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Role of Glutamine in Protection of Intestinal Epithelial Tight Junctions
Abstract and Figures
Glutamine, a conditionally essential amino acid, is consumed predominantly in the gastrointestinal tract as a source of energy, particularly under the conditions of trauma, sepsis and surgery. In this article, we discuss the unique role of glutamine in the preservation of epithelial barrier function in the gastrointestinal tract. Glutamine supplementation protects the gastrointestinal mucosal homeostasis during total parenteral nutrition, diarrhea, radiation injury, starvation, sepsis and trauma. A significant body of evidence indicates that glutamine preserves the gut barrier function and prevents permeability to toxins and pathogens from the gut lumen into mucosal tissue and circulation. Recent studies demonstrated that the mucosal barrier protective effect of glutamine relates to its effect on preservation of epithelial tight junction integrity. The current understanding of glutamine-mediated protection of intestinal epithelial tight junction integrity and the potential mechanisms involved in this protective effect of glutamine are discussed.
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... Unlike protein-based ONSs, amino acid supplementation in cancer patients targets not only the restoration of nutritional status but also the reduction in systemic inflammation and the prevention of chemotherapy-induced gastrointestinal side-effects through mechanisms such as immune modulation and metabolic regulation [44,45]. This The simplest nutritional support to prevent alterations in nutritional status during chemotherapy in elderly cancer patients could be a multimodal intervention that includes personalized dietary counseling. ...
... Unlike protein-based ONSs, amino acid supplementation in cancer patients targets not only the restoration of nutritional status but also the reduction in systemic inflammation and the prevention of chemotherapy-induced gastrointestinal side-effects through mechanisms such as immune modulation and metabolic regulation [44,45]. This review included studies investigating supplementation of single or mixtures of amino acid ONSs in elderly cancer patients. ...
... The inconsistencies may be attributed to differences in supplement formulations, including variations in dosage, treatment duration, and patient compliance. Notably, ONSs of leucine, which enhances mitochondrial and protein metabolism via mTORC1 activation [44], and glutamine, which supports enteral mucosal integrity [45][46][47], as evidenced by elevated plasma diamine oxidase activity-a reliable marker of intestinal mucosal health [20]-were included. This effect is particularly significant in the prophylaxis of mucositis, a frequent complication associated with treatments like docetaxel, cisplatin, and 5-fluorouracil [24]. ...
Simple Summary
Elderly cancer patients represent a population particularly susceptible to nutritional alterations, which can have an impact on overall survival and chemotherapy tolerance. The effects of nutritional interventions in this frail population have not been adequately examined in previous review studies. We conducted a systematic review of the existing literature on the effects of oral nutritional supplements (ONSs) and dietary counseling during chemotherapy in older oncology patients. Various types of ONS were investigated, including multimodal intervention with tailored nutritional counseling, whey protein supplements, amino acids supplements (including immune nutrition supplements), and fish oil omega-3-enriched supplements. ONSs showed promise in reducing chemotherapy side-effects and improving nutritional status in older cancer patients, but further studies are needed to explore their efficacy on chemotherapy adherence and overall survival. Further studies are needed to investigate the effects of ONS considering chronological age and frailty criteria, different dietary habits, and specific nutritional assessment like Bioelectrical Impedance Analysis.
Abstract
This study aims to review existing literature on the effect of oral nutritional supplements (ONSs) during chemotherapy in older cancer patients. Electronic databases were searched for relevant studies up to March 2024. The risk of bias in the included studies was evaluated using the Cochrane tool. Eligible studies included randomized, prospective, and retrospective studies evaluating the effect of ONSs in elderly (median age > 65 years) cancer patients during chemotherapy. Data regarding chemotherapy adherence, toxicity, overall survival, and nutritional status were extracted. A total of ten studies, involving 1123 patients, were included. A meta-analysis of the results was not conducted due to the scarcity and heterogeneity of results. Some ONSs were associated with reduced incidence of chemotherapy side-effects, particularly oral mucositis, and improved nutritional status. There was limited or no evidence regarding the impact of ONSs on chemotherapy adherence or overall survival. Various types of ONS were investigated, including multimodal intervention with tailored nutritional counseling, whey protein supplements, amino acids supplements (including immune nutrition supplements), and fish oil omega-3-enriched supplements. ONSs showed promise in reducing chemotherapy side-effects and improving nutritional status in older cancer patients, but further studies are needed to explore their efficacy on chemotherapy adherence and overall survival. Future research should consider both chronological age and frailty criteria, account for dietary habits, and use specific nutritional assessment like Bioelectrical Impedance Analysis.
... For example, Krishna et al. demonstrated a two-to threefold increase in intestinal glutamine extraction during exercise in dogs [67]. Glutamine's actions in intestinal epithelial cells during stress are to support enterocyte metabolism, dietary nitrogen and carbon processing, cell proliferation, and gut barrier maintenance [74][75][76][77]. Te GI tract is considered the principal consumer of glutamine with evidence suggesting that > 50% of enterally administered glutamine is metabolized within the intestinal mucosa [78]. ...
A rise in body temperature caused by physical work, including exercise, in a hot climate can lead to heat-related illnesses such as exertional heat exhaustion and stroke. Individuals who work physically demanding occupations in hot environments are at heightened risk of heat injury. The mechanisms that contribute to heat illness resulting from physical work in the heat are complex and include dehydration, tissue ischemia and damage, oxidative stress, and inflammatory events. Therefore, it is important to develop strategies that address these mechanistic underpinnings to prevent exacerbation to heat illness. Glutamine is an amino acid that has been considered conditionally essential during situations of biological stress (e.g., tissue burn, exercise, sepsis) due to high rates of tissue consumption. Evidence suggests that glutamine may serve as an important nutrient during heat stress and when combined with other preventative measures (e.g., cooling techniques, work/rest ratios, clothing) may help to mitigate heat illness among individuals working in extreme climates. The aim of this review is to examine the current literature on the role of glutamine during heat stress.
... Maintaining normal morphometric characteristics, intestinal barrier function, and intestinal permeability are critical for preventing the translocation of bacteria from the gut, proper digestion and absorption of nutrients, and consequently, optimum growth and general well-being of poultry (Burkholder et al. 2008;Quinteiro-Filho et al. 2010). When the intestinal mucosal barrier is damaged, it will evoke self-protection and repair processes, including releasing some amino acids, short-chain fatty acids, cytokines, and other substances (Huda-Faujan et al. 2010;Rao and Samak 2012). Diamine oxidase is found exclusively in the lumen of the small intestine, whereas DLA is the metabolite of bacteria in the gut (Wang et al. 2020;Hosseindoust et al. 2022). ...
... The work carried out by Clark et al. [6] provides a notable overview of exercise-related disorders by analyzing the implications of the microbiota-gut-brain axis. The functionality of the intestinal barrier is guaranteed and regulated by the work of over 50 proteins that intervene in the regulation of endothelial and mucosal functionality, with particular reference to the tight junctions that intervene in the regulation of intestinal permeability, allowing the paracellular passage of desired molecules such as ions and water in leukocytes while controlling the translocation of microorganisms and the by-products of their metabolism [57,58]. This process is of fundamental importance for maintaining general and especially immune health [12]. ...
Intense physical exercise can be related to a significant incidence of gastrointestinal symptoms , with a prevalence documented in the literature above 80%, especially for more intense forms such as running. This is in an initial phase due to the distancing of the flow of blood from the digestive system to the skeletal muscle and thermoregulatory systems, and secondarily to sympathetic nervous activation and hormonal response with alteration of intestinal motility, transit, and nutrient absorption capacity. The sum of these effects results in a localized inflammatory process with disruption of the intestinal microbiota and, in the long term, systemic inflammation. The most frequent early symptoms include abdominal cramps, flatulence, the urge to defecate, rectal bleeding , diarrhea, nausea, vomiting, regurgitation, chest pain, heartburn, and belching. Promoting the stability of the microbiota can contribute to the maintenance of correct intestinal permeability and functionality, with better control of these symptoms. The literature documents various acute and chronic alterations of the microbiota following the practice of different types of activities. Several nutraceuticals can have functional effects on the control of inflammatory dynamics and the stability of the microbiota, exerting both nutraceutical and prebiotic effects. In particular, curcumin, green tea catechins, boswellia, berberine, and cranberry PACs can show functional characteristics in the management of these situations. This narrative review will describe its application potential.
Introduction – Luffa (Luffa cylindrica M. Roem.), a popular local vegetable food in Okinawa, has abundant nutrients including GABA, citrulline, and other free amino acids. Focusing on the contents of these functional compounds in luffa is important because they should be considered while registering it as Foods with Functional Claims in Japan. Incidentally, cut and pickled luffas ought to be browned during processing due to air exposure and other causes because most of the local varieties in Okinawa, including ‘Southern Hechima’, are browned. Objective and method – The degree of browning of cut and pickled luffas using the varieties was investigated along with polyphenol content and free amino acids, including GABA and citrulline. Results and discussion – Cut luffa of ‘Southern Hechima’ browned, whereas pickled luffa of this variety did not. Cut and pickled luffas of ‘Chura Hechima®’ and ‘Ajimakura’ did not brown. Among the free amino acids, Gln, GABA, Arg, Cit, Asn, Ala, and Ser contents were relatively high in each variety’s cut and pickled luffas. The Gln, GABA, Arg, and Cit content levels in luffa are the same as those in spinach, eggplant, Chinese cabbage, and cucumber, respectively. Conclusion – According to this study’s findings, luffa products have a high potential to be registered as Foods with Functional Claims for containing these free amino acids.
Background: the gut barrier is a sophisticated and dynamic system that forms the frontline defense between the external environment and the body's internal milieu and includes various structural and functional components engaged not only in digestion and nutrient absorption but also in immune regulation and overall health maintenance. Summary: when one or more components of the intestinal barrier lose their structure and escape their function, this may result in a leaky gut. Mounting evidence emphasizes the crucial role of the gut microbiome in preserving the integrity of the gut barrier and provides insights into the pathophysiological implications of conditions related to leaky gut in humans. Assessment of intestinal permeability has evolved from invasive techniques to non-invasive biomarkers, but challenges remain in achieving consensus about the best testing methods and their accuracy. Research on the modulation of gut permeability is just starting, and although no medical guidelines for the treatment of leaky gut syndrome are available, several treatment strategies are under investigation with promising results Key messages: this review discusses the composition of the intestinal barrier, the pathophysiology of the leaky gut and its implications on human health, the measurement of intestinal permeability, and the therapeutic strategies to restore gut barrier integrity.
Elemental diets have been employed for the management of various diseases for over 50 years, with several mechanisms mediating their beneficial effects. Yet, they are underutilized due to poor palatability, access, cost, and lack of awareness regarding their clinical efficacy. Therefore, in this review, we aimed to systematically search and review the literature to summarize the formulation variability, mechanisms of action, clinical applications, and tolerability of the elemental diets in gastrointestinal diseases. While large prospective trials are lacking, elemental diets appear to exhibit objective and subjective clinical benefit in several diseases, including eosinophilic esophagitis, eosinophilic gastroenteritis, inflammatory bowel diseases, small intestinal bacterial overgrowth, intestinal methanogen overgrowth, chemoradiotherapy-associated mucositis, and celiac disease. Although some data support the long-term use of elemental diets as an add-on supplement for chronic pancreatitis and Crohn’s disease, most of the literature on exclusive elemental diets focuses on inducing remission. Therefore, subsequent treatment strategies for maintaining remission need to be adopted in chronic/relapsing diseases. Several mechanistic pathways were identified to mediate the effects of elemental diets, including food additive and allergen-free content, high passive absorption rate, and anti-inflammatory properties. High rates of intolerance up to 40% are seen in the trials where exclusive elemental diets were administered orally due to poor organoleptic acceptability; however, when tolerated, adverse events were rare. Other limitations of elemental diets are cost, access, and lifestyle/social restrictions. Moreover, judicious use is advised in presence of a concomitant restrictive food intake disorders. Elemental diets offer a potentially highly efficacious dietary intervention with minor side effects. Palatability, cost, access, and social restrictions are common barriers of use. Prospective clinical trials are needed to elucidate the role of elemental formulas in the management of individual diseases.
Simple Summary
Glutamine, vital for the body’s functions, is pivotal in cancer metabolism as it influences tumor growth. However, cancer cells’ complex adaptive metabolic dynamics raise concerns about potential limitations in glutamine antagonism strategies to impede tumor growth. Similarly, while glutamine supplementation shows promise in supporting cancer patients, careful considerations are necessary to address possible interactions with ongoing treatments and concerns about inadvertent tumor growth stimulation. Recent studies have shed light on the effects of glutamine on the epigenetic regulation of cancer cells and the enhancement of anti-cancer immune functions, providing valuable insights for potential therapeutic advancements. Understanding the intricacies and challenges of glutamine interventions is essential for optimizing their potential benefits in cancer treatment and patient well-being.
Abstract
Glutamine, a multifaceted nonessential/conditionally essential amino acid integral to cellular metabolism and immune function, holds pivotal importance in the landscape of cancer therapy. This review delves into the intricate dynamics surrounding both glutamine antagonism strategies and glutamine supplementation within the context of cancer treatment, emphasizing the critical role of glutamine metabolism in cancer progression and therapy. Glutamine antagonism, aiming to disrupt tumor growth by targeting critical metabolic pathways, is challenged by the adaptive nature of cancer cells and the complex metabolic microenvironment, potentially compromising its therapeutic efficacy. In contrast, glutamine supplementation supports immune function, improves gut integrity, alleviates treatment-related toxicities, and improves patient well-being. Moreover, recent studies highlighted its contributions to epigenetic regulation within cancer cells and its potential to bolster anti-cancer immune functions. However, glutamine implementation necessitates careful consideration of potential interactions with ongoing treatment regimens and the delicate equilibrium between supporting normal cellular function and promoting tumorigenesis. By critically assessing the implications of both glutamine antagonism strategies and glutamine supplementation, this review aims to offer comprehensive insights into potential therapeutic strategies targeting glutamine metabolism for effective cancer management.
Epidermal growth factor (EGF) protects the intestinal epithelial tight junctions from acetaldehyde-induced insult. The role of phospholipase Cγ (PLCγ) and protein kinase C (PKC) isoforms in the mechanism of EGF-mediated protection of tight junction from acetaldehyde was evaluated in Caco-2 cell monolayers. EGF-mediated prevention of acetaldehyde-induced decrease in transepithelial electrical resistance and an increase in inulin permeability, and subcellular redistribution of occludin and ZO-1 was attenuated by reduced expression of PLCγ1 by short hairpin RNA. EGF induced a rapid activation of PLCγ1 and PLC-dependent membrane translocation of PKCϵ and PKCβI. Inhibition of PKC activity or selective interference of membrane translocation of PKCϵ and PKCβI by RACK interference peptides attenuated EGF-mediated prevention of acetaldehyde-induced increase in inulin permeability and redistribution of occludin and ZO-1. BAPTA-AM and thapsigargin blocked EGF-induced membrane translocation of PKCβI and attenuated EGF-mediated prevention of acetaldehyde-induced disruption of tight junctions. EGF-induced translocation of PKCϵ and PKCβI was associated with organization of F-actin near the perijunctional region. This study shows that PLCγ-mediated activation of PKCϵ and PKCβI and intracellular calcium is involved in EGF-mediated protection of tight junctions from acetaldehyde-induced insult.
In this study, we aimed to determine the contribution of substrates to tricarboxylic acid (TCA) cycle fluxes in rumen epithelial cells (REC) and duodenal mucosal cells (DMC) isolated from Angus bulls (n = 6) fed either a 75% forage (HF) or 75% concentrate (HC) diet. In separate incubations, [(13)C(6)]glucose, [(13)C(5)]glutamate, [(13)C(5)]glutamine, [(13)C(6)]leucine, or [(13)C(5)]valine were added in increasing concentrations to basal media containing SCFA and a complete mixture of amino acids. Lactate, pyruvate, and TCA cycle intermediates were analyzed by GC-MS followed by (13)C-mass isotopomer distribution analysis. Glucose metabolism accounted for 10-19% of lactate flux in REC from HF-fed bulls compared with 27-39% in REC from HC and in DMC from bulls fed both diets (P < 0.05). For both cell types, as concentration increased, an increasing proportion (3-63%) of alpha-ketoglutarate flux derived from glutamate, whereas glutamine contributed <3% (P < 0.05). Although leucine and valine were catabolized to their respective keto-acids, these were not further metabolized to TCA cycle intermediates. Glucose, glutamine, leucine, and valine catabolism by ruminant gastrointestinal tract cells has been previously demonstrated, but in this study, their catabolism via the TCA cycle was limited. Further, although glutamate's contribution to TCA cycle fluxes was considerable, it was apparent that other substrates available in the media also contributed to the maintenance of TCA fluxes. Lastly, the results suggest that diet composition alters glucose, glutamate, and leucine catabolism by the TCA cycle of REC and DMC.
There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).
The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs.
Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).
The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.
During the growth of a tumor, there are very relevant changes in the metabolism of the host to produce the metabolites rapidly consumed by the tumor. In this context, the exchanges of amino acids between the tumor and its host are especially important; however, they have received little attention. A rigorous study must provide data on the growth curve of the tumor, as well as on amino acid levels in tumor cells, plasma, and metabolically relevant tissues and organs from the host during the whole growth of the tumor. The main conclusions arising from a complete study in a tumor model are discussed.
Glutamine (Gln) is important for intestinal barrier function and regulation of tight junction (TJ) proteins, but the intracellular mechanisms of action remain undefined. The purpose of this study was to test the hypothesis that Gln regulates intercellular junction integrity and TJ proteins through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in Caco-2 cells. Deprivation of exogenous and endogenous glutamine decreased transepithelial electrical resistance (TER) (P < 0.01) and increased permeability (P < 0.01). Both wortmannin and LY294002, PI3K inhibitors, prevented the TER decrease and the permeability increase induced by Gln deprivation (P < 0.001). Gln deprivation also caused decreased TJ protein claudin-1 (P < 0.001). Both wortmannin and LY294002 treatment prevented this effect (P < 0.001). Deprivation of Gln increased phosphor-Akt protein. Gln supplementation reversed this effect. Decreased TER and increased permeability associated with Gln deprivation were not observed in small interfering RNA for p85 transfected Caco-2 cells. In conclusion, Gln regulates intercellular junction integrity and TJ proteins through the PI3-Kinase/Akt pathway.
Malnutrition is a major contributor to mortality and is increasingly recognized as a cause of potentially lifelong functional disability. Yet, a rate-limiting step in achieving normal nutrition may be impaired absorptive function due to multiple repeated enteric infections. This is especially problematic in children whose diets are marginal. In malnourished individuals, the infections are even more devastating. This review documents the evidence that intestinal infections lead to malnutrition and that malnutrition worsens intestinal infections. The clinical data presented here derive largely from long-term cohort studies that are supported by controlled animal studies. Also reviewed are the mechanisms by which enteric infections lead to undernutrition and by which malnutrition worsens enteric infections, with implications for potential novel interventions. Further intervention studies are needed to document the relevance of these mechanisms and, most importantly, to interrupt the vicious diarrhea-malnutrition cycle so children may develop their full potential.
This study was performed to determine whether the addition of alanyl-glutamine (Ala-Gln) can prevent intestinal mucosal atrophy induced by standard solution of total parenteral nutrition (S-TPN). Forty-one male Sprague-Dawley rats weighing 250 g were randomly divided into four groups: group I was killed after overnight fasting; group II received S-TPN. The other groups received S-TPN supplemented with amino acids other than glutamine (group III) or supplemented with Ala-Gln 2 g/100 mL (group IV); both solutions were isocaloric and isonitrogenous. After 1 week of TPN the rats were killed, and the duodenum, proximal jejunum, mid-small bowel, and distal ileum were obtained for morphologic and functional analysis. Weight gain did not differ significantly among these four groups, and there was no difference in nitrogen balance between groups III and IV. Serum glutamine in group IV (102.8 +/- 13.3 mumol/dL) was significantly increased (p less than .05) compared with groups I, II, and III (66.2 +/- 3.9, 55.7 +/- 7.8, and 61.3 +/- 10.8 mumol/dL, respectively). Mucosal wet weight, protein, RNA, sucrase, and maltase of group IV were significantly increased (p less than .05) compared with groups II and III. Villus height was significantly increased (p less than .05) in the jejunum of group IV rats compared with groups II and III, but not in any other segments of the intestine. No significant changes were observed in crypt depth among all groups. Diamine oxidase in groups II, III, and IV was significantly decreased (p less than .05) compared with group I in all segments except for the ileum.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of the combination of total parenteral nutrition (TPN) and systemic sepsis on mucosal morphology and protein synthesis was investigated. Rats were given a standard TPN mixture consisting of glucose (216 kcal.kg-1.day-1), lipid (24 kcal.kg-1.day-1), and amino acids (1.5 g N.kg-1.day-1) for 5 days. On the 5th day the rats (n = 37) were randomized into four groups according to diet as follows: 1) control nonseptic on standard TPN, 2) control nonseptic on TPN with glutamine, 3) septic on standard TPN, and 4) septic with the TPN supplemented with glutamine. Twenty hours after the injection of Escherichia coli, the rats were given a 4-h constant infusion of [U-14C]leucine to determine the mucosal fractional protein synthesis rates. The following results were obtained. 1) Histological examination showed that systemic sepsis caused tissue damage to the ileum and jejunum. 2) Glutamine supplementation attenuated these changes. 3) There were no visible changes to the colon either from glutamine supplementation or sepsis. 4) Sepsis was associated with an increase in mucosal protein synthesis and decreased muscle synthesis. 5) Addition of glutamine to the TPN mix further increased protein synthesis in the intestinal mucosa of septic rats.