Glutamine is a non-essential amino acid that is the primary fuel source for the intestinal epithelial cells (enterocytes) that line the gastrointestinal tract and the most important nutrient for the maintenance of gut barrier integrity, immune function, and the prevention of the bacterial translocation that is associated with sepsis in critically ill patients. Glutamine is synthesised in the body from glutamate and from the branched-chain amino acid valine, but during critical illness, infection, major surgery, chemotherapy, radiation therapy, and other conditions that produce physiological stress, the demand for glutamine by the gut, the immune system, and the rapidly proliferating cells of the intestinal epithelium exceeds the body capacity to synthesise it, making glutamine a conditionally essential amino acid in these contexts. This glutamine-dependent vulnerability of the gut and the immune system is one of the most important and least appreciated factors in critical care nutrition and in the metabolic response to physiological stress.
Glutamine and the Intestinal Epithelium
The intestinal epithelial cell (enterocyte) is one of the most rapidly proliferating cell types in the body — it is completely renewed every 3-5 days, and this rapid turnover requires a constant supply of glutamine, which is the primary fuel for enterocyte metabolism. Glutamine is oxidised in enterocytes via the TCA cycle (after conversion to glutamate and then to alpha-ketoglutarate) and provides the ATP that powers the transporters, the enzymes, and the cell division machinery of the rapidly proliferating enterocyte. The importance of glutamine for intestinal epithelial function is underscored by the observation that glutamine deprivation (as occurs in critical illness when glutamine levels fall dramatically due to the combined effects of stress-induced consumption and inadequate intake) produces intestinal mucosal atrophy, gut barrier dysfunction, bacterial translocation (the passage of bacteria from the gut lumen into the portal circulation), and in severe cases, the sepsis that is one of the most common causes of death in critically ill patients.
The clinical importance of glutamine for gut barrier function is demonstrated by the observation that glutamine supplementation in critical illness reduces the incidence of infectious complications (including pneumonia, sepsis, and wound infections) and may reduce mortality in some subgroups of critically ill patients. A meta-analysis of 20 RCTs in critically ill patients found that glutamine supplementation at 0.5-1g/kg body weight daily significantly reduced the incidence of infectious complications and the length of hospital stay, with a non-significant trend toward reduced mortality. However, the evidence is mixed — some large RCTs have failed to show a benefit of glutamine in critical illness, and the 2013 REDOXS trial found that glutamine supplementation in critically ill patients with multi-organ failure was associated with increased mortality. The reasons for this discordant finding are not entirely clear but may relate to the high dose of glutamine used in the REDOXS trial (0.75g/kg four times daily) and to the inclusion of the most severely ill patients, in whom glutamine may be contraindicated.
Glutamine and Immune Function
Beyond its role as a fuel for the intestinal epithelium, glutamine is also a critical nutrient for the immune system — it is required for the proliferation and function of lymphocytes (T cells, B cells, NK cells), for the production of cytokines by immune cells, and for the maintenance of the gut-associated lymphoid tissue (GALT), which is the largest immune organ in the body. The lymphocytes of the immune system have a very high rate of proliferation (they must rapidly expand in number in response to infection), and this rapid proliferation requires glutamine as a fuel and as a precursor for the synthesis of the nucleic acids, proteins, and signalling molecules that are essential for lymphocyte function. When glutamine is limiting (as in critical illness), the proliferation of lymphocytes is impaired, the immune response to infection is blunted, and the risk of infectious complications is increased.
Practical Application
For general glutamine supplementation (as a gut barrier and immune support strategy), the evidence-based dose is 2-5g of L-glutamine daily, divided into 2 doses and taken between meals for optimal absorption. Glutamine is generally well-tolerated with no significant adverse effects at therapeutic doses. The primary clinical indications for glutamine supplementation are gut barrier dysfunction (as an adjunct to the standard treatment of inflammatory bowel disease, celiac disease, and small intestinal bacterial overgrowth), immune support during periods of physiological stress (post-surgery, post-infection, during chemotherapy or radiation therapy), and athletic performance support (for the reduction of exercise-induced gut dysfunction and for the support of the immune system during intense training). For comprehensive gut barrier support, glutamine pairs well with the probiotics (which support the gut microbiota and which complement the gut barrier-supporting effects of glutamine), with the omega-3 fatty acids (which have anti-inflammatory effects in the gut), with zinc (which is required for the tight junction proteins that regulate intestinal permeability), with vitamin D (which has immunomodulatory effects in the gut and which supports the gut immune system), and with the mucosal healing nutrients (including deglycyrrhizinated licorice, zinc carnosine, and the amino acid glutamine itself, which together constitute the comprehensive mucosal healing regimen that is appropriate for people with gut barrier dysfunction).
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