1. Introduction
Among the 20 amino acids detailed in the genetic code, glutamine provides the best example of the versatility of amino acid metabolism and immune function. Glutamine is the most abundant and versatile amino acid in the body, and is of fundamental importance to intermediary metabolism, interorgan nitrogen exchange via ammonia (NH3) transport between tissues, and pH homeostasis. In almost every cell, glutamine can be used as a substrate for nucleotide synthesis (purines, pyrimidines, and amino sugars), nicotinamide adenine dinucleotide phosphate (NADPH), antioxidants, and many other biosynthetic pathways involved in the maintenance of cellular integrity and function [2,3,4].
Most cells in the body function with a constant turnover and/or supply of nutrients, however, cells of the immune system frequently have to function under nutrient restricted microenvironments [1]. Although glucose is a vital metabolite, and the main fuel for a large number of cells in the body, cells of the immune system, such as lymphocytes, neutrophils, and macrophages, utilize glutamine at high rates similar to or greater than glucose under catabolic conditions, such as sepsis, recovery from burns or surgery, and malnutrition, as well as high intensity/volume physical exercise [5,6]. This theory was first experimentally confirmed in the 1980’s by the laboratory of Eric Newsholme (1935–2011, widely accepted now as the origin of hypotheses and evidence for the concept of “immunometabolism”) [3,7] in the University of Oxford, and subsequently by many other laboratories worldwide [4,8,9]. For this reason, glutamine is considered as a “fuel for the immune system”, where a low blood concentration may impair immune cell function, resulting in poor clinical outcomes and increased risk of mortality [10].
2. A Brief Overview of Glutamine Metabolism
Glutamine tissue and blood concentrations are dependent on GS or GLS activities. Endogenous glutamine synthesis does not meet the human body’s demands in catabolic conditions, such as in cancer [25], sepsis [4,26], infections [27,28], surgeries [8], traumas [10], as well as during intense and prolonged physical exercise [29,30].
However, it is worth emphasizing that, although plasma glutamine concentration is reduced from its normal concentration (i.e., 500–800 μmol/L) to 300–400 μmol/L, cells depending on this amino acid, such as immune cells, are in fact poorly influenced in terms of proliferation and function [6]. On the other hand, the high tissue catabolism leads to reduced glutamine stock in human tissues, mainly in the muscle and liver (Figure 3). The low glutamine concentration in human tissues affects the whole body since this amino acid provides nitrogen atoms to the synthesis of purines, pyrimidines, and amino sugars [31]. If the high glutamine degradation in these tissues persists, a large number of metabolic pathways and mechanisms that depend on glutamine availability are affected, resulting in immunosuppression.
3. Key Metabolic Organs in Glutamine Homeostasis
3.1. The Gut
3.2. Skeletal Muscles
3.3. The Liver
4. Glutamine and Immune Cell Function
During infection and/or high catabolism, the rate of glutamine consumption by all immune cells is similar or greater than glucose [89,90].
In immune cells, glucose is mainly converted into lactate (glycolysis), whereas glutamine is converted into glutamate, aspartate, and alanine by undergoing partial oxidation to CO2, in a process called glutaminolysis [3] (Figure 3). This unique conversion plays a key role in the effective functioning of immune system cells.
4.1. Neutrophils
The primary substrate for neutrophil survival endocytosis and ROS generation is glucose. However, glucose is not the only energy metabolite source by these cells. Interestingly, when compared to other leukocytes, such as macrophages and lymphocytes, neutrophils consume glutamine at the highest rates [98,99]. Much of the glutamine is converted to glutamate, aspartate (via Krebs cycle activity), and lactate in neutrophils.
4.2. Macrophages
Metabolism of glucose and glutamine is profoundly affected during the macrophage activation process [103,104]. The effects of thioglycollate (an inflammatory stimulus) and Bacillus Calmette-Guérin—BCG (an activation stimulus) on macrophage glucose and glutamine metabolism have been studied [105]. Either thioglycollate or BCG enhances activities of hexokinase and citrate synthase, and also glucose oxidation whereas BCG markedly increases glutamine metabolism. Lipopolysaccharide (LPS) administration also causes pronounced changes in macrophage metabolism and function (for a review, see Nagy and Haschemi [106].
Treatment of macrophages with LPS promotes a switch from glucose-dependent oxidative phosphorylation to aerobic glycolysis—the Warburg effect [116].
4.3. Lymphocytes
Lymphocyte activation is associated with specific metabolic pathways to optimize its function. The integration of multiple extracellular signals affects transcriptional programs and signalling pathways that determine, in CD4+ T cells, for example, multiple events that include modulation of energy metabolism, cell proliferation, and cytokine production.
Glycolysis and glutaminolysis are strongly associated to ensure appropriateness for lymphocyte function.
5. Immunomodulatory Properties of Glutamine Supplementation
Plasma glutamine concentration may be decreased during intense immune cell activity in patients with critical disease conditions; as occurs in sepsis, burn, and injury. Skeletal muscle is the main source of glutamine in mammals. This tissue synthesizes, stores, and releases this amino acid to be used by several organs and cells, such as lymphoid organs and leukocytes [89], as mentioned above. A decrease in plasma/bloodstream glutamine levels results of either insufficient glutamine production in skeletal muscle or excessive consumption by utilizing-cells or both (Figure 2). The decrease in plasma glutamine availability has been reported to contribute to the impaired immune function in several clinical conditions.
Concerning the mechanism of action, glutamine regulates the expression of several genes of cell metabolism, signal transduction proteins, cell defence, and repair regulators, and to activate intracellular signalling pathways [2].
5.1. Glutamine-GSH Axis and the Redox State of the Cell
5.2. Heat Shock Protein Response
The ability of all living organisms to respond with rapid and appropriate modifications against physiological challenges is an essential feature for survival. At the most basic cellular level, living organisms respond to unfavourable conditions, such as heat shock, toxins, oxidants, infection, inflammation, and several other stressful situations, by changing the expression of stress-related genes, also known as heat shock genes. This response involves the rapid induction of a specific set of genes encoding for cytoprotective proteins, known as HSP’s [94].
Glutamine found at concentrations similar to those recorded for human plasma leads to a significant HSP72 gene expression increase in peripheral blood mononuclear cells subjected to LPS treatment. On the other hand, reduced glutamine concentration results in reduced HSP72 expression in monocytes; this effect depends on mRNA stability.
6. Clinical Translation of Glutamine Delivery
Glutamine is found in relatively high concentrations in vegetable and animal protein-based foods (Table 1)
On the contrary, during major and/or critical illness, sepsis, trauma, and post-surgery circumstances, patients suffer from chronic weakness and several nutritional limitations (e.g., state of unconsciousness, gastrointestinal disturbances, and/or chew related problems), which impair homeostasis, and are associated with poor clinical outcomes. Severe disturbances in amino acid metabolism and/or intermediary metabolism followed by skeletal muscle proteolysis are key characteristics of hypermetabolic/hypercatabolic states [167]. During hypercatabolism, some non-essential amino acids, including glutamine, become conditionally essential.
Glutamine is usually administrated by utilizing its free form (also known as an isolated amino acid), or bond with another amino acid, also known as the dipeptide form (Figure 4). Several glutamine dipeptides with potential recovery health benefits have been described, such as l-glycyl-l-glutamine (Gly-Gln) and l-arginyl-l-glutamine (Arg-Gln); however, the most well-known is possibly l-alanyl-l-glutamine (Ala-Gln) [170]. Given parenterally, many clinical and experimental studies and appropriate systematic reviews [168] have concluded that glutamine dipeptides can reduce the rate of infectious complications [171,172,173,174], length of hospital stay [9,175], and mortality of critically ill patients [10,176,177].
Glutamine metabolism and supplementation in cancer has also raised many concerns among the scientific community, and deserve some comments. It is well established that cancer cells are extremely dependent of glutamine metabolism and availability, however, the role played by glutamine in cancer/tumours cells in vivo is still controversial, and thus the effects of the supplementation. Cancer cells take advantage of aerobic glycolysis (also known as the Warburg effect), and therefore glucose to maintain the supraphysiological survival and growth [185,186]. On the other hand, there is an increasing evidence of the role of oncogenes and tumour suppressors in the regulation of nutrient metabolism [187]. Aberrant mutations in these genes lead to altered nutrient metabolism, and can significantly contribute to the development and/or progression of cancer cells [186]. For instance, glucose, glutamine, lipids, and acetate can be utilized as carbon and energy sources [25].
The variances in cancer cells’ nutrient metabolism suggest that different nutritional approaches should be taken into consideration. However, studies have also targeted whether a glutamine exogenous supply may attenuate the side effects promoted by chemotherapy and radiation in cancer patients [193]. In a systematic review, Sayles, et al. [194] reported that in 11 of 15 studies, oral glutamine supplementation (dose range: 30 g/day in 3 divided doses, or 7.5–24 g/day) significantly reduced the grade of mucositis (common in 90% of head/neck cancer patients) [193] and/or attenuated weight loss in cancer patients. In a double-blind, placebo-controlled, randomized trial, colorectal cancer patients undergoing chemotherapy were supplemented with 18 g/day of glutamine (five days before and during the treatment). Glutamine treatment reduced the side-effects induced by chemotherapy, such as intestinal absorption and permeability, diarrhea, and gut mucositis [195].
Low plasma glutamine level (hypoglutaminemia) is usually used as a parameter to indicate the need for a glutamine exogenous supply. However, the correlation between the concentration of glutamine in plasma and tissue vary significantly between hypercatabolic patients, and therefore among studies [150].
Referência:
Nutrients. 2018;10(11):1564.