Protective mechanisms of glutamine in intestinal diseases



Ключевые слова:

glutamine, intestinal function, tight junction, microbiota, animal models, inflammatory bowel disease, glutamine supplementation, clinical outcomes


Glutamine, the most abundant free amino acid in the human body, is a major molecule utilized by intestinal cells. It has been reported that glutamine is involved in intestinal physiology and management of multiple intestinal diseases. In gut physiology, glutamine promotes enterocyte proliferation, regulates tight junction proteins, suppresses pro-inflammatory signaling pathways, helps regain microbiota composition, and protects cells against apoptosis and cellular stresses during normal and pathologic conditions. The promising reported protective effects of glutamine supplementations on different experimental animal models of DSS-induced, TNBS-induced and NSAID-induced colitis, speculated a similar effect on clinical settings. As glutamine stores are depleted during severe metabolic stresses, including those associated with trauma, sepsis, and inflammatory bowel diseases, the effect of glutamine supplementation has been examined in patients to improve their clinical outcomes. In this review, we discuss the physiological roles of glutamine in intestinal health and its underlying mechanisms. In addition, we discuss recent evidence regarding the efficacy of glutamine supplementation in treating intestinal diseases.

Библиографические ссылки

Albrecht, J., Sidoryk-Węgrzynowicz, M., Zielińska, M. et al. (2010) Roles of glutamine in neurotransmission. Neuron Glia Biology, vol. 6, no. 4, pp. 263–276. (In English)

Amagase, K., Kimura, Y., Wada, A. et al. (2014) Prophylactic effect of monosodium glutamate on NSAID-induced enteropathy in rats. Current Pharmaceutical Design, vol. 20, no. 16, pp. 2783–2790. (In English)

Amagase, K., Ochi, A., Kojo, A. et al. (2012) New therapeutic strategy for amino acid medicine: Prophylactic and healing promoting effect of monosodium glutamate against NSAID-induced enteropathy. Journal of Pharmacological Sciences, vol. 118, no. 2, pp. 131–137. (In English)

Ameho, C. K., Adjei, A. A., Harrison, E. K. et al. (1997) Prophylactic effect of dietary glutamine supplementation on interleukin 8 and tumour necrosis factor α production in trinitrobenzene sulphonic acid induced colitis. Gut, vol. 41, no. 4, pp. 487–493. (In English)

Amores-Sánchez, M. I., Medina, M. A. (1999) Glutamine, as a precursor of glutathione, and oxidative stress. Molecular Genetics and Metabolism, vol. 67, no. 2, pp. 100–105. (In English)

Anderson, J. M., van Itallie, C. M. (1995) Tight junctions and the molecular basis for regulation of paracellular permeability. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 269, no. 4, pp. G467–G475. (In English)

Askanazi, J., Carpentier, Y. A., Michelsen, C. B. et al. (1980) Muscle and plasma amino acids following injury. Influence of intercurrent infection. Annals of Surgery, vol. 192, no. 1, pp. 78–85. (In English)

Basuroy, S., Seth, A., Elias, B. et al. (2006) MAPK interacts with occludin and mediates EGF-induced prevention of tight junction disruption by hydrogen peroxide. Biochemical Journal, vol. 393, no. 1, pp. 69–77. (In English)

Beaugerie, L., Carbonnel, F., Hecketsweiler, B. et al. (1997) Effects of an isotonic oral rehydration solution, enriched with glutamine, on fluid and sodium absorption in patients with short-bowel syndrome. Alimentary Pharmacology & Therapeutics, vol. 11, no. 4, pp. 741–746. (In English)

Bjerknes, M., Cheng, H. (2005) Gastrointestinal stem cells. II. Intestinal stem cells. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 289, no. 3, pp. G381–G387. (In English)

Blikslager, A. T., Rhoads, J. M., Bristol, D. G. et al. (1999) Glutamine and transforming growth factor-α stimulate extracellular regulated kinases and enhance recovery of villous surface area in porcine ischemic-injured intestine. Surgery, vol. 125, no. 2, pp. 186–194. (In English)

Boelens, P. G, Melis, G. C., van Leeuwen, P. A. et al. (2006) Route of administration (enteral or parenteral) affects the contribution of L-glutamine to de novo L-arginine synthesis in mice: A stable-isotope study. American Journal of Physiology. Endocrinology and Metabolism, vol. 291, no. 4, pp. E683–E690. (In English)

Buchman, A. L., Moukarzel, A. A., Bhuta, S. et al. (1995) Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. Journal of Parenteral and Enteral Nutrition, vol. 19, no. 6, pp. 453–460. (In English)

Cairns, R. A., Harris, I. S., Mak, T. W. (2011) Regulation of cancer cell metabolism. Nature Reviews Cancer, vol. 11, no. 2, pp. 85–95. (In English)

Calder, P. (1994) Glutamine and the immune system. Clinical Nutrition, vol. 13, no. 1, pp. 2–8. (In English)

Carneiro, B. A., Fujii, J., Brito, G. A. et al. (2006) Caspase and bid involvement in Clostridium difficile toxin A-induced apoptosis and modulation of toxin A effects by glutamine and alanyl-glutamine in vivo and in vitro. Infection and Immunity, vol. 74, no. 1, pp. 81–87. (In English)

Coleman, J. W. (2001) Nitric oxide in immunity and inflammation. International Immunopharmacology, vol. 1, no. 8, pp. 1397–1406. (In English)

Coster, J., McCauley, R., Hall, J. (2004) Glutamine: Metabolism and application in nutrition support. Asia Pacific Journal of Clinical Nutrition, vol. 13, no. 1, pp. 25–31. (In English)

Crespo, I., San-Miguel, B., Prause, C. et al. (2012) Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS ONE, vol. 7, no. 11, article e50407. (In English)

DeBerardinis, R. J., Cheng, T. (2010) Q’s next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, vol. 29, no. 3, pp. 313–324. (In English)

Dechelotte, P., Darmaun, D., Rongier, M. et al. (1991) Absorption and metabolic effects of enterally administered glutamine in humans. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 260, no. 5, pp. G677–G682. (In English)

Demehri, F. R., Barrett, M., Ralls, M. W. et al. (2013) Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation. Frontiers in Cellular and Infection Microbiology, vol. 3, article 105. (In English)

Fan, T.-J., Han, L.-H., Cong, R.-S., Liang, J. (2005) Caspase family proteases and apoptosis. Acta Biochimica et Biophysica Sinica, vol. 37, no. 11, pp. 719–727. (In English)

Fujishima, Y., Nishiumi, S., Masuda, A. et al. (2011) Autophagy in the intestinal epithelium reduces endotoxin-induced inflammatory responses by inhibiting NF-kB activation. Archives Biochemistry and Biophysics, vol. 506, no. 2, pp. 223–235. (In English)

Ganeshan, K., Chawla, A. (2014) Metabolic regulation of immune responses. Annual Review of Immunology, vol. 32, pp. 609–634. (In English)

González-Huix, F., Fernandez-Bañares, F., Esteve-Comas, M. et al. (1993) Enteral versus parenteral nutrition as adjunct therapy in acute ulcerative colitis. American Journal of Gastroenterology, vol. 88, no. 2, pp. 227–232. (In English)

Hampe, J., Franke, A., Rosenstiel, P. et al. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics, vol. 39, no. 2, pp. 207–211. (In English)

Harhaj, N. S., Antonetti, D. A. (2004) Regulation of tight junctions and loss of barrier function in pathophysiology. The International Journal of Biochemistry & Cell Biology, vol. 36, no. 7, pp. 1206–1237. (In English)

Hecker, M., Sessa, W. C., Harris, H. J. et al. (1990) The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: Cultured endothelial cells recycle L-citrulline to L-arginine. Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 21, pp. 8612–8616. (In English)

Hou, Y.-C., Chu, C.-C., Ko, T.-L. et al. (2013) Effects of alanyl-glutamine dipeptide on the expression of colon-inflammatory mediators during the recovery phase of colitis induced by dextran sulfate sodium. European Journal of Nutrition, vol. 52, no. 3, pp. 1089–1098. (In English)

Houdijk, A. P. J., Visser, J. J., Rijnsburger, E. R. et al. (1998) Dietary glutamine supplementation reduces plasma nitrate levels in rats. Clinical Nutrition, vol. 17, no. 1, pp. 11–14. (In English)

Hsiung, Y.-C., Liu, J.-J., Hou, Y.-C. et al. (2014) Effects of dietary glutamine on the homeostasis of CD4+ T cells in mice with dextran sulfate sodium-induced acute colitis. PLoS ONE, vol. 9, no. 1, article e84410. (In English)

Hubert-Buron, A., Leblond, J., Jacquot, A. et al. (2006) Glutamine pretreatment reduces IL-8 production in human intestinal epithelial cells by limiting IκBα ubiquitination. The Journal of Nutrition, vol. 136, no. 6, pp. 1461–1465. (In English)

Kaplan, M. H. (2013) STAT signaling in inflammation. JAK-STAT, vol. 2, no. 1, article e24198. (In English)

Kaser, A., Lee, A.-H., Franke, A. et al. (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, vol. 134, no. 5, pp. 743–756. (In English)

Kato, S., Hamouda, N., Kano, Y. et al. (2017) Probiotic Bifidobacterium bifidum G9-1 attenuates 5-fluorouracil-induced intestinal mucositis in mice via suppression of dysbiosis-related secondary inflammatory responses. Clinical and Experimental Pharmacology & Physiology, vol. 44, no. 10, pp. 1017–1025. (In English)

Kim, H. (2011) Glutamine as an immunonutrient. Yonsei Medical Journal, vol. 52, no. 6, pp. 892–897. (In English)

Kim, M. H., Kim, H. (2013) Oncogenes and tumor suppressors regulate glutamine metabolism in cancer cells. Journal of Cancer Prevention, vol. 18, no. 3, pp. 221–226. (In English)

Ko, T. C., Beauchamp, R. D., Townsend, C. M. Jr. et al. (1993) Glutamine is essential for epidermal growth factor-stimulated intestinal cell proliferation. Surgery, vol. 114, no. 2, pp. 147–153, discussion 153–154. (In English)

Koizumi, J., Kojima, T., Ogasawara, N. et al. (2008) Protein kinase C enhances tight junction barrier function of human nasal epithelial cells in primary culture by transcriptional regulation. Molecular Pharmacology, vol. 74, no. 2, pp. 432–442. (In English)

Kretzmann, N. A., Fillmann, H., Mauriz, J. L. et al. (2008) Effects of glutamine on proinflammatory gene expression and activation of nuclear factor κB and signal transducers and activators of transcription in TNBS-induced colitis. Inflammatory Bowel Diseases, vol. 14, no. 11, pp. 1504–1513. (In English)

Lee, S. H. (2015) Intestinal permeability regulation by tight junction: Implication on inflammatory bowel diseases. Intestinal Research, vol. 13, no. 1, pp. 11–18. (In English)

Li, N., Lewis, P., Samuelson, D. et al. (2004) Glutamine regulates Caco-2 cell tight junction proteins. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 287, no. 3, pp. G726–G733. (In English)

Liboni, K. C., Li, N., Scumpia, P. O. et al. (2005) Glutamine modulates LPS-induced IL-8 production through IkappaB/NF-κB in human fetal and adult intestinal epithelium. The Journal of Nutrition, vol. 135, no. 2, pp. 245–251. (In English)

Malhotra, V., Eaves-Pyles, T., Odoms, K. et al. (2002) Heat shock inhibits activation of NF-κB in the absence of heat shock factor-1. Biochemical and Biophysical Research Communications, vol. 291, no. 3, pp. 453–457. (In English)

Matés, J. M., Pérez-Gómez, C., Núñez de Castro, I. et al. (2002) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. The International Journal of Biochemistry & Cell Biology, vol. 34, no. 5, pp. 439–458. (In English)

McCauley, R., Kong, S.-E., Hall, J. (1998) Glutamine and nucleotide metabolism within enterocytes. Journal of Pare0nteral and Enteral Nutrition, vol. 22, no. 2, pp. 105–111. (In English)

Mitic, L. L., Anderson, J. M. (1998) Molecular architecture of tight junctions. Annual Review of Physiology, vol. 60, pp. 121–142. (In English)

Newsholme, E. A., Carrie, A.-L. (1994) Quantitative aspects of glucose and glutamine metabolism by intestinal cells. Gut, vol. 35, no. 1, pp. S13–S17. (In English)

Newsholme, P. (2001) Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? The Journal of Nutrition, vol. 131, no. 9, pp. 2515S–2522S. (In English)

Newsholme, P., Curi, R., Pithon Curi, T. C. et al. (1999) Glutamine metabolism by lymphocytes, macrophages, and neutrophils: Its importance in health and disease. The Journal of Nutritional Biochemistry, vol. 10, no. 6, pp. 316–324. (In English)

Noyer, C. M., Simon, D., Borczuk, A. et al. (1998) A double blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. The American Journal of Gastroenterology, vol. 93, no. 6, pp. 972–975. (In English)

Pai, M.-H., Liu, J.-J., Yeh, S.-L. et al. (2014) Glutamine modulates acute dextran sulphate sodium-induced changes in small-intestinal intraepithelial γδ-T-lymphocyte expression in mice. The British Journal of Nutrition, vol. 111, no. 6, pp. 1032–1039. (In English)

Papaconstantinou, H. T., Hwang, K. O., Rajaraman, S. et al. (1998) Glutamine deprivation induces apoptosis in intestinal epithelial cells. Surgery, vol. 124, no. 2, pp. 152–159, discussion 159–160. (In English)

Patience, J. F. (1990) A review of the role of acid-base balance in amino acid nutrition. Journal of Animal Science, vol. 68, no. 2, pp. 398–408. (In English)

Que, F. G., Gores, G. J. (1996) Cell death by apoptosis: Basic concepts and disease relevance for the gastroenterologist. Gastroenterology, vol. 110, no. 4, pp. 1238–1243. (In English)

Rhoads, J. M., Wu, G. (2009) Glutamine, arginine, and leucine signaling in the intestine. Amino Acids, vol. 37, no. 1, pp. 111–122. (In English)

Rigor, R. R., Shen, Q., Pivetti, C. D. et al. (2013) Myosin light chain kinase signaling in endothelial barrier dysfunction. Medicinal Research Reviews, vol. 33, no. 5, pp. 911–933. (In English)

Rioux, J. D., Xavier, R. J., Taylor, K. D. et al. (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genetics, vol. 39, no. 5, pp. 596–604. (In English)

Roth, E., Oehler, R., Manhart, N. et al. (2002) Regulative potential of glutamine—relation to glutathione metabolism. Nutrition, vol. 18, no. 3, pp. 217–221. (In English)

Sánchez de Medina, F., Romero-Calvo, I., Mascaraque, C. et al. (2014) Intestinal inflammation and mucosal barrier function. Inflammatory Bowel Diseases, vol. 20, no. 12, pp. 2394–2404. (In English)

Sido, B., Seel, C., Hochlehnert, A. et al. (2006) Low intestinal glutamine level and low glutaminase activity in Crohn’s disease: A rational for glutamine supplementation? Digestive Diseases and Sciences, vol. 51, no. 12, pp. 2170–2179. (In English)

Souba, W. W., Klimberg, V. S., Hautamaki, R. D. et al. (1990) Oral glutamine reduces bacterial translocation following abdominal radiation. Journal of Surgical Research, vol. 48, no. 1, pp. 1–5. (In English)

Suh, G. J., Youn, Y. K., Song, H. G. et al. (2003) The effect of glutamine on inducible nitric oxide synthase gene expression in intestinal ischemia-reperfusion injury. Nutrition Research, vol. 23, no. 1, pp. 131–140. (In English)

Swierkosz, T. A., Mitchell, J. A., Sessa, W. C. et al. (1990) L-Glutamine inhibits the release of endothelium-derived relaxing factor from the rabbit aorta. Biochemical and Biophysical Research Communications, vol. 172, no. 1, pp. 143–148. (In English)

Turner, J. R., Rill, B. K., Carlson, S. L. et al. (1997) Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. American Journal of Physiology. Cell Physiology, vol. 273, no. 4, pp. C1378–C1385. (In English)

Ullman, T. A., Itzkowitz, S. H. (2011) Intestinal inflammation and cancer. Gastroenterology, vol. 140, no. 6, pp. 1807–1816. (In English)

Van der Flier, L. G., Clevers, H. (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annual Review of Physiology, vol. 71, pp. 241–260. (In English)

Wang, B., Wu, G., Zhou, Z. et al. (2015) Glutamine and intestinal barrier function. Amino Acids, vol. 47, no. 10, pp. 2143–2154. (In English)

Wang, B., Wu, Z., Ji, Y. et al. (2016) L-glutamine enhances tight junction integrity by activating CaMK kinase 2–AMP-activated protein kinase signaling in intestinal porcine epithelial cells. The Journal of Nutrition, vol. 146, no. 3, pp. 501–508. (In English)

Wischmeyer, P. E. (2002) Glutamine and heat shock protein expression. Nutrition, vol. 18, no. 3, pp. 225–228. (In English)

Wu, G. (1998) Intestinal mucosal amino acid catabolism. The Journal of Nutrition, vol. 128, no. 8, pp. 1249–1252. (In English)

Xue, H., Sufit, A. J., Wischmeyer, P. E. (2011) Glutamine therapy improves outcome of in vitro and in vivo experimental colitis models. Journal of Parenteral and Enteral Nutrition, vol. 35, no. 2, pp. 188–197. (In English)

Yasuda, M., Kato, S., Yamanaka, N. et al. (2012) Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 302, no. 10, pp. G1133–G1142. (In English)

Zatorski, H., Marynowski, M., Fichna, J. (2016) Is insulin-like growth factor 1 (IGF-1) system an attractive target inflammatory bowel disease? Benefits and limitation of potential therapy. Pharmacological Reports, vol. 68, no. 4, pp. 809–815. (In English)

Zhang, W., Liu, H. T. (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Research, vol. 12, no. 1, pp. 9–18. (In English)

Ziegler, T. R., Mantell, M. P., Chow, J. C. et al. (1996) Gut adaptation and the insulin-like growth factor system: Regulation by glutamine and IGF-I administration. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 271, no. 5, pp. G866–G875. (In English)

Zihni, C., Mills, C., Matter, K. et al. (2016) Tight junctions: From simple barriers to multifunctional molecular gates. Nature Reviews. Molecular Cell Biology, vol. 17, no. 9, pp. 564–580. (In English)