Glutamine Metabolism in Sepsis and Infection

Abstract

Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.

Corticosteroids increase glutamine utilization in human splanchnic bed

“…This result is consistent with those of SuojarantaYlinen et al (41), who showed that 2 h after a coronary bypass the splanchnic extraction of glutamine rose by 56%, along with that of alanine, serine, and threonine. In sepsis, glutamine uptake by the gut is decreased (27). In contrast, endotoxemia was found to be associated with a dramatic rise in glutamine uptake by the liver (2).…”

“…In several animal models of sepsis, increased rates of glutamine splanchnic extraction have been reported (27,40,41), but little is known in humans. In the present paper, the fate of splanchnic glutamine was examined by using the concomitant infusion of (18), the choice of tracer is unlikely to account for the observed changes in glutamine kinetics associated with prednisone.…”

“…Glutamine is known to play a pivotal role in the gut, because glutamine not only serves as a preferred fuel for the enterocytes but also helps maintain rates of intestinal protein synthesis (8,30,31) and cell integrity and stimulates immune function as well (9). During inflammation, increased glutamine consumption by lymphocytes and macrophages in gut-associated lymphoid tissue (GALT) could occur, as these cells are avidly utilizing glutamine (27). Yet increased use of glutamine by GALT should increase its oxidation.…”

“…By using this technique, ϳ50 to 75% of enterally administered glutamine undergoes first-pass extraction within the splanchnic bed, presumably by the gut and liver, in healthy humans (4, 17, 18, 34). Additionally, the major fate of splanchnic glutamine after enteral administration was oxidation, since 83% of the total tracer extracted was oxidized and only 10% was used for gluconeogenesis (17).A dramatic rise in the rate of glutamine uptake in splanchnic tissues has been documented in animal models of stress or after administration of glucocorticoids, which are believed to mediate some of the protein catabolic response to stress (2,27,38,40,42). It is well known that glucocorticoids mimic some of the alterations in amino acid metabolism observed in stressinduced protein wasting (5,24,35).…”

“…A dramatic rise in the rate of glutamine uptake in splanchnic tissues has been documented in animal models of stress or after administration of glucocorticoids, which are believed to mediate some of the protein catabolic response to stress (2,27,38,40,42). It is well known that glucocorticoids mimic some of the alterations in amino acid metabolism observed in stressinduced protein wasting (5,24,35).…”