Oral Glutamine: DoesIt Make Sense?Several studies in the 1980s about the interorgan metabolism ofamino acids showed that, in starvation and in the catabolic state,glutamine (GLN) is released from skeletal muscle and delivered tothe intestine.1 The influence of glucocorticoids on GLN releasefrom skeletal muscle was demonstrated 1984 by Muhlbacher et al.2who showed that chronic administration of dexamethasone re-sulted in a fourfold increase in alanine and GLN release fromskeletal muscle. Furthermore, GLN is the only amino acid releasedfrom skeletal muscle in the postprandial state. Therefore, skeletalmuscle works as an endogenous GLN generator by using evenessential amino acids for GLN synthesis. Thus, nature regards acontinuous GLN outflow from skeletal muscle as a necessaryrequisite of life. Skeletal muscle can be considered the GLNinfusion bag of the human body.
GLN-dependent organs are the kidneys, hemapoietic cells, andthe intestine. Under physiologic conditions and in the postopera-tive state, the small intestine is the principal organ of GLN con-sumption. Studies by Windmueller suggested that the most impor-tant cells involved in the intestinal metabolism of this amino acidare the enterocytes, which remove 80% to 90% of the GLNextracted by the bowel.3 Forty percent of GLN nitrogen is con-verted to ammonia, and 25% appears in alanine. Only a smallportion is used for synthetic purposes, such as protein synthesis. Inthis issue of Nutrition, Boza et al. present a study showing thatboth GLN-rich protein and free GLN equally increase proteinsynthesis in the jejunum by approximately 25% in glucocorticoid-treated rats.4 This study indicates that orally and enterally admin-istered GLN is metabolized effectively by the intestine under stressconditions. Previous experimental investigations have shown thatorally and enterally applied GLN has a number of biologicalconsequences on gut mucosa. GLN reduces bacterial translocationafter abdominal irradiation,5 it increases growth and the absorptivecapacity of intestinal mucosa in the malnourished rat,6 and itenhances bacterial clearance in protracted bacterial peritonitis.7These experimental studies have recently received an impressiveclinical confirmation. It was shown that enteral GLN nutrition,started 48 h after the trauma, significantly reduced the incidence ofpneumonia, bacteremia, and severe sepsis.8 However, this benefi-cial effect on the morbidity state could not be reproduced in a moreheterogeneous group of patients under intensive care who werecapable of tolerating enteral feeding. Interestingly, the overallpostintervention hospital costs were significantly reduced inenteral-GLN recipients in the latter study.9
Beneficial effects of enteral and oral GLN administration onintestinal physiology include the delivery of energy to the entero-cytes, the stimulation of protein synthesis for mucosal regenerationand maintainance of gut integrity, and improvement of intestinalimmune reactivity. Sepsis and endotoxemia markedly influenceintestinal GLN metabolism. Souba et al. presented evidence thatgut GLN extraction was diminished by 75% in critical illness.10This reduced intestinal GLN uptake was accompanied by dimin-ished gut oxygen extraction. However, endotoxin stimulates lym-phocyte glutaminase expression, indicating that the intestinal lym-
phocytes in particular are prevalent in an increased GLN turnoverin endotoxemia.11 I and my colleagues have shown that endotox-emia in mice significantly reduces the number of lymphocytes inthe Peyers patches (PP). Oral GLN pretreatment could preventatrophy of the PP (Manhart et al. Unpublished data). In this study,we did not measure the influence of GLN on protein synthesis butdetermined the glutathione (GSH) levels in the PP. Endotoxemiasignificantly reduced the GSH concentration in the PP, which wasprevented by oral GLN administration. Correspondingly, enteralsupply of buthionine sulfoximine, an inhibitor of GSH synthesis,caused a depletion of lymphocytes and of the GSH level in the PPof the mice. We concluded that administration of GLN maintainsthe intestinal lymphocyte number, which we believe to be associ-ated with an increased protein synthesis of the intestine. However,a GLN deficiency in endotoxemia leads to a diminished lympho-cyte number in the PP, which is logically accompanied by alowered overall intestinal protein synthesis. Interestingly, GLNadministered parenterally was also associated with an increase oflymphocyte yield in the PP, the intraepithelial layer, and thelamina propria,12 indicating that the route of GLN supply was notrelevant.
Long et al. investigated the impact of GLN-supplemented en-teral nutrition on whole-body protein kinetics and glucose metab-olism in critically ill patients.13 They compared an enteral formulaproviding a mean intake of 0.35 g of GLN per kilogram of bodyweight per day with a nutrition providing only 0.05 g of GLN totrauma patients. They could not find a difference in nitrogenbalance, whole-body protein turnover, synthesis, and breakdownbetween the two groups. They concluded that GLN-enriched for-mulas do not provide additional nutritional advantage as comparedwith standard enteral formulas. However, in my opinion, analysisof whole-body protein synthesis or breakdown alone is insufficientto monitor the different organ-specific effects of GLN in an or-ganism because several studies have indicated that the nutrientGLN also functions as a cell signal. In this respect, the work ofRhoads et al. is of extreme importance. This group was able toshow that GLN stimulates intestinal-cell proliferation and activatesmitogen-activated protein kinases.14 This study demonstrated thatGLN not only stimulates proliferation by delivering energy butalso activates extracellular signal-regulated kinases and Jun nu-clear kinases. This GLN dependent activation of the kinases re-sulted in a fourfold increase in activating protein-1dependentgene transcription. GLN is also required for EGF signaling throughextracellular signal-regulated kinases. Thus, GLN may promoteintestinal protein synthesis not only by delivering substrate andenergy but also by stimulating transcription of genes in the pro-motor region.
Boza et al. demonstrated that both free GLN and GLN-enrichedprotein stimulate protein synthesis in a similar way. A similarresult was obtained by Furukawa et al.7 They demonstrated thatintragastric infusion of GLN enriched with GLN in free amino-acid form or GLN enriched with GLN in oligopeptide form in a ratprotracted-peritonitis model enhanced peritoneal and hepatic bac-terial clearance. Thus, the chemical form in which GLN is applieddoes not appear to be relevant for its biological effect. As pointedout in a recent publication, the amount of GLN in commerciallyavailable enteral products is too low.15 The GLN content in theprotein-based preparations differed between 5.2 and 8.1 g per 16 gof nitrogen. In the peptide-based products, considerably lowerGLN contents were measured (1.3 to 5.6 g per 16 g of nitrogen).In our experimental studies in which we were able to prevent PPatrophy in endotoxemic mice by oral premedication with GLN, theamount of administered GLN was 60 g/2000 kcal. These experi-
Correspondence to: Erich Roth, PhD, Director, Surgical Research Labora-tory, University of Vienna/AKH, Wahringer Gurtel 18-20, A-1090 Wien,Austria
Nutrition 17:5266, 2001 0899-9007/01/$20.00Elsevier Science Inc., 2001. Printed in the United States. All rights reserved.
mental data indicate that a rather high oral or enteral supply ofGLN is necessary to evoke positive biological effects in endotox-emia. Therefore, it will be of special interest whether commercialproducts with an appropriate amount of protein-bound GLN willbe available in future.
The study by Boza et al. also raises the question of whetherparenteral or enteral GLN supply may be of advantage underclinical conditions. Very few studies have compared GLN-enriched parenteral with enteral feeding in humans. In postopera-tive patients, it was shown that plasma GLN concentration did notdiffer significantly by feeding group, although a trend suggestedthat GLN recovered more slowly in the patients fed with a tubethan in those fed by total parenteral nutrition.16 We comparedpostfeeding hyperammonemia in patients with transjugular intra-hepatic portosystemic shunt and liver cirrhosis after either paren-teral or enteral GLN supply.17 Our data indicated that parenterallyadministered GLN caused a lower degree of systemic hyperam-monemia than did enteral GLN in cirrhotic patients. Therefore, infuture, GLN application in parenteral or enteral or oral form maybe disease dependent.17
In conclusion, GLN influences several biological processesincluding intestinal protein synthesis. It has to be clarified whetherGLN-related stimulation of intestinal protein synthesis is due to anincreased delivery of substrate or energy or by stimulating GSHformation and protein transcription. At any rate, the therapeuticalpotential of GLN seems to be closely associated with that ofglutathione.18 Thus, the food constituent GLN may be the primeexample of a nutrient that develops into an essential dietary sup-plement because of its druglike activities.19
Erich Roth, PhDUniversity of Vienna
1. Souba WW, Wilmore DW. Postoperative alteration of arteriovenous exchange ofamino acids across the gastrointestinal tract. Surgery 1983;94:342
2. Muhlbacher F, Kapadia CR, Colpoys MF, Smith RJ, Wilmore DW. Effects ofglucocorticoids on glutamine metabolism in skeletal muscle. Am J Physiol1984;247:E75
3. Windmueller HG. Glutamine utilization by the small intestine. Adv Enzymol1982;53:202
4. Boza JJ, Turini M, Moennoz D, et al. Effect of glutamine supplementation of thediet on tissue protein synthesis rate of glucocorticoid-treated rats. Nutrition2001;17:46
5. Souba WW, Klimberg VS, Hautamaki RD, et al. Oral glutamine reduces bacterialtranslocation following abdominal radiation. J Surg Res 1990;48:1
6. Panigrahi P, Gewolb IH, Bambord P, Horvath K. Role of glutamine in bacterialtranscytosis and epithelial cell injury. JPEN 1997;21:75
7. Furukawa S, Saito H, Inaba T, et al. Glutamine-enriched enteral diet enhancesbacterial clearance in protracted bacterial peritonitis, regardless of glutamineform. JPEN 1997;21:208
8. Houdijk AP, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multipletrauma. Lancet 1998;352:772
9. Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study ofcritically ill patients given glutamine-supplemented enteral nutrition. Nutrition1999;15:108
10. Souba WW, Herskowitz K, Klimberg VS, et al. The effects of sepsis andendotoxemia on gut glutamine metabolism. Ann Surg 1990;211:543
11. Sarantos P, Ockert K, Souba WW. Endotoxin stimulates lymphocyte glutaminaseexpression. Arch Surg 1993;128:920
12. Li J, Kudsk KA, Janu P, Renegar KB. Effect of glutamine-enriched total paren-teral nutrition on small intestinal gut-associated lymphoid tissue and upperrespiratory tract immunity. Surgery 1997;121:542
13. Long CL, Nelson KM, DiRienzo DB, et al. Glutamine supplementation of enteralnutrition; impact on whole body protein kinetics and glucose metabolism incritically ill patients. JPEN 1995;19:470
14. Rhoads JM, Argenzio RA, Chen W, et al. L-Glutamine stimulates intestinal cell
proliferation and activates mitogen-activated protein kinases. Am J Physiol1997;272:G943
15. Kuhn KS, Stehle P, Furst P. Glutamine content of protein and peptide-basedenteral products. JPEN 1996;20:292
16. Fish J, Sporay G, Beyer K, et al. A prospective randomized study of glutamine-enriched parenteral compared with enteral feeding in postoperative patients. Am JClin Nutr 1997;65:977
17. Plauth M, Roske A-E, Roth E, Ziebig R, Lochs H. Post-feeding hyperammon-aemia in patients with transjugular intrahepatic portosystemic shunt and livercirrhosis: role of small intestinal ammonia release and route of nutrient admin-istration. Gut 2000;46:849
18. Exner R, Wessner B, Manhart N, Roth E. Therapeutic potential of glutathione.Wien Klin Wochenschr 2000;112:610
19. Winklhofer-Roob BM. From food constituent to dietary supplement and drug. Isthere a role for antioxidants in treatment strategies? Wien Klin Wochenschr2000;14:607
Nutrition in Intensive Care: GiveEnough but Choose the RouteWisely?As an intensivist I weigh the risks and benefits to judge whom tofeed and then hopefully deliver the feedings in a safe and practicalmanner. Over the last decade the debate in intensive care hasfocused for good reasons on increased use of the enteral route andthe specific constituents of feeds rather than on how much and towhom. A culture has developed of early enteral feeding and settingvery modest targets.
Is providing intakes grossly less than expenditure beyond thefirst day or so beneficial, or should we be achieving targets closerto metabolic requirements? Recent work in the field of metabolicstudy suggest that in sepsis and trauma the total energy expendi-ture (TEE) of critically ill patients rises from 25 and 31 kcal/kg/day in the first week to 47 and 59 kcal/kg/day in the second week.1The ratio of TEE/REE (resting energy expenditure) rises probablybecause with newer approaches of ventilator assist patients aremore awake and physically active. This challenges the nutritionaltarget of 25 kcal/kg/day that many intensive care doctors try toreach and even this is not achieved in one third of patientsreceiving enteral nutrition in intensive care. Numerous studiesshow that the real practice of enteral nutrition is partial feeding2 forreasons that include setting too low targets, not using protocols,3slow initiation, and a tendency to stop too readily.4
DOES IT MATTER IF WE DONT GIVE ENOUGH?
It is worth being reminded that inadequacy of recent dietary intakerather than the absolute nutritional status determines injury re-sponse and healing.5 Preventing the harmful effect of even short-term starvation reduces the postoperative insulin resistance,6 and 3days of hypocaloric nutrition, not immobilization after surgery, isresponsible for maintaining the marked postoperative insulin re-sistance.7 Study results that show that this improves the outcomefollowing surgery are due shortly; however, if we are to see benefitfrom the nutrition we provide, we must balance this with the risksand complications of the intervention.
Do we have any evidence that the underfed intensive care unit
Correspondence to: R. D. Griffiths, BSc, MD, FRCP, Reader in Medicine(Intensive Care), Intensive Care Research Group, Department of Medicine,Duncan Building, UCD, Daulby Street, University of Liverpool, L69 3GA,UK. E-mail: email@example.com
Nutrition Volume 17, Number 1, 2001 53Editorial Opinions