Immunomodulatory Nutrients Research Articles

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health.

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

In-utero exposures and the evolving epidemiology of paediatric allergy.

Emerging evidence suggests that the rising prevalence of early-onset 'noncommunicable' diseases, such as paediatric atopy, is related to modern environmental changes, the effects of which appear to commence in utero or even preconception. Here, we review how recent publications have contributed further to our understanding of the influence of in-utero exposures on the predisposition to immune dysregulation, with a particular focus on the evolving epidemiology of paediatric allergy. New evidence suggests that inter-individual variations in immune function development are principally driven by nonheritable factors, for example periconceptional environment. One of the most significant influences is maternal nutrition during pregnancy. New studies further support a healthy balanced maternal diet that contains immunomodulatory nutrients, prebiotics and probiotics, which benefit multiple aspects of fetal development, including immune development. In addition, declining maternal biodiversity, maternal stress and exposures to environmental pollutants further interact to have adverse influences on the developing immune system. The in-utero period appears to be a critical time point. Further investigations of gene-environmental interaction mechanisms are essential prior to further recommendations of early-life preventive strategies to reduce the growing global burden of allergic disease, as well as other 'noncommunicable' diseases.

The Role of Immunonutrients in the Prevention of Necrotizing Enterocolitis in Preterm Very Low Birth Weight Infants

Necrotizing enterocolitis (NEC) is a critical intestinal emergency condition, which mainly occurs in preterm very low birth weight (PVLBW) infants. Despite remarkable advances in the care of PVLBW infants, with considerable improvement of the survival rate in recent decades, the incidence of NEC and NEC-related mortality have not declined accordingly. The fast progression from nonspecific signs to extensive necrosis also makes primary prevention the first priority. Recently, increasing evidence has indicated the important role of several nutrients in primary prevention of NEC. Therefore, the aim of this review is to summarize some potential immunomodulatory nutrients in the prevention of NEC, including bovine colostrum, probiotics, prebiotics (e.g., human milk oligosaccharides), long chain polyunsaturated fatty acids, and amino acids (glutamine, cysteine and N-acetylcysteine, l-arginine and l-citrulline). Based on current research evidence, probiotics are the most documented effective method to prevent NEC, while others still require further investigation in animal studies and clinical randomized controlled trials.

The regulation and role of L-glutamine in B-lymphocyte activation (LYM7P.618)

Abstract B lymphocyte activation is a highly energetic event that promotes cell survival and growth. Aberrant activation of B lymphocytes can lead to disease states such as lymphomas or autoimmune diseases. To meet the metabolic demands of activation, B cells increase nutrient uptake to provide energy and intermediates for macromolecule synthesis. We have investigated the role of L-glutamine, which is emerging as a critical immunomodulatory nutrient; however, the precise role of L-glutamine in B cell growth responses is poorly understood. Depletion of extracellular L-glutamine results in impaired cell growth and proliferation in response to B-cell antigen receptor (BCR) ligation, although, early activation events such as induction of CD86 are unaffected. We show that L-glutamine uptake is induced in response to BCR ligation. This corresponds to an increase in the surface expression of the high affinity L-glutamine transporter, ASCT2, indicating its involvement in L-glutamine uptake. Further, inhibition of ASCT2 by the small molecule N-glutaryl-L-phenylalanine p-nitroanilide (GPNA) caused impaired B lymphocyte activation similar to that observed in response to L-glutamine depletion. The addition of L-leucine abated some of the effects of GPNA treatment on B lymphocyte growth responses, indicating mTORC involvement. These data provide new insight on the requirement of L-glutamine in B lymphocyte activation and suggest a possible underlying mechanism of growth regulation by mTORC.

Immune Response to a Salmonella Enteritidis Infection in Chickens Fed Different Immunomodulatory Nutrients

Immunomodulatory nutrients alter the immune response to pathogens; modulating that individual's resistance to pathogen challenges. Salmonella enterica serovar Enteritidis (SE) causes mild illness in poultry, but causes over 1 million cases of human illness yearly, mostly due to contaminated eggs or undercooked meat. Pathogens undergo fast‐paced evolution creating problems for vaccination and antibiotic control; therefore it is important to investigate alternative avenues. The objective of this study was to characterize the immune response of juvenile chicks treated with known immunomodulatory nutrients: corn oil (control), fish oil, conjugated linoleic acid (CLA), and lutein, during a SE infection. Diets were isocaloric and isonitrogenous, with the basal diet consisting of soy‐bean meal, and rice. Four‐week‐old Hyline W‐36 chicks (n=96), were randomly allotted to 1 of 4 dietary treatments replicated in 6 pens of 4 birds per diet. All birds were orally dosed with 1 ml of 7.3 x 106 CFU/ ml SE in PBS after a 7 day diet adaptation. Liver, spleen, and duodenal (DMS) and ileal mucosal scrapings (IMS) were collected for immune related gene expression by rtPCR. The corn oil diet increased IL‐6 and iNOS expression across tissues. The fish oil and lutein diets increased IL‐1β, TLR‐4, and IL‐10 expression in DMS. The lutein diet decreased iNOS and TLR‐4 expression in the spleen. The lutein diet decreased SE presence in the DMS, but increased presence in the spleen where inflammatory cytokine expression was suppressed. The CLA diet decreased inflammatory cytokine expression across tissues, and SE presence was correspondingly increased in both the DMS and spleen. Thus, each dietary treatment altered the immune response to SE differently and this was reflected in the invasion of SE into tissues.

The Regulation and Role of L‐Glutamine in B‐cell Activation

B cell activation is a highly energetic event that induces cell growth, rapid proliferation, and antibody production. Aberrant activation or expansion of these cells can lead to disease states such as lymphomas or autoimmune diseases. To meet the metabolic demands of this process, the cell induces rapid uptake of nutrients that can be utilized in cellular processes and macromolecule synthesis. We have investigated the role of the amino acid glutamine, which is emerging as a critical immunomodulatory nutrient, but the role of which in the B cell responses is poorly understood. Our data show that B cells are unable to increase cell size, increase total cellular protein levels, or engage in DNA synthesis in the absence of glutamine, however, very early activation events are unaffected by glutamine availability. The high affinity glutamine transporter protein, ASCT2, is rapidly upregulated at both the mRNA and protein level following B cell stimulation, indicating this transporter's involvement in the glutamine uptake process. Further, specific inhibition of ASCT2 by the small molecule GPNA induced defects in activation response similar to those induced by a lack of extracellular glutamine. Supplementation with high levels of extracellular leucine was shown to abate some of the defects associated with GPNA treatment, indicating the possibility of mTORC involvement as previously observed in T cells. Overall these data shed light on the glutamine requirement of B cells during the activation response, and indicate a possible underlying mechanism of growth regulation by mTORC.

The dietary polysaccharide from Ommastrephes bartrami prevents chemotherapeutic mucositis by promoting the gene expression of antimicrobial peptides in Paneth cells

Gastrointestinal mucositis (GIM), induced by chemotherapy, is associated with alterations in the function of the intestinal barrier due to the potential damage induced by anti-cancer drugs on the epithelial cells. The Paneth cells, an important epithelial lineage in the intestine, contribute to the innate immunity by releasing antimicrobial proteins onto the mucosal surfaces. Polysaccharide, as a widely used immunomodulatory nutrient, was reported to have an effect of modulating the intestinal immune system. However, the effect of dietary polysaccharides in protecting the Paneth cells from injuries induced by chemotherapy was poorly investigated. In the current study, with a mouse model of cyclophosphamide (Cy)-induced gastrointestinal injury, the polysaccharide extracted from the ink of Ommastrephes bartrami (OBP) were found to protect the mouse Paneth cells from chemotherapeutic injury. Ommastrephes bartrami polysaccharide (OBP) treatment could enhance the mRNA expression of antimicrobial proteins in the Paneth cells, such as lysozyme, Ang4, Defa-5, and sPLA2. The increased production of the microbicidal proteins in the Paneth cells was dependent on the relatively highly developed endoplasmic reticulum (ER) structure but was not dependent on the increase in the quantity of the ER. The Ommastrephes bartrami polysaccharide (OBP) activated the IRE-1 mediated XBP-1s pathway to cope with antimicrobial protein secretion. Our results may have important implications with regard to the role of OBP in chemotherapy-induced Paneth cell injury in intestinal disorders involving inflammation and infection.

Inflammatory T Cell Responses Rely on Amino Acid Transporter ASCT2 Facilitation of Glutamine Uptake and mTORC1 Kinase Activation

Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.

Update on postinjury nutrition

Nutritional supplementation is paramount to the care of severely injured patients. Despite its widespread use in trauma, many areas of clinical nutrition remain controversial and not well defined. The benefit of early enteral nutrition in the care of injured patients has been well established, with further benefit derived by the administration of immune-enhancing formulas supplemented with glutamine, arginine, nucleotides, and omega-3-fatty acids. A new paradigm of pharmaconutrition has been developed that separates the administration of immunomodulatory nutrients from that of nutritional support. The optimal utilization and benefit of pharmaconutrients, however, remains unclear, as does the need for full caloric provision in the early postinjury phase. Nutrition studies with the greatest reduction in morbidity and mortality are those utilizing specific nutrients. The use of pharmaconutrients to modulate the inflammatory and immune response associated with critical illness seems to provide benefit to critically ill and injured patients. Additionally, studies at least suggest that trauma patients derive comparable if not additional benefit from hypocaloric feeding during the acute phase of injury. Building upon previous well performed studies in trauma patients, the current focus of nutritional investigations center on the use of pharmaconutrients to modulate the inflammatory response and the use of hypocaloric feeds. These practices will be reviewed and evidence presented for their use in critically ill and injured patients.

181 POSTER Parathyroid Hormone-related Protein (PTHrP) expression in human bone and liver metastases

Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.

183 POSTER TGF-beta-induced Stat3 phosphorylation mediated growth regulation in lung cancer

Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.

Glutamine: Role in the Fetus and Low-birthweight Infant

After completing this article, readers should be able to: 1. Describe the glutamine-glutamate shuttle. 2. Delineate the effects of glutamine supplementation during total parenteral nutrition, chemotherapy, and radiotherapy in animals. 3. Describe the beneficial effects of glutamine supplementation in low-birthweight infants and in critically ill adults. 4. List the primary actions of glutamine in the intestine. The importance of glutamine for optimal growth of cells in culture has been known since the 1950s, when Eagle published his landmark paper in Science .1 His work demonstrated that of all the amino acids, cell growth in culture relied most on glutamine. Numerous subsequent studies have established the importance of glutamine for a variety of metabolic processes in the entire organism and are beginning to demonstrate that nutritional supplementation of this amino acid may be highly beneficial under certain circumstances. Glutamine and glutamate are structurally similar five-carbon amino acids. Glutamine is a neutral amino acid at pH 7.0 that contains an alpha-amino group and a deltaamide group. In glutamate, the amide nitrogen of glutamine is replaced by a carboxy-group, conferring to it a net negative charge at pH 7.0. This at least partially accounts for the transport of these two amino acids across cell membranes via different transport systems. The presence or absence of the amide group is responsible for different metabolic interactions of these amino acids. The array of metabolic processes in which glutamine is involved is highlighted by its relationship to its metabolites and the citric acid cycle (Fig. 1⇓ ).Glutamine, via glutamate, is readily converted to alpha-ketoglutarate, an integral component of the citric acid cycle. Deamidation of glutamine via glutaminase produces glutamate, a precursor of gamma-amino butyric acid (GABA), a neurotransmission inhibitor. Proline also is produced by the cyclization of glutamate. Proline is an important amino acid component of collagen and …

Immunonutrition and surgical practice

Immunonutrition generally refers to the effect of the provision of specific nutrients on the immune system. These nutrients typically have immunoenhancing properties, and recent advances in nutrition support involve studies designed to exploit the desirable biological properties of these nutrients. The term immunonutrition strictly implies that we are focusing on the effect of certain nutrients on aspects of the immune system. However, in reality immunonutrition also refers to studies that not only examine the function of lymphocytes and leucocytes, but which also study the influence of key nutrients on the acute-phase response, the inflammatory response and on gastrointestinal structure and function. The interest, therefore, is on the impact of immunonutrition on all aspects of host defence mechanisms in response to a catabolic stress. Major surgery evokes an acute-phase response, a transient immunosuppression and alterations in gastrointestinal function. Normal function is usually restored after a few days; however, in a subgroup of patients homeostasis may be lost and development of the systemic inflammatory response syndrome (SIRS) ensues. Results of recent clinical trials suggest that provision of immunomodulatory nutrients, including glutamine, arginine, n-3 polyunsaturated fatty acids and dietary nucleotides, may promote restoration of normal tissue function post-operatively and prevent the occurrence of SIRS.

Parenteral use of medium-chain triglycerides: A reappraisal

Over the last two decades, the clinical use of intravenous fat emulsions for the nutritional support of hospitalized patients has become routine. During this time long-chain triglycerides (LCT) derived from soybean and/or safflower oils were the exclusive lipid source for these emulsions, providing both a safe calorically dense alternative to dextrose and essential fatty acids needed for biologic membranes and the maintenance of immune function. During the past decade, the availability of novel experimental triglycerides for parenteral use has generated interest in the use of these substrates for nutritional and metabolic support. Medium-chain triglycerides (MCT), long advocated as a superior substrate for parenteral use, possess many unique physiochemical and metabolic properties that make them theoretically advantageous over their LCT counterparts. Although not yet approved in the United States, preparations containing MCT have been widely available in Europe. Intravenous MCT preparations, either as physical mixtures or structured lipids, have been used clinically in patients with immunosuppresion, critical illness, liver and pulmonary disease and in premature infants. Despite great promise, the clinical data comparing the efficacy of MCT-based lipid emulsions to their LCT counterparts has been equivocal. This may be due in part to the limited nature of the published clinical trials. Measures of efficacy for parenteral or enteral nutritional products has taken on new meaning, in light of the reported experience using immunomodulatory nutrients. Current concerns about cost of medical care and resource use warrant careful deliberation about the utility of any new and expensive therapy. Until clinical data can fulfill expectations derived from animal studies, it is difficult to advocate the general use of MCT-based lipid emulsions. Future clinical studies with MCT-based emulsions should have clear outcome objectives sufficient to prove their theorized metabolic superiority.

The effect of alcohol consumption on nutritional status during murine AIDS

As alcohol (ETOH) abusers and AIDS patients have nutritional disorders, the influence of chronic ETOH consumption (5% v/v for 10 weeks) on levels of immunomodulatory nutrients (vitamins A and E, Zn, and Cu) in the serum, liver, small intestine, spleen, and thymus was determined during murine AIDS. The hepatic levels of vitamins A and E and Zn in both normal and LP-BM5 retrovirus-infected female C56BL/6 mice fed ETOH were significantly reduced compared to controls, whereas the level of Cu in the liver was not affected. Intestinal levels of vitamin A and Cu were not affected by ETOH, whereas vitamin E and Zn were significantly reduced in both normal mice and those with AIDS fed ETOH. The splenic levels of vitamin A and Zn in the normal mice were significantly reduced by ETOH compared to controls, but vitamin E and Cu were not. All splenic levels of nutrients measured were reduced in ETOH-fed mice with AIDS. The levels of vitamins A and E, Zn, and Cu in the thymus in murine AIDS were also significantly affected by ETOH consumption. The serum levels of vitamins A and E in both normal mice and murine AIDS were significantly decreased by dietary ETOH. These data produced evidence that chronic ETOH can directly aggravate undernutrition initiated by retrovirus infection. Such ETOH-induced malnutrition in AIDS may be a cofactor, accelerating development of AIDS via immunosuppression secondary to nutritional deficiencies.