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Glutamine or glutamic acid effects on intestinal growth and disaccharidase activity in infant
piglets receiving total parenteral nutrition.

Burrin DG; Shulman RJ; Storm MC; Reeds PJ
JPEN J Parenter Enteral Nutr, 1991 May, 15:3, 262-6

This study was designed to measure the effect of free glutamine or glutamic acid
supplementation on small intestinal growth and disaccharidase enzyme activity in 7-day-old
miniature piglets. The piglets received one of three total parenteral nutrition solutions
exclusively for 7 days. All three solutions were isonitrogenous and isocaloric, and glutamine
or glutamic acid was included at physiological levels (5% of the total amino acid content) in
two of the three solutions; the third (control) contained neither glutamine nor glutamic acid.
No differences were seen between groups in plasma glutamine or glutamic acid
concentrations. Similarly, no effect was observed on small intestinal protein or DNA
content or on the specific activities of lactase, sucrase, or maltase. These data demonstrate
that in the healthy miniature piglet, parenteral glutamine or glutamic acid supplemented at
physiological doses does not influence small intestinal growth and development.


Effects of hypothyroidism on glucose and glutamine metabolism by the gut of the rat.

Ardawi MS; Jalalah SM
Clin Sci (Colch), 1991 Sep, 81:3, 347-55

1. The metabolism of glucose and glutamine was studied in the small intestine and the colon
of rats after 4-5 weeks of hypothyroidism. 2. Hypothyroidism resulted in increases in the
plasma concentrations of ketone bodies (P less than 0.05), cholesterol (P less than 0.001)
and urea (P less than 0.001), but decreases in the plasma concentrations of free fatty acids (P
less than 0.05) and triacylglycerol (P less than 0.001). These changes were associated with
decreases in the plasma concentrations of total tri-iodothyronine, free tri-iodothyronine, total
thyroxine and free thyroxine. 3. Hypothyroidism decreased both the DNA content (by
30.5%) and the protein content (by 23.6%) of intestinal mucosa, with the protein/DNA ratio
remaining unchanged. The villi in the jejunum were shorter (P less than 0.05) and the crypt
depth was decreased by about 26.5% in hypothyroid rats. 4. Portal-drained visceral blood
flow showed no marked change in response to hypothyroidism, but was accompanied by
decreased rates of extraction of glucose, lactate and glutamine and release of glutamate,
alanine and ammonia. 5. Enterocytes and colonocytes isolated from hypothyroid rats
showed decreased rates of utilization and metabolism of glucose and glutamine. 6. The
maximal activities of hexokinase (EC, 6-phosphofructokinase (EC,
pyruvate kinase (EC, citrate synthase (EC, oxoglutarate dehydrogenase
(EC and phosphate-dependent glutaminase (EC were decreased in
intestinal mucosal scrapings from hypothyroid rats. Similar decreases were obtained in
colonic mucosal scrapings (except for citrate synthase and oxoglutarate dehydrogenase)
from hypothyroid rats.(Abstract TRUNCATED AT 250 WORDS)


Protection from radiation injury by elemental diet: does added glutamine change the effect?

McArdle AH
Gut, 1994 Jan, 35:1 Suppl, S60-4

The feeding of a protein hydrolysate based 'elemental' diet supplemented with added
glutamine did not provide superior protection to the small intestine of dogs subjected to
therapeutic pelvic irradiation. Comparison of diets with and without the added glutamine
showed significant protection of the intestine from radiation injury. Both histological
examination and electron microscopy showed lack of tissue injury with both diets. The
activity of the free radical generating enzymes, scavengers, and antioxidants were similar in
the intestinal mucosa of dogs fed either diet. After radiation, however, the activity of
xanthine oxidase, superoxide dismutase, and glutathione peroxidase were significantly (p <
0.002) higher in the intestine of dogs fed elemental diet without the added glutamine. If the
activities of these enzymes are important in the protection of the intestine from radiation
injury, then the addition of extra glutamine may provide no benefit.


Inter-organ communication between intestine and liver in vivo and in vitro.

Plauth M; Raible A; Gregor M; Hartmann F
Semin Cell Biol, 1993 Jun, 4:3, 231-7

The maintenance of body homeostasis requires a finely tuned system of interorgan
communication. The intimate metabolic interrelation between intestine and liver is
characterized by the unique anatomic position of both tissues using the portal vein as a
private channel with the pancreas in optimal position to modulate hepatic metabolism.
Gut-derived peptides (such as glucagon-like peptide-1) appear to be involved in the process
of liver regeneration by regulating the release of pancreatic hormones (e.g. insulin).
Extensive bowel resection or functional exclusion of small intestine may lead to severe liver
dysfunction and even cirrhosis, which may be due to the lack of some intestine-derived and
as yet unknown factor(s). Here a close cooperation between small intestinal mucosa and
hepatocytes is demonstrated leading to the concept of a metabolic gut-liver unit. This
metabolic interaction forms a wide spectrum ranging from the secretion of peptide
hormones to changes in (portal-venous) substrate availability or hepatocyte cell volume.
Further investigation and identification of the mechanisms of such regulatory processes may
be facilitated by combined perfusion of isolated rat intestine and liver. Using this in vitro
approach we could demonstrate the presence of metabolic interorgan communication
between isolated perfused tissues independent of plasma borne hormones or extrinsic neural


Characteristics and mechanism of glutamine-dipeptide absorption in human intestine.

Minami H; Morse EL; Adibi SA
Gastroenterology, 1992 Jul, 103:1, 3-11

Using in vivo and in vitro techniques, the mechanism by which intestinal mucosa obtains
glutamine from luminal oligopeptides was investigated in humans. The rate of hydrolysis
by mucosal brush border membrane was more than threefold greater for alanylglutamine
than for glycylglutamine. Despite this difference, rates of dipeptide and amino acid
disappearance during intestinal perfusion were greater from test solutions containing
glycylglutamine than alanylglutamine. Furthermore, rates of intraluminal appearance of
products of hydrolysis during the infusion of two dipeptides were similar and less than 5%
of the disappearance rate of the parent dipeptide. In contrast to free glutamine, uptake of
peptide-bound glutamine by brush border membrane vesicles was not inhibited by deletion
of sodium or addition of free amino acids to the incubation medium but was inhibited by
other oligopeptides and stimulated by a proton gradient. Inhibition constants for the
saturable uptake of glycylglutamine and alanylglutamine by vesicles were not significantly
different, suggesting similar affinities for the peptide transporter. It is concluded that in
human intestine the predominant mechanism for assimilation of glutamine-dipeptides is
absorption as intact dipeptide rather than hydrolysis.


Enteral nutrition as primary therapy in short bowel syndrome.

Booth IW
Gut, 1994 Jan, 35:1 Suppl, S69-72

The spectacular success of parenteral nutrition in supporting patients during small intestinal
adaptation after massive resection, tends to obscure the prolonged periods often needed for
such adaptation to take place. After neonatal small intestinal resection for example, it may
take more than five years before adaptation is complete. There is therefore a strong
argument for examining ways in which adaptation can be facilitated, in particular, by the
addition of novel substrates to enteral feeds. Pectin is completely fermented by colonic
bacteria to short chain fatty acids. In the rat, addition of pectin to enteral feeds led to a more
rapid adaptive response in both the small and large intestine after massive small intestinal
resection, although faecal nitrogen losses were increased. In a similar rat model, the
provision of 40% of non-protein energy as short chain triglycerides facilitated the adaptive
response in the jejunum, colon, and pancreas. The importance of glutamine as a metabolic
substrate for the small intestine makes it another potential candidate and some, but not all
animal studies, have suggested a therapeutic effect: increasing the glutamine content of feeds
to 25% of total amino acids produced enhanced jejunal and ileal hyperplasia, even on a
hypocaloric feed, and an improved overall weight gain. Studies in humans are very limited,
but such promising results in the experimental animal suggest that this is probably a fruitful
area for further study.


Intestinal glutamine metabolism during critical illness: a surgical perspective.

Herskowitz K; Souba WW
Department of Surgery, University of Florida College of Medicine, Gainesville 32610.
Nutrition, 1990 May, 6:3, 199-206

In critically ill surgical patients, various therapeutic maneuvers are required to maintain a
healthy gastrointestinal tract. Provision of adequate amounts of glutamine to the
gastrointestinal mucosa and possibly to the gut-associated lymphatic tissue appears to be
just one of these necessary maneuvers. The concept that the intestine is inactive after surgical
stress merits reconsideration, as the intestinal tract plays a central role in interorgan
glutamine metabolism and is a key regulator of nitrogen handling in this situation. Clinical
studies to examine the benefits of glutamine-enriched nutrition in hospitalized patients are
under way.


Glutamine synthetase: a key enzyme for intestinal epithelial differentiation?

Weiss MD; DeMarco V; Strauss DM; Samuelson DA; Lane ME; Neu J
JPEN J Parenter Enteral Nutr, 1999 May, 23:3, 140-6

BACKGROUND: We have previously shown that glutamine synthetase protein and
mRNA are concentrated in the crypt region of the rat small intestine and that the activity of
this enzyme is highest around the time of weaning. This anatomical location and time of
peak activity are sites and periods of active enterocyte differentiation. This led to our current
hypothesis that glutamine synthetase is important in the differentiation of enterocytes.
METHODS: To test our hypothesis, we treated Caco-2 cells with physiologic (0.6 mM)
glutamine concentrations in cell culture medium. The experimental group was treated with
methionine sulfoximine, an irreversible glutamine synthetase inhibitor, and the control
group with phosphate buffered saline. Three standard and well-defined markers of intestinal
differentiation-sucrase-isomaltase activity, microvillus formation, and electrical impedance
in transwell plates-were compared between the two groups. RESULTS: The
methionine-sulfoximine-inhibited group was found to have lower sucrase-isomaltase
activity, a lower density of microvilli, and lower electrical impedance values over time
compared with the control group. CONCLUSION: The experimental group was found to
be less differentiated by all three markers of differentiation. Therefore, glutamine synthetase
is important for Caco-2 cell differentiation.


Effects of decreased glutamine supply on gut and liver metabolism in vivo in rats.

Heeneman S; Deutz NE
Clin Sci (Colch), 1993 Oct, 85:4, 437-44

1. It has recently been suggested that glutamine may be a conditionally essential nutrient
rather than a non-essential amino acid. Therefore, administration of methionine
sulphoximine was used to create a model of decreased arterial glutamine concentrations for
4 days. Glutamine consumption in portal-drained viscera and liver was measured after an
overnight fast by determining fluxes and intracellular concentrations in normal rats,
methionine sulphoximine-treated rats and pair-fed controls. Moreover, fluxes and
intracellular concentrations of several other amino acids and ammonia and production of
urea by the liver were determined concomitantly. 2. Methionine sulphoximine treatment for
4 days resulted in a 50% decrease in arterial glutamine concentration. Although the
glutamine consumption and the intracellular glutamine concentration of the intestine were
reduced by 50% at day 4, no changes in intestinal amino acid and ammonia metabolism
were observed. 3. In the liver, glutamine consumption was reduced and ammonia uptake
was increased, but urea synthesis was not changed. The decreased intracellular glutamine,
glutamate, aspartate and ammonia concentrations coincided with a substantial reduction in
liver branched-chain amino acid production. 4. These results suggest that reduced intestinal
glutamine uptake does not induce marked changes in intestinal amino acid metabolism. The
decreased liver branched-chain amino acid production suggests a reduction in the net liver
protein degradation rate during methionine sulphoximine treatment.


Glutamine: is it a conditionally required nutrient for the human gastrointestinal system?[see

Buchman AL
J Am Coll Nutr, 1996 Jun, 15:3, 199-205

Glutamine is a nonessential amino acid which 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 parental 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.


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