L-Glutamine 500 Grams

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GLUTAMINE 

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 areenriched 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. 

Title 
Glutamine or glutamic acid effects on intestinal growth and disaccharidase activity in infant piglets receiving total parenteral nutrition. 
Author 
Burrin DG; Shulman RJ; Storm MC; Reeds PJ 
Source 
JPEN J Parenter Enteral Nutr, 1991 May, 15:3, 262-6 
Abstract 
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. 

Title 
Effects of hypothyroidism on glucose and glutamine metabolism by the gut of the rat. 
Author 
Ardawi MS; Jalalah SM 
Source 
Clin Sci (Colch), 1991 Sep, 81:3, 347-55 
Abstract 
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 2.7.1.1), 6-phosphofructokinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40), citrate synthase (EC 4.1.3.28), oxoglutarate dehydrogenase (EC 1.2.4.2) and phosphate-dependent glutaminase (EC 3.5.1.2) 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) 

Title 
Protection from radiation injury by elemental diet: does added glutamine change the effect? 
Author 
McArdle AH 
Source 
Gut, 1994 Jan, 35:1 Suppl, S60-4 
Abstract 
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. 

Title 
Inter-organ communication between intestine and liver in vivo and in vitro. 
Author 
Plauth M; Raible A; Gregor M; Hartmann F 
Source 
Semin Cell Biol, 1993 Jun, 4:3, 231-7 
Abstract 
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 control. 

Title 
Characteristics and mechanism of glutamine-dipeptide absorption in human intestine. 
Author 
Minami H; Morse EL; Adibi SA 
Source 
Gastroenterology, 1992 Jul, 103:1, 3-11 
Abstract 
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. 

Title 
Enteral nutrition as primary therapy in short bowel syndrome. 
Author 
Booth IW 
Source 
Gut, 1994 Jan, 35:1 Suppl, S69-72 
Abstract 
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. 

Title 
Intestinal glutamine metabolism during critical illness: a surgical perspective. 
Author 
Herskowitz K; Souba WW 
Address
Department of Surgery, University of Florida College of Medicine, Gainesville 32610. 
Source 
Nutrition, 1990 May, 6:3, 199-206 
Abstract 
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. 

Title 
Glutamine synthetase: a key enzyme for intestinal epithelial differentiation? 
Author 
Weiss MD; DeMarco V; Strauss DM; Samuelson DA; Lane ME; Neu J 
Source 
JPEN J Parenter Enteral Nutr, 1999 May, 23:3, 140-6 
Abstract 
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. 

Title 
Effects of decreased glutamine supply on gut and liver metabolism in vivo in rats. 
Author 
Heeneman S; Deutz NE 
Source 
Clin Sci (Colch), 1993 Oct, 85:4, 437-44 
Abstract 
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. 

Title 
Glutamine: is it a conditionally required nutrient for the human gastrointestinal system?[see
comments] 
Author 
Buchman AL 
Source 
J Am Coll Nutr, 1996 Jun, 15:3, 199-205 
Abstract 
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 ofexclusive parental nutrition. Furthermore, the clinical significance of these changes is largelyundefined in humans. The existing data on the use of parenteral and enteral glutamine for thepurpose of preserving intestinal morphology and function, and the prevention of bacterialtranslocation in humans are reviewed. Pertinent animal data are also described.