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EDITORIAL OPINIONS patients receiving the glutamine-enriched nutrition, there was significantly less bacteremia, probably explaining the lower TNFsoluble levels. In addition, no gram-negative bacteremias were found in the glutamine group versus 54% in the patients fed the control diet, possibly because glutamine maintained intestinal integrity, thus preventing bacterial translocation and reducing the inflammatory response. As attractive as this suggestion may be, the study was not designed to monitor intestinal integrity or bacterial translocation, and further research in this area is needed. An additional benefit of glutamine-enriched nutrition is the stimulation of renal production of arginine, another important immunomodulator. Arginine stimulates lymphocyte responsiveness and is involved in wound healing.27 Glutamine increases the intestinal production of citrulline, which is converted to arginine in the kidneys.28 In rats, a glutamine-enriched enteral diet stimulates renal arginine production resulting in higher arginine plasma levels which was also seen in the multiple trauma patients.29 This may seem advantageous in terms of immunomodulation but again complicates drawing any conclusion on the particular effects of glutamine alone. In our experience and that of others, the rate of feeding in our study was higher than what normally is achieved. This result is explained by setting goals for high delivery rates and the attention of a nutritional research fellow.30 In normal clinical practice, physicians tend to feed their patients later and at a lower rate. Nevertheless, despite the high rate of enteral nutrition, a period of more than 3 d was necessary to significantly increase plasma levels of glutamine compared with the control nutrition. In light of the promising effects of glutamine-enriched nutrition on the rate of infections in trauma patients, it would be desirable to start the administration of glutamine as soon as possible. For future studies, this may be achieved by the immediate administration of glutamine by the parenteral route followed by the more preferrable enteral administration as soon as possible. Despite the promising effects of glutamine and other immunonutrients on reducing infection rates, immunonutrition in the critically ill still is not accepted as standard care. The lack of large randomized trials investigating a single immunonutritional supplement given to well-defined homogeneous patient populations probably underlies this problem. Such studies are needed to help define what nutritonal supplement is best suited for selective patient populations and will provide the facts needed to end the discussion between believers and non-believers in the field of immunonutrition.
Alexander P. J. Houdijk, MD Paul A. M. van Leeuwen, MD, PhD Department of Surgery Slotervaart Ziekenhuis Ziekenhuis Vrije Universiteit Amsterdam, The Netherlands REFERENCES 1. Border JR, Hassett J, LaDuca J, et al. The gut origin states in blunt multiple trauma (ISS ⫽ 40) in the ICU. Ann Surg 1987;206:427 2. O’Mahoney JB, Palder SB, Wood JJ, et al. Depression of cellular immunity after multiple trauma in the absence of sepsis. J Trauma 1984;10:869 3. Levy EM, Alharbi SA, Grindlinger G, Black PH. Changes in mitogen responsiveness of lymphocyte subsets after traumatic injury: relation to development of sepsis. Clin Immunol Immunopathol 1984;32:224 4. Pape HC, Dwenger A, Regel G, et al. Increased gut permeability after multiple trauma. Br J Surg 1994;81:850 5. Frayn KN. Hormonal control of metabolism in trauma and sepsis. Clin Endocrinol 1986;24:577 6. Souba WW, Klimberg VS, Plumley DA, et al. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990;48:383
71 7. McAnena OJ, Moore FA, Moore EE, Jones TN, Parsons P. Selective uptake of glutamine in the gastrointestinal tract: confirmation in a human study. Br J Surg 1991:78:480 8. Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alanyl-glutamine counteracts the depletion of free glutamine and the postoperative decline in protein synthesis in skeletal muscle. Ann Surg 1990;212:637 9. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989;1:231 10. Newsholme EA, Crabtree B, Ardawi MSM. The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci Rep 1985;5:393 11. Windmueller HG, Spaeth AE. Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. J Biol Chem 1978;253:69 12. O’Dwyer ST, Smith RJ, Hwang TL, Wilmore DW. Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. JPEN 1989;13:579 13. Souba WW, Klimberg VS, Hautamaki RD, et al. Oral glutamine reduces bacterial translocation following abdominal radiation. J Surg Res 1990;48:1 14. Bai MX, Jiang ZM, Liu YW, et al. Effects of alanyl-glutamine on gut barrier function. Nutrition 1996;12:793 15. Furukawa S, Saito H, Inaba T, et al. Glutamine-enriched enteral diet enhances bacterial clearance in protracted bacterial peritonitis, regardless of glutamine form. JPEN 1997;21:208 16. Van der Hulst RWJ, van Kreel BK, von Meyenfeldt MF, et al. Glutamine and the preservation of gut integrity. Lancet 1993;341:1363 17. Tremel H, Kienle B, Weilemann LS, Stehle P, Furst P. Glutamine dipeptidesupplemented parenteral nutrition maintains intestinal function in the critically ill. Gastroenterology 1994;107:1595 18. O’Riordain MG, Fearon KC, Ross JA, et al. Glutamine-supplemented total parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg 1994;220:212 19. Morilion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double blind controlled study. Ann Surg 1998;227:302 20. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine supplemented parenteral nutrition after bone marrow transplantation. A randomized double blind controlled study. Ann Intern Med 1992;116:821 21. Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for very low birth weight infants decreases morbidity. J Pediatr 1997;131:691 22. Griffiths RD, Jones C, Palmer A. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295 23. Long CL, Borghesi L, Stahl R, et al. Impact of enteral feeding of a glutaminesupplemented formula on the hypoaminoacidemic response in trauma patients. J Trauma 1996;40:97 24. Kudsk KA, Minard G, Croce MA, et al. A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Ann Surg 1996;224:531 25. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503 26. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamineenriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772 27. Barbul A, Lazarou SA, Efron DT, et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990;108:331 28. Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Physiol 1981;241:E473 29. Houdijk APJ, van Leeuwen PAM, Teerlink T, et al. Glutamine enriched enteral diet increases renal arginine synthesis. JPEN 1994;18:422 30. Houdijk APJ, Haarman HJTM, van Leeuwen PAM. Glutamine-enriched enteral nutrition in patients with multiple trauma. Lancet 1998;352:1553
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More Good News About Glutamine Glutamine is synthesized in skeletal muscle and released into the circulation. Important consumers of glutamine from the blood-
Correspondence to: Philip C. Calder, PhD, Institute of Human Nutrition, University of Southampton, Bassett Crescent East, Southampton S016 7PX, UK. E-mail: [email protected]
72 stream include the gastrointestinal tract, the kidney, the liver, and the immune system. During stress situations, the demand by these and perhaps other tissues may exceed the ability of skeletal muscle to supply glutamine. As a result, blood and skeletal muscle glutamine concentrations fall. It is proposed that in such situations glutamine becomes conditionally essential1 and that in an attempt to meet the demand skeletal muscle breakdown occurs, leading to muscle wasting. Muscle wasting is commonly observed in patients with human immunodeficiency virus (HIV) infection,2 and it has been proposed that this is driven by the demand for glutamine in such patients.3 Because it appears that death from wasting in AIDS is related to the magnitude of tissue depletion and is independent of the cause of wasting,2 maintenance of body mass should prolong survival. It has previously been shown that administration of an enteral feed (glutamine free) to weight-losing AIDS patients increases body cell mass.4 The study by Shabert et al.5 reported in the 15(11/12) issue of Nutrition is based on the hypothesis that oral glutamine provision to weight-losing HIV patients will decrease the demand for endogenous glutamine and thus will decrease muscle wasting. These authors elected to include antioxidants (a mix of vitamins C and E, -carotene, selenium, and N-acetyl cysteine) in the regimen on the basis that HIV patients are commonly deficient in these6 and that this deficiency may be exacerbated by an increased oxidative stress. The article does not report plasma glutamine concentrations before or during the treatment period, which seems an important omission. Glutamine was provided as 10 g four times daily (i.e., 40 g/d) in a double-blind manner using glycine (40 g/d) as placebo. By the start of the study, patients in the glutamine group had lost an average of 10.7% of weight since the onset of the disease, although all had body mass indexes in the “desirable” range (i.e., 20 to 25 kg/m2). Treatment with glutamine (plus antioxidants) for 12 wk resulted in weight gain (2.2 kg) and an increase in body cell mass (1.8 kg), total body water (1.5 L), and intracellular water (1.7 L); the latter were based on bioelectric impedance measurements. About 75% of the effect of glutamine (plus antioxidants) occurred over the first 4 wk of treatment. Curiously, the measures in the placebo group increased almost as much as those in the glutamine group over the first 4 wk, but the measures then returned to starting values. The results are encouraging and suggest that exogenous glutamine (plus antioxidants) can at least in part reverse the decrease in lean tissue mass which accompanies HIV infection. A longer term, larger trial is needed to verify these results and to look at other relevant outcome measures. It seems important that the effects of glutamine and antioxidants be studied separately and together (as in the study by Shabert et al.) to identify the active component of the mixture and to optimize the treatment regimen. This study follows a number of others in recent years that have identified a role for glutamine as an inexpensive yet effective component in the therapy of a variety of conditions involving catabolic stress. For example, glutamine (or its precursors) has been shown to have some beneficial effects (e.g., decreasing the negative nitrogen balance and maintenance of muscle mass and gut integrity) after major surgery,7–9 after bone marrow transplantation,10 in patients in intensive care,11–13 and in very low birthweight babies.14 One common component of catabolic states is the increased susceptibility to infection, which occurs through the combination of increased gut permeability to infectious agents and diminished immune defense. Because the immune system appears to have a requirement for glutamine to retain optimal function,15,16 maintenance of plasma glutamine concentrations in catabolic patients might have an added benefit of improving immune function and thus help to combat infection. There is now evidence for this emerging from both animal and clinical studies. Enrichment of the diet with glutamine increases ex vivo proliferation of T lymphocytes from rats,17 pigs,18 and mice.19 The latter study has reported that a glutamine-enriched diet also increases the proportion of CD4⫹ lymphocytes in the murine spleen, increases the proportion
EDITORIAL OPINIONS of stimulated lymphocytes bearing the interleukin-2 receptor, and increases interleukin-2 production. In another recent murine study, the production of tumor necrosis factor-␣ and of interleukins-1 and 6 was greater by stimulated macrophages from mice fed a glutamine-enriched diet.20 That such immunoenhancing effects of glutamine are important has been demonstrated by a series of studies in which glutamine-supplemented parenteral nutrition markedly improved survival of rats after cecal ligation and puncture21 and after intraperitoneal administration of live Escherichia coli.22,23 Likewise, dietary glutamine markedly increased the survival of mice inocculated intravenously with live Staphylococcus aureus.24 Taken together, these animal studies indicate that provision of glutamine either parenterally or enterally increases the function of various immune cells and that this might lead to enhanced resistance to infection. The provision of glutamine intravenously to patients after bone marrow transplantation resulted in a lower level of infection (12% of patients with clinical infections versus 42% in the control group) and a shorter stay in the hospital (29 ⫾ 1 d versus 36 ⫾ 2 d) than seen for patients receiving glutamine-free parenteral nutrition.10 A subsequent report by this group showed that glutamine treatment resulted in greater numbers of total lymphocytes, T lymphocytes, and CD4⫹ lymphocytes (but not B lymphocytes or natural killer cells) in the bloodstream after the patients were discharged.25 Very-low-birthweight babies who received a glutamine-enriched premature feeding formula had a much lower rate of sepsis (11% versus 31%) than did babies who received a standard formula.14 In a study of patients in intensive care, glutamine provision decreased mortality compared with standard parenteral nutrition (43% versus 67%) and changed the pattern of mortality.12 In a recent study, patients who received enteral glutamine from within 48 h of the trauma showed a significant reduction in the 15-d incidence of pneumonia (17% versus 45% in the control group), bacteremia (7% versus 42%), and severe sepsis (4% versus 26%).13 Such effects may be related to improved immune function because enteral glutamine increased the blood lymphocyte CD4:CD8 ratio in patients in intensive care,11 and parenteral glutamine increased mitogen-stimulated proliferation of blood lymphocytes from patients after colorectal surgery.8 Thus, there is increasing evidence that glutamine has beneficial effects on nitrogen balance, lean tissue mass, gut integrity, and immune function. This evidence supports the use of glutamine in different patient groups, and it is now regarded by some as the quintessential pharmaconutrient. The article by Shabert et al.5 suggests a novel application of glutamine, which will need confirmation. Furthermore, more needs to be known about the mechanism of action of glutamine, particularly within gut and immune cells, if we are to maximize the benefit that can be obtained from its provision.
Philip C. Calder, PhD, DPhil Institute of Human Nutrition University of Southampton Southampton, UK REFERENCES 1. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990;48:297 2. Kotler DO, Tierney AR, Wang J, Pierson RN. Magnitude of body cell mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 1989;50:444 3. Shabert J, Wilmore DW. Glutamine deficiency as a cause of human immunodeficiency virus wasting. Med Hypoth 1996;46:252 4. Kotler DP, Tierney A, Ferraro R, et al. Enteral alimentation and repletion of body cell mass in malnourished patients with acquired immunodeficiency syndrome. Am J Clin Nutr 1991;53:149 5. Shabert JK, Winslow C, Lacey JM, Wilmore DW. Glutamine-antioxidant sup-
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plementation increases body cell mass in AIDS patients with weight loss: a randomised, double blind controlled trial. Nutrition 1999;15:860 Semba RD, Tang AM. Micronutrients and the pathogenesis of human immunodeficiency virus infection. Br J Nutr 1999;81:181 Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine dipeptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989;i:231 O’Riordain M, Fearon KC, Ross JA, et al. Glutamine supplemented parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg 1994;220:212 Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alanyl-glutamine counteracts the depletion of free glutamine and post-operative decline in protein synthesis in muscle. Ann Surg 1990;212:637 Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition following bone marrow transplantation: a double-blinded, randomized, controlled trial. Ann Intern Med 1992;116: 821 Jensen GL, Miller RH, Talabiska DG, Fish J, Gianferante L. A double blind, prospective, randomized study of glutamine-enriched compared with standard peptide-based feeding in critically ill patients. Am J Clin Nutr 1996;64:615 Griffiths RD, Jones C, Palmer TEA. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295 Houdijk APK, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamineenriched parenteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772 Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for very low birthweight infants decreases morbidity. J Pediatr 1997;131:691 Calder PC. Glutamine and the immune system. Clin Nutr 1994;13:2 Wilmore DW, Shabert JK. Role of glutamine in immunologic responses. Nutrition 1998;14:618 Shewchuk LD, Baracos VE, Field CJ. L-glutamine supplementation reduces growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats. J Nutr 1997;127:158 Yoo SS, Field CJ, McBurney MI. Glutamine supplementation maintains intramuscular glutamine concentrations and normalizes lymphocyte function in infected early weaned pigs. J Nutr 1997;127:2253 Kew S, Wells SM, Yaqoob P, et al. Dietary glutamine enhances murine T-lymphocyte responsiveness. J Nutr 1999;129:1524 Wells SM, Kew S, Yaqoob P, Wallace FA, Calder PC. Dietary glutamine enhances cytokine production by murine macrophages. Nutrition 1999;15:881 Ardawi MSM. Effect of glutamine-enriched total parenteral nutrition on septic rats. Clin Sci 1991;81:215 Inoue Y, Grant JP, Snyder PJ. Effect of glutamine-supplemented intravenous nutrition on survival after Escherichia coli-induced peritonitis. JPEN 1993;17:41 Naka S, Saito H, Hashiguchi Y, et al. Alanyl-glutamine-supplemented total parenteral nutrition improves survival and protein metabolism in rat protracted bacterial peritonitis model. JPEN 1996;20:417 Suzuki I, Matsumoto Y, Adjei AA, et al. Effect of a glutamine-supplemented diet in response to methicillin-resistant Staphylococcus aureus infection in mice. J Nutr Sci Vitaminol 1993;39:405 Ziegler TR, Bye RL, Persinger RL, et al. Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 1998;315:4
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Arginine and Immunonutrition: A Reevaluation Arginine has been classified as a semiessential amino acid because of its nutritional requirement for the optimal growth of some species, but not humans. Over the past two decades, studies have shown arginine to be a powerful mediator of multiple biological processes including the release of several hormones, collagen synthesis during wound healing, antitumor activity, and immune
Correspondence to: Adrian Barbul, MD, Department of Surgery, Sinai Hospital, 2401 West Belvedere Avenue, Baltimore, MD 21215, USA. E-mail: [email protected]
FIG. 1. Amounts of arginine in specialized enteral diets (US products).
cell responses. Although all hold significant interest to clinicians, the latter has the furthest reaching implications. Early animal experiments have delineated some of the effects that arginine has on the immune system. Normal rodents given a 1% arginine HCl supplementation to their normal diet (1.8% arginine content) have demonstrated increased thymic weight secondary to increased numbers of total thymic T lymphocytes.1 This thymotropic effect correlates functionally with increased thymic lymphocyte blastogenesis in response to mitogens. Supplemental dietary arginine also minimizes or abrogates posttraumatic thymic involution and T cell suppression.2 In the athymic mouse, supplemental arginine increases the number of T cells and heightens delayed-type hypersensitivity responses, suggesting a thymicindependent mechanism for the effect of arginine on T cell activity.3 Although the function of other cells of the immune system has not been studied after dietary arginine supplementation, there is increasing evidence that arginine and its metabolites are integral to the activity and interactions of macrophages and polymorphonuclear cells. The clinical significance of arginine’s immunomodulatory ability has been evaluated primarily in experimental models of bacterial peritonitis and burns. Rats subjected to cecal ligation and puncture have demonstrated a significantly increased survival when given doses of 100 mg of arginine HCl by gavage three times a day; the survival advantage was further improved when gavage treatment preceded the onset of sepsis.4 Balb/C mice undergoing cecal ligation and puncture and fed a 2% arginine supplemented diet had a doubling of survival rates (28% to 56%).5 Guinea pigs subjected to 30% total body surface burns and supplemented with 2% arginine had a 30% greater survival rate.6 The same level of supplementation decreased bacterial translocation to liver and spleen in mice subjected to 20% body surface burn injury.5 Human studies have shown that arginine increases T cell mitogenic responses when given at doses of 30 g/d. This effect has been noted in healthy volunteers and in severely ill intensive care patients.7,8 There is a lack of well-conducted studies examining the effect of arginine supplementation on clinical outcome benefits in patients. Recently, special enteral diets have been formulated to contain high amounts of arginine together with -3 fatty acids, glutamine, and nucleic acids. The intent is to enhance or preserve the responsiveness of the cellular components of the immune system and/or to reduce harmful and exaggerated inflammatory responses. This therapeutic approach has been termed immunonutrition. Previous animal and human investigation has demonstrated that a supplementation of 5 to 12 g of arginine/1000 kcal induces enhanced T cell activity. The arginine concentrations of the commercially available dietary formulations vary greater than two-fold, but all contain higher amounts than those required for normal or postinjury nutriture (Fig. 1). The concept of immunonutrition has gained much clinical
Alexander P. J. Houdijk, MD Paul A. M. van Leeuwen, MD, PhD Department of Surgery Slotervaart Ziekenhuis Ziekenhuis Vrije Universiteit Amsterdam, The Netherlands REFERENCES 1. Border JR, Hassett J, LaDuca J, et al. The gut origin states in blunt multiple trauma (ISS ⫽ 40) in the ICU. Ann Surg 1987;206:427 2. O’Mahoney JB, Palder SB, Wood JJ, et al. Depression of cellular immunity after multiple trauma in the absence of sepsis. J Trauma 1984;10:869 3. Levy EM, Alharbi SA, Grindlinger G, Black PH. Changes in mitogen responsiveness of lymphocyte subsets after traumatic injury: relation to development of sepsis. Clin Immunol Immunopathol 1984;32:224 4. Pape HC, Dwenger A, Regel G, et al. Increased gut permeability after multiple trauma. Br J Surg 1994;81:850 5. Frayn KN. Hormonal control of metabolism in trauma and sepsis. Clin Endocrinol 1986;24:577 6. Souba WW, Klimberg VS, Plumley DA, et al. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990;48:383
71 7. McAnena OJ, Moore FA, Moore EE, Jones TN, Parsons P. Selective uptake of glutamine in the gastrointestinal tract: confirmation in a human study. Br J Surg 1991:78:480 8. Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alanyl-glutamine counteracts the depletion of free glutamine and the postoperative decline in protein synthesis in skeletal muscle. Ann Surg 1990;212:637 9. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989;1:231 10. Newsholme EA, Crabtree B, Ardawi MSM. The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci Rep 1985;5:393 11. Windmueller HG, Spaeth AE. Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. J Biol Chem 1978;253:69 12. O’Dwyer ST, Smith RJ, Hwang TL, Wilmore DW. Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. JPEN 1989;13:579 13. Souba WW, Klimberg VS, Hautamaki RD, et al. Oral glutamine reduces bacterial translocation following abdominal radiation. J Surg Res 1990;48:1 14. Bai MX, Jiang ZM, Liu YW, et al. Effects of alanyl-glutamine on gut barrier function. Nutrition 1996;12:793 15. Furukawa S, Saito H, Inaba T, et al. Glutamine-enriched enteral diet enhances bacterial clearance in protracted bacterial peritonitis, regardless of glutamine form. JPEN 1997;21:208 16. Van der Hulst RWJ, van Kreel BK, von Meyenfeldt MF, et al. Glutamine and the preservation of gut integrity. Lancet 1993;341:1363 17. Tremel H, Kienle B, Weilemann LS, Stehle P, Furst P. Glutamine dipeptidesupplemented parenteral nutrition maintains intestinal function in the critically ill. Gastroenterology 1994;107:1595 18. O’Riordain MG, Fearon KC, Ross JA, et al. Glutamine-supplemented total parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg 1994;220:212 19. Morilion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double blind controlled study. Ann Surg 1998;227:302 20. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine supplemented parenteral nutrition after bone marrow transplantation. A randomized double blind controlled study. Ann Intern Med 1992;116:821 21. Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for very low birth weight infants decreases morbidity. J Pediatr 1997;131:691 22. Griffiths RD, Jones C, Palmer A. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295 23. Long CL, Borghesi L, Stahl R, et al. Impact of enteral feeding of a glutaminesupplemented formula on the hypoaminoacidemic response in trauma patients. J Trauma 1996;40:97 24. Kudsk KA, Minard G, Croce MA, et al. A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Ann Surg 1996;224:531 25. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503 26. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamineenriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772 27. Barbul A, Lazarou SA, Efron DT, et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990;108:331 28. Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Physiol 1981;241:E473 29. Houdijk APJ, van Leeuwen PAM, Teerlink T, et al. Glutamine enriched enteral diet increases renal arginine synthesis. JPEN 1994;18:422 30. Houdijk APJ, Haarman HJTM, van Leeuwen PAM. Glutamine-enriched enteral nutrition in patients with multiple trauma. Lancet 1998;352:1553
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More Good News About Glutamine Glutamine is synthesized in skeletal muscle and released into the circulation. Important consumers of glutamine from the blood-
Correspondence to: Philip C. Calder, PhD, Institute of Human Nutrition, University of Southampton, Bassett Crescent East, Southampton S016 7PX, UK. E-mail: [email protected]
72 stream include the gastrointestinal tract, the kidney, the liver, and the immune system. During stress situations, the demand by these and perhaps other tissues may exceed the ability of skeletal muscle to supply glutamine. As a result, blood and skeletal muscle glutamine concentrations fall. It is proposed that in such situations glutamine becomes conditionally essential1 and that in an attempt to meet the demand skeletal muscle breakdown occurs, leading to muscle wasting. Muscle wasting is commonly observed in patients with human immunodeficiency virus (HIV) infection,2 and it has been proposed that this is driven by the demand for glutamine in such patients.3 Because it appears that death from wasting in AIDS is related to the magnitude of tissue depletion and is independent of the cause of wasting,2 maintenance of body mass should prolong survival. It has previously been shown that administration of an enteral feed (glutamine free) to weight-losing AIDS patients increases body cell mass.4 The study by Shabert et al.5 reported in the 15(11/12) issue of Nutrition is based on the hypothesis that oral glutamine provision to weight-losing HIV patients will decrease the demand for endogenous glutamine and thus will decrease muscle wasting. These authors elected to include antioxidants (a mix of vitamins C and E, -carotene, selenium, and N-acetyl cysteine) in the regimen on the basis that HIV patients are commonly deficient in these6 and that this deficiency may be exacerbated by an increased oxidative stress. The article does not report plasma glutamine concentrations before or during the treatment period, which seems an important omission. Glutamine was provided as 10 g four times daily (i.e., 40 g/d) in a double-blind manner using glycine (40 g/d) as placebo. By the start of the study, patients in the glutamine group had lost an average of 10.7% of weight since the onset of the disease, although all had body mass indexes in the “desirable” range (i.e., 20 to 25 kg/m2). Treatment with glutamine (plus antioxidants) for 12 wk resulted in weight gain (2.2 kg) and an increase in body cell mass (1.8 kg), total body water (1.5 L), and intracellular water (1.7 L); the latter were based on bioelectric impedance measurements. About 75% of the effect of glutamine (plus antioxidants) occurred over the first 4 wk of treatment. Curiously, the measures in the placebo group increased almost as much as those in the glutamine group over the first 4 wk, but the measures then returned to starting values. The results are encouraging and suggest that exogenous glutamine (plus antioxidants) can at least in part reverse the decrease in lean tissue mass which accompanies HIV infection. A longer term, larger trial is needed to verify these results and to look at other relevant outcome measures. It seems important that the effects of glutamine and antioxidants be studied separately and together (as in the study by Shabert et al.) to identify the active component of the mixture and to optimize the treatment regimen. This study follows a number of others in recent years that have identified a role for glutamine as an inexpensive yet effective component in the therapy of a variety of conditions involving catabolic stress. For example, glutamine (or its precursors) has been shown to have some beneficial effects (e.g., decreasing the negative nitrogen balance and maintenance of muscle mass and gut integrity) after major surgery,7–9 after bone marrow transplantation,10 in patients in intensive care,11–13 and in very low birthweight babies.14 One common component of catabolic states is the increased susceptibility to infection, which occurs through the combination of increased gut permeability to infectious agents and diminished immune defense. Because the immune system appears to have a requirement for glutamine to retain optimal function,15,16 maintenance of plasma glutamine concentrations in catabolic patients might have an added benefit of improving immune function and thus help to combat infection. There is now evidence for this emerging from both animal and clinical studies. Enrichment of the diet with glutamine increases ex vivo proliferation of T lymphocytes from rats,17 pigs,18 and mice.19 The latter study has reported that a glutamine-enriched diet also increases the proportion of CD4⫹ lymphocytes in the murine spleen, increases the proportion
EDITORIAL OPINIONS of stimulated lymphocytes bearing the interleukin-2 receptor, and increases interleukin-2 production. In another recent murine study, the production of tumor necrosis factor-␣ and of interleukins-1 and 6 was greater by stimulated macrophages from mice fed a glutamine-enriched diet.20 That such immunoenhancing effects of glutamine are important has been demonstrated by a series of studies in which glutamine-supplemented parenteral nutrition markedly improved survival of rats after cecal ligation and puncture21 and after intraperitoneal administration of live Escherichia coli.22,23 Likewise, dietary glutamine markedly increased the survival of mice inocculated intravenously with live Staphylococcus aureus.24 Taken together, these animal studies indicate that provision of glutamine either parenterally or enterally increases the function of various immune cells and that this might lead to enhanced resistance to infection. The provision of glutamine intravenously to patients after bone marrow transplantation resulted in a lower level of infection (12% of patients with clinical infections versus 42% in the control group) and a shorter stay in the hospital (29 ⫾ 1 d versus 36 ⫾ 2 d) than seen for patients receiving glutamine-free parenteral nutrition.10 A subsequent report by this group showed that glutamine treatment resulted in greater numbers of total lymphocytes, T lymphocytes, and CD4⫹ lymphocytes (but not B lymphocytes or natural killer cells) in the bloodstream after the patients were discharged.25 Very-low-birthweight babies who received a glutamine-enriched premature feeding formula had a much lower rate of sepsis (11% versus 31%) than did babies who received a standard formula.14 In a study of patients in intensive care, glutamine provision decreased mortality compared with standard parenteral nutrition (43% versus 67%) and changed the pattern of mortality.12 In a recent study, patients who received enteral glutamine from within 48 h of the trauma showed a significant reduction in the 15-d incidence of pneumonia (17% versus 45% in the control group), bacteremia (7% versus 42%), and severe sepsis (4% versus 26%).13 Such effects may be related to improved immune function because enteral glutamine increased the blood lymphocyte CD4:CD8 ratio in patients in intensive care,11 and parenteral glutamine increased mitogen-stimulated proliferation of blood lymphocytes from patients after colorectal surgery.8 Thus, there is increasing evidence that glutamine has beneficial effects on nitrogen balance, lean tissue mass, gut integrity, and immune function. This evidence supports the use of glutamine in different patient groups, and it is now regarded by some as the quintessential pharmaconutrient. The article by Shabert et al.5 suggests a novel application of glutamine, which will need confirmation. Furthermore, more needs to be known about the mechanism of action of glutamine, particularly within gut and immune cells, if we are to maximize the benefit that can be obtained from its provision.
Philip C. Calder, PhD, DPhil Institute of Human Nutrition University of Southampton Southampton, UK REFERENCES 1. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990;48:297 2. Kotler DO, Tierney AR, Wang J, Pierson RN. Magnitude of body cell mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 1989;50:444 3. Shabert J, Wilmore DW. Glutamine deficiency as a cause of human immunodeficiency virus wasting. Med Hypoth 1996;46:252 4. Kotler DP, Tierney A, Ferraro R, et al. Enteral alimentation and repletion of body cell mass in malnourished patients with acquired immunodeficiency syndrome. Am J Clin Nutr 1991;53:149 5. Shabert JK, Winslow C, Lacey JM, Wilmore DW. Glutamine-antioxidant sup-
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plementation increases body cell mass in AIDS patients with weight loss: a randomised, double blind controlled trial. Nutrition 1999;15:860 Semba RD, Tang AM. Micronutrients and the pathogenesis of human immunodeficiency virus infection. Br J Nutr 1999;81:181 Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine dipeptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989;i:231 O’Riordain M, Fearon KC, Ross JA, et al. Glutamine supplemented parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg 1994;220:212 Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alanyl-glutamine counteracts the depletion of free glutamine and post-operative decline in protein synthesis in muscle. Ann Surg 1990;212:637 Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition following bone marrow transplantation: a double-blinded, randomized, controlled trial. Ann Intern Med 1992;116: 821 Jensen GL, Miller RH, Talabiska DG, Fish J, Gianferante L. A double blind, prospective, randomized study of glutamine-enriched compared with standard peptide-based feeding in critically ill patients. Am J Clin Nutr 1996;64:615 Griffiths RD, Jones C, Palmer TEA. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295 Houdijk APK, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamineenriched parenteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772 Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for very low birthweight infants decreases morbidity. J Pediatr 1997;131:691 Calder PC. Glutamine and the immune system. Clin Nutr 1994;13:2 Wilmore DW, Shabert JK. Role of glutamine in immunologic responses. Nutrition 1998;14:618 Shewchuk LD, Baracos VE, Field CJ. L-glutamine supplementation reduces growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats. J Nutr 1997;127:158 Yoo SS, Field CJ, McBurney MI. Glutamine supplementation maintains intramuscular glutamine concentrations and normalizes lymphocyte function in infected early weaned pigs. J Nutr 1997;127:2253 Kew S, Wells SM, Yaqoob P, et al. Dietary glutamine enhances murine T-lymphocyte responsiveness. J Nutr 1999;129:1524 Wells SM, Kew S, Yaqoob P, Wallace FA, Calder PC. Dietary glutamine enhances cytokine production by murine macrophages. Nutrition 1999;15:881 Ardawi MSM. Effect of glutamine-enriched total parenteral nutrition on septic rats. Clin Sci 1991;81:215 Inoue Y, Grant JP, Snyder PJ. Effect of glutamine-supplemented intravenous nutrition on survival after Escherichia coli-induced peritonitis. JPEN 1993;17:41 Naka S, Saito H, Hashiguchi Y, et al. Alanyl-glutamine-supplemented total parenteral nutrition improves survival and protein metabolism in rat protracted bacterial peritonitis model. JPEN 1996;20:417 Suzuki I, Matsumoto Y, Adjei AA, et al. Effect of a glutamine-supplemented diet in response to methicillin-resistant Staphylococcus aureus infection in mice. J Nutr Sci Vitaminol 1993;39:405 Ziegler TR, Bye RL, Persinger RL, et al. Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 1998;315:4
PII S0899-9007(99)00233-6
Arginine and Immunonutrition: A Reevaluation Arginine has been classified as a semiessential amino acid because of its nutritional requirement for the optimal growth of some species, but not humans. Over the past two decades, studies have shown arginine to be a powerful mediator of multiple biological processes including the release of several hormones, collagen synthesis during wound healing, antitumor activity, and immune
Correspondence to: Adrian Barbul, MD, Department of Surgery, Sinai Hospital, 2401 West Belvedere Avenue, Baltimore, MD 21215, USA. E-mail: [email protected]
FIG. 1. Amounts of arginine in specialized enteral diets (US products).
cell responses. Although all hold significant interest to clinicians, the latter has the furthest reaching implications. Early animal experiments have delineated some of the effects that arginine has on the immune system. Normal rodents given a 1% arginine HCl supplementation to their normal diet (1.8% arginine content) have demonstrated increased thymic weight secondary to increased numbers of total thymic T lymphocytes.1 This thymotropic effect correlates functionally with increased thymic lymphocyte blastogenesis in response to mitogens. Supplemental dietary arginine also minimizes or abrogates posttraumatic thymic involution and T cell suppression.2 In the athymic mouse, supplemental arginine increases the number of T cells and heightens delayed-type hypersensitivity responses, suggesting a thymicindependent mechanism for the effect of arginine on T cell activity.3 Although the function of other cells of the immune system has not been studied after dietary arginine supplementation, there is increasing evidence that arginine and its metabolites are integral to the activity and interactions of macrophages and polymorphonuclear cells. The clinical significance of arginine’s immunomodulatory ability has been evaluated primarily in experimental models of bacterial peritonitis and burns. Rats subjected to cecal ligation and puncture have demonstrated a significantly increased survival when given doses of 100 mg of arginine HCl by gavage three times a day; the survival advantage was further improved when gavage treatment preceded the onset of sepsis.4 Balb/C mice undergoing cecal ligation and puncture and fed a 2% arginine supplemented diet had a doubling of survival rates (28% to 56%).5 Guinea pigs subjected to 30% total body surface burns and supplemented with 2% arginine had a 30% greater survival rate.6 The same level of supplementation decreased bacterial translocation to liver and spleen in mice subjected to 20% body surface burn injury.5 Human studies have shown that arginine increases T cell mitogenic responses when given at doses of 30 g/d. This effect has been noted in healthy volunteers and in severely ill intensive care patients.7,8 There is a lack of well-conducted studies examining the effect of arginine supplementation on clinical outcome benefits in patients. Recently, special enteral diets have been formulated to contain high amounts of arginine together with -3 fatty acids, glutamine, and nucleic acids. The intent is to enhance or preserve the responsiveness of the cellular components of the immune system and/or to reduce harmful and exaggerated inflammatory responses. This therapeutic approach has been termed immunonutrition. Previous animal and human investigation has demonstrated that a supplementation of 5 to 12 g of arginine/1000 kcal induces enhanced T cell activity. The arginine concentrations of the commercially available dietary formulations vary greater than two-fold, but all contain higher amounts than those required for normal or postinjury nutriture (Fig. 1). The concept of immunonutrition has gained much clinical