Skip to main content

Advertisement

Log in

Glutamine analogues as adjunctive therapy for infectious diarrhea

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Glutamine is the major fuel for the gut as well as for many cells in the immune system that becomes conditionally essential during catabolic states. Glutamine supplementation improves intestinal mucosal repair and function. Glutamine, even at high doses, is without side effects and is well tolerated. Though unstable in solution, this is overcome by creating stable dipeptides such as alanyl-glutamine. In HIVpositive patients with wasting, glutamine enhances intestinal absorptive function and weight gain. Glutamine enhances sodium and water absorption in a rabbit model of cholera and Cryptosporidium-infected piglet intestine. Both glutamine and alanyl-glutamine have recently proven effective in a bovine model of Cryptosporidium as well. Finally, a rat model of cholera toxin-induced diarrhea also showed that alanyl-glutamine enhanced water and electrolyte intestinal absorption even better than the traditional glucose solutions. Clearly glutamine and its stabler derivatives hold promise for enhancing repair of mucosal injury by a wide range of infections or toxic agents, and hence have great potential as a new oral rehydration and nutrition therapy for patients with enteric infection, malnutrition, or chemotherapy- or radiationinduced enteritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Windmueller HG, Spaeth AE: Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 1974, 249:5070–5079.

    PubMed  CAS  Google Scholar 

  2. Lacey JM, Wilmore DW: Is glutamine a conditionally essential amino acid? Nutr Rev 1990, 48:297–309.

    Article  PubMed  CAS  Google Scholar 

  3. Ziegler TR, Young LS, Benfell K, et al.: Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med 1992, 116:821–828.

    PubMed  CAS  Google Scholar 

  4. Yoshida S, Matsui M, Shirouzu Y, et al.: Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer. Ann Surg 1998, 227:485–491.

    Article  PubMed  CAS  Google Scholar 

  5. Tremel H, Kienle B, Weilemann LS, et al.: Glutamine dipeptidesupplemented parenteral nutrition maintains intestinal function in the critically ill. Gastroenterology 1994, 107:1595–1601.

    PubMed  CAS  Google Scholar 

  6. Silva AC, Santos-Neto MS, Soares AM, et al.: Efficacy of a glutamine-based oral rehydration solution on the electrolyte and water absorption in a rabbit model of secretory diarrhea induced by cholera toxin with editorial, “glutamine-based oral rehydration solutions: the magic bullet revisited?” by Christopher Duggan, pp 533 to 535, same issue. J Pediatr Gastroenterol Nutr 1998, 26:513–519.

    Article  PubMed  CAS  Google Scholar 

  7. Lima AA, Carvalho GH, Figueiredo AA, et al.: Effects of an alanyl-glutamine-based oral rehydration and nutrition therapy solution on electrolyte and water absorption in a rat model of secretory diarrhea induced by cholera toxin. Nutrition 2002, 18:458–462. The authors investigated the effect of Ala-Gln and glutamine-based ORS on electrolyte and water absorption in a rat model of secretory diarrhea induced by cholera toxin. Ala-Gln and glutamine reduced the sodium secretory effect of cholera toxin by 128% and 36%, and net water secretion by 95% and 60%, respectively. This study shows that Ala-Gln is even more effective than glutamine in driving sodium cotransport absorption in experimental cholera diarrhea.

    Article  PubMed  CAS  Google Scholar 

  8. van der HulstRR, van Kreel BK, von Meyenfeldt MF, et al.:Glutamine and the preservation of gut integrity. Lancet 1993, 341:1363–1365.

    Article  PubMed  Google Scholar 

  9. Ribeiro Junior H, Ribeiro T, Mattos A, et al.: Treatment of acute diarrhea with oral rehydration solutions containing glutamine. J Am Coll Nutr 1994, 13:251–255.

    PubMed  Google Scholar 

  10. Rhoads JM, Argenzio RA, Chen W, et al.: Glutamine metabolism stimulates intestinal cell MAPKs by a cAMP-inhibitable, Rafindependent mechanism. Gastroenterology 2000, 118:90–100.

    Article  PubMed  CAS  Google Scholar 

  11. Rhoads JM, Argenzio RA, Chen W, et al.: L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases. Am J Physiol 1997, 272:G943-G953.

    PubMed  CAS  Google Scholar 

  12. Mates JM, Perez-Gomez C, Nunez DC, et al.: Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 2002, 34:439–458.

    Article  PubMed  CAS  Google Scholar 

  13. Chang W, Yang K, Chuang H, et al.: Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and bcl-2 levels. Clin Immunol 2002,104:151.

    Article  PubMed  CAS  Google Scholar 

  14. Wischmeyer PE: Glutamine and heat shock protein expression. Nutrition 2002, 18:225–228. Review article that summarizes data on the capacity of glutamine to induce HSPs.

    Article  PubMed  CAS  Google Scholar 

  15. Brito GAC, Alcantara C, Guerrant RL: Effect of glutamine an alanyl-glutamine on apoptosis induced by C. difficile toxin A on intestinal epithelial cells. Am J Trop Med Hyg 2001, 65(suppl):293.

    Google Scholar 

  16. Burke DJ, Alverdy JC, Aoys E, et al.: Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg 1989, 124:1396–1399.

    PubMed  CAS  Google Scholar 

  17. Ersin S, Tuncyurek P, Esassolak M, et al.: The prophylactic and therapeutic effects of glutamine- and arginine-enriched diets on radiation-induced enteritis in rats. J Surg Res 2000, 89:121–125.

    Article  PubMed  CAS  Google Scholar 

  18. Wischmeyer PE, Lynch J, Liedel J, et al.: Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med 2001, 29:2075–2080.

    Article  PubMed  CAS  Google Scholar 

  19. Houdijk AP, Rijnsburger ER, Jansen J, et al.: Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998, 352:772–776.

    Article  PubMed  CAS  Google Scholar 

  20. Khan K, Elia M: Factors affecting the stability of L-glutamine in solution. Clin Nutr 1991, 1:186–192.

    Article  Google Scholar 

  21. Furst P, Albers S, Stehle P: Availability of glutamine supplied intravenously as alanylglutamine. Metabolism 1989, 38:67–72.

    Article  PubMed  CAS  Google Scholar 

  22. 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 1998, 227:302–308.

    Article  PubMed  CAS  Google Scholar 

  23. Scheppach W, Loges C, Bartram P, et al.: Effect of free glutamine and alanyl-glutamine dipeptide on mucosal proliferation of the human ileum and colon. Gastroenterology 1994, 107:429–434.

    PubMed  CAS  Google Scholar 

  24. Bai MX, Jiang ZM, Liu YW, et al.: Effects of alanyl-glutamine on gut barrier function. Nutrition 1996, 12:793–796.

    Article  PubMed  CAS  Google Scholar 

  25. Blikslager A, Hunt E, Guerrant R, et al.: Glutamine transporter in crypts compensates for loss of villus absorption in bovine cryptosporidiosis. Am J Physiol Gastrointest Liver Physiol 2001, 281:G645-G653.

    PubMed  CAS  Google Scholar 

  26. Suttmann U, Ockenga J, Selberg O, et al.: Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. J Acquir Immune Defic Syndr Hum Retrovirol 1995, 8:239–246.

    PubMed  CAS  Google Scholar 

  27. Wheeler DA, Gibert CL, Launer CA, et al.: Weight loss as a predictor of survival and disease progression in HIV infection. Terry Beirn Community Programs for Clinical Research on AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1998, 18:80–85.

    PubMed  CAS  Google Scholar 

  28. Grinspoon S, Corcoran C, Rosenthal D, et al.: Quantitative assessment of cross-sectional muscle area, functional status, and muscle strength in men with the acquired immunodeficiency syndrome wasting syndrome. J Clin Endocrinol Metab 1999, 84:201–206.

    Article  PubMed  CAS  Google Scholar 

  29. Young L, Gatzen C, Wilmore K, et al.: Glutamine (gln) supplementation fails to increase plasma gln levels in asymptomatic HIV + individuals. J Am Diet Assoc 1992, 92:A88.

    Google Scholar 

  30. Shabert JK, Winslow C, Lacey JM, et al.: Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial. Nutrition 1999, 15:860–864. A double-blind, placebo-controlled trial in 26 HIV-positive patients with more than 5% weight loss showing that the glutamine and antioxidant supplemented group had a 1.8-kg increment in body cell mass as opposed to 0.4 kg in the placebo group (P = 0.007).

    Article  PubMed  CAS  Google Scholar 

  31. Clark RH, Feleke G, Din M, et al.: Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study. JPEN J Parenter Enteral Nutr 2000, 24:133–139.

    PubMed  CAS  Google Scholar 

  32. Schambelan M, Mulligan K, Grunfeld C, et al.: Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med 1996, 125:873–882.

    PubMed  CAS  Google Scholar 

  33. Waters D, Danska J, Hardy K, et al.: Recombinant human growth hormone, insulin-like growth factor 1, and combination therapy in AIDS-associated wasting. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996, 125:865–872.

    PubMed  CAS  Google Scholar 

  34. Lima AA, Silva TM, Gifoni AM, et al.: Mucosalninjury and disruption of intestinal barrier function in HIV-infected individuals with and without diarrhea and cryptosporidiosis in northeast Brazil. Am J Gastroenterol 1997, 92:1861–1866. Forty HIV-infected patients (20 with and 20 without diarrhea) and 13 healthy volunteers were studied with markers of barrier disruption and mucosal surface area. They were able to show that HIV-positive patients with diarrhea had a 2.8-fold higher lactulose:mannitol excretion ratio (L:M) than HIV-positive patients without diarrhea and a 10.4-fold higher ratio than healthy volunteers. Patients with cryptosporidial diarrhea had a nearly sixfold higher L:M ratio than those without diarrhea and a nearly threefold higher ratio than those with noncryptosporidial diarrhea.

    PubMed  CAS  Google Scholar 

  35. Tepper RE, Simon D, Brandt LJ, et al.: Intestinal permeability in patients infected with the human immunodeficiency virus. Am J Gastroenterol 1994, 89:878–882.

    PubMed  CAS  Google Scholar 

  36. Noyer CM, Simon D, Borczuk A, et al.: A double-blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Am J Gastroenterol 1998, 93:972–975.

    Article  PubMed  CAS  Google Scholar 

  37. Yarasheski KE, Zachwieja JJ, Gischler J, et al.: Increased plasma gln and Leu Ra and inappropriately low muscle protein synthesis rate in AIDS wasting. Am J Physiol 1998, 275:E577-E583.

    PubMed  CAS  Google Scholar 

  38. Newsholme P: Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J Nutr 2001, 131:2515S-2522S.

    PubMed  CAS  Google Scholar 

  39. Yaqoob P, Calder PC: Glutamine requirement of proliferating T lymphocytes. Nutrition 1997, 13:646–651.

    Article  PubMed  CAS  Google Scholar 

  40. Parry-Billings M, Evans J, Calder PC, et al.: Does glutamine contribute to immunosuppression after major burns? Lancet 1990, 336:523–525.

    Article  PubMed  CAS  Google Scholar 

  41. Kohler H, Ruggeberg J, Langer K, et al.: Glycyl-glutamine improves in vitro lymphocyte proliferation in AIDS patients. Eur J Med Res 2000, 5:263–267.

    PubMed  CAS  Google Scholar 

  42. Ziegler TR, Bye RL, Persinger RL, et al.: Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 1998, 315:4–10.

    Article  PubMed  CAS  Google Scholar 

  43. Wallace C, Keast D: Glutamine and macrophage function. Metabolism 1992, 41:1016–1020.

    Article  PubMed  CAS  Google Scholar 

  44. Murphy C, Newsholme P: Macrophage-mediated lysis of a beta-cell line, tumour necrosis factor-alpha release from bacillus Calmette-Guerin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism. Clin Sci (Lond) 1999, 96:89–97.

    Article  CAS  Google Scholar 

  45. Furukawa S, Saito H, Inoue T, et al.: Supplemental glutamine augments phagocytosis and reactive oxygen intermediate production by neutrophils and monocytes from postoperative patients in vitro. Nutrition 2000, 16:323–329.

    Article  PubMed  CAS  Google Scholar 

  46. Newman RD, Sears CL, Moore SR, et al.: Longitudinal study of Cryptosporidium infection in children in northeastern Brazil. J Infect Dis 1999, 180:167–175.

    Article  PubMed  CAS  Google Scholar 

  47. Wuhib T, Silva TM, Newman RD, et al.: Cryptosporidial and microsporidial infections in human immunodeficiency virus-infected patients in northeastern Brazil. J Infect Dis 1994, 170:494–497.

    PubMed  CAS  Google Scholar 

  48. Guerrant DI, Moore SR, Lima AAM, et al.: Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four--seven years later in a poor urban community in Northeast Brazil. Am J Trop Med Hyg 1999, 61:707–713.

    PubMed  CAS  Google Scholar 

  49. Guerrant RL, Kosek M, Lima AA, et al.: Updating the DALYs for diarrhoeal disease. Trends Parasitol 2002, 18:191–193.

    Article  PubMed  Google Scholar 

  50. Kosek M, Alcantara C, Lima AA, et al.: Cryptosporidiosis: an update. Lancet Infect Dis 2001, 1:262–269.

    Article  PubMed  CAS  Google Scholar 

  51. Rhoads JM, Keku EO, Bennett LE, et al.: Development of Lglutamine-stimulated electroneutral sodium absorption in piglet jejunum. Am J Physiol 1990, 259:t-107.

    Google Scholar 

  52. Argenzio RA, Rhoads JM, Armstrong M, et al.: Glutamine stimulates prostaglandin-sensitive Na(+)-H+ exchange in experimental porcine cryptosporidiosis. Gastroenterol 1994, 106:1418–1428.

    CAS  Google Scholar 

  53. Hwang ES, Hirayama BA, Wright EM: Distribution of the SGLT1 Na+/glucose cotransporter and mRNA along the cryptvillus axis of rabbit small intestine. Biochem Biophys Res Commun 1991, 181:1208–1217.

    Article  PubMed  CAS  Google Scholar 

  54. Abely M, Dallet P, Boisset M, et al.: Effect of cholera toxin on glutamine metabolism and transport in rabbit ileum. Am J Physiol Gastrointest Liver Physiol 2000, 278:G789-G796.

    PubMed  CAS  Google Scholar 

  55. Van Loon FP, Banik AK, Nath SK, et al.: The effect of L-glutamine on salt and water absorption: a jejunal perfusion study in cholera in humans. Eur J Gastroenterol Hepatol 1996, 8:443–448.

    PubMed  Google Scholar 

  56. Punjabi NH, Kumala S, Rasidi C, et al.: Glutamine supplemented ORS is superior to standard citrate glucose ORS for the maintenance therapy of adult cholera patients in Jakarta. Am J Trop Med Hyg 1991, 45(Suppl):114.

    Google Scholar 

  57. Rhoads JM, Keku EO, Quinn J, et al.: L-glutamine stimulates jejunal sodium and chloride absportion in pig rotavirus enteritis. Gastroenterology 1991, 100:683.

    PubMed  CAS  Google Scholar 

  58. Nath SK, Dechelotte P, Darmaun D, et al.: [15N]-and [14C]glutamine fluxes across rabbit ileum in experimental bacterial diarrhea. Am J Physiol 1992, 262:G312-G3188.

    PubMed  CAS  Google Scholar 

  59. Curthoys NP, Watford M: Regulation of glutaminase activity and glutamine metabolism. Ann Rev Nutr 1995, 15:133–159.

    Article  CAS  Google Scholar 

  60. Qiu B, Pothoulakis C, Castagliuolo I, et al.: Participation of reactive oxygen metabolites in Clostridium difficile toxin Ainduced enteritis in rats. Am J Physiol 1999, 276:G485-G490.

    PubMed  CAS  Google Scholar 

  61. Brito G, Fujji J, Carneiro-Filho B, et al.: Mechanism of Clostridium difficile toxin A induced apoptosis in T84 cells. J Infect Dis 2002, 186:1438–1447.

    Article  PubMed  CAS  Google Scholar 

  62. Kregel KC: Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 2002, 92:2177–2186.

    PubMed  CAS  Google Scholar 

  63. Nissim I, States B, Hardy M, et al.: Effect of glutamine on heatshock-induced mRNA and stress proteins. J Cell Physiol 1993, 157:313–318.

    Article  PubMed  CAS  Google Scholar 

  64. Wischmeyer PE, Musch MW, Madonna MB, et al.: Glutamine protects intestinal epithelial cells: role of inducible HSP70. Am J Physiol 1997, 272:G879-G884.

    PubMed  CAS  Google Scholar 

  65. Wischmeyer PE, Kahana M, Wolfson R, et al.: Glutamine induces heat shock protein and protects against endotoxin shock in the rat. J Appl Physiol 2001, 90:2403–2410.

    PubMed  CAS  Google Scholar 

  66. Wischmeyer PE, Kahana M, Wolfson R, et al.: Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia. Shock 2001, 16:398–402.

    Article  PubMed  CAS  Google Scholar 

  67. Chu EK, Ribeiro SP, Slutsky AS: Heat stress increases survival rates in lipopolysaccharide-stimulated rats. Crit Care Med 1997, 25:1727–1732.

    Article  PubMed  CAS  Google Scholar 

  68. Ribeiro SP, Villar J, Downey GP, et al.: Effects of the stress response in septic rats and LPS-stimulated alveolar macrophages: evidence for TNF-alpha posttranslational regulation. Am J Respir Crit Care Med 1996, 154:1843–1850.

    PubMed  CAS  Google Scholar 

  69. Schloerb PR, Skikne BS: Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study. JPEN J Parenter Enteral Nutr 1999, 23:117–122.

    Article  PubMed  CAS  Google Scholar 

  70. Coghlin Dickson TM, Wong RM, Offrin RS, et al.: Effect of oral glutamine supplementation during bone marrow transplantation. JPEN J Parenter Enteral Nutr 2000, 24:61–66.

    Google Scholar 

  71. Decker-Baumann C, Buhl K, Frohmuller S, et al.: Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastatic colorectal cancer. Eur J Cancer 1999, 35:202–207.

    Article  PubMed  CAS  Google Scholar 

  72. 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 2001, 48:28–33.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carneiro-Filho, B.A., Bushen, O.Y., Brito, G.A.C. et al. Glutamine analogues as adjunctive therapy for infectious diarrhea. Curr Infect Dis Rep 5, 114–119 (2003). https://doi.org/10.1007/s11908-003-0046-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-003-0046-2

Keywords

Navigation