation (Hay et al. 1984
).
Is this glutamine-glutamate shuttle mechanism just an interesting
physiological finding or might it relate to critical physiological
processes or pathology? Recent studies have demonstrated that there are
increasing arterio-venous differences in glutamate in the week
before delivery and after the infusion of dexamethasone (Barbera et al. 1997
). At 25 h after dexamethasone infusion,
release of glutamate from the fetal liver fell to 25% of the
preinfusion levels. This led to a significant fall in fetal plasma
glutamate concentrations and placental glutamate uptake from the fetal
plasma. At the same time, a 60% drop in progesterone output from the
pregnant uterus was evidenced. This dexamethasone-induced drop in
progesterone output confirmed previous findings of Liggins and
colleagues performed in the late 1960s and early 1970s (Liggins 1969
, Liggins et al. 1972
), but added to our knowledge by
demonstrating the role that the glutamine/glutamate pathway plays in
this process. A likely mechanism underlying this was described by
Klimek et al. (1993
), who demonstrated the relationship
between placental mitochondrial NADPH reduction, the malate
dehydrogenase reaction and glutamate concentration in the incubation
medium. A decline in placental glutamate results in a decrease in the
synthesis of NADPH, which is necessary for steroidogenesis. Thus, the
events leading up to parturition are associated with profound changes
in fetal hepatic and placental glutamate and glutamine metabolism that
may relate to altered progesterone biosynthesis and raise the question
of whether disruption of this pathway might play a role in parturition.
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Glutamine as a nutritional supplement |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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Several studies in animals (Fox et al. 1998
, Klimberg et al. 1990
, O’Dwyer et al.1989
, Suzuki et al. l993
, Van der Hulst et al. 1993
, Yoshida et al. 1993
) suggested the possibility that
glutamine supplementation might prove beneficial in critically ill
humans, including very low birth weight neonates. The sudden cessation
of glutamine supply to very premature infants who are highly stressed
and undergoing rapid growth appeared to be potentially detrimental.
There is no glutamine in their total parenteral nutrition and
they are frequently not enterally fed for weeks. In the early 1990s we
hypothesized that glutamine supplementation in very low
birth-weight infants would decrease hospital acquired sepsis. A
randomized-masked pilot trial of 68 low birth-weight infants
receiving glutamine supplementation during their 1st mo of life
demonstrated that 30% of the infants in the control group developed
culture proven sepsis, whereas only 11% in the glutamine supplemented
group developed culture proven sepsis (Neu et al. 1997
).
Along with the drop in sepsis, there was a concurrent blunting of
HLA-DR + lymphocytes and CD 16 + T-lymphocytes, which was
consistent with decreased stimulation of the immune response secondary
to decreased translocation of bacteria or their antigens across mucosal
surfaces. Measurement of plasma amino acids showed that the control
group had a significant elevation in most of the amino acids during the
first two weeks of life. The glutamine-supplemented group
demonstrated a blunting of this elevation in several of the amino
acids, but most significantly in the gluconeogenic amino acids alanine,
glycine, serine and threonine (Roig et al. 1996
). A cost
analysis demonstrated significant cost reduction for the
glutamine-supplemented infants (Dallas et al. 1998
).
Another study of glutamine supplementation supplied by the parenteral
route (Lacey et al. 1996
) demonstrated decreased time
required for mechanical ventilation in the glutamine supplemented
infants weighing < 800 g.
There have also been several studies of glutamine supplementation in
critically ill adults. Ziegler et al. (1992
)
demonstrated decreased hospital acquired sepsis, improved nitrogen
balance and decreased costs of hospitalization (McBurney et al. 1994
) in bone marrow transplant recipients. Griffiths et al.
(1997
) demonstrated decreased mortality and hospital
costs in critically ill adults receiving glutamine-supplemented
total parenteral nutrition. Another study in the same institution using
enteral glutamine supplementation (Jones et al. 1999
)
showed decreased costs of hospitalization. An intriguing study on adult
trauma patients (Houdijk et al. 1998
) showed decreased
pneumonia and sepsis with enteral glutamine supplementation. Concurrent
with the decreased infections was a blunting of the cytokine response
to the injury. The authors speculated that the blunted cytokine
response was secondary to decreased bacterial translocation through
mucosal surfaces, as was speculated in our study in very low birth
weight infants.
The beneficial results of glutamine supplementation seen in these
preliminary studies in infants and adults have prompted two large
multicenter trials in low birth weight infants. The National Institutes
of Health Neonatal Network is conducting a study of glutamine
supplemented by the intravenous route, whereas the Pediatrix Neonatal
group is studying the effects of glutamine supplemented by the enteral
route. As of this writing, there have been 1000 infants
enrolled in these trials. At the conclusion of these studies, we will
know much more about the efficacy and safety of glutamine
supplementation by both the enteral and parenteral route. We may know
whether one route is more effective than the other in very low birth
weight neonates. Although very interesting results might occur from
these studies, very little is likely to be learned about the mechanisms
of action, the understanding of which will be critical if we are to use
this amino acid or its derivatives most effectively.
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Mechanisms of glutamine action |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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It is to be remembered that there is a major difference between
glutamine and glutamate that might provide for significant differences
in activity as either a nutrient or a signaling molecule. This lies
primarily in the amide moiety of glutamine. This amide nitrogen is
critical in the biosynthesis of purines and pyrimidines (Fig. 3
). Glutamine and nucleosides appear to act synergistically in intestinal
epithelial proliferation and differentiation. He et al.
(1994
) demonstrated that when glutamine is in short
supply, cell growth is retarded in two different types of intestinal
epithelial cells (IEC-6 and Caco-2). These effects could be reversed in
both cell types by the addition of nucleosides. The addition of
nucleosides to the glutamine poor medium also prevented the depletion
of ATP pools. These investigators concluded that nucleoside supplements
could enhance the rate of cell proliferation and differentiation as
well as spare the need for glutamine during enterocyte growth and
development. These studies support the strong interplay between
glutamine and nucleosides in the intestinal epithelium.
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). The biosynthesis of glucosamine 6-PO4, the precursor of all
hexosamines, requires the transfer of the amide nitrogen of glutamine
to fructose 6-PO4. Hexosamines, as components of glycoproteins and
amino sugars, are very important in maintaining absorptive (via
glucosylated membrane digestive hydrolases) and gut barrier functions
(via surface mucin and glycoproteins forming intercellular tight
junctions). The fuzzy glycocalyx coat of the villi, consisting of a
family of glycoproteins and proteoglycans (of which hexosamines are
major carbohydrate component), protects intestinal epithelial cells
from autodigestion by luminal enzymes and may protect from bacterial
invasion. The possibility of glutamine-mediated alteration of the
luminal mucus gel is supported by studies of rats nourished with
glutamine-free vs. glutamine dipeptide supplemented total
parenteral nutrition (Khan et al. 1999
). Rats
supplemented with glutamine demonstrated greater thickness and optical
density of mucus gel. A decrease in small intestinal permeability as
measured by fluorescein isothiocyanate-dextran was concomitantly
noted in the glutamine dipeptide supplemented rats.
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), inhibition of endogenous glutamine
synthetase with methionine sulfoximine results in a breakdown of small
intestinal interepithelial junctional integrity as determined by
electrical impedance and transmission electron microscopy. Preliminary
studies also have shown that deprivation of dietary glutamine in an
infant rat artificial feeding model increases bacterial translocation
and that this effect can be exacerbated by inhibiting intestinal
glutamine synthetase by enteral administration of methionine
sulfoximine (Neu et al. 2000
).
Although most studies point to a nutritional mode of
glutamine-mediated effects in the small intestine in terms of
proliferation and epithelial protection, some studies suggest that
these effects are at least partially mediated via cell signaling by
mitogen-activated protein kinases. Rhoads et al.
(1997
) demonstrated significant synergy between
Epidermal Growth Factor and glutamine in the stimulation of these
mitogen-activated protein kinases.
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Glutamine and the cytokine response |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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). With additional validation, we might have an
important modality to ameliorate morbidity in low birth weight infants.
The intestine is the largest immune organ of the body and is a major
organ from which the systemic inflammatory response can be initiated.
Over the past several years, it has become more evident that cytokine
responses as part of an uncontrolled systemic inflammatory response
syndrome play an integral role in premature labor, chronic lung
disease, cerebral palsy, necrotizing enterocolitis and sepsis. Whether
immunomodulatory nutrients such as glutamine play a role in
ameliorating these responses via a mechanism related to the scheme
hypothesized in Figure 5
could be an exciting new area of investigation.
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONOverview of glutamine metabolismGlutamine in the fetusGlutamine as a nutritional...Mechanisms of glutamine actionGlutamine and the cytokine...LITERATURE CITED |
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1. Barbera A., Wilkening R., Battaglia F. C. & Meschia G. (1997) Metabolic alterations in the fetal hepatic and umbilical circulations during glucocorticoid induced parturition in sheep. Pediatr. Res. 41:242-248.[Medline]
2. Battaglia F. C. (2000) Glutamine and glutamate exchange between the fetal liver and the placenta. J. Nutr. 130:974S-977S.
3.
Chung M., Teng C., Timmerman M., Meschia G. & Battaglia F. C. (1998) Production and utilization of amino acids by ovine placenta in vivo. Am. J. Physiol. 274:E13-E22.
4.
Dallas M. J., Bowling D., Roig J. C., Auestad N. & Neu J. (1998) Enteral glutamine supplementation for very-low-birth-weight infants decreases hospital costs. J. Parenter. Enteral Nutr. 22:352-356.
5. DeMarco V., McCain M. D., Strauss D., Chakrabarti R. & Neu J. (1997) Characterization of glutamine synthetase transcript, protein, and enzyme activity in the human placenta. Placenta 18:541-545.[Medline]
6.
Eagle H. (1955) Nutrition needs of mammalian cells in tissue culture. Science 122:501-504.
7. Fox A. D., Kripke S. A., DePaula J., Berman J. M., Settle R. G. & Rombeau J. L. (1998) Effect of a glutamine supplemented enteral diet on metotrexate-induced enterocolitis. J. Parenter. Enteral Nutr. 12:325-331.
8. Griffiths R. D., Jones C. & Palmer T. E. (1997) Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 13:295-302.[Medline]
9.
Hay W. W., Jr, Sparks J. W., Wilkening R. B., Battaglia F. C. & Meschia G. (1984) Fetal glucose uptake and utilization as functions of maternal glucose concentration. Am. J. Physiol. 246:E237-E242.
10. He Y., Sanderson I. R. & Walker W. A. (1994) Uptake, transport and metabolism of exogenous nucleosides in intestinal epithelial cell cultures. J. Nutr. 124:1942-1949.
11. Houdijk A. P., Rijnsburger E. R., Jansen J., Wesdrop R. I., Weiss J. K., McCamish M. A., Teerlink T., Meuwissen S. G., Haarman H. J., Thijs L. G. & Van Leeuwen P. A. (1998) Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 352:772-776.[Medline]
12. Jones C., Palmer T. E. & Griffiths R. D. (1999) Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition 15:108-115.[Medline]
13.
Khan J., Iiboshi Y., Cui L., Wasa M., Sando K., Tagaki Y. & Okada A. (1999) Alanyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine. J. Parenter. Enteral Nutr. 23:24-31.
14.
Klimberg V. S., Salloum R. M., Kaspar M., Plumley D. A., Dolson D. J., Hautamaki R. D., Mendenhall W. R., Bova F. C., Bland K. I. & Copeland E. M. (1990) Oral glutamine accelerates healing of the small intestine and improves outcome following whole abdominal radiation. Arch. Surg. 125:1040-1045.
15. Klimek J., Makarewicz W., Swierczynski J., Bossy-Bukato G. & Zelewski L. (1993) Mitochondrial glutamine and glutamate metabolism in human placenta and its possible link with progesterone biosynthesis. Troph. Res. 7:77-86.
16.
Lacey J. M., Crouch J. B., Benfell K., Ringer S. A., Wilmore C. K., Maguire D. & Wilmore D. W. (1996) The effects of glutamine-supplemented parenteral nutrition in premature infants. J. Parenter. Enteral Nutr. 20:74-80.
17. Lemons J. A., Adcock E. W., III, Jones M. D., Jr, Naughton M. A., Meschia G. & Battaglia F. C. (1976) Umbilical uptake of amino acids in the unstressed fetal lamb. J. Clin. Invest. 58:1428-1434.
18. Liggins G. C. (1969) Premature parturition after infusion of corticotrophin or cortisol into fetal lambs. J. Endocrinol. 45:515-523.
19. Liggins G. C., Grieves S. A., Kendall J. Z. & Knox B. S. (1972) The physiological roles of progesterone, oestradiol-17b and prostaglandin F2a in the control of ovine parturition. J. Reprod. Fert. 16:85-103.
20. McBurney M., Young L. S., Ziegler T. R. & Wilmore D. W. (1994) A cost-evaluation of glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients. J. Am. Diet. Assoc. 94:1263-1266.[Medline]
21. Neu J., DeMarco V. G. & Gulig P. A. (2000) Bacterial translocation is exacerbated by inhibition of glutamine synthetase. Pediatr. Res. 47:293A.
22. Neu J., Roig J. C., Meetze W. H., Veerman M., Carter C., Millsaps M., Bowling D., Dallas M. J., Sleasman J., Knight T. & Auestad N. (1997) Enteral glutamine supplementation for very low birth weight infants decreases morbidity. J. Pediatr. 131:691-699.[Medline]
23.
O’Dwyer S. T., Smith R. J., Hwang T. L. & Wilmore D. W. (1989) Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. J. Parenter. Enteral Nutr. 13:579-585.
24.
Rhoads J. M., Argenzio R. A., Chen W., Rippe R. A., Westwick J. K., Cox A. D., Berschneider H. M. & Brenner D. A. (1997) L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases. Am. J. Physiol. 272:G943-G953.
25. Roig J. C., Meetze W. H., Auestad N., Jasionowski T., Veerman M., McMurray C. A. & Neu J. (1996) Enteral glutamine supplementation for the very low birth weight infant: plasma amino acid concentrations. J. Nutr. 126:1115S-1120S.
26. Suzuki I., Matsumoto Y., Adjei A. A., Asoto L., Shinjo S. & Yamamoto S. (1993) Effect of a glutamine-supplemental diet on response to methicillin-resistant Staphylococcus aureus infection in mice. J. Nutr. Sci. Vitaminol. (Tokyo) 39:405-410.[Medline]
27. Van der Hulst R. R., Van Kreel B. K., Von Meyenfeldt M., Brummer R. J., Arends J. W., Deutz N. E. & Soeters P. B. (1993) Glutamine and the preservation of gut integrity. Lancet 334:1363-1365.
28.
Weiss M. D., DeMarco V., Strauss D. M., Samuelson D. A., Lane M. E. & Neu J. (1999) Glutamine synthetase: a key enzyme for intestinal epithelial differentiation?. J. Parenter. Enteral Nutr. 23:140-146.
29. Yoshida S., Yamasaki K. & Kaibera A. (1993) Glutamine supplementation in septic rats. Nippon Geka Gakki Zasshi 94:1078-1085.
30. Ziegler T. R., Young L. S., Benfell K., Scheltinga M., Hortos K., Bye R., Morrow F. D., Jacobs D. O., Smith R. J. & Antin J. H. (1992) Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation: a randomized, double-blind, controlled study. Ann. Intern. Med. 116:821-828.
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