Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation

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.

Keywords: amino acids; gut; leukocytes; liver; nutrition; skeletal muscle.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Glutamine synthesis and hydrolysis. Glutamine is mainly synthesized by the enzyme glutamine synthetase (GS) and hydrolysed by the enzyme, glutaminase (GLS). GS catalyses glutamine biosynthesis using glutamate and ammonia (NH3) as a source. In this reaction, one ATP is consumed. Glutamate can be donated by many amino acids obtained exogenously (i.e., diet) and/or from endogenous amino acids’ catabolism. On the other hand, GLS is responsible for glutamine hydrolysis to glutamate and ammonium ion (NH4). Almost all cells in the body express GS and GLS, and their predominant expression and activity will dictate if the tissue is more likely to produce or consume glutamine in health and disease.

Figure 2

Intertissue glutamine production and utilisation in health and catabolic/hypercatabolic situations. Filled arrows indicate tissues that exhibit GS activity and thus produce glutamine; white arrows indicate tissues that exhibit GLS activity, and thus consume glutamine. In health and/or fed states, glutamine stores are in equilibrium in plasma/bloodstream and tissues, and are maintained constantly mainly by the liver and skeletal muscles, two major stores of glutamine in the body. On the other hand, cells of the immune system are extremely dependent on glucose and glutamine in situation (A), and even more in situation (B). Although the gut is a major site of glutamine consumption, in situation (B), there is a dramatic increase in glutamine consumption from both the luminal and basolateral membrane, when compared to situation (A). In addition, the liver switches the role of a major producer to a major glutamine consumer to maintain gluconeogenesis, and the whole body relies on the skeletal muscle’s ability/stores to maintain glutamine levels. However, this process is usually accompanied by a dramatic increase in muscle proteolysis, atrophy, and cachexia. The lungs and adipose tissue exhibit both GS and GLS enzymes, and hence can produce and consume glutamine in situations (A) and (B). The brain and the kidneys do not exhibit GS, only GLS, and hence are mainly dependent on plasma glutamine availability in situations (A) and (B).

Figure 3

Glutamine inter-tissue metabolic flux starting in skeletal muscle, liver, and gut continues in the immune cells. Abbreviations: Glutamine, GLN; glutamate, GLU; aspartate, ASP; arginine, ARG; leucine, LEU; alanine, ALA; glucose, Gluc; pyruvate, Pyr; pyruvate dehydrogenase; PDC; pyruvate carboxylase, PC; malate dehydrogenase, MD; glyceraldehyde-3-Phosphate, G3-P; lactate, Lac; triacylglycerol, TG; ribose 5-phosphate, R5P; alanine aminotransferase, ALT; glutamate dehydrogenase, GDH; glutamine synthetase, GS; glutaminase, GLS; inducible nitric oxide synthase, iNOS; intracellular heat shock protein, iHSP; heat Shock Factor 1, HSF-1; heat shock elements, HSEs; sirtuin 1, SIRT1; hexosamine biosynthetic pathway, HBP; ammonia, NH3; glutathione, GSH; oxidized GSH, GSSG; glutathione S-reductase, GSR; protein kinase B, Akt; AMP-activated protein kinase, AMPK; mTOR complex 1 and 2, mTORC1/2, extracellular signal-regulated kinases, ERK; c-Jun N-terminal kinases, JNK; gamma-Aminobutyric acid, GABA.

Figure 4

Mechanisms of enteral and parenteral glutamine (GLN) supply. Glutamine is an important substrate for rapidly dividing cells, such as enterocytes. This is a major site of glutamine consumption obtained from both exogenous/diet (luminal membrane) and/or endogenous glutamine synthesis (basolateral membrane). Free glutamine supplementation is mainly metabolized in the gut and poorly contribute to glutaminemia and tissue stores. On the other hand, glutamine dipeptides (e.g., Ala-Gln, Gly-Gln, Arg-Gln) escape from the gut metabolization and quickly supply glutamine to the plasma and target tissues. This effect is mainly attributed to the oligopeptide transporter 1 (Pept-1) located in the luminal membrane of the enterocytes.