谷氨酰胺对肠道损伤药理作用研究

doi:10.3969/j.issn.1009-976X.2020.05.026

摘要/Abstract

摘要： 肠粘膜上皮细胞、粘膜下免疫细胞和肠腔微生物群之间微妙而复杂的相互作用决定了黏膜的内环境平衡。肠道受到不良刺激情况下可能导致肠损伤,或者肠屏障的破坏,如腹部肿瘤的化疗和放疗、炎性肠病以及肠应激状态下反应,后者如创伤、休克、炎症。受损的上皮屏障和伴随的对肠道微生物群的过度免疫反应导致腹痛、腹泻和炎性肠病,同时肠屏障破坏所致的肠通透性增加可能是引发肠外组织与脏器损伤的因素。谷氨酰胺在营养中是一种真正的具有功能性的氨基酸。膳食或补充的谷氨酰胺通过调节参与细胞增殖、分化和凋亡、蛋白质周转、抗氧化性和免疫反应的基因和蛋白表达,对维持肠黏膜屏障具有重要作用。但谷氨酰胺作用的潜在机制在很大程度上仍然是未知的,因此,谷氨酰胺的重要作用不断激励研究人员在实验动物、基础和临床研究。本文回顾了肠屏障受损的机制及谷氨酰胺对肠道损伤药理作用,对于更好地理解谷氨酰胺的作用以及改善生物体内谷氨酰胺的营养利用是必要的。

关键词: 损伤, 肠屏障, 药理, 谷氨酰胺

Abstract: Delicate and complex interactions between epithelial cells, immune cells, and luminal microbiota determine mucosal homeostasis. The stimulation of the intestine may lead to intestinal damage （intestinal barrier damage）, such as chemotherapy and radiotherapy of abdominal tumors, inflammatory bowel disease, and intestinal stress, the latter such as trauma, shock, inflammation. The damaged intestinal epithelial barrier and the accompanying excessive immune response to the intestinal microbiota lead to inflammatory bowel disease and enteritis. At the same time, the increased intestinal permeability （bacterial translocation） caused by the intestinal barrier damage may result ininjury in extraintestinal tissues and organs. Glutamine （Gln） is a truly functional amino acid in nutrition. Dietary Gln has been shown to be important formaintenance of the intestinal mucosal barrier by regulatingexpression of genes and proteins involved in cellproliferation, differentiation and apoptosis, protein turnover,anti-oxidative property, and immunity responses. However, the underlying mechanism of Gln is still largely unknown. Therefore, the important role of glutamine continues to motivate researchers in experimental animal, basic and clinical research. This article reviews the mechanism of intestinal barrier damage and the pharmacological effects of glutamine on intestinal injury. It is necessary to better understand the role of glutamine and improve the nutritional utilization of glutamine in organisms.

Key words: pharmacology, glutamine, intestinal barrier, damage

中图分类号:

R656

林杰茹, 常惠礼, 冯正富, 汤锐明, 王馨, 冯汩. 谷氨酰胺对肠道损伤药理作用研究[J]. 岭南现代临床外科, 2020, 20(05): 664-667.

LIN Jie-ru, CHANG Hui-li, FENG Zheng-fu, TANG Rui-ming, WANG Xin, FENG Gu. Study on pharmacological effects of glutamine on intestinal injury[J]. Lingnan Modern Clinics in Surgery, 2020, 20(05): 664-667.

参考文献

[1] Camilleri M.Leaky gut: mechanisms, measurement and clinical implications in humans[J]. Gut, 2019, 68(8):1516-1526.
[2] Baumgart DC, Dignass AU.Intestinal barrier function[J]. Curr Opin Clin Nutr Metab Care, 2002, 5(6):685-694.
[3] Ren Z, Guo C, Yu S, et al.Progress in Mycotoxins Affecting Intestinal Mucosal Barrier Function[J]. Int J Mol Sci, 2019, 20(11):2777.
[4] Yi D, Hou Y, Wang L, et al.L-Glutamine enhances enterocyte growth via activation of the mTOR signaling pathway independently of AMPK[J]. Amino Acids, 2015, 47(1): 65-78.
[5] Zou XP, Chen M, Wei W, et al.Effects of enteral immunonutrition on the maintenance of gut barrier function and immune function in pigs with severe acute pancreatitis[J]. JPEN J Parenter Enteral Nutr, 2010, 34(5): 554-566.
[6] Zhang X, Jiang X.Effects of enteral nutrition on the barrier function of the intestinal mucosa and dopamine receptor expression in rats with traumatic brain injury[J]. JPEN J Parenter Enteral Nutr, 2015, 39(1):114-123.
[7] Santos RG, Quirino IE, Viana ML, et al.Effects of nitric oxide synthase inhibition on glutamine action in a bacterial translocation model[J]. Br J Nutr 2014, 111(1):93-100.
[8] Li Y, Chen Y, Zhang J, et al.Protective effect of glutamine-enriched early enteral nutrition on intestinal mucosal barrier injury after liver transplantation in rats[J]. Am J Surg, 2010, 199(1):35-42.
[9] Hou YC, Chu CC, Ko TL, et al.Effects of alanyl-glutamine dipeptide on the expression of colon-inflammatory mediators during the recovery phase of colitis induced by dextran sulfate sodium[J]. Eur J Nutr, 2013; 52(3):1089-1098.
[10] Mondello S, Galuppo M, Mazzon E, et al.Glutamine treatment attenuates the development of ischaemia/reperfusion injury of the gut[J]. Eur J Pharmacol, 2010, 643(2-3):304-315.
[11] Bertrand J, Goichon A, De' chelotte P, Co¨ effier M. Regulation of intestinal protein metabolism by amino acids[J]. Amino Acids, 2013, 45(3):443-450.
[12] Beutheu S, Ouelaa W, Guerin C, et al.Glutamine supplementation, but not combined glutamine and arginine supplementation, improves gut barrier function during chemotherapy-induced intestinal mucositis in rats[J]. Clin Nutr, 2014, 33(4):694-701.
[13] Wang B, Wu Z, Ji Y, et al.L-Glutamine enhances tight junction integrity by activating CaMK kinase 2-AMP-activated protein kinase signaling in intestinal porcine epithelial cells[J]. J Nutr, 2016, 146(3):501-508.
[14] Ghouzali I, Lemaitre C, Bahlouli W, et al.Targeting immunoproteasome and glutamine supplementation prevent intestinal hyperpermeability[J]. Biochim Biophys Acta Gen Subj, 2017, 1861(1 Pt A):3278-3288.
[15] Noth R, Häsler R, Stüber E, et al.Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graftvs.-host disease model[J]. Am J Physiol Gastrointest Liver Physiol, 2013, 304: G646-G654.
[16] Dai ZL, Li XL, Xi PB, et al.L-Glutamine regulates amino acid utilization by intestinal bacteria[J]. Amino Acids, 2013, 45(3): 501-512.
[17] Ren W, Duan J, Yin J, et al.Dietary L-glutamine supplementation modulates microbial community and activates innate immunity in the mouse intestine[J]. Amino Acids, 2014, 46(10): 2403-2413.
[18] de Souza AZ, Zambom AZ, Abboud KY, et al. Oral supplementation with Lglutamine alters gut microbiota of obese and overweight adults: a pilot study[J]. Nutrition, 2015, 31(6): 884-889.
[19] Wang A, Keita AV, Phan V, et al.Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis[J]. Am J Pathol, 2014, 184(9):2516-2527.
[20] Coeffier M, Marion-Letellier R, Dechelotte P.Potential for amino acids supplementation during inflammatory bowel diseases[J]. Inflamm Bowel Dis, 2010, 16(3):518-524.
[21] Bertrand J, Marion-Letellier R, Azhar S, et al.Glutamine enema regulates colonic ubiquitinated-proteins but not proteasome activities during TNBSinduced colitis leading to increased mitochondrial activity[J]. Proteomics, 2015, 15(13):2198-2210.
[22] Leite RD, Lima NL, Leite CA, et al.Improvement of intestinal permeability with alanyl-glutamine in HIV patients: a randomized, double blinded, placebocontrolled clinical trial[J]. Arq Gastroenterol, 2013, 50(1): 56-63.
[23] Bertiaux-Vandaёle N, Youmba SB, Belmonte L, et al.The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype[J]. Am J Gastroenterol, 2011, 106(12): 2165-2173.
[24] Zhou Q, Costinean S, Croce CM, et al. MicroRNA 29 targets nuclear factorkappaB-repressing factor and Claudin 1 to increase intestinal permeability [J]. Gastroenterology, 2015, 148(1): 158-169.e8.
[25] Zhou Q, Souba WW, Croce CM, Verne GN.MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome[J]. Gut, 2010, 59(6): 775-784.
[26] Bertrand J, Ghouzali I, Guérin C, et al.Glutamine restores tight junction protein claudin-1 expression in colonic mucosa of patients with diarrhea-predominant irritable bowel syndrome[J]. JPEN J Parenter Enteral Nutr, 2016, 40(8): 1170-1176.
[27] Benjamin J, Makharia G, Ahuja V, et al.Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn’s disease: a randomized controlled trial[J]. Dig Dis Sci, 2012, 57(4): 1000-1012.
[28] Akobeng AK, Elawad M, Gordon M. Glutamine for induction of remission in Crohn’s disease [J]. Cochrane Database Syst Rev, 2016, 2:CD007348.
[29] Anderson PM, Lalla RV.Glutamine for Amelioration of Radiation and Chemotherapy Associated Mucositis during Cancer Therapy[J]. Nutrients, 2020, 12(6): 1675.
[30] Filho JC, Bergström J, Stehle P, Fürst P.Simultaneous measurements of free amino acid patterns ofplasma, muscle and erythrocytes in healthy human subjects[J]. Clin Nutr, 1997, 16(6): 299-305.
[31] Souba WW, Klimberg VS, Plumley DA, et al.The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection[J]. J Surg Res, 1990, 48(4): 383-391.
[32] Yarom N, Hovan A, Bossi P, et al.Systematic review of natural and miscellaneous agents for the management of oral mucositis in cancer patients and clinical practice guidelines-part 1: Vitamins, minerals, and nutritional supplements[J]. Support Care Cancer, 2019, 27(10): 3997-4010.
[33] Labow BI, Souba WW.Glutamine[J]. World J Surg, 2000, 24(12): 1503-1513.
[34] Cockerham MB, Weinberger BB, Lerchie SB.Oral glutamine for the prevention of oral mucositis associated with high-dose paclitaxel and melphalan for autologous bone marrow transplantation[J]. Ann Pharmacother,2000, 34(3): 300-303.
[35] Schloerb PR, Skikne BS.Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study[J]. JPEN J Parenter Enteral Nutr, 1999, 23(3): 117-122.
[36] Peterson DE, Jones JB, Petit RG 2nd. Randomized, placebo-controlled trial of Saforis for prevention and treatment of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy[J]. Cancer, 2007, 109(2): 322-331.
[37] Pytlík R, Benes P, Patorková M, et al.Standardized parenteral alanyl-glutamine dipeptide supplementation is not beneficial in autologous transplant patients: a randomized, double-blind, placebo controlled study[J]. Bone Marrow Transplant, 2002, 30(12):953-961.
[38] Anderson PM.Supportive care after chemotherapy and radiation with a swish and swallow glutamine+disaccharide nutritional supplement to reduce mucositis and improve enteral nutrition[C]. In Proceedings of the 46th Congress of The International Society of Paediatric Oncology (SIOP), Toronto, ON, Canada, October 2014.
[39] Kaufmann Y, Klimberg VS.Effect of glutamine on gut glutathione fractional release in the implanted tumor model[J]. Nutr Cancer, 2007, 59(2): 199-206.