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People with obesity had on average lower levels of glutamine in their fat tissue than normal-weight people. Lower glutamine-levels were also associated with larger fat cell size and higher body fat percentage independently of body-mass index BMIaccording to the study.
The researchers also showed through a combination of animal and cell analyses that glutamine levels influenced the expression of different genes and that low glutamine levels induced an increase in the expression of pro-inflammatory genes in the fat tissue.
Obese mice injected with glutamine for two weeks had less fat tissue inflammation than mice who received a control saline solution. Their body fat mass, fat cell volume and blood glucose levels were also reduced. In an analysis of cultured human fat cells, the expression of pro-inflammatory genes and the lipid content were attenuated after incubation with increasing concentrations of glutamine.
The largest effect was observed after treatment with millimolar mM glutamine for 11 days, according to the study. The researchers also studied in detail what happens inside the fat cell when glutamine levels are altered. They found that glutamine impacts a mechanism called O-GlcNAcylation that can control epigenetic changes, that is changes in gene expression caused by environmental and lifestyle factors rather than by alterations in our underlying DNA sequence.
People with obesity had higher levels of O-GlcNAcylation in their fat tissue while mice and human cells treated with glutamine had lower levels of O-GlcNAcylation in the cell nucleus. Further research is needed to fully understand which genes and cellular processes are affected the most, according to the researchers.
Wheelock, Peter Arner, Mark McCarthy, Martin O. Bergo, Laurienne Edgar, Robin P. Choudhury, Myriam Aouadi, Anna Krook and Mikael Rydén, Cell Metabolismonline December 19, Published: Updated: Glutamine could be of value against obesity.
Can control epigenetic changes The researchers also studied in detail what happens inside the fat cell when glutamine levels are altered.
: Glutamine and inflammation| What is Glutamine? | Axe on Facebook Dr. However, those results are still controversial, and it is important to consider the timing of glutamine administration. Br J Nutr. We then interrogated if GLS inhibition can modulate the inflammatory response similar to glutamine deprivation. Because of the potential for side effects and interactions with medications, you should take dietary supplements only under the supervision of a knowledgeable health care provider. |
| Wound healing and recovery from illness | Wilmore DW, Shabert JK. Gluutamine the catabolic process continues Berger Glutakine Normalizing digestive system et al. Glutamine and inflammation inflam,ation is Weight management community given inflam,ation malnourished cancer patients undergoing chemotherapy or radiation treatments, and sometimes used in people undergoing bone marrow transplants. They identified glutamine as the amino acid that displayed the largest differences when comparing the two groups. Researchers also have reported that supplementation after exercise exerts many beneficial effects; especially in muscle recovery and connective tissue damage Grassi et al. |
| Glutamine for treatment of active Crohn's disease | Cochrane | Numerous studies show that serum inflammatory factors interleukins such as IL6, IL1β, and TNF-α are elevated in these patients Robinson et al. Curr Med Chem 20 10 — No study has discussed whether glutamine mitigates oxidative damage on RBC or enhances the regeneration of RBC after exhaustive exercise. Dosing and efficacy of glutamine supplementation in human exercise and sport training. One review that included data from 55 studies observed that glutamine improved some fatigue markers, such as increased glycogen synthesis and reduced ammonia accumulation, but this intervention did not always increase physical performance. Foods that Make You Poop Immediately. |
| Glutamine may decrease obesity-linked inflammation | Karolinska Institutet | Malnutrition also exacerbates infection and increases mortality in COVID by weakening the immune system. In some animal studies, it has been shown that infection reduces appetite, and eventually, the animal loses weight Li et al. Possible mechanisms of malnutrition in infectious patients include increased inflammatory factors such as elevated serum CRP levels Derouiche and inflammatory interleukins such as IL1, IL6, and α-TNF. Numerous studies show that serum inflammatory factors interleukins such as IL6, IL1β, and TNF-α are elevated in these patients Robinson et al. IL1β strongly promotes anorexia, increased energy expenditure, muscle protein loss, and leptin release Rao et al. Oxidative stress also exacerbates malnutrition in these patients through changes in metabolism and energy Hsieh et al. It has been reported that nutritional support can improve nutritional status and anthropometric factors in patients with respiratory infections Baumgartner et al. On the other hand, it has been shown that glutamine can regulate appetite by affecting the secretion of Glucagon-like peptide 1 from the gastrointestinal tract Andersson et al. Glucagon-like peptide 1 is a physiological regulator of energy intake and appetite Adams et al. Glutamine is also involved in the formation of glutamate and GABA Qureshi et al. Glutamate and GABA can stimulate appetite Varela et al. Glutamine has the effect of reducing pro-inflammatory cytokines and may play a role in reducing mortality by controlling the infection de Urbina et al. Only one study Cengiz et al. Based on the COVID treatment importance and reduction in mortality and morbidity, this case-control study aimed to assess and compare serum levels of some inflammatory factors, oxidative stress, and appetite in COVID patients with respiratory infections that receive glutamine treatment with a control group. Before the written consent, all patients were given complete information about the study protocol. A total of COVID patients were screened and patients who met the inclusion criteria were included in the study. Patients who applied to the COVID outpatient clinics of the Hospital between Jan 28 and Mar 10, those who had lower respiratory tract involvement in computed thorax tomography thorax CT , and positive real-time reverse-transcriptase-polymerase chain reaction RT-PCR test in the oro-nasopharyngeal swab, were included in the study. In this study, patients who consented to use glutamine were considered as the case group and other patients who did not use glutamine were considered as the control group. were excluded from the study. The Sequential Organ Failure Assessment SOFA scoring was performed on all patients for evaluating the severity of the disease before the beginning of the study. When a patient had malnutrition or was at risk of malnutrition at the beginning or in the following period of the hospital stay, we planned a nutritional care plan and excluded them from the study. The patients whose clinical courses and laboratory parameters worsened through all given treatments were classified as severe sepsis according to the criteria of SOFA and excluded from the study. SOFA measures individual or aggregate organ dysfunction in six organ systems respiratory, coagulatory, liver, cardiovascular, renal, and neurologic in the ICU and mostly predict hospital mortality. Thorax CT screenings of all patients were taken at the time of hospital admission. As stated in the guidelines, and the oropharyngeal sample was first taken with a swab, then a nasal sample was taken using the same swab, and placed in the same transport medium for diagnosis. Samples were tested by RT-PCR assay developed from the virus sequence. Before giving the supplement, 2 cc blood samples were taken from both groups. At the end of glutamine consumption, blood samples were taken again to assess serum levels of IL1β, tumor necrosis factor-α, malondialdehyde, and total antioxidant capacity, then all data were analyzed. COVID patients with certain diseases, such as heart and liver disease, and those who were unwilling to cooperate were excluded from the study. To measure this cytokine, the sandwich ELISA method was used using the human ELISA kit manufactured by Diaclone Company with serial number The basis of this measurement is based on the incubation of a special substrate with peroxidase and hydrogen peroxide and the production of a radical substrate cation that produces a stable green-blue color that can be measured at a wavelength of nm. To measure hs-CRP protein, Pars test diagnostic kit was used by immunoturbidimetric. According to the kit brochure, first 20 μl of serum with μl of reagent 1 was placed at 37 °C for 5 min, then μl of reagent 2 containing mouse monoclonal and goat polyclonal antibodies against human CRP antibody was added. Interleukins β 1 were measured by ELISA using Bender Med Systems kits Vienna, Austria. After discharging the patients before 5 days before the hospitalization period, according to the present project, the necessary recommendations regarding the use of supplements and placebo were provided to the parents and the patients were followed up to control them in terms of taking supplements. The nutrition status as considering the first level of this screening was evaluated by the variables; Body Mass Index BMI , weight loss in the last 3 months, and decreased food intake in the last week. The severity degrees of disease as considering the second level of NRS was defined as absent, mild, moderate, or severe that was converted to a numeric score between 1 and 3 according to recommendations. A total score under 3 suggested no nutritional risk. To obtain all information a data collection sheet was used. All given meals for this study patients were prepared based on the appropriate guidelines in COVID and consisted of equal protein and calorie contents. The case group consumed 10 g of glutamine powder three times per day for 5 days. In this study, a subjective index and an objective index for appetite measurement were considered. To measure the food greasiness degree, food greasiness was added to the VAS. The scale 0—10 was adopted to evaluate the sensation before or after eating, and the higher the scale indicated the stronger the sensation. Based on their experience, the subjects were free to calibrate on each line that best matched how they were. The normal distribution of the data was tested using the one-sample Kolmogorov—Smirnov test. Continuous variables are presented as mean ± standard deviation. Categorical variables are presented as counts. The statistical comparisons were performed using the one-way ANOVA and SIDAK test. Categorical variables were compared using the Chi-square test or Fisher exact test for small samples. The statistical analysis was performed using SPSS Demographic characteristics of the study participants are given in Table 1. Symptoms, medications for COVID, and physical examination findings of the study groups are given in Table 2. There was no significant difference in all of the symptoms, medications, and physical examination findings between the study groups. Necessity of intensive care unit, duration of hospitalization, and the number of mortality of the groups of study are given in Table 3. Duration of hospitalization was found as There was a significant difference in mortality rates between the groups, 38 3. Laboratory and physical examination findings before and after the study are given in Table 4. This study is the first study that evaluated the effect of glutamine on serum antioxidants, TNF-α, CRP, MDA, interleukin-β 1 , and the level of appetite in COVID patients admitted to the intensive care unit. Decreased appetite has been reported in COVID patients Høier et al. Therefore, improving the appetite level in COVID patients is a very important issue and it is recommended to use glutamine to improve the appetite of these patients. Decreased appetite leads to a low intake of nutrients that are effective in immunity such as vitamin C, zinc, selenium, and protein, so the complications of this disease increase. The results of the present study showed that the amount of appetite during the 5 days of glutamine supplementation was significantly increased compared to the control group. Also in this present study results showed that the mean serum interleukin-1 β and tumor necrosis factor-α were significantly reduced by taking a five-day glutamine supplement. Increased levels of oxidative stress have been observed in patients with COVID Chernyak et al. Oxidative stress is responsible for the deterioration of these patients and cell damage Laforge et al. Proper and healthy nutrition that is rich in antioxidants has a very important role in these patients , recovery Iddir et al. Glutamine is a supplement that is used as an antioxidant in some intensive care units of hospitals for critically ill patients, especially those with respiratory infections Cruzat et al. Skeletal muscle is the main reservoir of glutamine, and during infection the release of glutamine from the muscle doubles, so its serum level remains normal Levitt and Levitt Cytokines and glucocorticoids increase the absorption of glutamine by the liver in infectious conditions Cruzat et al. On the other hand, Cytokines regulate bowel movements and alter various brain signals involved in appetite Vázquez-Frias et al. IL1β strongly promotes anorexia, increased energy expenditure, muscle protein loss, and leptin secretion Peixoto da Silva et al. It has been shown that glutamine administration may play a role in improving the immune system Cetinbas et al. Consistent with the results of this study, a study by Fan et al. Inconsistent with our result, the findings of the study by Delgado et al. showed that glutamine supplementation for 8 weeks did not affect inflammatory factors in the pulmonary sputum of cystic fibrosis patients that had a respiratory infection Delgado This different result may be related to the different types of studies sample. The results of the present study showed that the serum level of hs-CRP was significantly reduced with five days of glutamine supplementation. Glutamine is a dietary supplement that has antioxidant properties Yuan et al. In COVID patients, the level of hs-CRP in the blood increases Li et al. Animal studies have shown that glutamine can improve the antioxidant capacity of the body by increasing glutathione stores Yeh et al. Consistent with the findings of our study, Faghihzadeh et al. Faghihzadeh et al. in smokers Bo et al. The possible effect of glutamine in reducing serum hs-CRP may be due to its antioxidant properties, which can increase the activity of serum antioxidant enzymes Tanha et al. In the present study, the serum level of TAC, in COVID patients with glutamine consumption, was significantly increased. Increased oxidative stress is seen in patients with COVID, which may play a role in the pathogenesis of this disease. The end product of lipid peroxidation is active aldehydes such as malondialdehyde MDA Tanha et al. Oxidative stress occurs when free radical production is more than antioxidant capacity. Antioxidant enzymes and a variety of antioxidant compounds are produced in the body to counteract oxidative stress Wang et al. There is a significant change in the level of TAC and MDA after the use of glutamine in COVID with respiratory infection. Reducing the amount of TNF-α, hs-CRP, and IL B 1 can be useful to improve the inflammation in these patients. The duration of the intervention, the problems of preparing laboratory kits, and the low cooperation of the COVID patients , families were some of the limitations of this study. It is suggested that future studies be performed with more COVID patients and with a longer intervention duration. Daily consumption of 10 g of glutamine three times per day in COVID patients with respiratory infection decreases the serum interleukin-β level, the level of alpha necrosis tumor factor, the serum hs-CRP level and increases the appetite of COVID patients, so using this supplement can prevent malnutrition of COVID patients with respiratory infectious diseases. Adams JM, Pei H, Sandoval DA, Seeley RJ, Chang RB, Liberles SD, Olson DP Liraglutide modulates appetite and body weight through glucagon-like peptide 1 receptor-expressing glutamatergic neurons. Diabetes 67 8 — CAS PubMed PubMed Central Google Scholar. Andersen AD, Nguyen DN, Langhorn L, Renes IB, van Elburg RM, Hartog A, Tims S, van de Looij Y, Sangild PT, Thymann T Synbiotics combined with glutamine stimulate brain development and the immune system in preterm pigs. J Nutr 1 — PubMed Google Scholar. Andersson LE, Shcherbina L, Al-Majdoub M, Vishnu N, Arroyo CB, Carrara JA, Wollheim CB, Fex M, Mulder H, Wierup N Glutamine-elicited secretion of glucagon-like peptide 1 is governed by activated glutamate dehydrogenase. Diabetes 67 3 — CAS PubMed Google Scholar. GlutaSolve® contains 15 grams glutamine and 90 kilocalories per packet in a tasteless, quick-dissolving powder. It dissolves best in clear liquids juice, water and moist foods pudding, yoghurt, applesauce. As a naturally occurring amino acid, glutamine is thought to be a safe supplement when taken at recommended dosages. However, those who are hypersensitive to monosodium glutamate MSG should use glutamine with caution, as the body metabolizes glutamine into glutamate. Also, because many anti-epilepsy drugs work by blocking glutamate stimulation in the brain, high dosages of glutamine may overwhelm these drugs and pose a risk to people with epilepsy. In one report, high doses of the supplement L-glutamine may have triggered episodes of mania in two people not previously known to have bipolar disorder. Maximum safe dosages for young children, pregnant or nursing women, or those with severe liver or kidney disease have not been determined. If you are taking antiseizure medications, including carbamazepine, phenobarbital, phenytoin Dilantin® , primidone Mysoline® , and valproic acid Depakene® , use glutamine only under medical supervision. Finally, glutamine is not recommended in protein-restricted diets i. end-stage liver or renal diseases. Some studies on glutamine have shown promising results in patients with metabolic or gastrointestinal disorders. Oral glutamine is well tolerated and easily administered in most liquids or semi-solid foods. For more information regarding oral glutamine i. Resource GlutaSolve® , contact your physician or dietitian. Singleton KD, Serkova N, Beckey VE, Wischmeyer PE. Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression. Cavalcante AA, Campelo MW, de Vasconcelos MP, Ferreira CM, Guimarães SB, Garcia JH, de Vasconcelos PR. Enteral nutrition supplemented with L-glutamine in patients with systemic inflammatory response syndrome due to pulmonary infection. Wang X, Xue Y, Liang M, Jiang W. Glutamine treatment decreases plasma and lymph cytotoxicity during sepsis in rats. Acta Biochim Biophys Sin. de Oliveira GP, Silva JD, de Araújo CC, Prota LF, Abreu SC, Madeira C, Morales MM, Takiya CM, Diaz BL, Capelozzi VL, Panizzutti R, Pelosi P, Rocco PR. Intravenous glutamine administration reduces lung and distal organ injury in malnourished rats with sepsis. Koksal GM, Erbabacan E, Tunali Y, Karaoren G, Vehid S, Oz H. The effects of intravenous, enteral and combined administration of glutamine on malnutrition in sepsis: a randomized clinical trial. Briassoulis G, Venkataraman S, Thompson A. Cytokines and metabolic patterns in pediatric patients with critical illness. Clin Dev Immunol. Holecek M, Sispera L. Glutamine deficiency in extracellular fluid exerts adverse effects on protein and amino acid metabolism in skeletal muscle of healthy, laparotomized, and septic rats. Amino Acids. Roth E. Nonnutritive effects of glutamine. Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG, Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. Heyland DK, Elke G, Cook D, Berger MM, Wischmeyer PE, Albert M, Muscedere J, Jones G, Day AG, Canadian Critical Care Trials Group. Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial. J Parenter Enteral Nutr. Article CAS Google Scholar. Wilmore DW, Shabert JK. Role of glutamine in immunologic responses. Marino LV, Pathan N, Meyer R, Wright V, Habibi P. Glutamine depletion and heat shock protein 70 HSP70 in children with meningococcal disease. Tsan MF, Gao B. Heat shock proteins and immune system. J Leukoc Biol. Jordan I, Balaguer M, Esteban ME, Cambra FJ, Felipe A, Hernández L, Alsina L, Molero M, Villaronga M, Esteban E. Glutamine effects on heat shock protein 70 and interleukines 6 and randomized trial of glutamine supplementation versus standard parenteral nutrition in critically ill children. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA. Ko HM, Oh SH, Bang HS, Kang NI, Cho BH, Im SY, Lee HK. Glutamine protects mice from lethal endotoxic shock via a rapid induction of MAPK phosphatase Lee CH, Kim HK, Jeong JS, Lee YD, Jin ZW, Im SY, Lee HK. Mechanism of glutamine inhibition of cytosolic phospholipase A2 cPLA2 : evidence of physical interaction between glutamine-induced MAPK phosphatase-1 and cPLA2. Clin Exp Immunol. Zhu Y, Lin G, Dai Z, Zhou T, Li T, Yuan T, Wu Z, Wu G, Wang J. L-Glutamine deprivation induces autophagy and alters the mTOR and MAPK signaling pathways in porcine intestinal epithelial cells. Gerondakis S, Grumont R, Gugasyan R, Wong L, Isomura I, Ho W, Banerjee A. Unravelling the complexities of the NF-kB signalling pathway using mouse knockout and transgenic models. Liou HC, Hsia CY. Distinctions between c-Rel and other NF-kappaB proteins in immunity and disease. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. Cruzat VF, Bittencourt A, Scomazzon SP, Leite JS, de Bittencourt Jr PI, Tirapegui J. Oral free and dipeptide forms of glutamine supplementation attenuate oxidative stress and inflammation induced by endotoxemia. Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. Br J Anaesth. Rinaldi S, Landucci F, De Gaudio AR. Antioxidant therapy in critically septic patients. Curr Drug Targets. Lin Z, Cai F, Lin N, Ye J, Zheng Q, Ding G. Effects of glutamine on oxidative stress and nuclear factor-kB expression in the livers of rats with nonalcoholic fatty liver disease. Exp Ther Med. Rogero MM, Borelli P, Fock RA, Borges MC, Vinolo MA, Curi R, Nakajima K, Crisma AR, Ramos AD, Tirapegui J. Effects of glutamine on the nuclear factor-kappaB signaling pathway of murine peritoneal macrophages. da Silva Lima F, Rogero MM, Ramos MC, Borelli P, Fock RA. Modulation of the nuclear factor-kappa B NF-kB signalling pathway by glutamine in peritoneal macrophages of a murine model of protein malnutrition. Eur J Nutr. Chu CC, Hou YC, Pai MH, Chao CJ, Yeh SL. Pretreatment with alanyl-glutamine suppresses T-helper-cell-associated cytokine expression and reduces inflammatory responses in mice with acute DSS-induced colitis. J Nutr Biochem. Rogero MM, Tirapegui J, Vinolo MA, Borges MC, de Castro IA, Pires IS, Borelli P. Dietary glutamine supplementation increases the activity of peritoneal macrophages and hemopoiesis in early-weaned mice inoculated with Mycobacterium bovis bacillus Calmette-Guérin. Kim DS, Jue SS, Lee SY, Kim YS, Shin SY, Kim EC. Effects of glutamine on proliferation, migration, and differentiation of human dental pulp cells. J Endod. Zou J, Wang YX, Mu HJ, Xiang J, Wu W, Zhang B, Xie P. Down-regulation of glutamine synthetase enhances migration of rat astrocytes after in vitro injury. Hou YC, Wu JM, Wang MY, Wu MH, Chen KY, Yeh SL, Lin MT. Glutamine supplementation attenuates expressions of adhesion molecules and chemokine receptors on T cells in a murine model of acute colitis. Mediators Inflamm. Jersmann HP, Hii CS, Ferrante JV, Ferrante A. Bacterial lipopolysaccharide and tumor necrosis factor alpha synergistically increase expression of human endothelial adhesion molecules through activation of NF-kappaB and p38 mitogen-activated protein kinase signaling pathways. Infect Immun. Rogero MM, Borelli P, Fock RA, de Oliveira Pires IS, Tirapegui J. Glutamine in vitro supplementation partly reverses impaired macrophage function resulting from early weaning in mice. Rogero MM, Borelli P, Vinolo MA, Fock RA, de Oliveira Pires IS, Tirapegui J. Dietary glutamine supplementation affects macrophage function, hematopoiesis and nutritional status in early weaned mice. Yeh CL, Hsu CS, Yeh SL, Lin MT, Chen WJ. Dietary glutamine supplementation reduces cellular adhesion molecule expression and tissue myeloperoxidase activity in mice with gut-derived sepsis. Lin MT, Chou SY, Tsou SS, Wang MY, Wu MH, Yeh SL. Effects of parenteral glutamine supplementation on modulating the immune response in rats undergoing a total gastrectomy. Tsai PH, Liu JJ, Chiu WC, Pai MH, Yeh SL. Effects of dietary glutamine on adhesion molecule expression and oxidative stress in mice with streptozotocin-induced type 1 diabetes. Pai MH, Chien YW, Tsai YH, Hu YM, Yeh SL. Glutamine reduces the expression of leukocyte integrins leukocyte function-associated antigen-1 and macrophage antigen-1 in mice exposed to arsenic. Nutr Res. Spittler A, Winkler S, Götzinger P, Oehler R, Willheim M, Tempfer C, Weigel G, Függer R, Boltz-Nitulescu G, Roth E. Influence of glutamine on the phenotype and function of human monocytes. Download references. The authors thank Conselho Nacional de Pesquisa e Tecnologia CNPq and Fundação de Amparo à Pesquisa do Estado de São Paulo FAPESP. MMR and RAF are fellows of the CNPq. DCO participated in the design of the study and wrote the introduction and molecular mechanism and gene expression sections. FSL wrote the glutamine, muscle metabolism, liver metabolism, and critical illness sections. TS wrote the glutamine, intestine metabolism, and immunologic response sections. ACAS wrote the role of glutamine on cell migration and adhesion molecules section. MMR participated in the design of the study and worked in all sections. RAF participated in the design of the study and drafting the manuscript, contributing in all review section. All authors read and approved the final manuscript. Department of Clinical and Toxicological Analyzes, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Department of Food and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil. Department of Clinical and Toxicological Analyzes, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, , Bloco 17, Butantã, São Paulo, SP, Brazil, You can also search for this author in PubMed Google Scholar. Correspondence to Ricardo Ambrosio Fock. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. de Oliveira, D. et al. Glutamine metabolism and its effects on immune response: molecular mechanism and gene expression. Nutrire 41 , 14 Download citation. Received : 19 February Accepted : 12 September Published : 20 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF. Abstract This article aims to review glutamine metabolism and its effects on the immune response. Glutamine Uptake and Immunomodulation: An Overview Chapter © Web-Based Resources and Suggested Readings Chapter © The Role of Mitochondria in the Immune Response in Critical Illness Article 22 March Use our pre-submission checklist Avoid common mistakes on your manuscript. Background Glutamine is an α-amino acid and is the most abundant free amino acid in the body. Full size image. Glutamine: critical illness The systemic inflammatory response syndrome SIRS and the compensatory inflammatory response syndrome CARS were conceptually described in the s [ 51 ]. Nuclear factor-Kb The nuclear factor kappa B NF-kB signaling pathway serves a crucial role in regulating the transcriptional responses of physiological processes including cell division, cell survival, differentiation, immunity, and inflammation [ 83 ]. Conclusions Glutamine supplementation leads to a range of reactions and modulatory effects of processes across different organisms. 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Glutamine and inflammation -
However, more research is needed before glutamine supplementation may be recommended as a treatment for obesity. The study is published in the journal Cell Metabolism. Glutamine is an important amino acid with many key functions such as providing energy and maintaining good intestinal health.
It also has anti-inflammatory effects on for example white blood cells and T-cells that are important for the immune system. In the current study, the researchers examined how the metabolic processes differed in fat tissue collected from the abdomen of 52 obese and 29 non-obese women.
They identified glutamine as the amino acid that displayed the largest differences when comparing the two groups. People with obesity had on average lower levels of glutamine in their fat tissue than normal-weight people. Lower glutamine-levels were also associated with larger fat cell size and higher body fat percentage independently of body-mass index BMI , according to the study.
Glutamine transport in the muscle is performed by the N m system, which controls the concentration of intramuscular glutamine and appears to be responsible for both the outflow and inflow of glutamine. However, their activity is sensitive to insulin and glucocorticoids [ 15 , 17 , 18 ].
Glutamine also participates in the synthesis of glycogen in the muscle. In rats, intraperitoneal administration of glutamine increased glycogen in the skeletal muscle [ 19 ].
In humans that showed a decrease in glutamine and muscle glycogen after exercise, an intravenous infusion of glutamine increased the plasma concentrations of this amino acid [ 20 ].
In intestinal epithelial cells, glutamine is quantitatively the most important fuel. It is metabolized to glutamate, which undergoes transamination, so the metabolites of this reaction are oxidized in the TCA cycle to generate pyruvate.
Pyruvate then undergoes amination to produce L-alanine via the action of alanine aminotransferase [ 7 ]. For many years, the intestine was investigated merely as an organ of digestion, nutrient absorption, and fermentation.
However, it is now known that the intestine is a complex organ that performs a diversity of critical physiologic functions.
The intestinal mucosa contains secretory, immune, and neuroendocrine cells besides the absorptive enterocytes [ 21 ]. Besides serving as a major organ for nutrient digestion and absorption, the single layer of epithelium lining the gastrointestinal tract creates a selective barrier to prevent the transferring of damaging agents as toxins, allergens, and pathogens to the systemic blood circulation [ 22 ].
Newer research has shown since the studies conducted by Windmueller and Spaeth in [ 23 ] that glutamine is the main energy substrate of enterocytes. Rapidly dividing cells require glutamine, as glutamine supplies of half of nitrogen requirement for purine and pyrimidine synthesis via action the carbamoyl phosphate synthetase II within cytosol [ 24 ].
Glutamine is also a potential precursor in the synthesis of N -acetyl-glucosamine and N -acetyl-galactosamine, which may play a critical role in the intestinal mucin synthesis and therefore for the maintenance of passive barrier to bacterial invasion [ 25 ].
The high absorptive capacity in the apical region of enterocytes is the reason this cells capture glutamine priority from the lumen, and apparently, almost all glutamine contained in the diet is utilized by the enterocytes [ 23 ].
The measurements of intestinal glutamine metabolism also showed that glutamine is the precursor for a number of important metabolic pathways, especially those leading to the synthesis of ornithine, citrulline, proline, and arginine. Glutamine dipeptides induce mucosa proliferation of the ileum and colon in human in vitro [ 27 ].
It has been reported that glutamine supplementation increased villus height and area of the jejunum, but did not alter the mass of protein or DNA 4-day old piglets [ 21 , 28 ]. Wu et al. In , Wu [ 30 ] demonstrated that dietary glutamine supplementation prevents jejunal atrophy in weaned piglets and glutamine supplementation reversed the elevation of jejunal corticotropin-releasing factor CRF , which block the release of proteases and TNF-α from mast cells in the jejunum, thereby conferring a protective functional of the intestinal mucosa [ 31 ].
According to Li and Neu et al. The liver plays a central role in the nitrogen metabolism in the body. Transportation of nitrogen is performed mainly from the muscle and lung to the liver, as glutamine, alanine, and aspartate. The breakdown of glutamine releases NH 3 that through mitochondrial enzymes enters the urea cycle as a substrate.
The urea cycle consumes two molecules of ammonia and one molecule of carbon dioxide, creates one molecule of urea, and regenerates a molecule of ornithine for another turn. In the kidney, the action of glutaminase produces the NH 3 and because that glutamine is quantitatively the most important donor of NH 3 in this tissue.
Thereby, glutamine metabolism is essential for acid-base buffering [ 33 ] and also plays an important role in the biosynthesis of nucleotides, detoxification of ammonia, glutathione synthesis, and maintenance of nitrogen transfer between organs [ 5 , 12 , 34 ].
GS and GA are present in the liver, with the GS being expressed in perivenous hepatocytes and the GA in the periportal zone [ 12 ]. Krebs [ 35 ] was the first to describe hepatic metabolism of glutamine and hydrolysis of this amino acid to glutamate and ammonia. In the liver, glutamine metabolism is important in the regulation of the urea cycle, detoxification of ammonia, and the pH maintenance [ 12 ].
Such carriers include SNAT2, SNAT4, SNAT3, SNAT5, Lat2, and LAT1, and SNAT 3 and 5 are considered the most important in plasma membrane of hepatocytes [ 12 , 35 , 36 ]. Studies have shown the role of these transporters in the hepatic metabolism and glutamine flow [ 37 — 39 ]. The role of FXR nuclear receptor in hepatic glutamine has been also investigated.
It is believed that this receptor and its ligand are involved in the regulation of glutamine and glutamate metabolism [ 40 , 41 ]. Other studies have highlighted the importance of hepatic metabolism of glutamine in hepatic encephalopathy [ 42 ] and cancer [ 43 ].
Due to the important role of glutamine in hepatic metabolism, many studies have investigated this amino acid in liver injury situations [ 44 — 46 ]. In a study evaluating parenteral nutrition in premature infants, it was found that parenteral glutamine supplementation was beneficial to the liver in these individuals [ 46 ].
Previously, Wu et al. For example, Newsholme and Parry-Billings [ 9 ] demonstrated a close relationship between the rate of phagocytosis in murine macrophages and glutamine concentrations.
Macrophages are metabolically active cells, characterized by high rates of protein secretion and membrane recycling. Accordingly, macrophages are dependent upon extracellular sources of glutamine [ 6 , 48 ].
The maintenance of glutamine plasma concentrations has considerable influence on the function of some cells and tissues. It has been described in the literature that decreased glutamine plasma concentrations may have important influences on the lymphoid system, as well as the function of macrophages [ 6 , 48 ].
Ogle et al. With glutamine, neutrophils were better able to kill Staphylococcus aureus. Glutamine addition resulted in restoration of cell function to normal levels. Furthermore, glutamine is important to the maintenance of functional integrity mitochondrial and the ATP production, protecting the neutrophils from apoptosis.
Cells of the immune system have higher glutamine requirements during inflammatory states such as sepsis and injury. As the consequence of the increased requirement, the demand for this nutrient may exceed production, leading to an imbalance.
As a result, the bloodstream and tissue concentrations fall. These low concentrations of glutamine limit the ability of various tissues to achieve optimal function, especially for immunological tissues. Plasma glutamine concentrations reflect only the environment of cells in the lymph nodes or in the spleen, which are adjacent to the capillaries.
As glutamine is extracted from the extracellular fluid, cells located a greater distance from the capillaries are exposed to a reduced glutamine concentration compared to the plasma.
Kupffer cells may also be exposed to lower glutamine concentrations than observed in the plasma because their sinusoidal arrangement within the hepatic lobule does not allow all cells to come into direct contact with circulating blood. In addition, the blood supply to the liver via the portal system has a lower glutamine concentration because the small bowel has already extracted some of the glutamine for its own use.
Therefore, based on the present knowledge, immunologic tissue is compromised by low concentrations of glutamine [ 6 , 50 ]. The systemic inflammatory response syndrome SIRS and the compensatory inflammatory response syndrome CARS were conceptually described in the s [ 51 ]. The consensus for severe sepsis definition includes, among other factors, the presence of two or more criteria for SIRS; however, a recent study addressed cases of individuals with SIRS-negative severe sepsis [ 53 ].
Moreover, recently, the definition of sepsis was revised, the new definition consist in a systemic response to infection with the presence of some degree of organ dysfunction [ 53 , 54 ].
The major pro-inflammatory factors that contribute to SIRS are TNFα, IL-1, neutrophil degranulation products, coagulation factors, platelet-activating factor and arachidonic acid derivatives, and others [ 52 ]. As with SIRS, CARS is a complex immune response involving anti-inflammatory and immunosuppressive mechanisms that are able to restore homeostasis after injury and SIRS or, if unchecked leads to a state of profound immunosuppression, predisposing the individual to infections [ 52 , 55 ].
Mixed anti-inflammatory response syndrome MARS represents the transition from SIRS to CARS followed by homeostasis or predominance of one over the other [ 52 ] and even switching between the increase and decrease of anti- and pro-inflammatory mediators [ 56 ].
In the context of regulation of the immune system, the role of nutrients and bioactive compounds in the modulation of inflammatory responses is often discussed [ 57 — 59 ]. In recent decades, the immunomodulatory potential of glutamine has been demonstrated [ 59 ] as being essential for metabolism of immune cells such as neutrophils, lymphocytes, and macrophages which in some cases use more glutamine than glucose [ 5 , 7 , 59 ].
Additionally, glutamine is a precursor to glutathione which is responsible for preventing oxidative stress by reacting directly with reactive oxygen species [ 60 , 61 ].
In critical situations, the reduction in plasma glutamine concentration affects the redox state and the metabolism of cells of the immune system, resulting in compromised immune response contributing to the development of sepsis.
Thus, studies have evaluated the benefits of maintaining glutamine concentration in critically ill patients [ 62 — 64 ], especially in cases related to inflammatory response syndrome SIRS and sepsis [ 65 — 68 ]. Studies have been performed in an attempt to gather data demonstrating the effectiveness of glutamine supplementation in critically ill patients [ 62 , 63 ].
Lin et al. Bollhalder et al. However, both studies had methodological inconsistencies such as start and time of supplementation, glutamine dose, disease severity, among other factors, and more clinical trials are needed to assess the effectiveness of glutamine supplementation in critically ill patients.
Recent research has shown that septic patients are usually hypercatabolic. Because of the impairment of the ability to use glucose and fat, there is an increasing dependency on muscle breakdown, providing essential substrates for acute phase protein synthesis and energy production [ 69 ].
Glutamine requirements increase markedly, and its utilization may exceed endogenous production [ 51 , 70 ]. Glutamine depletion decreases proliferation of lymphocytes, influences expression of surface activation markers on lymphocytes, affects the production of cytokines, and induces apoptosis [ 71 ].
The authors attribute the difference in the results obtained in relation to literature to factors such as doses, route of administration, patient status, start of supplementation, and also the possibility of publications bias, once conclusions about the benefits of supplemental glutamine in critically ill patients started from meta-analyzes with small numbers of clinical trials, methodologically less robust [ 72 ].
However, those results are still controversial, and it is important to consider the timing of glutamine administration. In studies where glutamine was administered before the onset of infection, it prevented the infection, both in animals and in humans.
This is most likely by maintaining glutamine concentrations and preventing a state of glutamine deficiency. Therefore, such patients are protected from the inadequacies of present day conventional nutrition, which makes them susceptible to infections [ 74 ].
Given the lack of full knowledge and the necessity to clarify some beneficial effects of glutamine supplementation in critically ill patients, this highlights the need to conduct more well-designed clinical studies. They exert roles in antigen presentation, activation of lymphocytes and macrophages, and activation and maturation of dendritic cells, as well as acting as a stimulator of pro-inflammatory cytokine production.
Thus, it has been suggested that HSPs provide the link between innate and adaptive immune systems [ 76 ]. HSP, one of the members of the HSP protein family, has powerful immune regulatory effects, providing cellular protection by preventing apoptosis and cell death.
A model of sepsis, in vitro, reported that glutamine promoted HSP70 release, and addition of 2 mM glutamine significantly increased HSP levels and promoted an early pro-inflammatory response [ 75 ].
In accordance with that, Jordan et al. MAPK pathways coordinately regulate gene expression, mitosis, metabolism, motility, survival, apoptosis, and differentiation [ 78 ]. Glutamine uptake is enhanced in activated lymphocytes. ERK signaling, a MAPK family member, is required for enhanced glutamine uptake and increased activity of key metabolic enzymes.
Carr et al. In addition, glutamine inactivates p38 and JNK and exhibits a protective effect against endotoxic shock when administered after LPS injection [ 80 ]. Glutamine also possesses anti-inflammatory activity via deactivating cytosolic phospholipase A2 cPLA2. Glutamine indirectly deactivates cPLA2 by dephosphorylating p38 MAPK, the major kinase for cPLA2 phosphorylation, through inducing MAPK phosphatase-1 MKP Lee et al.
demonstrated a physical interaction between glutamine-induced MKP-1 and pcPLA2, suggesting that glutamine can directly deactivate cPLA2 via early induction of MKP-1 [ 81 ]. Zhu et al. Thus, glutamine supplementation suppresses autophagy, increases cellular protein content, and promotes cell proliferation.
The nuclear factor kappa B NF-kB signaling pathway serves a crucial role in regulating the transcriptional responses of physiological processes including cell division, cell survival, differentiation, immunity, and inflammation [ 83 ].
The IkB family of inhibitory proteins sequester inactive NF-kB in the cytosol, therefore regulating NF-kB dimers. The central role of NF-kB in both innate and adaptive immunity is mediated by the coordinate expression of multiple genes essential for the immune response.
The importance of NF-kB is revealed by the extensive list of NF-kB-inducible genes, including those for pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α as well as chemokines [ 85 ] Fig. Representation of the nuclear factor kappa B NF-kB pathway activation.
An external inflammatory signal activates the signaling pathway, leading to the phosphorylation of proteins that culminated in the IKB activation and degradation, allowing the NF-kB to migrate to the nucleus and binding to specific regions of the DNA.
There is evidence for redox imbalance and oxidative stress in human sepsis, as demonstrated by increased markers of oxidative damage with higher activation of NF-kB [ 87 , 88 ]. Glutamine appears to be one of the antioxidants of possible clinical benefit.
It is the most abundant amino acid in the body, and it is an important precursor of glutathione GSH. Its supplementation in enteral and parenteral nutrition solutions can be used to maintain high levels of GSH and prevent oxidative stress-induced damage [ 88 ].
Glutamine treatment in a model of non-alcoholic fatty liver disease decreased NF-kB activation, and it was able to mediate the reduced transcription of downstream inflammatory factors, thereby decreasing hepatic damage and reducing ROS generation, alleviating the oxidative stress of the liver cells [ 89 ].
Macrophages supplemented with glutamine have revealed that stimulation with LPS increased NF-kB activation under 2 and 10 mM of glutamine supplementation in comparison to macrophages treated with 0 and 0. Alternatively, da Silva et al.
Several studies have demonstrated the influence of glutamine on cell migration and adhesion molecules. Chu et al. Both groups exhibited mucosal ulceration, gland distortion, and leukocyte infiltration, but pre-treatment with glutamine reduced leukocyte infiltration to tissues and resulted in less severe mucosal inflammation compared to animals without the addition of glutamine.
A study examining early-weaned mice at the age of 14 days and intraperitoneally inoculated with BCG Mycobacterium bovis cepa Moreau reported that glutamine supplementation increased leukocytes, lymphocytes, and neutrophils in the peripheral blood, while BCG inoculation reduced the percentage of lymphocyte and increased the count and percentage of neutrophils.
Both in the spleen and in the bone marrow, glutamine supplementation led to an increase in granulocytes and lymphocytes. Thereby, the authors evidenced that the function of macrophages and hemopoiesis were increased by the intake of glutamine-supplemented diet in early-weaned and BCG-inoculated mice [ 93 ].
In addition, Kim et al. They also demonstrated that glutamine favors growth, migration, and differentiation in HDPCs through the BMP-2, Wnt, and MAPK pathways, developing a better response in pulp repair and regeneration.
Zou et al. Using siRNA-mediated GS knock-down to suppress astrocytic GS, the authors demonstrated increased cell migration into the scratch wound zone and decreased substrate adhesion.
In addition, they showed that glutamine-enhanced migration and glutamate suppressed it. Glutamine is also known to regulate the expression of extracellular matrix ligands and their receptors.
This may explain the increased motility observed in the presence of exogenous glutamine since the GS-silenced astrocytes express a considerably lower affinity for the extracellular matrix ECM.
Adhesion molecules and chemokine receptors strictly regulate leukocyte migration to specific tissues through several mechanisms. Adhesion molecules present on the vascular endothelium allow leukocytes to tether, roll, and adhere [ 96 ].
The expressions of those molecules are upregulated by proinflammatory cytokines TNF-α and IL-1 and NF-kB pathway [ 97 ]. Rogero et al. EW macrophages have a decreased ability to adhere when compared with the control group, but glutamine supplementation at 1 and 2 mM were capable of reversing this effect.
EW macrophages also showed less spreading ability when compared to the control group, an effect that was reversed by in vitro glutamine supplementation.
Opsonization and phagocytic capacity are increased during inflammation when macrophages and monocytes are able to adhere to the extracellular matrix. Therefore, they hypothesized that the decreased phagocytic and fungicidal activities and the lower synthesis of TNF-α in the absence of glutamine is associated with diminished adhesion observed in peritoneal macrophages.
However, it is necessary to define if the modulation caused by glutamine is due to its metabolism in these cells or their substrates generated by various biochemical pathways, or else the effect of direct or indirect action of this amino acid on the expression of genes involved in phagocytosis or inflammatory processes [ 98 , 99 ].
Yeh et al. The progression of sepsis raised the concentrations of intracellular adhesion molecule-1 ICAM-1 reaching the maximum at 12 and then declining by 24 h after CLP.
The glutamine group displayed significantly lower plasma ICAM-1 levels at 6, 12, and 24 h after CLP compared with the control group. So, under a septic condition, glutamine administration may improve lymphocyte function, decreased PMN—endothelium interactions, and thus may diminish neutrophil infiltration into tissues.
Hou et al. Oral glutamine administration suppressed T cell expression of adhesion molecules and CCR9, downregulated the mRNA levels of adhesion molecules expressed by endothelium in colon tissues, and suppressed Th-cell infiltration into the colonic mucosa.
A study investigated the effect of parenteral glutamine supplementation on leukocyte integrin expression and immune cell recruitment after gastrectomy in Wistar rats. Other researchers evaluated the effects of glutamine supplementation in adhesion molecules in diabetic mice.
Soluble adhesion molecule levels in diabetic patients are significantly higher than those in healthy controls, and excessive expression of adhesion molecules may induce an inflammatory response and tissue injury.
Diabetic mice had higher concentrations of ICAM-1 and VCAM-1 than the normal group, but glutamine did not affect ICAM-1 and VCAM-1 level in the diabetic group. Thus, in a diabetic condition, leukocyte adhesion may be decreased when glutamine is administered [ , ].
Human cells were also evaluated in the presence or the absence of glutamine in some studies. Spittler et al. With the aim to better understand the effect of glutamine in the treatment of sickle cell anemia, the adhesion of sickle RBC to human umbilical vein endothelial cells HUVEC was determined.
Oral l -glutamine therapy significantly reduced adhesion of sickle RBC to HUVEC in both assays with autologous plasma-incubated cells and LPS-incubated cells, similar to the levels in healthy control.
This effect may be explained by improvement of NAD redox potential of sickle RBC, which prevents oxidant damage, therefore decreasing stimulation of inflammation and expression of adhesion molecules [ ].
In contrast with the other findings, a study performed with seven different concentrations between 0. Over time, many studies have been demonstrated the importance of glutamine concentration in cell migration and the expression of adhesion molecules. Although most studies have demonstrated that the presence of glutamine decreased cellular infiltrates in tissues and reduced the expression of adhesion molecules, there are still controversial data.
This can be explained by the use of different cell types, concentrations, time, and model study. The mechanisms by which glutamine modulates these parameters still need to be studied in order to improve understanding. Glutamine supplementation leads to a range of reactions and modulatory effects of processes across different organisms.
Although many studies have unveiled and evaluated the glutamine effects in numerous biological processes, further studies are necessary to provide information about safe dose usage of glutamine supplementation in patients.
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Glutamine, an amino acid, Fat intake and dietary preferences potent and found throughout inflammatiln body. In fact, Normalizing digestive system Glutamime considered the most abundant Maca root and fertility all Glutaminr acids. Glutamine is converted into energy by the intestinal cells, helps with muscle recovery, detoxifies the liverand improves immunity. Most importantly, glutamine is used by the body to heal the gut and promote health. Learn more about the benefits of glutamine and how it can help you.
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