Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation

Vinicius Cruzat; Marcelo Macedo Rogero; Kevin Noel Keane; Rui Curi; Philip Newsholme

doi:10.3390/nu10111564

journal article Open Access Oct 23, 2018

Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation

Vinicius Cruzat

Marcelo Macedo Rogero Kevin Noel Keane Rui Curi Philip Newsholme

Nutrients Vol. 10 No. 11 pp. 1564 · MDPI AG

View at Publisher Save 10.3390/nu10111564

Abstract

Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.

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References

201

[1]

Grohmann "Amino-acid sensing and degrading pathways in immune regulation" Cytokine Growth Factor Rev. (2017) 10.1016/j.cytogfr.2017.05.004

[2]

Curi "Molecular mechanisms of glutamine action" J. Cell. Physiol. (2005) 10.1002/jcp.20339

[3]

Curi "Regulatory principles in metabolism-then and now" Biochem. J. (2016) 10.1042/bcj20160103

[4]

Cruzat "Oral supplementations with free and dipeptide forms of l-glutamine in endotoxemic mice: Effects on muscle glutamine-glutathione axis and heat shock proteins" J. Nutr. Biochem. (2014) 10.1016/j.jnutbio.2013.11.009

[5]

Newsholme "Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?" J. Nutr. (2001) 10.1093/jn/131.9.2515s

[6]

Cruzat "Amino acid supplementation and impact on immune function in the context of exercise" J. Int. Soc. Sports Nutr. (2014) 10.1186/s12970-014-0061-8

[7]

Ardawi "Maximum activities of some enzymes of glycolysis, the tricarboxylic acid cycle and ketone-body and glutamine utilization pathways in lymphocytes of the rat" Biochem. J. (1982) 10.1042/bj2080743

[8]

Flaring "Glutamine attenuates post-traumatic glutathione depletion in human muscle" Clin. Sci. (2003) 10.1042/cs1040275

[9]

Roth "Nonnutritive effects of glutamine" J. Nutr. (2008) 10.1093/jn/138.10.2025s

[10]

Rodas "Glutamine and glutathione at icu admission in relation to outcome" Clin. Sci. (2012) 10.1042/cs20110520

[11]

Newsholme "Properties of glutamine release from muscle and its importance for the immune system" J. Parenter. Enter. Nutr. (1990) 10.1177/014860719001400406

[12]

Wernerman "Clinical use of glutamine supplementation" J. Nutr. (2008) 10.1093/jn/138.10.2040s

[13]

Berg "Glutamine kinetics during intravenous glutamine supplementation in icu patients on continuous renal replacement therapy" Intensive Care Med. (2007) 10.1007/s00134-007-0547-9

[14]

Labow "Mechanisms governing the expression of the enzymes of glutamine metabolism—Glutaminase and glutamine synthetase" J. Nutr. (2001) 10.1093/jn/131.9.2467s

[15]

Cruzat, V.F., and Newsholme, P. (2017). An introduction to glutamine metabolism. Glutamine, CRC Press. 10.1201/9781315373164-1

[16]

Cooney "Activities of some key enzymes of carbohydrate, ketone-body, adenosine and glutamine-metabolism in liver, and brown and white adipose tissues of the rat" Biochem. Biophys. Res. Commun. (1986) 10.1016/s0006-291x(86)80551-4

[17]

Tan "Glutamine metabolism regulates autophagy-dependent mtorc1 reactivation during amino acid starvation" Nat. Commun. (2017) 10.1038/s41467-017-00369-y

[18]

Ardawi "Glutamine metabolism in the lungs of glucocorticoid-treated rats" Clin. Sci. (1991) 10.1042/cs0810603

[19]

Dimitriadis "Effects of hyperthyroidism and hypothyroidism on glutamine metabolism by skeletal muscle of the rat" Biochem. J. (1990) 10.1042/bj2720319

[20]

Dimitriadis "The effects of growth hormone administration in vivo on skeletal muscle glutamine metabolism of the rat" Horm. Metab. Res. (1993) 10.1055/s-2007-1002101

[21]

Cruzat "Alanyl-glutamine improves pancreatic beta-cell function following ex vivo inflammatory challenge" J. Endocrinol. (2015) 10.1530/joe-14-0677

[22]

Krebs "Metabolism of amino-acids: The synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues" Biochem. J. (1935) 10.1042/bj0291951

[23]

Neu "Glutamine nutrition and metabolism: Where do we go from here?" FASEB J. (1996) 10.1096/fasebj.10.8.8666159

[24]

Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements

Milan Holeček

Nutrition & Metabolism 2018 10.1186/s12986-018-0271-1

[25]

Altman "From krebs to clinic: Glutamine metabolism to cancer therapy" Nat. Rev. Cancer (2016) 10.1038/nrc.2016.71

[26]

Kao "Alterations in glutamine metabolism and its conversion to citrulline in sepsis" Am. J. Physiol. Endocrinol. Metab. (2013) 10.1152/ajpendo.00628.2012

[27]

Rogero "Ffect of glutamine supplementation and in vivo infection with mycobacterium bovis (bacillus calmette-guerin) in the function of peritoneal macrophages in early weaned mice" Ann. Nutr. Metab. (2007)

[28]

Karinch "Glutamine metabolism in sepsis and infection" J. Nutr. (2001) 10.1093/jn/131.9.2535s

[29]

Leite "l-glutamine and l-alanine supplementation increase glutamine-glutathione axis and muscle hsp-27 in rats trained using a progressive high-intensity resistance exercise" Appl. Physiol. Nutr. Metab. (2016) 10.1139/apnm-2016-0049

[30]

Cruzat "Effects of supplementation with free glutamine and the dipeptide alanyl-glutamine on parameters of muscle damage and inflammation in rats submitted to prolonged exercise" Cell Biochem. Funct. (2010) 10.1002/cbf.1611

[31]

Curi "Glutamine-dependent changes in gene expression and protein activity" Cell Biochem. Funct. (2005) 10.1002/cbf.1165

[32]

Djoko "Interplay between tolerance mechanisms to copper and acid stress in Escherichia coli" Proc. Nat. Acad. Sci. USA (2017) 10.1073/pnas.1620232114

[33]

Wernerman "Feeding the gut: How, when and with what—The metabolic issue" Curr. Opin. Crit. Care (2014) 10.1097/mcc.0000000000000066

[34]

Beutheu "Glutamine supplementation, but not combined glutamine and arginine supplementation, improves gut barrier function during chemotherapy-induced intestinal mucositis in rats" Clin. Nutr. (2014) 10.1016/j.clnu.2013.09.003

[35]

Souba "Glutamine metabolism by the intestinal tract" J. Parenter. Enter. Nutr. (1985) 10.1177/0148607185009005608

[36]

Holecek "Side effects of long-term glutamine supplementation" J. Parenter. Enter. Nutr. (2013) 10.1177/0148607112460682

[37]

Kim, M.H., and Kim, H. (2017). The roles of glutamine in the intestine and its implication in intestinal diseases. Int. J. Mol. Sci., 18. 10.3390/ijms18051051

[38]

Souba "Gut glutamine metabolism" J. Parenter. Enter. Nutr. (1990)

[39]

Cruzat "Oral free and dipeptide forms of glutamine supplementation attenuate oxidative stress and inflammation induced by endotoxemia" Nutrition (2014) 10.1016/j.nut.2013.10.019

[40]

Aosasa "Influence of glutamine-supplemented caco-2 cells on cytokine production of mononuclear cells" J. Parenter. Enter. Nutr. (2003) 10.1177/0148607103027005333

[41]

Coeffier "Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa" Am. J. Physiol. Gastrointest. Liver Physiol. (2003) 10.1152/ajpgi.00385.2002

[42]

Jobin "Mediation by nf-kappa b of cytokine induced expression of intercellular adhesion molecule 1 (icam-1) in an intestinal epithelial cell line, a process blocked by proteasome inhibitors" Gut (1998) 10.1136/gut.42.6.779

[43]

Coeffier "Influence of glutamine on cytokine production by human gut in vitro" Cytokine (2001) 10.1006/cyto.2000.0813

[44]

Rajendram, R., Preedy, V.R., and Patel, V.B. (2015). Glutamine and skeletal muscle. Glutamine in Clinical Nutrition, Springer. 10.1007/978-1-4939-1932-1

[45]

Cruzat "Effects of oral supplementation with glutamine and alanyl-glutamine on glutamine, glutamate, and glutathione status in trained rats and subjected to long-duration exercise" Nutrition (2009) 10.1016/j.nut.2008.09.014

[46]

Walsh "Glutamine, exercise and immune function. Links and possible mechanisms" Sports Med. (1998) 10.2165/00007256-199826030-00004

[47]

Rowbottom "The emerging role of glutamine as an indicator of exercise stress and overtraining" Sports Med. (1996) 10.2165/00007256-199621020-00002

[48]

Curi "Glutamine, gene expression, and cell function" Front. Biosci. (2007) 10.2741/2068

[49]

Rogero "Effect of alanyl-glutamine supplementation on plasma and tissue glutamine concentrations in rats submitted to exhaustive exercise" Nutrition (2006) 10.1016/j.nut.2005.11.002

[50]

Rogero "Plasma and tissue glutamine response to acute and chronic supplementation with l-glutamine and l-alanyl-l-glutamine in rats" Nutr. Res. (2004) 10.1016/j.nutres.2003.11.002

Showing 50 of 201 references

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Details

Published: Oct 23, 2018
Vol/Issue: 10(11)
Pages: 1564
License: View

Authors

V

Vinicius Cruzat

School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia; Faculty of Health, Torrens University, Melbourne 3065, Australia

M

Marcelo Macedo Rogero

Department of Nutrition, Faculty of Public Health, University of São Paulo, Avenida Doutor Arnaldo 715, São Paulo 01246-904, Brazil

K

Kevin Noel Keane

School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia

R

Rui Curi

Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil

P

Philip Newsholme

School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia

Cite This Article

Vinicius Cruzat, Marcelo Macedo Rogero, Kevin Noel Keane, et al. (2018). Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients, 10(11), 1564. https://doi.org/10.3390/nu10111564

Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation

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