IMMUNONUTRIENT The role of certain nutrients that seem to have pharmacologic effects on immune and inflammatory parameters has 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.
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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 fornucleotides 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 IL-
2 production. Moreover reduced phagocytosis and an impaired clearance of experimantallyapplied 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,delayed-type 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
Human immune cells incorporate BCAA into proteins; incorporation of isoleucine is greatestinto lymphocytes, followed by eosinophils, followed by neutrophils, and perhaps reflecting cell
specific differences in protein-synthetic rates and in the types of proteins made. Furthermore,
human immune cells express branched-chain alpha keto acid dehydrogenase and decarboxylaseactivities and so can oxidize BCAA. Indeed, human lymphocytes take up and oxidize leucine.
Isoleucine is oxidized by human neutrophils and lymphocytes. Mitogen stimulation of
lymphocytes increases leucine transport by 270%, leucine transamination by 195% and leucineoxidation by 122%. The uptake of BCAA by a B cell line was studied as a function of progressthrough the cell cycle . The pattern of uptake of all three BCAAs through the cell cycle is the
same, although the order of the rate of uptake is leucine> isoleucine >>valine. The highest rate of
uptake of BCAA is during the S phase, with a progressive decline in uptake through the G2 and
M phases
BCAA and immune cell function
Leucine, isoleucine, and valine are among the 13 amino acids absolutely required by culturedmammalian cells including lymphocytes. 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. Omission of leucine, isoleucine, or valine from the
medium of cultured lymphocytes also abolishes the ability of lymphocytes to proliferate inresponse to phytohemagglutinin by 82%, 90%, and 100%, respectively. However, this most
likely reflects an inability to synthesize proteins required for cellular proliferation to occur.
Surgical and critically ill patients
Branched-chain amino acids serve as important fuel for skeletal muscle, especially during stress.
They promote protein synthesis, reduce protein degradation, and serve as substrates for
gluconeogenesis. All metabolism occurs in skeletal muscle. This increases their usefulness in the
presence of liver dysfunction. 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. In laboratory and clinical experience, branched-chain amino acids
have been shown to improve nitrogen balance. The most demonstrable clinical benefit from
administering branched-chain amino acids appears to be during times of maximal stress. A 45%
branched-chain enrichment is considered most optimal for nitrogen sparing and proteinsynthesis.
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, and various
disturbances in plasma amino-acid levels were found in underweight COPD patients.Plasma
levels of amino acids and hypermetabolism in patients with chronic obstructive pulmonarydisease.
Amino acids are the building blocks of protein and several studies have to date reported an
abnormal plasma amino acid pattern in COPD. Of interest are the consistently reduced plasmalevels of branched chain amino acids (BCAAs) in underweight COPD patients and in those with
low muscle mass.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. Leucine isan interesting nutritional substrate since it not only serves as precursor, 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.
BCAAs are also important precursors for glutamate (GLU), which is one of the most important
non-essential amino acids in muscle. BCAA derived from net protein breakdown and by uptakeinto the muscle pool, undergo transamination to yield branched-chain keto acid and GLU.Intracellular GLU is involved in numerous metabolic processes including substrate
phosphorylation and replenishment of tricarboxylic acid (TCA) intermediates to preserve high-
energy phosphates at rest and during exercise. Moreover intracellular GLU is known as animportant precursor for antioxidant glutathione (GSH) and glutamine synthesis in muscle.
Recently, a consistently reduced muscle GLU status of severe COPD patients was reported,that
further decreased during a submaximal exercise bout. While muscle redox potential (glutathione
disulphide/GSH) increases after endurance exercise training in healthy subjects, patients withCOPD showed a reduced ability to adapt in this way as reflected by a lower capacity to
synthesise GSH. These observations provide perspective for amino acid supplementation to
modulate exercise-induced protein synthesis as well as exercise-induced oxidative stress.
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.rate of ingestion: 0.02 gprotein/kg body weight/20 min
The anorexia-cachexia syndrome is highly prevalent in patients suffering from acute and chronicdiseases, including cancer, chronic renal failure and liver cirrhosis.
Branched-chain amino acids are neutral amino acids with interesting and clinically relevant
metabolic effects. Their potential role as antianorexia and anticachexia agents was proposedmany years ago, but only recent experimental studies and clinical trials have tested their ability
to stimulate food intake and counteract muscle wasting in anorectic, weight-losing patients. Byinterfering with brain serotonergic activity and by inhibiting the overexpression of critical
muscular proteolytic pathways, branched-chain amino acids have been shown to induce
beneficial metabolic and clinical effects under different pathological conditions.
their supplementation may represent a viable intervention not only for patients suffering from
chronic diseases, but also for those individuals at risk of sarcopenia due to age, immobility or
prolonged bed rest, including trauma, orthopedic or neurologic patients.
SEPSIS
Under circumstances of severe stress and sepsis, marginal improvements in nitrogen retentionare observed. Plasma short-turnover protein concentrations tend to be higher in the BCAA
solution enriched largely with leucine. In situations in which brain function is affected, BCAA
normalizes the plasma amino acid pattern, both by increasing protein synthesis and decreasingproteolysis as well as competing with the toxic aromatic amino acids at the blood-brain barrier.
oil)- group2. Parenteral nutrition was initiated immediately after surgery and ended on day 5
after surgery.
Plasma levels of eicosapentaenoic acid, leukotriene B5, and antioxidant content were
significantly increased in group I. There was a significantly shorter length of hospital stay of
approximately 21% in group I. (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, particularly
prostaglandin E2 (PGE2), which has been implicated in the immune response to inflammation,
cell proliferation, differentiation, apoptosis, angiogenesis and metastasis. The n-3 PUFAs might
alter the growth of tumour cells by influencing cell replication, by interfering with components
of the cell cycle or by increasing cell death either by way of necrosis or apoptosis.
In an in vitro study two lines of human breast cancer cells were treated with AA, EPA or DHA.
EPA and DHA induce cell apoptosis, a reduction the expression of Bcl2 and procaspase-8. . Both
EPA and DHA reduce the activation of EGFR. (Corsetto et al. 2011)
EGFR is usually activated in response to extracellular ligands (EGF) by its phosphorylation;
ligand binding leads to homo- or heterodimerization with another ligand-bound ErbB receptor,
and transmits extracellular mitogenic signals to downstream target signalling cascades that
involve cell survival and proliferation.
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.
iNOS and COX-2/prostaglandins appear to be involved in the pathogenesis of colon cancerOverexpression of the COX-2 gene in colonic epithelial cells leads to altered adhesion properties
and resistance to apoptosis. High levels of iNOS may increase the invasiveness and metastatic
potential of human colon cancer.
DHA induce apoptosis, and inhibit COX-2 and iNOS activity in colon tumors. Possibility that
several proinflammatory factors that activate iNOS could be inactivated by DHA via down-
regulation of NF-kB and other target genes. Results indicated that DHA inhibited cell growth by
>54%, partly by inducing apoptosis. (Narayanan,et al 2003)a
In nutritional intervention study with 2.2 g of Fish oil per day provided a benefit of maintenance
of weight and muscle mass during chemotherapy.
Patients not recieving Fish oil(FO) experienced an average weight loss of 2.3 ± 0.9 kg whereas
patients receiving FO maintained their weight (0.5 ± 1.0 kg). Approximately 69% of patients in
the FO group gained or maintained muscle mass. Comparatively, only 29% of patients in the
other group maintained muscle mass, and overall the group lost 1 kg of muscle. (Murphy et al
2011)
In another similar study with FO group (2.5 g EPA + DHA/day). One-year survival tended to be
greater in the FO group (60.0% vs 38.7%; P = .15).
According to A.S.P.E.N. Clinical Guidelines (2009)
A target dose of 2 g of eicosapentanoic acid daily appears appropriate. This may be administered
as commercially available ω-3 enriched liquid nutritional supplements or as over-the-counter ω-3
fatty acid supplements.
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) [1.4% ALA, 2.14% LA, and 6.8%
soybeans protein (omega-3 PUFAs, 0.6 g in total calories; omega-6 PUFAs, 0.4 g in total
calories)]; or an omega-3 PUFA-nonrich supplement (n-6 group)[0.18% ALA, 3.36% LA, 5.8%soybeans protein (omega-3 PUFAs, 0.07 g in total calories; omega-6 PUFAs, 0.93 g in total
The amino acid arginine, which is classified as a semiessential amino acid and conditionally as
an essential nutrient for adults in injured or stressed states, is important in a number of biological
and physiological processes. In trauma and sepsis states, its bioavailability is reduced. In clinical
studies, 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.
However,
immunonutrition with arginine has also been implicated in an intensification of the systemic
inflammatory response system in critically ill patients, resulting in increased morbidity. In
patients with shock, sepsis or organ failure, immunonutrition with arginine may not be beneficial
and may actually have harmful effects.
(Stechmiller and Childress, 2004)
Function of Arginine
Arginine plays a role in protein synthesis, as a substrate for the urea cycle and the production of
nitric oxide, and as a secretagogue for growth hormone, prolactin, and insulin. Arginine is
synthesized primarily in the kidney from gut-derived citrulline via the urea cycle, which also
detoxifies ammonia and facilitates excretion of nitrogen. Ornithine is a metabolite of arginine
and is involved in the synthesis of polyamines, which are important for cellular division.Arginine is metabolized via 2 pathways. In the first pathway arginine is broken down by either
arginase I or arginase II. Arginase I break down arginine into ornithine and urea. Although
arginase I may be more directly responsible for the production of polyamines, arginase II may
direct the synthesis of arginine into ornithine and proline. Proline is converted into
hydroxyproline and then to collagen, a substance necessary for wound healing.
The second pathway of arginine metabolism is responsible for producing nitric oxide, which is
associated with alterations in the structure and function of the intestinal mucosa, the liver, and
the kidney and with dysfunction in gastrointestinal motility.
Nitric oxide has several properties that aid local response to acute injury and reduce the risk of
wound
infection. Synthesized by the vascular endothelium via eNOS, nitric oxide causes vascular
and routine biochemical variables were similar between the two groups. However, taurine
supplementation appeared to modulate the post-operative cytokine profile. Two key cytokines
were regulated by taurine. The pro-inflammatory cytokine IL-1β was significantly reduced and
anti-inflammatory cytokine IL-10 was enhanced on post-operative days 1 and 3. (Flaherty and
Bouchier-Hayes, 1999)
GLUTAMINE
Glutamine is the most prevalent free amino acid in the human body. In skeletal muscle glutamine
constitutes > 60 % of the total free amino acid pool (Bergström et al. 1974). It is a precursor that
donates N for the synthesis of purines, pyrimidines, nucleotides, amino sugars and glutathione(GSH), and is the most important substrate for renal ammoniagenesis (regulation of the acid – base balance).
Glutamine serves as a N transporter between various tissues, and represents the major metabolicfuel for the cells of the gastrointestinal tract (enterocytes, colonocytes; Windmueller, 1982;
Souba, 1991) as well as for many rapidly proliferating cells, including those of the immune
system (Calder, 1994). Consequently, the morphological and functional integrity of the intestinal
mucosa appears to be protected by sufficient availability of glutamine. There is much evidencethat hypercatabolic and hypermetabolic situations are accompanied by marked depressions in
muscle intracellular glutamine.
A number of roles have been ascribed to glutamine as
an immunonutrient like:
(i) as an essential nutrient for immune cells.
Glutamine has been reported to enhance many functional parameters of immune cellssuch as T-cell proliferation, B-lymphocyte differentiation, macrophage phagocytosis,
antigen presentation and cytokine production plus neutrophil superoxide production
and apoptosis.
(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. It has more specific effect on the function of
lymphocytes via the thioredoxin system. It is also principal metabolic fuel of gut mucosal cell,
lymphocytes and monocytes.Normal range of plasma glutamine level is 500 to 750 micro mol/L after an overnight fasting.
It is a precursor of glutathione, an important anti-oxidant, and is required for lymphocyte and
macrophage function. Ziegler et al,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. Griffiths et al,also recorded a significant reduction in mortality in critically
ill patients at six months following parenteral glutamine supplementation.
Much of the glutamine is converted to glutamate, aspartate (via TCA cycle
activity), lactate and under appropriate conditions, CO2.Aspartate and glutamate play versatile roles in the metabolism and function of leucocytes.
Aspartate is crucial for the proliferation of lymphocytes. Aspartate is required for the recycling
of the citrulline produced by Inos into arginine
in activated macrophages. This helps maintain an adequate intracellular concentration of argininefor sustaining a high rate of NO production in response to
immunological challenges.
Importantly, dietary aspartate and glutamate, along with glutamine, are the major fuels forenterocytes. Together, these amino acids help maintain intestinal
barrier integrity and prevent the translocation of intestinal microorganisms to the systemic
circulation, both are excitatory neurotransmitters in central and peripheral nervous systems,acting on ionotropic and metabotropic receptors, which play
a role in modulating the immune systems
Glutamate is involved in a number of key functions, in addition to amino acid transamination, in
lymphocytes, macrophages and neutrophils. Provision of NADPH, via action of NADPþ-
dependent malic enzyme, which catalyses the conversion of malate (which is derived fromglutamate via formation of 2 oxoglutarate, succinate, and fumarate) to pyruvate, may be one of
its functions. 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.
NADPH is also required for glutathione reductase activity and as such plays an important role inincreasing reduced glutathione concentration and
hence antioxidant defenses and delay in apoptosis via stabilization of neutrophil mitochondria.
Glutamate is also required as a precursor for ornithine synthesis in macrophages and monocytes.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.Moreover, glutamate is a substrate for the synthesis of g-aminobutyrate (GABA), which is
present in both lymphocytes (Tian et al. 2004) and macrophages (Stuckey et al.2005).
Interestingly, T cells express GABA receptors, which mediate an inhibitory effect of GABA ontheir proliferation. Further, as an immediate precursor for glutathione synthesis, glutamate plays
an important role in the
removal of oxidants and regulation of the immune response. These results suggest that dietaryglutamate is necessary for maintaining an optimal immune status under conditions of
immunosuppression.
Glutamine and cancer:
Glutamine has been shown to be an unusually good substrate for oxidation by tumor cellmitochondria; predictably, tumor glutaminase activity is relatively
high. Glutaminase activity correlates well with tumor glutamine consumption
and growth rates,’ “’ Physiologic concentrations of circulating glutamine are required for optimalgrowth of malignant cells in culture, although many cancerous cells do not have an absolute
requirement for glucose. Glutamine was consumed at a rate faster than that of any other amino
supply. Fast-growing fibrosarcomas are also avid glutamine consumers.’Glutamine extraction by
this tumor has been quantified and may be as high as 45%,greater than the rate of glutamine extraction for any organ
under conditions of health The tumor thus behaves a “glutamine trap.” It is unclear why
malignant cells consume such large amounts of glutamine. In the majority of patients with
cancer, glutamine depletion develops with time, both from the disease process itself and from thecatabolic effects of antineoplastic therapies. Two glutamine analogues that compete with
glutamine in replicating cells are L-DON (6-diazo-5-oxo-Lnorleucine) and acivicin (a-amino-3-
chloro-4,5-dihydro-5-isoxazoleacetic acid). The keto acid L-DON is an antitumor antibiotic isolated from
Streptomyces that inhibits a number of biochemical reactions requiring glutamine. DON have
been disappointing and have been limited by side effects, which include nausea, mucositis, andpancytopenia. Acivicin also inhibits glutamine-requiring enzymes, especially the rate-limiting
enzymes of de novo purine and pyrimidine biosynthesis.
Effects of glutamine- enriched TPN in patients with cancer is a randomized,
double-blind controlled trial supplemented with L-glutamine (0.57 g/kg/day). The patientsreceiving glutamine-supplemented parenteral nutrition after this procedure had improved
nitrogen balance, a diminished incidence of clinical infections, less fluid accumulation, and ashortened hospital stay.These clinical improvements
were consistent with a role for glutamine in stimulating protein synthesis in skeletal muscle,
supporting endothelial function and integrity, and augmenting
immune function.
It has been hypothesized that glutamine may become a conditionally essential amino acid inpatients with catabolic disease . Several studies have shown that glutamine levels drop following
extreme physical exercise , after major surgery and during critical illness .Lower levels of
glutamine have been associated with immune dysfunction and higher mortality in critically ill
patients. In animal studies, glutamine supplementation decreases gut mucosal atrophyduring total parenteral nutrition and preserves both intestinal and extra intestinal
immunoglobulin-A levels .
• Glutamine may exist for surgical and critically ill patients, using parenterally delivered
glutamine at a dose of 0.20g/kg/day.
• In a catabolic state such as surgery, glutamine supplementation has been shown to
increase protein synthesis.
• In patients with (COPD), the plasma glutamine and glutamate and skeletal muscle
glutamate concentrations were low.
Supplementation with glutamine (29.8 mg/ kg /body wt )→ higher plasma citrulline and arginineconc and glutamate(30.0 mg/ kg body wt)→ reduce citrulline conc and no changes in plasma
arginine conc and increase ornithine conc in COPD patients. The water drink contained the equalamount of only water (1.25 mLwater · kg body wt_1 · 20 min_1).
• Even same effect is seen postoperative surgery patient receive TPP supp with OKG
0.35g/kg.
• Optimal levels remain unknown, though 10 grams per day has been used in clinical trials.
Although the amino acids that comprise OKG are present in protein foods such as meat andpoultry and fish, the OKG compound is found only in supplements.
ESPEN GUIDLINES.
Use EN preferably with immuno-modulating substrates (arginine, o-3 fatty acids and
nucleotides) perioperatively independent of the nutritional risk for those patients
undergoing major neck surgery for cancer (laryngectomy, pharyngectomy)
undergoing major abdominal cancer surgery (oesophagectomy, gastrectomy, andpancreatoduodenectomy)
after severe trauma.
Immune-modulating formulae (formulae enrichedwith arginine, 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, however, immune-modulating formulae may be harmfuland are therefore not recommended.
in patients with trauma
in patients with ARDS (formulae containing o-3fatty acids and antioxidants).
No recommendation for immune-modulating formulae can be given for burned patients due to
insufficient data.In burned patients trace elements (Cu, Se and Zn)
should be supplemented in a higher than standard
dose.
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, nucleotides and
o-3 fatty acids.
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.
The optimal parenteral nutrition regimen for critically ill surgical patients should probablyinclude supplemental n-3 fatty acids. The evidence-base for such recommendations requires