bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–03–28
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Inhibition of guanosine monophosphate synthetase (GMPS) blocks glutamine metabolism and prostate cancer growth.
  2. Structure and activation mechanism of the human liver-type glutaminase GLS2.
  3. The role of GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals in Th17 responses counteracted by PPARγ agonists.
  4. CircRUNX1 functions as an oncogene in colorectal cancer by regulating circRUNX1/miR-485-5p/SLC38A1 axis.
  5. Expression of activated VEGFR2 by R1051Q mutation alters the energy metabolism of Sk-Mel-31 melanoma cells by increasing glutamine dependence.
  6. Altered glycolysis results in drug-resistant in clinical tumor therapy.
  7. Spatially resolved metabolomics combined with multicellular tumor spheroids to discover cancer tissue relevant metabolic signatures.
  8. SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition.
  9. Long non‑coding RNAs: Key regulators involved in metabolic reprogramming in cancer (Review).
  10. LncRNA GIRGL drives CAPRIN1-mediated phase separation to suppress glutaminase-1 translation under glutamine deprivation.
  11. The amino acid metabolism is essential for evading physical plasma-induced tumour cell death.
  12. A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.
  13. Effects of glutamine supplementation on inflammatory bowel disease: A systematic review of clinical trials.
  1. J Pathol. 2021 Mar 26.
    Inhibition of guanosine monophosphate synthetase (GMPS) blocks glutamine metabolism and prostate cancer growth.
    Qian Wang, Yi F Guan, Sarah E Hancock, Kanu Wahi, Michelle van Geldermalsen, Blake K Zhang, Angel Pang, Rajini Nagarajah, Blossom Mak, Natasha Freidman, Lisa G Horvath, Nigel Turner, Jeff Holst.
      Glutamine is a critical nutrient in cancer, however its contribution to purine metabolism in prostate cancer has not previously been determined. Guanosine monophosphate synthetase (GMPS) acts in the de novo purine biosynthesis pathway, utilizing a glutamine amide to synthesize the guanine nucleotide. This study demonstrates that GMPS mRNA expression correlates with Gleason score in prostate cancer samples, while high GMPS expression was associated with decreased rates of overall and disease/progression-free survival. Pharmacological inhibition or knockdown of GMPS significantly decreased cell growth in both LNCaP and PC-3 prostate cancer cells. We utilized 15 N-(amide)-glutamine and U-13 C5 -glutamine metabolomics to dissect the pathways involved, and despite similar growth inhibition by GMPS knockdown, we show unique metabolic effects across each cell line. Using a PC-3 xenograft mouse model, tumor growth was also significantly decreased after GMPS knockdown, highlighting the importance of glutamine metabolism and providing support for GMPS as a therapeutic target in prostate cancer. This article is protected by copyright. All rights reserved.
    Keywords:  GMPS; cell growth; glutamine; immunohistochemistry; knockdown; metabolism; metabolomics; prostate cancer; purine; xenograft
    DOI:  https://doi.org/10.1002/path.5665
  2. Biochimie. 2021 Mar 18. pii: S0300-9084(21)00079-1. [Epub ahead of print]
    Structure and activation mechanism of the human liver-type glutaminase GLS2.
    Igor M Ferreira, José Edwin N Quesñay, Alliny Cs Bastos, Camila T Rodrigues, Melanie Vollmar, Tobias Krojer, Claire Strain-Damerell, Nicola A Burgess-Brown, Frank von Delft, Wyatt W Yue, Sandra Mg Dias, Andre Lb Ambrosio.
      Cancer cells exhibit an altered metabolic phenotype, consuming higher levels of the amino acid glutamine. This metabolic reprogramming depends on increased mitochondrial glutaminase activity to convert glutamine to glutamate, an essential precursor for bioenergetic and biosynthetic processes in cells. Mammals encode the kidney-type (GLS) and liver-type (GLS2) glutaminase isozymes. GLS is overexpressed in cancer and associated with enhanced malignancy. On the other hand, GLS2 is either a tumor suppressor or an oncogene, depending on the tumor type. The GLS structure and activation mechanism are well known, while the structural determinants for GLS2 activation remain elusive. Here, we describe the structure of the human glutaminase domain of GLS2, followed by the functional characterization of the residues critical for its activity. Increasing concentrations of GLS2 lead to tetramer stabilization, a process enhanced by phosphate. In GLS2, the so-called "lid loop" is in a rigid open conformation, which may be related to its higher affinity for phosphate and lower affinity for glutamine; hence, it has lower glutaminase activity than GLS. The lower affinity of GLS2 for glutamine is also related to its less electropositive catalytic site than GLS, as indicated by a Thr225Lys substitution within the catalytic site decreasing the GLS2 glutamine concentration corresponding to half-maximal velocity (K0.5). Finally, we show that the Lys253Ala substitution (corresponding to the Lys320Ala in the GLS "activation" loop, formerly known as the "gating" loop) renders a highly active protein in stable tetrameric form. We conclude that the "activation" loop, a known target for GLS inhibition, may also be a drug target for GLS2.
    Keywords:  Breast cancer; Cooperativity; Crystal structure; Glutaminase; Isozyme; Kinetics; Liver-type; Metabolism
    DOI:  https://doi.org/10.1016/j.biochi.2021.03.009
  3. Theranostics. 2021 ;11(9): 4531-4548
    The role of GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals in Th17 responses counteracted by PPARγ agonists.
    Yumeng Miao, Yun Zheng, Yanzhi Geng, Ling Yang, Na Cao, Yue Dai, Zhifeng Wei.
      Background: Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. Methods: MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied in vitro. Results: The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the il-17 gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression in vivo. Conclusion: PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.
    Keywords:  PPARγ; Th17 responses; glutaminase 1; glutaminolysis
    DOI:  https://doi.org/10.7150/thno.54803
  4. Eur J Clin Invest. 2021 Mar 26. e13540
    CircRUNX1 functions as an oncogene in colorectal cancer by regulating circRUNX1/miR-485-5p/SLC38A1 axis.
    Juan Yu, Xiaoguang Chen, Jing Li, Furang Wang.
       BACKGROUND: Circular RNAs (circRNAs) have emerged as vital regulators in human cancers, including colorectal cancer (CRC). In this study, we aimed to explore the roles of circRUNX1 in CRC.
    METHODS: The levels of circRUNX1, RUNX1 mRNA, solute carrier family 38 member 1 (SLC38A1) mRNA and microRNA-485-5p (miR-485-5p) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The protein level of SLC38A1 was measured by Western blot assay. Cell colony formation, migration, invasion and apoptosis were assessed by colony formation assay, wound-healing assay, Transwell assay and flow cytometry analysis, respectively. The interaction between miR-485-5p and circRUNX1 or SLC38A1 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The levels of extracellular glutamine, intracellular glutamate and α-ketoglutarate (α-KG) were measured with specific kits. The functional role of circRUNX1 in CRC development in vivo was explored by murine xenograft model assay.
    RESULTS: CircRUNX1 was upregulated in CRC tissues and cells compared with normal tissues and cells. CircRUNX1 deficiency restrained CRC cell colony formation, migration, invasion and glutaminolysis and induced apoptosis in vitro as well as blocked tumour growth in vivo. CircRUNX1 directly sponged miR-485-5p, which negatively modulated SLC38A1 expression in CRC cells. The effects of circRUNX1 knockdown on CRC cell colony formation, migration, invasion, apoptosis and glutaminolysis were reversed by miR-485-5p inhibition. Moreover, miR-485-5p overexpression repressed the malignant behaviours of CRC cells, with SLC38A1 elevation overturned the impacts.
    CONCLUSION: CircRUNX1 promoted CRC cell growth, metastasis and glutamine metabolism and repressed apoptosis by elevating SLC38A1 through sponging miR-485-5p, which might provide a novel target for CRC treatment.
    Keywords:  CRC; SLC38A1; circRUNX1; miR-485-5p
    DOI:  https://doi.org/10.1111/eci.13540
  5. Cancer Lett. 2021 Mar 17. pii: S0304-3835(21)00111-7. [Epub ahead of print]507 80-88
    Expression of activated VEGFR2 by R1051Q mutation alters the energy metabolism of Sk-Mel-31 melanoma cells by increasing glutamine dependence.
    Elisabetta Grillo, Michela Corsini, Cosetta Ravelli, Luca Zammataro, Marina Bacci, Andrea Morandi, Eugenio Monti, Marco Presta, Stefania Mitola.
      Vascular endothelial growth factor receptor 2 (VEGFR2) activating mutations are emerging as important oncogenic driver events. Understanding the biological implications of such mutations may help to pinpoint novel therapeutic targets. Here we show that activated VEGFR2 via the pro-oncogenic R1051Q mutation induces relevant metabolic changes in melanoma cells. The expression of VEGFR2R1051Q leads to higher energy metabolism and ATP production compared to control cells expressing VEGFR2WT. Furthermore, activated VEGFR2R1051Q augments the dependence on glutamine (Gln) of melanoma cells, thus increasing Gln uptake and their sensitivity to Gln deprivation and to inhibitors of glutaminase, the enzyme initiating Gln metabolism by cells. Overall, these results highlight Gln addiction as a metabolic vulnerability of tumors harboring the activating VEGFR2R1051Q mutation and suggest novel therapeutic approaches for those patients harboring activating mutations of VEGFR2.
    Keywords:  Energy metabolism; Glutamine; Mutation; VEGFR2
    DOI:  https://doi.org/10.1016/j.canlet.2021.03.007
  6. Oncol Lett. 2021 May;21(5): 369
    Altered glycolysis results in drug-resistant in clinical tumor therapy.
    Jinghui Peng, Yangyang Cui, Shipeng Xu, Xiaowei Wu, Yue Huang, Wenbin Zhou, Shui Wang, Ziyi Fu, Hui Xie.
      Cancer cells undergo metabolic reprogramming, including increased glucose metabolism, fatty acid synthesis and glutamine metabolic rates. These enhancements to three major metabolic pathways are closely associated with glycolysis, which is considered the central component of cancer cell metabolism. Increasing evidence suggests that dysfunctional glycolysis is commonly associated with drug resistance in cancer treatment, and aberrant glycolysis plays a significant role in drug-resistant cancer cells. Studies on the development of drugs targeting these abnormalities have led to improvements in the efficacy of tumor treatment. The present review discusses the changes in glycolysis targets that cause drug resistance in cancer cells, including hexokinase, pyruvate kinase, pyruvate dehydrogenase complex, glucose transporters, and lactate, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies. In addition, the association between increased oxidative phosphorylation and drug resistance is introduced, which is caused by metabolic plasticity. Given that aberrant glycolysis has been identified as a common metabolic feature of drug-resistant tumor cells, targeting glycolysis may be a novel strategy to develop new drugs to benefit patients with drug-resistance.
    Keywords:  cancer; drug resistance; glycolysis; metabolism; microenvironment
    DOI:  https://doi.org/10.3892/ol.2021.12630
  7. Anal Chim Acta. 2021 Apr 22. pii: S0003-2670(21)00168-9. [Epub ahead of print]1155 338342
    Spatially resolved metabolomics combined with multicellular tumor spheroids to discover cancer tissue relevant metabolic signatures.
    Qingce Zang, Chenglong Sun, Xiaoping Chu, Limei Li, Wenqiang Gan, Zitong Zhao, Yongmei Song, Jiuming He, Ruiping Zhang, Zeper Abliz.
      Spatially resolved metabolomics offers unprecedented opportunities for elucidating metabolic mechanisms during cancer progression. It facilitated the discovery of aberrant cellular metabolism with clinical application potential. Here, we developed a novel strategy to discover cancer tissue relevant metabolic signatures by high spatially resolved metabolomics combined with a multicellular tumor spheroid (MCTS) in vitro model. Esophageal cancer MCTS were generated using KYSE-30 human esophageal cancer cells to fully mimic the 3D microenvironment under physiological conditions. Then, the spatial features and temporal variation of metabolites and metabolic pathways in MCTS were accurately mapped by using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) with a spatial resolution at ∼12 μm. Metabolites, such as glutamate, tyrosine, inosine and various types of lipids displayed heterogeneous distributions in different microregions inside the MCTS, revealing the metabolic heterogenicity of cancer cells under different proliferative states. Subsequently, through joint analysis of metabolomic data of clinical cancer tissue samples, cancer tissue relevant metabolic signatures in esophageal cancer MCTS were identified, including glutamine metabolism, fatty acid metabolism, de novo synthesis phosphatidylcholine (PC) and phosphatidylethanolamine (PE), etc. In addition, the abnormal expression of the involved metabolic enzymes, i.e., GLS, FASN, CHKA and cPLA2, was further confirmed and showed similar tendencies in esophageal cancer MCTS and cancer tissues. The MALDI-MSI combined with MCTS approach offers molecular insights into cancer metabolism with real-word relevance, which would potentially benefit the biomarker discovery and metabolic mechanism studies.
    Keywords:  Cancer metabolism; Esophageal cancer; Mass spectrometry imaging; Multicellular tumor spheroids; Spatially resolved metabolomics
    DOI:  https://doi.org/10.1016/j.aca.2021.338342
  8. Nat Commun. 2021 03 25. 12(1): 1876
    SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition.
    Peter J Mullen, Gustavo Garcia, Arunima Purkayastha, Nedas Matulionis, Ernst W Schmid, Milica Momcilovic, Chandani Sen, Justin Langerman, Arunachalam Ramaiah, David B Shackelford, Robert Damoiseaux, Samuel W French, Kathrin Plath, Brigitte N Gomperts, Vaithilingaraja Arumugaswami, Heather R Christofk.
      Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.
    DOI:  https://doi.org/10.1038/s41467-021-22166-4
  9. Oncol Rep. 2021 May;pii: 54. [Epub ahead of print]45(5):
    Long non‑coding RNAs: Key regulators involved in metabolic reprogramming in cancer (Review).
    Chunxia Liu, Hao Li, Fenglan Chu, Xi Zhou, Rui Xie, Qiongqiong Wei, Shiming Yang, Tao Li, Sicheng Liang, Muhan Lü.
      Metabolism is defined as the biochemical processes that produce or consume energy in living organisms. Otto Warburg suggested that cancer is a metabolic disease, thus metabolic reprogramming is widely considered as an emerging hallmark of cancer cells. Long non‑coding RNAs (lncRNAs), which are defined as transcripts >200 nucleotides with limited protein coding potential, are involved in cancer metabolism. lncRNAs can control pathophysiological processes of cancer by regulating gene expression at epigenetic, transcriptional and post‑transcriptional levels. The process of tumorigenesis is usually accompanied by alterations in metabolic patterns, involving glycolysis, the tricarboxylic acid cycle, mitochondrial oxidative phosphorylation, the pentose phosphate signaling pathway, glutamine metabolism and lipid metabolism, which is also known as metabolic reprogramming. The present review summarized the functions of lncRNAs in cancer metabolism and discussed how the dysregulation of lncRNAs contributed to metabolic reprogramming and tumorigenesis, which may provide novel therapeutic targets for cancer.
    DOI:  https://doi.org/10.3892/or.2021.8005
  10. Sci Adv. 2021 Mar;pii: eabe5708. [Epub ahead of print]7(13):
    LncRNA GIRGL drives CAPRIN1-mediated phase separation to suppress glutaminase-1 translation under glutamine deprivation.
    Ruijie Wang, Leixi Cao, Rick Francis Thorne, Xu Dong Zhang, Jinming Li, Fengmin Shao, Lirong Zhang, Mian Wu.
      Glutamine constitutes an essential source of both carbon and nitrogen for numerous biosynthetic processes. The first and rate-limiting step of glutaminolysis involves the generation of glutamate from glutamine, catalyzed by glutaminase-1 (GLS1). Shortages of glutamine result in reductions in GLS1, but the underlying mechanisms are not fully known. Here, we characterize a long noncoding RNA, GIRGL (glutamine insufficiency regulator of glutaminase lncRNA), that is induced upon glutamine starvation. Manipulating GIRGL revealed a relationship between its expression and the translational suppression of GLS1. Cellular GIRGL levels are balanced by a combination of transactivation by c-JUN together with negative stability regulation via HuR/Ago2. Increased levels of GIRGL in the absence of glutamine drive formation of a complex between dimers of CAPRIN1 and GLS1 mRNA, serving to promote liquid-liquid phase separation of CAPRIN1 and inducing stress granule formation. Suppressing GLS1 mRNA translation enables cancer cells to survive under prolonged glutamine deprivation stress.
    DOI:  https://doi.org/10.1126/sciadv.abe5708
  11. Br J Cancer. 2021 Mar 25.
    The amino acid metabolism is essential for evading physical plasma-induced tumour cell death.
    Rajesh Kumar Gandhirajan, Dorothee Meyer, Sanjeev Kumar Sagwal, Klaus-Dieter Weltmann, Thomas von Woedtke, Sander Bekeschus.
       BACKGROUND: Recent studies have emphasised the important role of amino acids in cancer metabolism. Cold physical plasma is an evolving technology employed to target tumour cells by introducing reactive oxygen species (ROS). However, limited understanding is available on the role of metabolic reprogramming in tumour cells fostering or reducing plasma-induced cancer cell death.
    METHODS: The utilisation and impact of major metabolic substrates of fatty acid, amino acid and TCA pathways were investigated in several tumour cell lines following plasma exposure by qPCR, immunoblotting and cell death analysis.
    RESULTS: Metabolic substrates were utilised in Panc-1 and HeLa but not in OVCAR3 and SK-MEL-28 cells following plasma treatment. Among the key genes governing these pathways, ASCT2 and SLC3A2 were consistently upregulated in Panc-1, Miapaca2GR, HeLa and MeWo cells. siRNA-mediated knockdown of ASCT2, glutamine depletion and pharmacological inhibition with V9302 sensitised HeLa cells to the plasma-induced cell death. Exogenous supplementation of glutamine, valine or tyrosine led to improved metabolism and viability of tumour cells following plasma treatment.
    CONCLUSION: These data suggest the amino acid influx driving metabolic reprogramming in tumour cells exposed to physical plasma, governing the extent of cell death. This pathway could be targeted in combination with existing anti-tumour agents.
    DOI:  https://doi.org/10.1038/s41416-021-01335-8
  12. Proc Natl Acad Sci U S A. 2021 Mar 30. pii: e2012748118. [Epub ahead of print]118(13):
    A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.
    Lingfan Xu, Yu Yin, Yanjing Li, Xufeng Chen, Yan Chang, Hong Zhang, Juan Liu, James Beasley, Patricia McCaw, Haoyue Zhang, Sarah Young, Jeff Groth, Qianben Wang, Jason W Locasale, Xia Gao, Dean G Tang, Xuesen Dong, Yiping He, Daniel George, Hailiang Hu, Jiaoti Huang.
      Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.
    Keywords:  GAC; glutaminase; prostate cancer; therapeutic resistance
    DOI:  https://doi.org/10.1073/pnas.2012748118
  13. Clin Nutr ESPEN. 2021 Apr;pii: S2405-4577(21)00008-5. [Epub ahead of print]42 53-60
    Effects of glutamine supplementation on inflammatory bowel disease: A systematic review of clinical trials.
    Juliana Soares Severo, Vilk Janne da Silva Barros, Alda Cássia Alves da Silva, José Miguel Luz Parente, Murilo Moura Lima, Aldo Ângelo Moreira Lima, Armênio Aguiar Dos Santos, Emídio Marques Matos Neto, Moisés Tolentino.
       CONTEXT: Glutamine supplementation has been applied clinical practice to treat inflammatory bowel disease (IBD). However, scientific evidence about this is still controversial.
    OBJECTIVE: In this review, we systematically evaluated the effects of glutamine supplementation on IBD, based on evidence from randomized clinical trials.
    DATA SOURCE: This review was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We used the PubMed and SciVerse Scopus databases. The Cochrane collaboration tool was used to assess the risk of bias in clinical trials.
    DATA EXTRACTION: The review was carried out by two independent researchers according to the established inclusion criteria. The PICO (patient, intervention, comparison, and outcomes) strategy was used, with the descriptors: "glutamine," "supplementation," "inflammatory bowel diseases," "Crohn's disease," and "ulcerative colitis".
    DATA SYNTHESIS: Seven research articles were selected for this systematic review. In these studies, glutamine was administered to the participants through oral (21-30g or 0.5g per kg of participant's body weight), enteral (7.87g-8.3 g/100g of the enteral formula), and/or parenteral (0.3  g/kg of the participant's body weight) routes. No changes in anthropometry or biochemical parameters were observed. However, in one study reduced intestinal permeability and morphometry were reported. In two other studies, a slight effect of glutamine on inflammation and oxidative stress was observed. Additionally, two other studies reported an effect of glutamine supplementation on disease activity.
    CONCLUSIONS: The findings obtained through this systematic review indicate that glutamine supplementation has no effect on disease course, anthropometric measurements, intestinal permeability and morphology, disease activity, intestinal symptoms, biochemical parameters, oxidative stress and inflammation markers in patients with IBD, regardless of the route of administration, either treated at a hospital or as outpatients.
    Keywords:  Crohn's disease; Glutamine; Inflammatory bowel disease; Supplementation; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.clnesp.2020.12.023
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