Title: Glutamine And Immune Function In The Athlete.

Key words: amino acid, immune function, nucleotide biosynthesis, catabolic state, gluconeogenesis, plasma glutamine, over-training syndrome, lymphocytes, neutrophils, endotoxaemia, antibody synthesis, glutamine supplementation

Date: Aug 2000

Category: 12. Sports

Type: Article

Author: Dr Van Rhijn

 

 

Glutamine And Immune Function In The Athlete

 

Introduction

Glutamine, the most abundant and extensively studied non-essential amino acid in the body, is mainly synthesised and released by muscle. Overworked muscle after prolonged exercise may fail to supply adequate glutamine for normal immune function, and its role for supplementation for the athlete will be further discussed.

 

Precipitating Factors in Sport

Athletes, especially those involved in prolonged exercise, are often in catabolic state regarding their muscle proteins, thereby releasing mainly alanine and glutamine (nitrogen carrier)1, which are deaminated in the liver and kidney to provide an energy substrate in the form of increased gluconeogenesis2 at the cost of a negative nitrogen balance. The plasma level of glutamine (normal range 500 to 750 mmol/L after an overnight fast), an important fuel for cells of the immune system, is decreased in athletes after endurance exercise3,4. Glutamine may therefore become ‘conditionally essential’ to compensate for the usually transient (6-9 hrs) decrease in plasma glutamine levels (35-50%) during the post exercise recovery period, but may remain low for weeks despite rest5. 

 

Athletes are at risk of developing an ‘overtraining syndrome’6 (this may present as a chronic fatigue syndrome) when their bodies are subjected to heavy monotonous, intense interval training alternating with a sudden increase in training schedules. The enormous stress coincides with an increased susceptibility to infections7 reflecting on an immuno-suppression8, associated with and contributed to by the reduced plasma glutamine levels. The short term effects of heavy exercise on the low plasma glutamine levels (< 500 mmol/L) may be cumulative, as athletes experiencing discomfort from the overtraining syndrome exhibit lower resting levels of plasma glutamine, levels requiring prolonged recovery9.

 

Adverse Effects of Prolonged Exercise on Immune Function

Research has shown a number of adverse changes in the immune function of elite athletes after prolonged and exhaustive exercise. After an initial, brief increase in circulating neutrophils, the number of lymphocytes fall below pre-existing levels during the recovery phase10. Other main findings are lower circulating numbers of T-lymphocytes (3-4 hours after exercise) and a decrease in the proliferative ability of lymphocytes. There are also decreased immunoglobulin levels (IgA) (blood / saliva11), neutrophil activity, cytolytic activity of natural killer (NK) cells and suppressed lymphokine activated killer (LAK) cell activities12. Acute phase response markers13, such as cytokines, especially IL-1, IL-2, IL-6, TNF, CRP and complement-5 were also raised. Antibody synthesis is impaired and the CD4:CD8 cell ratio decreased, being a possible cause of immunosuppression in athletes. During the time of immune impairment (which may last 3-72 h, depending on the immune measure), referred to as "the open window", microbial agents (especially viruses) may gain a foothold, increasing the risk for sub-clinical and clinical infection14.

 

Glutamine and the Immune System

Lymphocytes and macrophages utilise glutamine (catalytic activity of glutaminase) at a high rate as an essential for fuel15  (especially when stimulated) and nitrogen for nucleotide biosynthesis16 (nucleotides: purine & pyrimidine during cell division), mRNA synthesis and DNA repair. As such, it is considered to be essential for proper immune function. Glutamine plays an essential and specific role in maintaining function of rapidly proliferating cells such as lymphocytes (immuno-enhancing17,18) & mucosal enterocytes19. It is the preferential fuel for the gut for its trophic20 effects (increased villus height and decreased gut permeability21), making it an essential amino acid22 in times of stress. There is an increased susceptibility to infections in catabolic states, and glutamine-enriched diets and in vitro studies show a boost of the immune system by T23,24, CD4+25,26 and interleukin-2 receptor27,28 bearing lymphocyte proliferation, increasing CD4:CD8 29 ratio, macrophage proportion of TNF-a30, interleukins-1b & 631 and neutrophil activity32. A chronic reduction in the synthesis rate of glutamine leads to gut atrophy, bacterial translocation, endotoxaemia and a weakened immune status33,34.

 

Glutamine Supplementation

Glutamine and branched chain amino acid (precursors of glutamine)35 supplementation during long-term exercise was shown to prevent this decrease in the plasma glutamine levels and subsequent reduction in infections in these athletes 36, supporting the notion that glutamine has an immuno-stimulatory effect. The ratio of T-helper/T-suppressor cells also appeared to be increased, confirming that supplementation of oral glutamine may reduce the risk of infection37,38.

 

Not all studies support the hypothesis that those aspects of post-exercise immune changes studied are caused by decreased plasma glutamine concentrations39. Although glutamine supplementation may increase plasma glutamine levels (2g/day increases plasma levels by 19%), its effect on enhancement of the immune system and prevention of adverse effects of the overtraining syndrome are equivocal40. There are many potential mechanisms for a disturbance of immune function and most changes in nutritional status are short-lived. With the possible exceptions of ultra-endurance events, chronic overtraining and drastic attempts to reduce body mass 41, there is little evidence that resistance to infection is reduced in athletes participating in less strenuous sports. No serious attempt has been made by investigators to demonstrate that athletes showing the most extreme post-exercise immuno suppression are those that contract an infection during the ensuing 1 to 2 weeks42. This link must be established before the 'open window' theory can be wholly accepted. Furthermore, reductions in neutrophil function after exercise at 80% VO2max were not related to changes in the plasma glutamine concentration, although both plasma glutamine and neutrophil function were decreased at 1 and 2.5h post-exercise in the long duration exercise trial43. As far as the precursors of glutamine are concerned, in contrast to the claims made on sport nutrition products, branched-chain amino acids do not improve endurance performance, and the evidence that glutamine supplements may improve immune function is rather weak44.

 

Athletes and health conscious exercisers may occasionally adopt an unusual diet: megadoses of vitamins, large quantities of protein, carbohydrate or polyunsaturated fat, specific amino acid supplements, or an overall energy deficit, all of which may be beneficial to the immune system.

Since injury, infection, nutritional status and acute exercise can all influence plasma glutamine level, these factors must be controlled and/or taken into consideration if plasma glutamine is to prove a useful marker of impending overtraining.

 

Conclusion

There is an abundance of clinical evidence supporting the need for exogenous glutamine. Supplementation has an immuno-stimulatory function thereby enhancing resistance to infection, promoting gut integrity, improving nitrogen balance and lean tissue mass, and it may be viewed as a pharmaconutrient45 for athletes. However, little work has been done that examines the potential utility of glutamine for athletes engaged in heavy exercise training, and the role of glutamine as a possible ergogenic aid has not been posited in the scientific literature. Based on the available clinical evidence, one can only speculate that glutamine has potential utility as a dietary supplement for athletes engaged in heavy exercise training 46, and further studies are required to resolve the mechanism of glutamine within the immune system 47.

 

 

References

1. Calder, P.C. & Yaqoob, P. Glutamine and the immune system. Review Article. Amino Acids. 1999; 17: 227 – 241.

 

2. Walsh, N.P. Glutamine, exercise and immune function. Links and possible mechanisms. Sports Med., 1998; 26, 3:  177 – 191.

 

3. Keast, D. et al. Depression of plasma glutamine concentration after exercise stress and its possible influence on the immune system. Med. J. Aust., 1995; 162: 15 - 18.

 

4. Walsh, N.P. et al. The effects of high-intensity intermittent exercise on the plasma concentrations of glutamine and organic acids. Eur. J. Appl. Physiol., 1998; 77, 5: 434 – 438.

 

5. Parry-Billings, M. et al. A communicational link between skeletal muscle, brain and cells of the immune system. Int. J. Sports Med., 1990a; 11,2 (Suppl): S122 – 128.

 

6. Parry-Billings, M. et al. Plasma amino acid concentrations in the overtraining syndrome: possible effects on the immune system. Med. Sci. Sports Exerc., 1992; 24,12:1353 – 1358.

 

7. Nieman, D. Immune response to heavy exertion. J. Appl. Physiol., 1997; 82: 1385 – 1395.

 

8. Shabert, J. & Wilmore, D.W. Glutamine deficiency as a cause of human immunodeficiency virus wasting. Med. Hypoth., 1996; 46: 252.

 

8. Rowbottom, D.G. The emerging role of glutamine as an indicator of exercise stress and overtraining. Sports Med., 1996; 21, 2: 80 – 97.

 

10. Castell, L.M. et al. Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation. Eur. J. Appl. Physiol., 1996; 75: 47 – 53.  

 

11. Pedersen, B.K. et al. Exercise and the immune system--influence of nutrition and ageing.  J. Sci. Med. Sport., 1999; 2, 3: 234 – 252.

 

12. Rohde, T. et al. The immune system and serum glutamine during a triathlon.  Eur. J. Appl. Physiol., 1996; 74, 5: 428 – 434.

 

13. Sharp, N.C. & Koutedakis, Y. Sport and the overtraining syndrome: immunological aspects.  Br. Med. Bull., 1992; 48, 3: 518 – 533.

 

14. Nieman, D.C. Nutrition, exercise, and immune system function.  Clin. Sports Med., 1999; 18, 3: 537 – 548.

 

15. Ardawi, M.S.M. & Newsholme, E.A. Glutamine metabolism in lymphocytes of the rat. Bioch. J., 1983; 212: 835 – 842.

 

16. Wagenmakers, A.J. Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. Exerc. Sport Sci. Rev., 1998; 26: 287 – 314.

 

17. Wilmore, D.W. & Shabert, J.K. The role of glutamine in immunologic responses. Nutrition, 1998; 14: 618 – 626.

 

18. Newsholme, E.A. Biochemical mechanisms to explain immunosuppression in well-trained and overtrained athletes. Int. J. Sports Med., 1994; 15 (Suppl) 3: S142 – S147.

 

19. Scheppach, W. et al. Effect of free glutamine and alanyl-glutamine dipeptide on mucosal proliferation of the human ileum and colon. Gastroent., 1994; 107: 429 – 434.

 

20. van der Hulst, R.R et al. Glutamine and the preservation of gut integrity. Lancet, 1993; 341: 1363 – 1365.

 

21. Hall, J.C. et al. Glutamine. Br. J. Surg., 1996; 83: 305 – 312.

 

22. Lacey, J.M. & Wilmore, D.W. Is glutamine a conditionally essential amino acid? Nutr. Rev., 1991; 48: 297.

 

23. Yoo, S.S. et al. Glutamine supplementation maintains intramuscular glutamine concentrations and normalises lymphocyte function in infected early-weaned pigs. J. Nutr., 1997; 127: 2253.

 

24. Yaqoob, P. & Calder, P.C. Glutamine requirement of proliferating T lymphocytes. Nutrition, 1997; 13: 646 - 651.

 

25. Kew, S. et al. Dietary glutamine enhances murine T-lymphocyte responsiveness. J. Nutr., 1999; 129: 1524.

 

26. Ziegler, T.R. et al. Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am. J. Med. Sci., 1998; 315: 4.

 

27. Calder, P.C. & Newholme, E.A. Glutamine promotes interleukin-2 production by concanavalin A-stimulated lymphocytes. Proc. Nutr. Soc., 1992; 51:105A.

 

28. Yaqoob, P. & Calder, P.C. Cytokine production by human peripheral blood mononuclear cells: differential sensitivity to glutamine availability. Cytokine, 1998; 10: 790 - 794.

 

29. Jensen, G.L. et al. A double blind prospective, randomised study of glutamine-enriched compared with standard peptide based feeding in critically ill patients. Am. J. Clin. Nutr., 1996; 64: 615.

 

30. Murphy, C. & Newsholme, P. Macrophage-mediated lysis of a b-cell line, tumour necrosis factor-a release from bacillus Calmette-Guerin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism. Clin. Sci. 1999; 96: 89 - 97.

 

31. Wells, S.M. et al. Dietary glutamine enhances cytokine production by murine macrophages. Nutrition, 1999; 15: 881.

 

32. Furukawa, S. et al. Glutamine-enhanced bacterial killing by neutrophils from post-operative patients. Nutrition, 1997; 13: 863 - 869.

 

33. Wagenmakers, A.J. Amino acid metabolism, muscular fatigue and muscle wasting: Speculations on adaptations at high altitude. Int. J. Sports Med., 1992; 13 (Suppl 1): S110 – S113.

 

34. Miles, M.P. Blood leukocyte and glutamine fluctuations after eccentric exercise.  Int. J. Sports Med., 1999; 20, 5: 322 – 327.

 

35. Basset, R.A. et al. The effect of BCAA supplementation upon the immune response of triathletes. Int. J. Sports Med., 1999.

 

36. Castell, L.M. et al. Does glutamine have a role in reducing infections in athletes? Eur. J. Appl. Physiol., 1996; 73, 5: 488 – 491.      

 

37. Castell, L.M. & Newsholme, E.A. The effects of oral glutamine supplementation on athletes after prolonged exhaustive exercise. Nutrition, 1997; 13, 7-8: 738 – 742.

 

38. Castell, L.M. & Newsholme, E.A. Glutamine and the effect of exhaustive exercise upon the immune response. Can. J. Physiol. Pharmacol., 1998; 76,5: 524 – 532.

 

39. Rohde, T. et al. Effect of glutamine supplementation on changes in the immune system induced by repeated exercise. Med. Sci. Sports Exerc., 1998; 30, 6: 856 – 862.

 

40. Williams, M.H. Facts and fallacies of purported ergogenic amino acid supplements. Clin. Sports Med., 1999; 18, 3: 633 – 649.

 

41. Shephard, R.J. & Shek, P.N. Heavy exercise, nutrition and immune function: is there a connection? Int. J. Sports Med., 1995; 16, 8: 491 – 497.

 

42. Nieman, D.C. & Pedersen, B.K. Exercise and immune function. Recent developments. Sports Med., 1999; 27, 2: 73 – 80.

 

43. Robson, P.J. et al. Effects of exercise intensity, duration and recovery on in vitro neutrophil function in male athletes. Int. J. Sports Med., 1999; 20, 2: 128 – 135.

 

44. Wagenmakers, A.J. Amino acid supplements to improve athletic performance.  Curr. Opin. Clin. Nutr. Metab. Care., 1999; 2, 6: 539 – 544.

 

45. Calder, P. More Good News About Glutamine. Editorial Opinions, 1999; 71 – 73.

 

46. Antonio, J. & Street, C. Glutamine: a potentially useful supplement for athletes. Can. J. Appl. Physiol., 1999; 24, 1: 1 – 14.

 

47. Shephard, R.J. et al. Exercise and the immune system. Sports. Med., 1994; 18: 340 – 369.