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been studied over the last two decades. Immunonutrition is defined as modulation of the activities of the immune activation by nutrients or specific food items fed in amounts above these normally encountered in the diet. Immunomodulatorysubstance interfere with 3 basic areas of the immune responses directly or indirectly; (i) the mucosal barrier function (ii) the cellular defence function (iii) the local or systemic inflammatory response.
At present there are a relatively limited number of nutrients employed in immunonutrients like: n-3 fatty acid, glutamine, arginine, nucleotides, taurine, BCAA and ornithin alpha glutarate.
NUCLEOTIDES Nucleotides are important components for synthesis of DNA, RNA and adenine nucleotides. Adequate nucleotide synthesis requires sufficient amounts of purines and pyrimidines. In case of adequate protein intake de novo synthesis is the main source of nucleotides , glutamine being the major N donor. During episodes of infection following injury and trauma the demand for nucleotides is increased in order to facilitate the synthetic capacity of the immune cells. The absence of nucleotides in the diet results in a selective loss of T-helper lymphocytes and a suppression of interleukin (IL) 2 production Adequate supply of nucleotides may be critical factor in promoting intestinal function and immune status. Dietary nucleotide removal was associated with impaired mucosal integrity and function which could be partly prevented or reversed by oral or intravenous supply of these substances. Decreased availability of nucleotide is associated with impaired T-cell function, weakened natural killer cell activity, suppressed lymphocyte proliferation as well as reduced IL2 production. Moreover reduced phagocytosis and an impaired clearance of experimantally applied pathogens were induced by dietary removal of nucleotides surgical and critically ill patients Involved in DNA and RNA structure, energy metabolism, signal transduction, biosynthesisof phospholipids, and regulation of enzyme activity; Activation of lymphocytes causes arapid increase in demands for nucleotides to cover an early increase in energy requirements and a later need to synthesize RNA for protein production and DNA for cell division In animal experiments nucleotides improve T cell functions, antibody responses,delayedtype hypersensitivity and resistance to pathogens Nucleotide supplementation has also been shown to improve some aspects of tissue recovery from ischaemia/reperfusion injury or radical resection Pizzini and colleagues(1990) observed that the suppression of splenic cell mitogen response and to alloantigenic challenge could not be corrected completely with refeeding using RNA-free diets, but were reversed completely if the refeeding diet contained 0.25% yeast RNA as a source of nucleotides.
and 100%.BCAA Utilization of BCAA by cells of the immune system Human immune cells incorporate BCAA into proteins. Surgical and critically ill patients Branched-chain amino acids serve as important fuel for skeletal muscle. respectively. reduce protein degradation. although the order of the rate of uptake is leucine> isoleucine >>valine. 90%. A 45% branched-chain enrichment is considered most optimal for nitrogen sparing and protein synthesis. The most demonstrable clinical benefit from administering branched-chain amino acids appears to be during times of maximal stress. with a progressive decline in uptake through the G2 and M phases BCAA and immune cell function Leucine. All metabolism occurs in skeletal muscle. The highest rate of uptake of BCAA is during the S phase. Isoleucine is oxidized by human neutrophils and lymphocytes. isoleucine. or valine from the medium of cultured lymphocytes also abolishes the ability of lymphocytes to proliferate in response to phytohemagglutinin by 82%. incorporation of isoleucine is greatest into lymphocytes. They promote protein synthesis. especially during stress. human immune cells express branched-chain alpha keto acid dehydrogenase and decarboxylase activities and so can oxidize BCAA. followed by eosinophils. . human lymphocytes take up and oxidize leucine. In laboratory and clinical experience. This increases their usefulness in the presence of liver dysfunction. isoleucine. Provision of increased amounts of branched-chain amino acids during acute stress can assist in meeting energy needs of the skeletal muscle mass without glucose or fat intolerance. However. Observations that the omission of a single BCAA from the medium of cultured lymphocytes results in complete abolition of protein synthesis simply reflect the essentiality of these amino acids. and serve as substrates for gluconeogenesis. Indeed. leucine transamination by 195% and leucine oxidation by 122%. Omission of leucine. this most likely reflects an inability to synthesize proteins required for cellular proliferation to occur. Furthermore. The uptake of BCAA by a B cell line was studied as a function of progress through the cell cycle . The pattern of uptake of all three BCAAs through the cell cycle is the same. Mitogen stimulation of lymphocytes increases leucine transport by 270%. followed by neutrophils. and perhaps reflecting cell specific differences in protein-synthetic rates and in the types of proteins made. branched-chain amino acids have been shown to improve nitrogen balance. and valine are among the 13 amino acids absolutely required by cultured mammalian cells including lymphocytes.
BCAA supplementation of soy protein resulted in a significantly higher increase in WbPS than did soy protein alone in COPD patients but not in the healthy elderly. While muscle redox potential (glutathione disulphide/GSH) increases after endurance exercise training in healthy subjects.There are some indications that low plasma BCAAs in COPD patients are due to specific alterations in leucine metabolism possibly mediated by altered insulin regulation and increased leucine oxidation in skeletal muscle to a noncarbohydrate energy substrate. BCAA derived from net protein breakdown and by uptake into the muscle pool. Moreover intracellular GLU is known as an important precursor for antioxidant glutathione (GSH) and glutamine synthesis in muscle. undergo transamination to yield branched-chain keto acid and GLU. These observations provide perspective for amino acid supplementation to modulate exercise-induced protein synthesis as well as exercise-induced oxidative stress. BCAAs are also important precursors for glutamate (GLU). patients with COPD showed a reduced ability to adapt in this way as reflected by a lower capacity to synthesise GSH. Intracellular GLU is involved in numerous metabolic processes including substrate phosphorylation and replenishment of tricarboxylic acid (TCA) intermediates to preserve highenergy phosphates at rest and during exercise.COPD A decrease in plasma levels of branched-chain amino acids in relation to hypermetabolism. possibly resulting from the severity of COPD and respiratory muscle weakness. Leucine is an interesting nutritional substrate since it not only serves as precursor. Of interest are the consistently reduced plasma levels of branched chain amino acids (BCAAs) in underweight COPD patients and in those with low muscle mass. Recently.02 g protein/kg body weight/20 min . Amino acids are the building blocks of protein and several studies have to date reported an abnormal plasma amino acid pattern in COPD.that further decreased during a submaximal exercise bout. and various disturbances in plasma amino-acid levels were found in underweight COPD patients. a consistently reduced muscle GLU status of severe COPD patients was reported. which is one of the most important non-essential amino acids in muscle.Plasma levels of amino acids and hypermetabolism in patients with chronic obstructive pulmonary disease. but also activates signalling pathways that enhance activity and synthesis of proteins involved in messenger ribonucleic acid (RNA) translocation to upregulate protein synthesis in skeletal muscle.rate of ingestion: 0.
BCAA normalizes the plasma amino acid pattern. By interfering with brain serotonergic activity and by inhibiting the overexpression of critical muscular proteolytic pathways. but only recent experimental studies and clinical trials have tested their ability to stimulate food intake and counteract muscle wasting in anorectic. Plasma short-turnover protein concentrations tend to be higher in the BCAA solution enriched largely with leucine. marginal improvements in nitrogen retention are observed. . immobility or prolonged bed rest. SEPSIS Under circumstances of severe stress and sepsis. chronic renal failure and liver cirrhosis. branched-chain amino acids have been shown to induce beneficial metabolic and clinical effects under different pathological conditions. but also for those individuals at risk of sarcopenia due to age.CANCER The anorexia-cachexia syndrome is highly prevalent in patients suffering from acute and chronic diseases. their supplementation may represent a viable intervention not only for patients suffering from chronic diseases. including cancer. both by increasing protein synthesis and decreasing proteolysis as well as competing with the toxic aromatic amino acids at the blood-brain barrier. including trauma. weight-losing patients. orthopedic or neurologic patients. In situations in which brain function is affected. Their potential role as antianorexia and anticachexia agents was proposed many years ago. Branched-chain amino acids are neutral amino acids with interesting and clinically relevant metabolic effects.
. eicosanoids formed from the omega-3 fatty acids are much less potent in causing biological responses than those formed from the omega-6 fatty acids.OMEGA 3 FATTY ACID These lipids influence membrane stability. resulting in decreased chemotactic migration and endothelial cell adherence.and docosahexaenoic acid-derived metabolites can be summarized as follows: (1) EPA-derived thromboxane A3 is less active in platelet aggregation than thromboxane A2. In general. as well as a large reduction in cytokine-induced synthesis of prostaglandin E2 and thromboxane B2 in the colonic mucosa. cell mobility. activation of intracellular signaling pathways either directly or through the formation of eicosanoids. as well as tumour necrosis factor-α and -β in response to an inflammatory stimulus. (2) alterations in products which arise from hydrolysis of membrane phospholipids. including stimulation of cytokine production and inflammatory responses Omega -3 PUFA has immunonutrient function due to their anti-inflammatory properties. and cell differentiation. The anti-inflammatory effects of fish oil may also include decreased production of inflammatory substances like LTB4 and platelet-activating factors released by the action of cytokines. (3) feeding with fish oils is associated with profound changes in immunoregulatory processes. As a consequence of the changes two interrelated phenomena may occur: (1) alteration in membrane fluidity. interleukines and interferons. gene expression. (2) LTB5. Changes in fluidity may alter the binding of cytokines and cytokine-inducing agonists to receptors. binding of ligands to their receptors. Consumption of EPA reduces the production of pro-inflammatory IL-1-α and -βand IL-6. including the production and release of various cytokines. The most likely way in which lipids might modulate pro-inflammatory cytokine biology is by changing the fatty acid composition in the cell membrane. membrane fluidity. which has only a small proportion of the activity of LTB4 and plateletactivating factors. The major advantages of EPA. the formation of receptors.
09 g/kg/d is equivalent to 2. and subsequent proliferation.001) and decreased concentration of plasma IL-6 and IL-10(p<0. in which n-6 linoleic acid comprises about 50% of fatty acids present. In a study conducted on 25 patients with sepsis recieveingparentral nutrition were randomised to either a 50:50 misture of medium chain fatty acids and soya bean oil or a 50:40:10 mixture of medium chain fatty acids.The average dose of fish oil administered in the current study 6. The fish oil group had increased EPA in plasma phosphatidylcholine by an average of 3.Fish oil supplementation suppresses autoimmune diseases and T-cell lymphocyte production of IL-2. soya bean oil and fish oil for 5 days. One approach to decreasing the linoleic acid content in lipid emulsions is partial replacement of soybean oil with long-chain n-3 fatty acid rich fish oil.8-fold(p<0. using lipid emulsions entirely based upon soybean oil is not optimal. Recent studies have shown that the suppressive effect of n-3 fatty acid administration on T-cell function can be prevented by vitamin E supplementation. thereby boosting the cellular defence function due to the ineffectiveness of feedback inhibition induced by prostaglandin E2. SEPSIS The lipid typically used in parenteral nutrition is soybean oil. 2010) SURGERY In a study conducted in 256 patients undergoing major abdominal surgery were randomized to receive either Lipoplus (30% soyabean oil. 10% fish oil)-group 1 or Intralipid (30% soyabean . They also reported a shorter hospital stay.001).3 g EPA plus DHA/d(Barbosa et al. In critically ill patients administration of n-3 PUFA is associated with a reduction in the 2-series of prostaglandins.4 g/day or 0.
and inhibit COX-2 and iNOS activity in colon tumors. EPA or DHA. and transmits extracellular mitogenic signals to downstream target signalling cascades that involve cell survival and proliferation. apoptosis. (Wichmann et al . . 2007) CANCER The most prominent mechanism for the chemopreventive action of n-3 PUFAs is their suppressive effect on the production of arachidonic acid (AA)-derived prostanoids. cell proliferation. EPA and DHA induce cell apoptosis. There was a significantly shorter length of hospital stay of approximately 21% in group I. In another invitro study done on Caco-2 cell(human epithelialcolorectaladenocarcinoma cells) the role of DHA in the expression of inducible nitric oxide synthase (iNOS) and of related proinflammatory genes were examined. and antioxidant content were significantly increased in group I. Both EPA and DHA reduce the activation of EGFR. In an in vitro study two lines of human breast cancer cells were treated with AA. The n-3 PUFAs might alter the growth of tumour cells by influencing cell replication. iNOS and COX-2/prostaglandins appear to be involved in the pathogenesis of colon cancer Overexpression of the COX-2 gene in colonic epithelial cells leads to altered adhesion properties and resistance to apoptosis. which has been implicated in the immune response to inflammation. High levels of iNOS may increase the invasiveness and metastatic potential of human colon cancer.oil). a reduction the expression of Bcl2 and procaspase-8. particularly prostaglandin E2 (PGE2). (Corsetto et al. DHA induce apoptosis. by interfering with components of the cell cycle or by increasing cell death either by way of necrosis or apoptosis.or heterodimerization with another ligand-bound ErbB receptor. Parenteral nutrition was initiated immediately after surgery and ended on day 5 after surgery. Possibility that several proinflammatory factors that activate iNOS could be inactivated by DHA via down- . angiogenesis and metastasis. differentiation. ligand binding leads to homo. Plasma levels of eicosapentaenoic acid.group2. 2011) EGFR is usually activated in response to extracellular ligands (EGF) by its phosphorylation. leukotriene B5.
et al 2003)a In nutritional intervention study with 2.8% soybeans protein (omega-3 PUFAs.9 kg whereas patients receiving FO maintained their weight (0.P. Comparatively.07 g in total calories. or an omega-3 PUFA-nonrich supplement (n-6 group)[0. . and 6. only 29% of patients in the other group maintained muscle mass. Results indicated that DHA inhibited cell growth by >54%.14% LA.6 g in total calories. One-year survival tended to be greater in the FO group (60.E. COPD Matsuyama et al conducted a study on sixty-four COPD patients received 400 kilocalories per day of an omega-3 PUFA-rich supplement (n-3 group) [1. 0. P = . and overall the group lost 1 kg of muscle.3 ± 0.S. 5. Patients not recieving Fish oil(FO) experienced an average weight loss of 2.7%.15). partly by inducing apoptosis.5 g EPA + DHA/day).18% ALA. omega-6 PUFAs.0% vs 38.regulation of NF-kB and other target genes. This may be administered as commercially available ω-3 enriched liquid nutritional supplements or as over-the-counter ω-3 fatty acid supplements.36% LA. Clinical Guidelines (2009) A target dose of 2 g of eicosapentanoic acid daily appears appropriate.2 g of Fish oil per day provided a benefit of maintenance of weight and muscle mass during chemotherapy. Approximately 69% of patients in the FO group gained or maintained muscle mass.4 g in total calories)].N. (Narayanan. (Murphy et al 2011) In another similar study with FO group (2. omega-6 PUFAs. According to A. 0.93 g in total calories)] for 2 years.5 ± 1. 2.0 kg). 3.4% ALA.8% soybeans protein (omega-3 PUFAs. 0. 0.
1200 mg alpha-linolenic acid (ALA.18:3n-3). Muscle wasting and decreased muscle oxidative capacity commonly occur in patients with chronic obstructive pulmonary disease (COPD). 700 mg eicosapentanoic acid (EPA. In a study conducted in eighty patients with COPD received PUFA or placebo daily during an 8 week rehabilitation programme. The duration of the constant work rate test also increased more in patients receiving PUFA. fat-free mass (FFM). a blend of 400 mg stearidonic acid (STA. . 22:6n-3). 20:5n-3). The peak load of the incremental exercise test increased more in the PUFA group than in the placebo group.4 g active fatty acids. and muscle strength. The daily dosage of PUFA consisted of 3.By the end of the study Leukotriene B4 levels in serum and sputum and tumor necrosis factoralpha and interleukin-8 levels in sputum decreased significantly in the n-3 group. 760 mg gamma-linoleinic acid (GLA. 18:4n-3). Both groups had similar increases in weight. After exercise.05)in those that took omega 3 fatty acids supp verses the control group. and 340 mg docosahexanoic acid (DHA. dyspnea & arterial O2 saturation improved (p< 0. 18:3n-6). while there was no significant change in the n-6 group.
immunonutrition with arginine has also been implicated in an intensification of the systemic inflammatory response system in critically ill patients. its bioavailability is reduced. In trauma and sepsis states.ARGININE The amino acid arginine. In clinical studies. the liver. However. and the kidney and with dysfunction in gastrointestinal motility. and insulin. is important in a number of biological and physiological processes. arginine supplementation enhanced nitrogen retention and protein synthesis in animals and in healthy human subjects. Nutritional formulas with arginine can enhance immune parameters after stress and surgery. Nitric oxide has several properties that aid local response to acute injury and reduce the risk of wound infection. which is classified as a semiessential amino acid and conditionally as an essential nutrient for adults in injured or stressed states. arginase II may direct the synthesis of arginine into ornithine and proline. 2004) Function of Arginine Arginine plays a role in protein synthesis. resulting in increased morbidity. Synthesized by the vascular endothelium via eNOS. In patients with shock. Although arginase I may be more directly responsible for the production of polyamines. Ornithine is a metabolite of arginine and is involved in the synthesis of polyamines. immunonutrition with arginine may not be beneficial and may actually have harmful effects. sepsis or organ failure. as a substrate for the urea cycle and the production of nitric oxide. which also detoxifies ammonia and facilitates excretion of nitrogen. . In the first pathway arginine is broken down by either arginase I or arginase II. (Stechmiller and Childress. The second pathway of arginine metabolism is responsible for producing nitric oxide. Arginine is metabolized via 2 pathways. and as a secretagogue for growth hormone. nitric oxide causes vascular relaxation. Proline is converted into hydroxyproline and then to collagen. a substance necessary for wound healing. which are important for cellular division. which is associated with alterations in the structure and function of the intestinal mucosa. Arginine is synthesized primarily in the kidney from gut-derived citrulline via the urea cycle. Arginase I break down arginine into ornithine and urea. prolactin.
and tumors.al. (Heyland et. 2001) . a nitric oxide–dependent mechanism is responsible for mediating neurogenic vasodilatation and for regulating functions of the respiratory. 2) improved wound healing. This increased NO could result in vasodilation and hypotension. parasites. (Zhou and Martindale. an effect that is directly correlated with an increase in the number of thymic T lymphocytes.which regulates blood pressure. mainly from arginase and iNOS. 3) increased net nitrogen balance. increased tissue uptake. delivering supplemental arginine as the substrate for upregulated iNOS will result in increased NO. Nitric oxide also regulates cardiac contractility via nNOS and acts as a neurotransmitter that facilitates numerous functions. and sepsis. Dietary L-arginine modulates the activities of immune cells in several ways. The numerous potential beneficial effects of arginine in the critically ill patient include: 1) stimulation of immune function via its influence on lymphocyte. Arginine also enhances phagocytosis by neutrophils and adhesion of polymorphonuclear cells. genitourinary. 2007) Dietary supplementation with arginine enhances immunocompetence in adults in humans and in animal models. 2004) The speculation that arginine may pose a threat to the critically ill patient is mainly based on the concept that critically ill patients are often hemodynamically unstable and that this population is in a state in which iNOS is commonly upregulated. (Stechmiller and Childress. activities that help produce nitric oxide for immunomodulation. including memory formation. 2009) Arginine in crically ill patients: Arginine plasma levels rapidly decline in critical illness. Consequently. In addition. (Zheng et. and gastrointestinal tracts. 4) increased blood flow to key vascular beds. trauma. and 5) decreased clinical infections and length of hospital stay. Platelet aggregation is also controlled by nitric oxide. and dendritic cells. The oxide also has cytotoxic properties and is thought to mediate the cytotoxic effects of macrophages on microbes. and increased metabolism. leading to greater hemodynamic instability. macrophage. dietary arginine can increase the weight of the thymus in healthy animals. Intravenous infusion of arginine is also associated with an increase in the release of T cells from the thymus. This decrease in plasma levels is thought to result from decreased intake. For example.al.
immunonutrition with arginine led to improvements in cellular immunity in patients with postoperative or posttraum-atic stress. He reported that in 12 of the 13 studies. 1999) Arginine in cancer: (controversial) Both arginine and its product nitric oxide (NO) are important mediators in the defense against tumor cells. NO may contribute to tumor progression from a colorectal adenoma to a colorectal carcinoma. natural killer cell’s cytotoxic effects and generation of lymphokine activated killer cells and also by producing NO to improve macrophage effects and bactericidal activity has shown to decrease infection risk in postoperative patients. IL-2 production. . cytokine induction. administration of enteral formulas containing arginine can cause transient hypotension. increases in cardiac index. 2009) Sepsis. because both influence T cell–mediated immunity. and Osmolite HN in 326 critically ill patients. the experimental groups had improved outcomes.4%). hospital and ICU lengths of stay. SIRS and trauma: In patients with severe SIRS and sepsis. and prolongs survival. Arginine-derived NO is also implicated in carcinogenesis in several other organs. There is also decrease in rate of infectious complications. arginine augments both specific and nonspecific antitumor mechanisms. Specifically. and decreases in systemic and pulmonary vascular resistance. (Flaherty and Bouchier-Hayes. In some animal tumor models. Zaloga reviewed 13 prospective randomized clinical studies in which an enteral immunonutritional formula with arginine was compared with a standard one in surgical and critically ill patients.7%) than in the control group (8. Arginine has been shown to potentiate IL-2 antitumour immunotherapy. vascular permeability and stimulation of angiogenic growth factors. retards tumor growth.Surgery: In early studies. an immunonutritional supplement with arginine. and number of infections decreased after immunonutrition with arginine. Arginine by stimulating T-cell proliferation. and macrophage-mediated tumor toxicity. NO promotes several steps required for tumor angiogenesis including endothelial cell proliferation. Bower et al compared the effect of IMPACT. (Zheng et. number of days of mechanical ventilation required. The results indicated that more deaths occurred in patients who received the arginine-supplemented formula (15.al.
and prolongs survival. (Lind. and in some tumour types arginine is essential for cell growth. Orally delivered arginine supplementation up to 30 g/d is safe with few gastrointestinal (GI) side effects. In some animal tumor models. 2005) Dosage: • • Normal arginine intake is between 5 and 7 g/d and endogenous production of arginine is estimated at 15–20 g. retards tumor growth. migration. eNOS. arginine augments both specific and nonspecific antitumor mechanisms. (Edwards et. 2004) Arginine is required for synthesis of polyamines. NOS activity has been detected in a variety of tumor cell lines and human tumors and its expression has been correlated with tumor grade and proliferation rate. . survival.Increased NOS activity is also associated with metaplastic changes in the breast and the esophagus NOS isoforms (iNOS.al. which are in turn regulators of cell growth. In normal healthy controls. nNOS) may be involved in tumor cell proliferation. 1-time doses >30 g usually result in mild diarrhea indicating 30g/d as a safe level. and invasiveness.
Disease condition I.5 g/kg 1.2 mmol/kg/min for 72 h No adverse hemodynamics Total parenteral nutrition Increased nitrogen balance enriched with arginine Decreased protein (129. No benefit could be established in patients with severe sepsis. 86.2 mmol/L vs.1 myofibriller catabolism mmol/L) (Source : Zhou and Martindale.v. dose Outcome Surgical wound Preterm labor Cardiac 28 g/d 30 g/30 min 30 g/45 min Decrease collagen deposition Decrease uterine contraction Normalized vasomotor tone in smokers Decreased pulmonary HTN Pulmonary HTN Sepsis Surgical ICU 0. . in whom an immunemodulating formula may be harmful and is therefore not recommended. 2007) Recommendations: Sepsis Patients with a mild sepsis (APACHE II<15) should receive immune modulating EN formula enriched with ω-3 fatty acids. arginine and nucleotides.
nucleotides and ω-3 fatty acids. This trial was a randomized placebo-controlled study. Interest in taurine as an immunomodulator was generated by the discovery of its antioxidant capacity and its ability to prime leucocytes and to regulate the release of pro-inflammatory cytokines. where its roles include membrane stabilization. gastrectomy. Burns No recommendation regarding supplementation with ω-3 fatty acids. glutamine or nucleotides can be given for burned patients due to insufficient data. those undergoing major cancer surgery of the neck (laryngectomy. Whenever possible administration of these supplemented formulae should be started before surgery and continued postoperatively for 5–7 days after uncomplicated surgery. promote the enterocyte cell cycle and prevent stress-induced apoptosis or cell death. as assessed by peritoneal macrophage superoxide generation. (ESPEN Guidelines) TAURINE Taurine is one of the most abundant amino acids in many cell types. which clearly indicates a gastrointestinal trophic effect. ICU patients with very severe illness and who do not tolerate more than 700 ml EN/day should not receive a formula enriched with arginine. In a murine model of sepsis taurine supplementation conferred immune benefits by down regulating TNF- release and upregulating anti-bacterial capacity.Surgery With special regard to patients with obvious severe nutritional risk. length of hospital stay . arginine. Supplemental taurine given to stressed intestinal cells in vitro can maintain absorption rates. and pancreatoduodenectomy) as well as after severe trauma benefit from the use of immune modulating EN formulae (enriched with arginine. Mortality rates. osmoregulation and Ca flux regulation. pharyngectomy) and of the abdomen (oesophagectomy. Intestinal absorption of taurine has been shown to be reduced under stressful conditions in vitro and depleted in trauma and elective cholecystectomy patients. comparing a standard enteral feed with a taurine supplemented feed (1 mg/ml) in the peri-operative period. The trial was conducted in seventeen elderly elective surgery patients. omega-3 fatty acids and nucleotides).
colonocytes. Ziegler et al. It has more specific effect on the function of lymphocytes via the thioredoxin system. and is the most important substrate for renal ammoniagenesis (regulation of the acid– base balance). 1991) as well as for many rapidly proliferating cells. the morphological and functional integrity of the intestinal mucosa appears to be protected by sufficient availability of glutamine. In skeletal muscle glutamine constitutes > 60 % of the total free amino acid pool (Bergström et al. an important anti-oxidant. Normal range of plasma glutamine level is 500 to 750 micro mol/L after an overnight fasting. However. The pro-inflammatory cytokine IL-1β was significantly reduced and anti-inflammatory cytokine IL-10 was enhanced on post-operative days 1 and 3. It is a precursor of glutathione. Glutamine has been reported to enhance many functional parameters of immune cells such as T-cell proliferation. There is much evidence that hypercatabolic and hypermetabolic situations are accompanied by marked depressions in muscle intracellular glutamine. taurine supplementation appeared to modulate the post-operative cytokine profile. It is a precursor that donates N for the synthesis of purines. and represents the major metabolic fuel for the cells of the gastrointestinal tract (enterocytes. (ii) an important modulator of gut barrier function (iii) (iii) as a substrate for glutathione synthesis Glutathione plays a pivotal role as it acts directly as an antioxidant and maintains other components of defence in a reduced state. 1974). 1982. Windmueller. Consequently. including those of the immune system (Calder. pyrimidines. (Flaherty and Bouchier-Hayes.and routine biochemical variables were similar between the two groups. macrophage phagocytosis. and is required for lymphocyte and macrophage function. lymphocytes and monocytes. A number of roles have been ascribed to glutamine as an immunonutrient like: (i) as an essential nutrient for immune cells. amino sugars and glutathione (GSH).also recorded a significant reduction in mortality in critically ill patients at six months following parenteral glutamine supplementation. It is also principal metabolic fuel of gut mucosal cell. nucleotides. . B-lymphocyte differentiation. antigen presentation and cytokine production plus neutrophil superoxide production and apoptosis. Two key cytokines were regulated by taurine.demonstrated a reduction in infections and length of hospital stay in bone marrow transplant patients fed with a parenteral glutamine preparation compared with a control group. 1994). 1999) GLUTAMINE Glutamine is the most prevalent free amino acid in the human body. Griffiths et al. Glutamine serves as a N transporter between various tissues. Souba.
in addition to amino acid transamination.’ “’ Physiologic concentrations of circulating glutamine are required for optimal growth of malignant cells in culture. both are excitatory neurotransmitters in central and peripheral nervous systems. tumor glutaminase activity is relatively high. dietary aspartate and glutamate. Moreover. along with glutamine. Glutaminase activity correlates well with tumor glutamine consumption and growth rates. aspartate (via TCA cycle activity). Glutamine was consumed at a rate faster than that of any other amino acid. Aspartate is required for the recycling of the citrulline produced by Inos into arginine in activated macrophages. acting on ionotropic and metabotropic receptors. This pathway connects with the urea cycle via synthesis of citrulline catalysed by ornithine carbamoyl transferaseGlutamate may also serve as a precursor for glutathione synthesis and as such may play a direct role in antioxidant defenses in these cells. NADPH is also required for glutathione reductase activity and as such plays an important role in increasing reduced glutathione concentration and hence antioxidant defenses and delay in apoptosis via stabilization of neutrophil mitochondria. although many cancerous cells do not have an absolute requirement for glucose. NADPH is required for biosynthetic reactions such as fatty acid synthesis or for production of free radicals such as O_ 2 or NO by the NADPH oxidase and Inos respectively. lactate and under appropriate conditions. which catalyses the conversion of malate (which is derived from glutamate via formation of 2 oxoglutarate. and fumarate) to pyruvate. which is present in both lymphocytes (Tian et al. 2004) and macrophages (Stuckey et al. Together. as an immediate precursor for glutathione synthesis. Interestingly. these amino acids help maintain intestinal barrier integrity and prevent the translocation of intestinal microorganisms to the systemic circulation. via action of NADPþdependent malic enzyme. Importantly. Glutamate is also required as a precursor for ornithine synthesis in macrophages and monocytes. Aspartate is crucial for the proliferation of lymphocytes. Aspartate and glutamate play versatile roles in the metabolism and function of leucocytes. T cells express GABA receptors. Further. This helps maintain an adequate intracellular concentration of arginine for sustaining a high rate of NO production in response to immunological challenges. macrophages and neutrophils. may be one of its functions. which play a role in modulating the immune systems Glutamate is involved in a number of key functions.Much of the glutamine is converted to glutamate. Provision of NADPH.2005). Glutamine and cancer: Glutamine has been shown to be an unusually good substrate for oxidation by tumor cell mitochondria. are the major fuels for enterocytes. which mediate an inhibitory effect of GABA on their proliferation. in lymphocytes. and its uptake was proportional to its . CO2. glutamate plays an important role in the removal of oxidants and regulation of the immune response. succinate. These results suggest that dietary glutamate is necessary for maintaining an optimal immune status under conditions of immunosuppression. glutamate is a substrate for the synthesis of g-aminobutyrate (GABA). predictably.
and augmenting immune function.57 g/kg/day).Lower levels of glutamine have been associated with immune dysfunction and higher mortality in critically ill patients.8 mg/ kg /body wt )→ higher plasma citrulline and arginine conc and glutamate(30.enriched TPN in patients with cancer is a randomized. Two glutamine analogues that compete with glutamine in replicating cells are L-DON (6-diazo-5-oxo-Lnorleucine) and acivicin (a-amino-3chloro-4. glutamine depletion develops with time. and a shortened hospital stay. glutamine supplementation has been shown to increase protein synthesis. mucositis.These clinical improvements were consistent with a role for glutamine in stimulating protein synthesis in skeletal muscle. • • • Glutamine may exist for surgical and critically ill patients. and pancytopenia. Fast-growing fibrosarcomas are also avid glutamine consumers. Several studies have shown that glutamine levels drop following extreme physical exercise . The keto acid L-DON is an antitumor antibiotic isolated from Streptomyces that inhibits a number of biochemical reactions requiring glutamine. In a catabolic state such as surgery. which include nausea.’Glutamine extraction by this tumor has been quantified and may be as high as 45%. In patients with (COPD). It has been hypothesized that glutamine may become a conditionally essential amino acid in patients with catabolic disease . using parenterally delivered glutamine at a dose of 0. a diminished incidence of clinical infections. Acivicin also inhibits glutamine-requiring enzymes.0 mg/ kg body wt)→ reduce citrulline conc and no changes in plasma arginine conc and increase ornithine conc in COPD patients. glutamine supplementation decreases gut mucosal atrophy during total parenteral nutrition and preserves both intestinal and extra intestinal immunoglobulin-A levels .25 mLwater · kg body wt_1 · 20 min_1). The patients receiving glutamine-supplemented parenteral nutrition after this procedure had improved nitrogen balance. less fluid accumulation. Supplementation with glutamine (29.5-dihydro5-isoxazoleacetic acid). DON have been disappointing and have been limited by side effects. Effects of glutamine. both from the disease process itself and from the catabolic effects of antineoplastic therapies. the plasma glutamine and glutamate and skeletal muscle glutamate concentrations were low. In the majority of patients with cancer. greater than the rate of glutamine extraction for any organ under conditions of health The tumor thus behaves a “glutamine trap. The water drink contained the equal amount of only water (1.” It is unclear why malignant cells consume such large amounts of glutamine. .20g/kg/day. double-blind controlled trial supplemented with L-glutamine (0. after major surgery and during critical illness .supply. especially the rate-limiting enzymes of de novo purine and pyrimidine biosynthesis. supporting endothelial function and integrity. In animal studies.
Burn patient were randomly assigned a single 10g bolus or a continous infusion in three doses 10. Improve measures of nutritional status→ +ve N balance. an immunomodulator & promoter of wound healing.57g/kg bdwt) in severly burned patient has an effect: on gram –ve bacteria. fish. proinflammatory cytokines.35g/kg/day) to 30g (0. Supp of TPN with OKG → improve nitrogen balance and preserved intramuscular glutamine as equally effective as glutamine. beets. respectively. arginine and proline were the main metabolites leading greater production. Decreased overall inflammation. reduce catabolic state. It has been estimated to have as much as 25g (o. Its mode of action is not fully clear but the secreation of anabolic hormones (insulin & GH) & synthesis of metabolites such as glutamine.42g/kg/day) of glutamine.20. polyamines and proline may be involved. beans. protein synthesis.2 & 3 wk of tumor growth. arginine. Prior to tumor-bearing and surgically treated animals. as it enhance gut barrier function and prevent bacterial translocation from the gut. These results suggest that glutamine decreases the overall systemic inflammatory response. Oral glutamine supplementation (30g/day) for 4 wks to the patient with esophageal cancer enhanced lymphocyte mitogenic function and reduced permeability of the gut during radiochemotherapy. • • • Ornithine alpha-ketoglutarate (OKG): • • • OKG is a salt formed from one molecule of alpha. OKG had no effect on tumor growth in untreated tumor rats but showed more +ve N balance. wheat.• Glutamine supplementation (0. It is through enternal nutrition studies in septic. spinach. Compare with glycine. diet containing 50g. and parsley. Small amounts of free L-glutamine are also found in vegetable juices and foods such as tofu. trauma and burns patients where 0KG has shown clinical benefits. 67g and 100g OKG/kgbdwt during wk 1. • • • • • .as decreases in serum concentrations of soluble tumor necrosis factor receptors. cabbage.30g/d → glutamine. Dietary sources of L-glutamine include beef. It is recognized as a nutritional modulator with anticatabolic activity. eggs. milk. dairy products. chicken. higher conc of glutamine and BCAA in muscle in postoperated tumor rats.ketoglutarate and two of ornithine.
Se and Zn) should be supplemented in a higher than standard dose. and pancreatoduodenectomy) after severe trauma.35g/kg. pharyngectomy) undergoing major abdominal cancer surgery (oesophagectomy. ICU patients with very severe illness who do not tolerate more than 700 ml enteral formulae per day should not receive an immune-modulating formula enriched with arginine. in patients with trauma in patients with ARDS (formulae containing o-3 fatty acids and antioxidants). Although the amino acids that comprise OKG are present in protein foods such as meat and poultry and fish. nucleotides and o-3 fatty acids. immune-modulating formulae may be harmful and are therefore not recommended. ESPEN GUIDLINES. No recommendation for immune-modulating formulae can be given for burned patients due to insufficient data.• • Even same effect is seen postoperative surgery patient receive TPP supp with OKG 0. the OKG compound is found only in supplements. nucleotides and x-3 fatty acids) are superior to standard enteral formulae: in elective upper GI surgical patients in patients with a mild sepsis in patients with severe sepsis. though 10 grams per day has been used in clinical trials. Use EN preferably with immuno-modulating substrates (arginine. however. o-3 fatty acids and nucleotides) perioperatively independent of the nutritional risk for those patients undergoing major neck surgery for cancer (laryngectomy. The optimal parenteral nutrition regimen for critically ill surgical patients should probably include supplemental n-3 fatty acids. . Immune-modulating formulae (formulae enriched with arginine. Optimal levels remain unknown. The evidence-base for such recommendations requires further input from prospective randomised trials. Glutamine should be added to standard enteral formula in burned patients trauma patients There are not sufficient data to support glutamine supplementation in surgical or heterogenous critically ill patients. In burned patients trace elements (Cu. gastrectomy.
ROLE OF IMMUNONUTRIENTS IN COPD AND HYPERMETABOLIC CONDITION. - BHAKTI MEHTA .
Msc CND) .KRUPA PAREKH NUDRAT KHAN SAFINA SHARIFF (Sr.
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