Glutamine

• How It Works

  Glutamine may be helpful for preventing some symptoms related to cancer treatments, such as oral inflammation. Combined with other nutrients, it can prevent muscle wasting and weight loss in patients with advanced cancer and AIDS, but more research is needed.

  Glutamine is the most abundant amino acid in the human body. It is made by most body tissues and is also found in foods such as wheat, corn, barley, peanuts, soybeans, and milk. Glutamine is important for several bodily functions, like acting as building blocks for protein. When the body is malnourished or breaks down its own muscle protein, known as cachexia, taking extra glutamine can help restore body levels and prevent adverse health effects. For example, glutamine is the major fuel source of cells that line the intestinal tract, and is therefore important in maintaining GI function. It is also the major fuel source for certain cells used in the body’s immune defense. It removes excess toxic ammonia from the body and synthesizes glutathione to help detoxify foreign substances in the liver.

  Glutamine may help treat muscle wasting in patients with advanced cancer and AIDS and prevent oral inflammation related to certain cancer treatments. Initial studies also suggest it may help chemotherapy-related nerve pain. Larger well-designed trials are needed to confirm these effects.

• Purported Uses
  • To prevent cachexia (muscle wasting) in advanced cancer and AIDS
    Preliminary results show that a combination of glutamine, arginine, and beta-hydroxy-beta-methylbutyrate (Juven®) can promote weight gain in these patients, but the long-term effectiveness is not known.
  • To prevent mucositis caused by cancer-related treatments
    Several studies suggest that oral glutamine supplementation may be helpful as supportive care for inflammation of oral mucous membranes caused by cancer treatment. Larger confirmatory trials are needed.
  • To reduce chemotherapy-induced gastrointestinal toxicity
    One study showed that glutamine given intravenously to patients receiving chemotherapy for gastric or colorectal cancer significantly reduced nausea, vomiting, and diarrhea.
  • To treat chemotherapy-related neuropathy
    Preliminary studies suggest that glutamine may help treat neuropathy caused by chemotherapy.
  • To improve tissue integrity
    Clinical research supports the use of intravenous glutamine to enhance the integrity of the intestines in critically ill patients.
  • To stimulate the immune system
    Although glutamine is a necessary fuel source for lymphocytes, a type of immune cell, there is no solid evidence that glutamine supplements can stimulate the immune system in healthy people. In some studies, intravenous glutamine helps improve immune status, prevent infection, and prevent depletion of intestinal immune cells in critically ill patients and those recovering from surgery.
  • Intravenously, to improve recovery from surgery
    Several clinical trials support this use.
• Side Effects

  Some studies in cancer patients suggest that oral glutamine is well tolerated. However, others that used specific oral preparations reported adverse events including swelling, gastrointestinal symptoms, headache, fever, and infections.

• Special Point

  Although related, glutamine should not be confused with another amino acid known as glutamate.

• Clinical Summary

  Glutamine is an amino acid that can be absorbed from food sources and synthesized and stored, mainly in the muscle and in the lungs. It is the building block of protein and a major cellular fuel source. Although abundant in the body, patients with cancer and AIDS-related cachexia or those recovering from catabolic states such as surgery, sepsis, and intense exercise may need to increase intake. Parenteral supplementation is used in hospitals, but oral formulations are available as medical food products. Glutamine is also marketed as a dietary supplement to enhance muscle building, wound healing, and for intestinal and immune system health.

  Glutamine improves nitrogen balance, preserves intestinal integrity ^(1) (2), maintains intracellular glutamine levels, and reduces hospital stay in post-surgical or critically ill patients ^(3) (4), but has no effects on preventing new infections ⁽⁵⁾. In patients with postinfectious irritable bowel syndrome (IBS), glutamine supplements reduced all major IBS-related symptoms ⁽³⁶⁾. In another study, perioperative intravenous glutamine restored disturbed renal arginine synthesis that occurred from abdominal aortic surgery ⁽⁶⁾. When used in total parenteral nutrition, glutamine improved nutritional status and reduced mortality and complications ^(7) (8), but effects in infants with gastrointestinal disease were minimal ^(9) (10). Among patients with sickle cell anemia, treatment with oral l-glutamine resulted in significantly fewer pain crises ⁽³⁵⁾. In a study conducted to determine the glycemic effects of glutamine, modest decreases in concentrations of circulating blood cells, total protein, and albumin were observed ⁽²⁸⁾.

  In oncology settings, glutamine has been investigated for its effects on cachexia ^{(11) (12) (13)}, peripheral neuropathy ^(14) (15), mucositis ^{(16) (17) (18) (19)}, and gastrointestinal toxicity ⁽²⁰⁾. Intravenous glutamine significantly reduced chemotherapy-induced nausea, vomiting, and diarrhea in patients with gastric or colorectal cancer ⁽²¹⁾. And enteral nutrition that includes arginine , glutamine, and omega-3 fatty acids may improve short-term survival in stage IV gastric cancer patients ⁽²²⁾. It was also effective against radiation morbidity in breast cancer patients ⁽²³⁾. Conclusions from a meta-analysis indicate glutamine reduces duration but not severity of diarrhea ⁽²⁴⁾. Additional studies indicate its effectiveness in reducing the incidence and severity of chemo-radiotherapy-induced oral mucositis and dysphagia in patients with oropharynx and larynx carcinoma ⁽³⁷⁾; for delaying onset of esophagitis in non-small cell lung cancer patients ⁽³⁸⁾; and a supplement containing HMB, L-arginine and glutamine was reported useful in preventing sorafenib-associated hand-foot skin reaction in patients with advanced hepatocellular carcinoma ⁽³⁹⁾. However, conflicting data indicate no impact of perioperative glutamine use on post-surgical complications or infection in gastrointestinal cancer patients ⁽²⁵⁾. Furthermore, findings suggest a role for glutamine in tumor cell growth and maintenance ^(26) (27). More research is needed to resolve the ambiguity.

• Food Sources

  Wheat, corn, barley, peanuts, soybeans, egg whites, and milk

• Purported Uses
  • Cancer-related cachexia
  • Cancer treatment-related mucositis
  • Chemotherapy-induced neuropathy
  • Chemotherapy-induced gastrointestinal toxicity
  • AIDS-associated wasting
  • Immunostimulation
  • Recovery from surgery
• Mechanism of Action

  Glutamine is essential for the maintenance of intestinal mucosal integrity and function ⁽¹⁾. It maintains immune function by serving as the principle metabolic fuel for cells, acts as a precursor for protein synthesis, and along with cysteine and glycine, is involved in glutathione (GSH) synthesis. Intravenous glutamine preserves liver and intestinal glutathione stores in animal models of oxidant damage. Glutamine is also involved in nitrogen exchange, as it neutralizes and eliminates excess ammonia formed during protein catabolism. As a nitrogen donor, it contributes to the synthesis of other non-essential amino acids, including the purines and pyrimidines, and is therefore essential for the proliferation of most cells ⁽²⁹⁾. It also plays a supportive role during biochemical stress and sepsis. Reduced oxidative stress and sickle cell-related pain with l-glutamine is attributed to increased proportions of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes ⁽³⁵⁾.

  Although the mechanism in treatment of cachexia is unclear, it is thought that glutamine, a modulator of protein turnover, enhances net protein synthesis ⁽¹¹⁾. Clinical evidence suggests that total parenteral nutrition supplemented with glutamine improves nitrogen balance, maintains the intracellular glutamine pool, enhances protein synthesis, and prevents deterioration of gut permeability in post-surgery patients ⁽¹²⁾.

  Glutamine prevented genotoxic and clastogenic damages caused by cisplatin in mice ⁽³⁰⁾. It may also potentiate the tumoricidal effect of methotrexate (MTX) since polyglutamation of MTX impairs its efflux from tumor cells and reduce its accumulation in the gut ⁽³¹⁾. The supplemental intravenous form lead to increases of GSH in the gut, but not in tumors, in a sarcoma-bearing rat model.

  However, other findings show that glutamine transporters are upregulated in tumor cells and that glutamine acts as a mitochondrial substrate and promotes protein translation. This indicates tumor cell dependence for growth and maintenance ⁽²⁶⁾. In addition, glutamine helps cancer cells survive acidic stress through enzymatic deamidation rather than provide nutrition  ⁽²⁷⁾.

• Adverse Reactions

  Some studies in cancer patients suggest that oral glutamine is well tolerated ^{(14) (17) (18) (19)}. However, others that used specific oral preparations reported adverse events including peripheral edema, gastrointestinal symptoms, headache, fever, and infections ^(32) (33).

• Herb-Drug Interactions

  Lactulose: Glutamine may reduce the ammonia-lowering effect of lactulose ⁽³⁴⁾. This interaction does not apply when lactulose is used as a laxative.
  Methotrexate: Glutamine may preferentially increase tumor retention of MTX, thereby increasing its therapeutic efficacy ⁽³¹⁾.

• References

  1. Wilmore DW. Metabolic support of the gastrointestinal tract: potential gut protection during intensive cytotoxic therapy. Cancer. May 1 1997;79(9):1794-1803.

  2. van der Hulst RR, van Kreel BK, von Meyenfeldt MF, et al. Glutamine and the preservation of gut integrity. Lancet. May 29 1993;341(8857):1363-1365.

  3. Morlion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double-blind, controlled study. Ann Surg. Feb 1998;227(2):302-308.

  4. Melis GC, ter Wengel N, Boelens PG, et al. Glutamine: recent developments in research on the clinical significance of glutamine. Curr Opin Clin Nutr Metab Care. Jan 2004;7(1):59-70.

  5. Andrews PJ, Avenell A, Noble DW, et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. Mar 17 2011;342:d1542.

  6. Brinkmann SJ, Buijs N, Vermeulen MA, et al. Perioperative glutamine supplementation restores disturbed renal arginine synthesis after open aortic surgery: a randomized controlled clinical trial. Am J Physiol Renal Physiol. Sep 1 2016;311(3):F567-575.

  7. Liu X, Sun XF, Ge QX. The role of glutamine supplemented total parenteral nutrition (TPN) in severe acute pancreatitis. Eur Rev Med Pharmacol Sci. Oct 2016;20(19):4176-4180.

  8. Asrani V, Chang WK, Dong Z, et al. Glutamine supplementation in acute pancreatitis: a meta-analysis of randomized controlled trials. Pancreatology. Sep-Oct 2013;13(5):468-474.

  9. Ong EG, Eaton S, Wade AM, et al. Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease. Br J Surg. Jul 2012;99(7):929-938.

  10. Wagner JV, Moe-Byrne T, Grover Z, et al. Glutamine supplementation for young infants with severe gastrointestinal disease. Cochrane Database Syst Rev. Jul 11 2012(7):Cd005947.

  11. May PE, Barber A, D’Olimpio JT, et al. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg. Apr 2002;183(4):471-479.

  12. Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition. Feb 1999;15(2):108-115.

  13. Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. Apr 1997;13(4):295-302.

  14. Sands S, Ladas EJ, Kelly KM, et al. Glutamine for the treatment of vincristine-induced neuropathy in children and adolescents with cancer. Support Care Cancer. Mar 2017;25(3):701-708.

  15. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist. Mar 2007;12(3):312-319.

  16. Choi K, Lee SS, Oh SJ, et al. The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test. Clin Nutr. Feb 2007;26(1):57-62.

  17. Aquino VM, Harvey AR, Garvin JH, et al. A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant. Oct 2005;36(7):611-616.

  18. Sayles C, Hickerson SC, Bhat RR, et al. Oral Glutamine in Preventing Treatment-Related Mucositis in Adult Patients With Cancer: A Systematic Review. Nutr Clin Pract. Apr 2016;31(2):171-179.

  19. Leung HW, Chan AL. Glutamine in Alleviation of Radiation-Induced Severe Oral Mucositis: A Meta-Analysis. Nutr Cancer. Jul 2016;68(5):734-742.

  20. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut. Jan 2001;48(1):28-33.

  21. Li Y, Ping X, Yu B, et al. Clinical trial: prophylactic intravenous alanyl-glutamine reduces the severity of gastrointestinal toxicity induced by chemotherapy—a randomized crossover study. Aliment Pharmacol Ther. Sep 1 2009;30(5):452-458.

  22. Klek S, Scislo L, Walewska E, et al. Enriched enteral nutrition may improve short-term survival in stage IV gastric cancer patients: A randomized, controlled trial. Nutrition. Apr 2017;36:46-53.

  23. Rubio I, Suva LJ, Todorova V, et al. Oral glutamine reduces radiation morbidity in breast conservation surgery. JPEN J Parenter Enteral Nutr. Sep 2013;37(5):623-630.

  24. Sun J, Wang H, Hu H. Glutamine for chemotherapy induced diarrhea: a meta-analysis. Asia Pac J Clin Nutr. 2012;21(3):380-385.

  25. Gianotti L, Braga M, Biffi R, et al. Perioperative intravenous glutamine supplemetation in major abdominal surgery for cancer: a randomized multicenter trial. Ann Surg. Nov 2009;250(5):684-690.

  26. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. Aug 2010;35(8):427-433.

  27. Huang W, Choi W, Chen Y, et al. A proposed role for glutamine in cancer cell growth through acid resistance. Cell Res. May 2013;23(5):724-727.

  28. Samocha-Bonet D, Chisholm DJ, Gribble FM, et al. Glycemic effects and safety of L-Glutamine supplementation with or without sitagliptin in type 2 diabetes patients-a randomized study. PLoS One. 2014;9(11):e113366.

  29. Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev. Aug 1999;4(4):239-248.

  30. Oliveira RJ, Sassaki ES, Monreal AC, et al. Pre-treatment with glutamine reduces genetic damage due to cancer treatment with cisplatin. Genet Mol Res. Dec 2 2013;12(4):6040-6051.

  31. Rubio IT, Cao Y, Hutchins LF, et al. Effect of glutamine on methotrexate efficacy and toxicity. Ann Surg. May 1998;227(5):772-778; discussion 778-780.

  32. Prescribing information. ENDARI (L-glutamine oral powder). Revised: 7/2017. Accessed December 29, 2017.

  33. Prescribing information. NutreStore [L-glutamine powder for oral solution]. Revised: 01/2008. Accessed December 29, 2017.

  34. Wright G, Jalan R. Management of hepatic encephalopathy in patients with cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):95-110.

  35. Niihara Y, Miller ST, Kanter J, et al. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. Jul 19 2018;379(3):226-235.

  36. Zhou Q, Verne ML, Fields JZ, et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut.2019 Jun;68(6):996-1002.

  37. Pathak S, Soni TP, Sharma LM, Patni N, Gupta AK. A Randomized Controlled Trial to Evaluate the Role and Efficacy of Oral Glutamine in the Treatment of Chemo-radiotherapy-induced Oral Mucositis and Dysphagia in Patients with Oropharynx and Larynx Carcinoma. Cureus. 2019 Jun 7;11(6):e4855.

  38. Chang SC, Lai YC, Hung JC, Chang CY. Oral glutamine supplements reduce concurrent chemoradiotherapy-induced esophagitis in patients with advanced non-small cell lung cancer. Medicine (Baltimore. 2019 Feb;98(8):e14463.

  39. Naganuma A, Hoshino T, Ohno N, et al. β-Hydroxy-β-methyl Butyrate/L-Arginine/L-Glutamine Supplementation for Preventing Hand-Foot Skin Reaction in Sorafenib for Advanced Hepatocellular Carcinoma. In Vivo. 2019 Jan-Feb;33(1):155-161.