Glutamine
homologues and derivatives: A limiting factor in current artificial
nutrition?
Nutrition Clinique et Metabolisme (France), 1996, 10/1
(7-17)
Glutamate, aspartate, arginine and glutamine can represent
a third to half of the protein content in food and are the
most amino acids rapidly cleared from plasma after IV administration.
However, their abundance is limited in artificial nutrition.
Along with alpha-ketoglutarate, ornithine, asparagine, oxalo-acetate,
they can be defined as glutamine homologues and derivatives
(GHD). Chemically, they share the same C4 and C5 carbon
skeletons. GHD are biochemically interchangeable, but their
synthesis from other substrates is quantitatively very limited
and costly in energy. Thus, muscular proteolysis becomes
the main source of GHD in the post-operative state. They
play an important role in all processes requiring rapid
cell division: wound healing, preservation of gut integrity,
immune response, and growth in childhood. In addition, they
participate in detoxication and neurotransmission in the
brain. Experimental and clinical data suggest considering
GHD content as a decisive criterion when choosing an amino
acid solution for parenteral nutrition and probably also
for enteral regimens. In human nutrition, they could be
at least as efficient as glutamine, whose presence in parenteral
mixtures is precluded by its poor stability. Enhanced supply
for GHD can be achieved with glutamine dipeptides or ornithine
alpha-ketoglutarate supplementation.
Regulation of protein turnover by glutamine in heat-shocked
skeletal myotubes
Biochimica et Biophysica Acta - Molecular Cell Research
(Netherlands), 1997, 1357/2 (234-242)
Skeletal muscle accounts for approximately one-half of
the protein pool in the whole body. Regulation of protein
turnover in skeletal muscle is critical to protein homeostasis
in the whole body. Glutamine has been suggested to exert
an anabolic effect on protein turnover in skeletal muscle.
In the present work, we characterized the effect of glutamine
on the rates of protein synthesis and degradation in cultured
rat skeletal myotubes under both normal and heat-stress
conditions. We found that glutamine has a stimulatory effect
on the rate of protein synthesis in stressed myotubes (21%,
P < 0.05) but not in normal-cultured myotubes. Glutamine
shows a differential effect on the rate of degradation of
short-lived and long-lived proteins. In both normal-cultured
and stressed myotubes, the half-life of short-lived proteins
was not altered while the half-life of long-lived proteins
increased with increasing concentrations of glutamine in
a concentration-dependent manner. In normal-cultured myotubes,
when glutamine concentration increased from 0 to 15 mM,
the half-life of long-lived proteins increased 35% (P <
0.001) while in stressed myotubes, it increased 27% (P <
0.001). We also found that glutamine can significantly (P
< 0.001) increase the levels of heat-shock protein 70
(HSP70) in stressed myotubes, indicating that HSP70 may
participate in the mechanism underlying the effect of glutamine
on protein turnover. We conclude that in cultured skeletal
myotubes the stimulatory effect of glutamine on the rate
of protein synthesis is condition-dependent, and that the
inhibitory effect of glutamine on the rate of protein degradation
occurs only on long-lived proteins.
Glutamine: From basic science to clinical applications
Nutrition (USA), 1996, 12/11-12 SUPPL. (S68-S70)
Glutamine (Gln) has been one of the most intensively studied
nutrients in the field of nutrition support in recent years.
Interest in provision of Gln derives from animal studies
in models of catabolic stress, primarily in rats. Enteral
or parenteral Gln supplementation improved organ function
and/or survival in most of these investigations. These studies
have also supported the concept that Gln is a critical nutrient
for the gut mucosa and immune cells. Recent molecular and
protein chemistry studies are beginning to define the basic
mechanism involved in Gln action in the gut, liver and other
cells and organs. Double blind prospective clinical investigations
to date suggest that Gln-enriched parenteral or enteral
feedings are generally safe and effective in catabolic patients.
Intravenous Gln (either as the L-amino acid or as Gln-dipeptides)
has been shown to increase plasma Gln levels, exert protein
anabolic effects, improve gut structure and/or function
and reduce important indices of morbidity, including infection
rates and length of hospital stay in selected patients subgroups.
Additional blinded studies of Gln administration in catabolic
patients and increasing clinical experience with Gln-enriched
nutrient products will determine whether routine Gln supplementation
should be given in nutrition support, and to whom. Taken
together, the data obtained over the pastdecade or so of
intensive research on Gln nutrition demonstrate that this
amino acid is an important dietary nutrient and is probably
conditionally essential in humans in certain catabolic conditions.
Effect of glutamine on leucine metabolism in humans
American Journal of Physiology ñ Endocrinology and
Metabolism (USA), 1996, 271/4 34-4 (E748-E754)
The aim of this study was to determine whether the putative
protein anabolic effect of glutamine 1) is mediated by increased
protein synthesis or decreased protein breakdown and 2)
is specific to glutamine. Seven healthy adults were administered
5-h intravenous infusions of L- (1-14C) leucine in the postabsorptive
state while receiving in a randomized order an enteral infusion
of saline on one day or L-glutamine (800 micromol. kg-1.
h-1, equivalent to 0.11 g N/kg) on the other day. Seven
additional subjects were studied using the same protocol
except they received isonitrogenous infusion of glycine.
The rates of leucine appearance (R (a Leu)), an index of
protein degradation, leucine oxidation (Ox (Leu)), and nonoxidative
leucine disposal (NOLD), an index of protein synthesis,
were measured using the 14C specific activity of plasma
alpha-ketoisocaproate and the excretion rate of 14CO2 in
breath. During glutamine infusion, plasma glutamine concentration
doubled (673 plus or minus 66 vs. 1,184 plus or minus 37
microM, P < 0.05), whereas R (a Leu) did not change (122
plus or minus 9 vs. 122 plus or minus 7 micromol . kg-1
. h-1), Ox(Leu) decreased (19 plus or minus 2 vs. 11 plus
or minus 1 micromol kg-1 . h-1, P < 0.01), and NOLD increased
(103 plus or minus 8 vs. 111 plus or minus 6 micromol .
kg-1 . h-1, P < 0.01). During glycine infusion, plasma
glycine increased 14-fold (268 plus or minus 62 vs. 3,806
plus or minus 546 microM, P < 0.01), but, in contrast
to glutamine, R (a Leu) (124 plus or minus 6 vs. 110 plus
or minus 4 micromol . kg- 1 . h-1, P = 0.02), Ox(Leu) (17
plus or minus 1 vs. 14 plus or minus 1 micromol . kg-1 .
h- 1, P = 0.03), and NOLD (106 plus or minus 5 vs. 96 plus
or minus 3 micromol . kg-1 . h-1, P < 0.65) all decreased.
We conclude that glutamine enteral infusion may exert its
protein anabolic effect by increasing protein synthesis,
whereas an isonitrogenous amount of glycine merely decreases
protein turnover with only a small anabolic effect resulting
from a greater decrease in proteolysis than protein synthesis.
Glutamine metabolism and transport in skeletal muscle and
heart and their clinical relevance
Journal of Nutrition (USA), 1996, 126/4 SUPPL. (1142S-1149S)
The glutamine and glutamate transporters in skeletal muscle
and heart appear to play a role in control of the steady-state
concentration of amino acids in the intracellular space
and, in the case of skeletal muscle at least, in the rate
of loss of glutamine to the plasma and to other organs and
tissues. This article reviews what is currently known about
transporter characteristics and mechanisms in skeletal muscle
and heart, the alterations in transport activity in pathophysiological
conditions and the implications for anabolic processes and
cardiac function of altering the availability of glutamine.
The possibilities that glutamine pool size is part of an
osmotic signaling mechanism to regulate whole body protein
metabolism is discussed and evidence is shown from work
on cultured muscle cells. The possible uses of glutamine
in maintaining cardiac function perioperatively and in promoting
glycogen metabolism are discussed.
Glutamine: Effects on the immune system, protein metabolism
and intestinal function
Wiener Klinische Wochenschrift (Austria), 1996, 108/21
(669-676)
Glutamine is the most abundant free amino acid of the human
body. In catabolic stress situations such as after operations,
trauma and during sepsis the enhanced transport of glutamine
to splanchnic organs and to blood cells results in an intracellular
depletion of glutamine in skeletal muscle. Glutamine is
an important metabolic substrate for cells cultivated under
in vitro conditions and is a precursor for purines, pyrimidines
and phospholipids. Increasing evidence suggests that glutamine
is a crucial substrate for immunocompetent cells. Glutamine
depletion in the cultivation medium decreases the mitogen-inducible
proliferation of lymphocytes, possibly by arresting the
cells in the G0-G1 phase of the cell cycle. Glutamine depletion
in lymphocytes prevents the formation of signals necessary
for late activation. In monocytes glutamine deprivation
downregulates surface antigens responsible for antigen preservation
and phagocytosis. Glutamine is a precursor for the synthesis
of glutathionine and stimulates the formation of heat-shock
proteins. Moreover, there are suggestions that glutamine
plays a crucial role in osmotic regulation of cell volume
and causes phosphorylation of proteins, both of which may
stimulate intracellular protein synthesis. Experimental
studies revealed that glutamine deficiency causes a necrotising
enterocolitis and increases the mortality of animals subjected
to bacterial stress. First clinical studies have demonstrated
a decrease in the incidence of infections and a shortening
of the hospital stay in patients after bone marrow transplantation
by supplementation with glutamine. In critically ill patients
parenteral glutamine reduced nitrogen loss and caused a
reduction of the mortality rate. In surgical patients glutamine
evoked an improvement of several immunological parameters.
Moreover, glutamine exerted a trophic effect on the intestinal
mucosa, decreased the intestinal permeability and thus may
prevent the translocation of bacteria. In conclusion, glutamine
is an important metabolic substrate of rapidly proliferating
cells, influences the cellular Hydration State and has multiple
effects on the immune system, on intestinal function and
on protein metabolism. In several disease states glutamine
may consequently, become an in dispensable nutrient, which
should be provided exogenously during artificial nutrition.
The emerging role of glutamine as an indicator of exercise
stress and overtraining
Sports Medicine (New Zealand), 1996, 21/2 (80-97)
Glutamine is an amino acid essential for many important
homeostatic functions and for the optimal functioning of
a number of tissues in the body, particularly the immune
system and the gut. However, during various catabolic states,
such as infection, surgery, trauma and acidosis, glutamine
homeostasis is placed under stress, and glutamine reserves,
particularly in the skeletal muscle, are depleted. With
regard to glutamine metabolism, exercise stress may be viewed
in a similar light to other catabolic stresses. Plasma glutamine
responses to both prolonged and high intensity exercises
are characterised by increased levels during exercise followed
by significant decreases during the post-exercise recovery
period, with several hours of recovery required for restoration
of pre-exercise levels, depending on the intensity and duration
of exercise. If recovery between exercise bouts is inadequate,
the acute effects of exercise on plasma glutamine level
may be cumulative, since overload training has been shown
to result in low plasma glutamine levels requiring prolonged
recovery. Athletes suffering from the overtraining syndrome
(OTS) appear to maintain low plasma glutamine levels for
months or years. All these observations have important implications
for organ functions in these athletes, particularly with
regard to the gut and the cells of the immune system, which
may be adversely affected. In conclusion, if methodological
issues are carefully considered, plasma glutamine level
may be useful as an indicator of an overtrained state.
The role of glutamine in nutrition in clinical practice
Arq Gastroenterol (BRAZIL) Apr-Jun 1996, 33 (2) p86-92
Nutritional therapy using nutrients with pharmacological
properties has been intensively discussed in the recent
literature. Among these nutrients, glutamine has gained
special attention. Glutamine is the most abundant amino
acid in the blood stream of the mammals and, besides it
has been considered a non-essential amino acid, glutamine
is a non-dispensable nutrient in catabolic states. In this
situation, there are alterations in its inter-organic flux,
leading to lower plasmatic concentrations. Glutamine is
the main fuel to enterocytes and it has an important role
in the maintenance of intestinal structure and functions.
Moreover, supplementation with glutamine has proved to be
beneficial to the immunological system functions, improves
nitrogen balance and nutritional parameters in the post-operative
period and lessens protein loss in severe catabolic states.
For these reasons, glutamine enriched-diets must be considered
in the nutritional support of many diseases; new controlled,
prospective and randomized studies will help to define what
group of patients can really benefit from glutamine supplementation.
(47 Refs.)
The metabolic role of glutamine
Minerva Gastroenterol Dietol (ITALY) Mar 1996, 42 (1) p17-26
Glutamine is a non-essential amino acid. Nevertheless it
has to be considered a "conditionally essential"
amino acid for several metabolic reactions in which it is
involved. Glutamine is the most abundant amino acid in human
plasma and muscle. Because glutamine is highly unsteady,
it was never used for enteral and parenteral nutrition in
the past. It appears to be a unique amino acid for rapidly
proliferating cells serving as a preferred fuel compared
to glucose. It seems to be essential for cellular replication
such as a "nitrogen carrier" between the tissues.
A deficiency state of glutamine causes morphology and functional
changing and negative nitrogen metabolism. The need for
glutamine is particularly high when metabolism is increased
as in the critically ill (surgical stress, sepsis, inflammatory
states, fasten, burns) especially in the tissues with a
rapid cell turn-over. In these conditions the body requirements
of glutamine appear to exceed the individual's muscle deposits
(muscle is the most important place of synthesis and storage),
causing an increased synthesis with a high-energy waste
and loss of muscle mass. Glutamine is essential for bowel
mucosa trophism and its deficiency in all the catabolic
states allows bacterial translocation. In these cases feeding
is not sufficient to restore basal conditions. At present
enteral or parenteral glutamine supplementations are of
high interest for the feeding of critically ill patients.
(96 Refs.)
Glutamine and arginine metabolism in tumor bearing rats
receiving total parenteral nutrition
Metabolism: Clinical and Experimental (USA), 1997, 46/4
(370-373)
Arginine supplementation increases glutamine levels in
muscle and plasma. Since glutamine production is increased
in catabolic states, these observations prompted us to investigate
whether the flux of arginine to glutamine was increased
in tumor-bearing (TB) rats, and we measured the synthesis
rate of glutamine from arginine in control versus TB rats
receiving standard total parenteral nutrition (TPN) solution.
Male Donryu rats (N = 36; body weight, 200 to 225 g) were
divided into two groups, control and TB rats. Yoshida sarcoma
cells (1 x 106) were inoculated into the back of the rats
(n = 18) subcutaneously on day 0. The rats were given free
access to water and rat chow. On day 5, all animals, including
non-TB rats (n = 18), were catheterized at the jugular vein
and TPN was begun. On day 10, TPN solution containing either
U-14C-glutamine (2.0 microCi/h) or U-14C-arginine (2.0 microCi/h)
was infused as a 6-hour constant infusion. At the end of
the isotope infusion, plasma was collected to determine
the glutamine production rate in rats receiving U-14C-glutamine,
and the ratio of specific activity of glutamine to specific
activity of arginine was measured in rats receiving U- 14C-arginine.
Only 2 g tumor caused a decrease in glutamine levels and
an increase in glutamine and arginine production. The low
flux rate of arginine to glutamine was observed in control
rats (Arg to Gln, 41.0 plus or minus 11.9 micromol/kg/h).
On the other hand, TB caused a significant increase in Arg
to Gln compared with the control (213.3 plus or minus 66.1
micromol/kg/h, P < .01 v control). An increase in the
flux rate of Arg to Gln was associated with an enhancement
in the ratio of specific activity of ornithine to specific
activity of arginine in TB rats (control 51.5% plus or minus
10.9% v 77.4% plus or minus 8.9%, P < .05). We conclude
that (1) glutamine and arginine metabolism is altered with
very small tumors, (2) although the flux of Arg to Gln was
increased in TB and rats, the small increase in Arg to Gln
cannot explain the observed large increase in Gln production.
Dietary modulation of amino acid transport in rat and human
liver
Journal of Surgical Research (USA), 1996, 63/1 (263-268)
Specialized diets enriched in the amino acids glutamine
and arginine have been shown to benefit surgical patients.
In the liver, glutamine supports glutathione biosynthesis,
arginine regulates nitric oxide synthesis, and both of these
amino acids serve as precursors for ureagenesis, gluconeogenesis,
and acute phase protein synthesis. The effects of a diet
enriched with glutamine and arginine on hepatic plasma membrane
transport activity have not been studied in humans. We hypothesized
that feeding supradietary amounts of these nutrients would
enhance the activities of the specific carriers that mediate
their transmembrane transport in the liver. We fed surgical
patients (n = 8) and rats (n = 6) one of three diets: a)
a regular diet, b) an enteral liquid diet containing arginine
and glutamine, or c) an enteral diet supplemented with pharmacologic
amounts of glutamine and arginine. Diets were isocaloric
and were administered for 3 days. Hepatic plasma membrane
vesicles were prepared from rat liver and from human wedge
biopsies obtained at laparotomy. The transport of glutamine
and arginine by rat and human vesicles was assayed. Vesicle
integrity and functionality were verified by osmolarity
plots, enzyme marker enrichments, and time courses. Provision
of both a standard enteral liquid diet and one enriched
with glutamine and arginine increased the activities of
Systems N (glutamine) and y' (arginine) in rat and human
liver compared to a control diet. The diet supplemented
with glutamine and arginine was the most effective in increasing
transport activity. We conclude that the liver responds
to diets enriched with specific amino acids by increasing
membrane transport activity. This adaptive response provides
essential precursors for hepatocytes that may enhance hepatic
synthetic functions during catabolic states. This study
provides insights into the mechanisms by which enteral nutrition
regulates nutrient transport at the cellular level and may
provide a biochemical rationale for the use of formulas
that are enriched with conditionally essential nutrients.
Development of an intravenous glutamine supply through
dipeptide technology
Nutrition (USA), 1996, 12/11-12 SUPPL. (S76-S77)
Glutamine is considered as semi-essential amino acid during
catabolic stress. Due to its chemical instability in aqueous
solutions during heat sterilization and long term storage,
it could not be added to infusion solutions so far. In contrast,
the dipeptide glycl-L-glutamine exhibits all properties
needed for use as glutamine derivative in parenteral nutrition.
It is freely soluble in water and does not decompose during
heat sterilization. The peptide undergoes rapid enzymatic
hydrolysis after infusion. This results in perfect utilization.
Glycyl-L-glutamine is already produced in large amounts
by chemical synthesis techniques. Both chemical and optical
purity of the dipeptide can be controlled by modem chromatographic
methods. Glamin, a newly developed complete amino acid solution,
contains 20 g of glutamine per liter in form of glycyl-L-glutamine.
Since no additional free glycine is added, no imbalances
are created by the amino-terminal amino acid of the peptide
structure.
Alanyl-glutamine prevents muscle atrophy and glutamine
synthetase induction by glucocorticoids
American Journal of Physiology ñ Regulatory Integrative
and Comparative Physiology (USA), 1996, 271/5 40-5 (R1165-R1172)
The aims of this work were to establish whether glutamine
infusion via alanyl-glutamine dipeptide provides effective
therapy against muscle atrophy from glucocorticoids and
whether the glucocorticoid induction of glutamine synthetase
(GS) is downregulated by dipeptide supplementation. Rats
were given hydrocortisone 21-acetate or the dosing vehicle
and were infused with alanyl-alanine (AA) or alanyl-glutamine
(AG) at the same concentrations and rates (1.15 micromol
. min-1 . 100 g body wt-1, 0.75 ml/h) for 7 days. Compared
with AA infusion in hormone-treated animals, AG infusion
prevented total body and fast-twitch muscle mass losses
by over 70%. Glucocorticoid treatment did not reduce muscle
glutamine levels. Higher serum glutamine was found in the
AG-infused (1.72 plus or minus 0.28 micromol/ml) compared
with the AA-infused group (1.32 plus or minus 0.06 micromol/ml),
but muscle glutamine concentrations were not elevated by
AG infusion. Following glucocorticoid injections, GS enzyme
activity was increased by two- to threefold in plantaris,
fast-twitch white (superficial quadriceps), and fast-twitch
red (deep quadriceps) muscle/fiber types of the AA group.
Similarly, GS mRNA was elevated by 3.3- to 4.1-fold in these
same muscles of hormone-treated, AA-infused rats. AG infusion
diminished glucocorticoid effects on GS enzyme activity
to 52-65% and on GS mRNA to 31-37% of the values with AA
infusion. These results provide firsthand evidence of atrophy
prevention from a catabolic state using glutamine in dipeptide
form. Despite higher serum and muscle alanine levels with
AA infusion than with AG infusion, alanine alone is not
a sufficient stimulus to counteract muscle atrophy. The
AG-induced muscle sparing is accompanied by diminished expression
of a glucocorticoid-inducible gene in skeletal muscle. However,
glutamine regulation of GS appears complex and may involve
more regulators than muscle glutamine concentration alone.
Tissue-specific regulation of glutamine synthetase gene
expression in acute pancreatitis is confirmed by using interleukin-1
receptor knockout mice
Surgery (USA), 1996, 120/2 (255-264)
Background. Acute pancreatitis causes a pronounced depletion
of plasma and muscle glutamine pools. In several other catabolic
disease states expression of the enzyme glutamine synthetase
(GS) is induced in lung and muscle to support glutamine
secretion by these organs. The hormonal mediators of GS
induction have not been conclusively identified. We used
mice deficient for the expression of the type 1 interleukin-1
receptor (IL-1R1 knockout mice) to investigate the expression
of GS during acute edematous pancreatitis.
Methods. Acute edematous pancreatitis ways induced in adult
male wild type and IL-1R1 knockout mice by means of the
intraperitoneal administration of cerulein, and their conditions
were monitored. Five organs, including lung, liver, gastrocnemius
muscle, spleen, and pancreas, were assayed for relative
GS messenger RNA (mRNA) content by Northern blotting. Results.
The ultimate severity of pancreatitis was reduced by IL-1R1
deficiency. GS mRNA levels increased during progression
of pancreatitis in lung, spleen, and muscle tissue from
each group. No consistent increase in GS mRNA level was
observed in liver. IL-1R1 deficiency did not affect GS mRNA
expression in lung tissue but consistently retarded GS induction
in the spleens of knockout animals. IL-1R deficiency altered
the kinetics of GS induction in muscle.
Conclusions. Cerulein-induced experimental pancreatitis
causes an induction in GS mRNA levels in a tissue-specific
fashion. IL-1R1 deficiency reduced the ultimate severity
of the condition and altered the induction of GS mRNA in
the spleen and muscle.
Glutamine content of protein and peptide-based enteral
products
Journal of Parenteral and Enteral Nutrition (USA), 1996,
20/4 (292-295)
Background: Glutamine is a conditionally essential amino
acid for patients with severe catabolic illness, intestinal
dysfunction, or immunodeficiency syndromes.
Glutamine is a natural component in many enteral preparations,
yet lacking methodology hampers its quantitative determination
in dietary products. Objective: The present study was assigned
to assess glutamine contents in selected enteral products
by using a newly developed method enabling the assessment
of protein/peptide bound glutamine.
Methods: Fourteen commercially available enteral diets
(10-protein based and 4 peptide based) were investigated.
After removal of interfering fat and carbohydrates, the
nitrogen content of the purified preparations was determined
by chemiluminescence and protein/peptide bound glutamine
was assessed using a three-step procedure; by using a novel
prehydrolysis derivatization technique with bis (1,1-trifluoroacetoxy)
iodobe nzene, glutamine is converted to acid stable diaminobutyric
acid. The derivatives are hydrolyzed with a new microwave
technology, and subsequently the amino acid composition
is determined by reversed phase-high-performance liquid
chromatography after dansyl-chloride derivatization.
Results: The content in the protein-based preparations
varied between 5.2 and 8.1
g/16 g nitrogen. In the peptide- based products, considerably
lower glutamine contents were measured (1.3 to 5.6 g/16
g nitrogen). Conclusion: In the present study, we report
for the first time glutamine contents in ready to use enteral
products. The dally amount might be satisfactory for healthy
individuals but probably not sufficient for the adequate
support of the stressed patient. Reliable assessment of
glutamine in enteral formulae is a prerequisite to perform
clinical studies investigating glutamine requirements in
the catabolic state.
Metabolic adaptation of terminal ileal mucosa after construction
of an ileoanal pouch
Chapman M.A.S.; Hutton M.; Grahn M.F.; Williams N.S.
United Kingdom British Journal of Surgery (United Kingdom),
1997, 84/1 (71-73)
Background - The major nutrients for the large bowel and
small bowel mucosa are, respectively, butyrate and glutamine.
The degree of mucosal adaptation that may occur in response
to changes in nutrient supply and faecal stasis after the
formation of an ileoanal pouch is poorly understood. Method
- The ability of ileal mucosal biopsies, from nine patients
with ulcerative colitis and from 18 with an ileoanal pouch,
to oxidize (14C)-glucose, glutamine and butyrate to carbon
dioxide was quantified. Results - Glucose, glutamine and
butyrate were oxidized respectively at a median of 12.5
(95 per cent confidence interval (4-22), 77 (34-207) and
194 (81-321) pmol microg-1 h-1 by ileal mucosa and 12.9
(6-21), 35 (11-57) and 194 (73-737) pmol microg-1 h-1 by
pouch mucosa. Conclusion - Ileoanal pouch construction and
subsequent bacterial colonization and faecal stasis resulted
in a significant (P < 0.05) reduction in the mucosal
ability to oxidize glutamine whereas there was no difference
in the rate of butyrate oxidation.
Nutrition and gastrointestinal disease
O'Keefe S.J.D. Gastrointestinal Clinic, Groote Schuur Hospital,
Observatory 7925, Cape Town, South Africa. Scandinavian
Journal of Gastroenterology, Supplement (Norway), 1996,
31/220 (52-59)
Nutrition and intestinal function are intimately interrelated.
The chief purpose of the gut is to digest and absorb nutrients
in order to maintain life. Consequently, chronic gastrointestinal
(GI) disease commonly results in malnutrition and increased
morbidity and mortality. For example, studies have shown
that 50-70% of adult patients with Crohn's disease were
weight-depleted and 75% of adolescents growth-retarded.
On the other hand, chronic malnutrition impairs digestive
and absorptive function because food and nutrients are not
only the major trophic factors to the gut but also provide
the building blocks for digestive enzymes and absorptive
cells. For example, recent studies of ours have shown that
a weight loss of greater than 30% accompanying a variety
of diseases was associated with a reduction in pancreatic
enzyme secretion of over 80%, villus atrophy and impaired
carbohydrate and fat absorption. Finally, specific nutrients
can induce disease, for example, gluten-sensitive enteropathy,
whilst dietary factors such as fibre, resistant starch,
short-chain fatty acids, glutamine and fish oils may prevent
gastrointestinal diseases such as diverticulitis, diversion
colitis, ulcerative colitis, colonic adenomatosis and colonic
carcinoma. The role of dietary antigens in the aetiology
of Crohn's disease is controversial, but controlled studies
have suggested that elemental diets may be as effective
as corticosteroids in inducing a remission in patients with
acute Crohn's disease. In conclusion, nutrition has both
a supportive and therapeutic role in the management of chronic
gastrointestinal diseases. With the development of modern
techniques of nutritional support, the morbidity and mortality
associated with chronic
GI disease can be reduced. On the other hand, dietary manipulation
may be used to treat or prevent specific GI disorders such
as coeliac disease, functional bowel disease, Crohn's disease
and colonic neoplasia. The future development of nutria-pharmaceuticals
is particularly attractive in view of their low cost and
wide safety margins.
Efficacy of glutamine-enriched enteral nutrition in an
experimental model of mucosal ulcerative colitis
Fujita T.; Sakurai K. First Department of Surgery, Jikei
University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku,
Tokyo 105 Japan British Journal of Surgery (United Kingdom),
1995, 82/6 (749-751)
Intact intestinal epithelium and associated lymphatic tissue
act as body defences against luminal toxins. This barrier
may become threatened or compromised in inflammatory bowel
disease, leading to an increase in mucosal permeability
and subsequent translocation of endotoxins. The effect of
oral glutamine on gut mucosal ornithine decarboxylase activity
and on endotoxin levels in portal vein blood was studied
in a guinea-pig model of carrageenan- induced colitis. Despite
failure to show induction of ornithine decarboxylase activity
by glutamine administration, the mean endotoxin level of
portal vein blood in guinea-pigs fed a glutamine-enriched
elemental diet was 25.3 pg/ml compared with 71.2 pg/ml in
animals given a standard elemental diet (P<0.01). A glutamine-enriched
elemental diet may be therapeutically beneficial in patients
with inflammatory bowel disease.
Ileal and colonic epithelial metabolism in quiescent ulcerative
colitis: Increased glutamine metabolism in distal colon
but no defect in butyrate metabolism
Finnie I.A.; Taylor B.A.; Rhodes J.M.
Department of Medicine, University of Liverpool, PO Box
147, Liverpool L69 3BX United Kingdom GUT (United Kingdom),
1993, 34/11 (1552-1558)
Previous studies have shown that butyrate is an important
energy source for the distal colon, and that its metabolism
may be defective in ulcerative colitis (UC). A similar metabolic
defect in the ileum might account for the occurrence of
'pouchitis' in UC patients after colectomy. A method has
been developed that allows the measurement of metabolism
in ileocolonoscopic biopsy specimens, and this has been
used to assess butyrate and glutamine metabolism in quiescent
UC and controls. Preliminary experiments showed optimal
metabolism of butyrate at 1 mmol/l. In controls glutamine
metabolism was greater in the ascending (mean (SD)) (4.9
(3.2) nmol/h/microg protein) than in the descending colon
(1.4 (0.7)) (p < 0.05, Mann-Whitney U test), but butyrate
metabolism was similar in the two regions (ascending 62.6
(44.2), descending 51.5 (32.0)). Consequently ratios of
butyrate/glutamine metabolism were higher in the descending
colon (20.6 (14.3)) than in the ascending colon (14.3 (9.6))
(p < 0.05). In UC, rates of butyrate metabolism were
similar in the ascending (92.5 (58.3) nmol/h/microg protein)
and descending (93.3 (115)) colon, and these were not significantly
different from controls. In UC, glutamine metabolism was
similar in the ascending (6.2 (7.7) nmol/h/microg protein)
and descending colon (7.8 (7.9)); the metabolism in the
descending colon was significantly greater than in controls
(p < 0.01). Butyrate (135 (56) nmol/h/microg protein)
and glutamine (24.1 (16.2)) metabolism in the ileum in UC,
were not significantly different from control values (butyrate
111 (57), glutamine 15.5 (15.6)). These results confirm
that there is regional variation of nutrient utilisation
throughout the colon, but they do not support the hypothesis
that UC is caused by a deficiency of butyrate metabolism.
Glutamine: Is it a conditionally required nutrient for
the human gastrointestinal system?
Journal of the American College of Nutrition (USA), 1996,
15/3 (199-205)
Glutamine is a nonessential amino acid that can be synthesized
from glutamate and glutamic acid by glutamine synthetase.
It is the preferred fuel for the rat small intestine. Animal
studies have suggested both glutamine- supplemented parenteral
nutrition and enteral diets may prevent bacterial translocation.
This effect is thought to be modulated via the preservation
and augmentation of small bowel villus morphology, intestinal
permeability and intestinal immune function. The existing
data are less compelling in humans. It remains unclear what,
if any, intestinal deficits actually occur in humans during
provision of exclusive parenteral nutrition. Furthermore,
the clinical significance of these changes is largely undefined
in humans. The existing data on the use of parenteral and
enteral glutamine for the purpose of preserving intestinal
morphology and function, and the prevention of bacterial
translocation in humans are reviewed. Pertinent animal data
are also described.
Induction of muscle glutamine synthetase gene expression
during endotoxemia is adrenal gland dependent. (1)
Shock (UNITED STATES) May 1997, 7 (5) p332-8
Skeletal muscle plays a crucial role in maintaining nitrogen
homeostasis during health and critical illness by exporting
glutamine, the most abundant amino acid in the blood. We
hypothesized that induction of glutamine synthetase (GS)
expression, the principal enzyme of de novo glutamine biosynthesis,
in skeletal muscle after endotoxin administration was adrenal
gland dependent. We studied the expression of GS in normal
and adrenalectomized rats after intraperitoneal administration
of Escherichia coli lipopolysaccharide (LPS). Treatment
of normal rats with LPS resulted in a marked increase in
GS mRNA that was dose and time dependent, and preceded the
increase in GS protein and specific activity. The increase
in muscle GS mRNA observed in normal rats in response to
LPS was abrogated in adrenalectomized rats at 3 h after
high dose LPS treatment and markedly attenuated at 5.5 h
after low dose LPS treatment. These and other studies implicate
glucocorticoid hormones as a key, but not exclusive, regulator
of skeletal muscle GS expression after a catabolic insult.
Induction of muscle glutamine synthetase gene expression
during endotoxemia is adrenal gland dependent. (2)
Ann Surg (UNITED STATES) Apr 1997, 225 (4) p391-400
OBJECTIVE: The objective of this study was to investigate
the role of gut-derived endotoxemia in postoperative glutamine
(GLN) metabolism of bile duct-ligated rats.
SUMMARY BACKGROUND DATA: Postoperative complications in
patients with obstructive jaundice are associated with gut-derived
endotoxemia. In experimental endotoxemia, catabolic changes
in GLN metabolism have been reported. Glutamine balance
is considered important in preventing postsurgical complications.
METHODS: Male Wistar rats were treated orally with the
endotoxin binder cholestyramine (n = 24, 150 mg/day) or
saline (n = 24). On day 7, groups received a SHAM operation
or a bile duct ligation (BDL). On day 21, all rats were
subjected to a laparotomy followed 24 hours later by blood
flow measurements and blood sampling. Glutamine organ handling
was determined for the gut, liver, and one hindlimb. Intracellular
GLN muscle concentrations were determined.
RESULTS: Compared to the SHAM groups, BDL rats showed lower
gut uptake of GLN (28%, p < 0.05); a reversal of liver
GLN release to an uptake (p < 0.05); higher GLN release
from the hindlimb (p < 0.05); and lower intracellular
muscle GLN concentration (32%, p < 0.05). Cholestyramine
treatment in BDL rats maintained GLN organ handling and
muscle GLN concentrations at SHAM levels. CONCLUSIONS: Disturbances
in postoperative GLN metabolism in BDL rats can be prevented
by gut endotoxin restriction. Gut-derived endotoxemia after
surgery in obstructive jaundice dictates GLN metabolism.
Butyrate metabolism in the terminal ileal mucosa of patients
with ulcerative colitis
Chapman M.A.S.; Grahn M.F.; Hutton M.; Williams N.S.
Department of Surgery, University Hospital, Queen's Medical
Centre, Nottingham NG7 2UH United Kingdom British Journal
of Surgery (United Kingdom), 1995, 82/1 (36-38)
The rate of oxidation of butyrate, glutamine and glucose
was investigated in terminal ileal mucosal biopsy samples
from nine patients with ulcerative colitis undergoing restorative
proctocolectomy and from 12 patients undergoing laparotomy
for reasons other than ulcerative colitis. Substrate oxidation
was assayed using a radiolabelled isotope technique. Butyrate
was the preferred fuel substrate, followed by glutamine
and then glucose (median (95 per cent confidence interval)
567 (262-894), 63 (35-123) and 8.1 (5.1-18) pmol microg-1
h-1 respectively; P < 0.01, Mann-Whitney U test) in normal
terminal ileal mucosa. The patients with ulcerative colitis
had a significantly reduced rate of butyrate oxidation compared
with the control group (194 (81-321) versus 567 (262-894)
pmol microg-1 h-1 P < 0.05). Normal terminal ileal mucosa
oxidized butyrate in greater quantities than glucose and
glutamine. Ulcerative colitic terminal ileal mucosa exhibited
an impaired rate of butyrate oxidation.
The colonic epithelium in ulcerative colitis: An energy-deficiency
disease?
Roediger W.E.W. Nuffield Dept. Surg., Radcliffe Infirm,
Univ. Oxford UNITED KINGDOM LANCET (ENGLAND), 1980, 2/8197
(712-715)
Suspensions of colonocytes (isolated colonic epithelial
cells) were prepared from mucosa of the descending colon
from 6 patients with quiescent ulcerative colitis (UC),
4 with acute UC, and 7 control subjects. In each group metabolic
performance was investigated by assessing utilization of
n-butyrate, the main respiratory fuel of the colonic mucosa,
as well as utilization of glucose and glutamine. In both
acute and quiescent UC oxidation of butyrate to COsub 2
and ketones was significantly lower than in the control
tissues and the decrease correlated with the state of the
disease. Enhanced glucose and glutamine oxidation compensated
for decreased butyrate oxidation in UC, indicating that
colonocytes in colitis were not metabolically degenerate
cells. Failure of butyrate oxidation reflects a variable
yet definite metabolic deficit in the mucosa in UC. Diminished
oxidation of butyrate can explain the characteristic distribution
of colitis along the colon, especially the frequency of
UC in the distal colon. It is suggested that failure of
fatty-acid (n-butyrate) oxidation in UC is an expression
of an energy-deficiency disease of the colonic mucosa.