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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.



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 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

of nucleotides.



BCAA

Utilization of BCAA by cells of the immune system

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.



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, 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



CANCER

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.



OMEGA 3 FATTY ACID

These lipids influence membrane stability, membrane fluidity, cell mobility, the formation of

receptors, binding of ligands to their receptors, activation of intracellular signaling pathways

either directly or through the formation of eicosanoids, gene expression, and cell differentiation.

In general, 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, including stimulation of

cytokine production and inflammatory responses

Omega -3 PUFA has immunonutrient function due to their anti-inflammatory properties.

The most likely way in which lipids might modulate pro-inflammatory cytokine biology is by

changing the fatty acid composition in the cell membrane.

As a consequence of the changes two interrelated phenomena may occur:(1) alteration in membrane fluidity;

(2) alterations in products which arise from hydrolysis of membrane phospholipids. Changes in

fluidity may alter the binding of cytokines and cytokine-inducing agonists to receptors.

The major advantages of EPA- and docosahexaenoic acid-derived metabolites can be

summarized as follows:

(1) EPA-derived thromboxane A3 is less active in platelet aggregation than thromboxane A2;

(2) LTB5, which has only a small proportion of the activity of LTB4 and plateletactivating

factors, resulting in decreased chemotactic migration and endothelial cell adherence.

(3) feeding with fish oils is associated with profound changes in immunoregulatory processes,

including the

production and release of various cytokines, interleukines and interferons.

Consumption of EPA reduces the production of pro-inflammatory IL-1-α and -βand IL-6, as well

as tumour necrosis factor-α and -β in response to an inflammatory stimulus.

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, as well

as a large reduction in cytokine-induced synthesis of prostaglandin E2 and thromboxane B2 in

the colonic mucosa.



Fish oil supplementation suppresses autoimmune diseases and T-cell lymphocyte production of

IL-2, and subsequent proliferation.

In critically ill patients administration of n-3 PUFA is associated with a reduction in the 2-series

of prostaglandins, thereby boosting the cellular defence function due to the ineffectiveness of

feedback inhibition induced by prostaglandin E2.

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.

SEPSIS

The lipid typically used in parenteral nutrition is soybean oil, in which n-6 linoleic acid

comprises about 50% of fatty acids present, using lipid emulsions entirely based upon soybean

oil is not optimal.

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.

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, soya bean oil and fish oil for 5 days. The fish oil group had increased

EPA in plasma phosphatidylcholine by an average of 3.8-fold(p<0.001) and decreased

concentration of plasma IL-6 and IL-10(p<0.001). They also reported a shorter hospital stay.The

average dose of fish oil administered in the current study 6.4 g/day or

0.09 g/kg/d is equivalent to 2.3 g EPA plus DHA/d(Barbosa et al. 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



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-

http://wiki/Epithelium

http://wiki/Adenocarcinoma

http://wiki/Adenocarcinoma





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

calories)] for 2 years.

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http://pubmed/?term=%22Murphy%20RA%22%5BAuthor%5D



By the end of the study Leukotriene B4 levels in serum and sputum and tumor necrosis factor-

alpha and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was

no significant change in the n-6 group. After exercise, dyspnea & arterial O2 saturation

improved (p< 0.05)in those that took omega 3 fatty acids supp verses the control group.

Muscle wasting and decreased muscle oxidative capacity commonly occur in patients with

chronic obstructive pulmonary disease (COPD). In a study conducted in eighty patients with

COPD received PUFA or placebo daily during an 8 week rehabilitation programme.

The daily dosage of PUFA consisted of 3.4 g active fatty acids, a blend of 400 mg stearidonic

acid (STA, 18:4n-3), 760 mg gamma-linoleinic acid (GLA, 18:3n-6), 1200 mg alpha-linolenic

acid (ALA,18:3n-3), 700 mg eicosapentanoic acid (EPA, 20:5n-3), and 340 mg docosahexanoic

acid (DHA, 22:6n-3).

Both groups had similar increases in weight, fat-free mass (FFM), and muscle strength. The peak

load of the incremental exercise test increased more in the PUFA group than in the placebo

group. The duration of the constant work rate test also increased more in patients receiving

PUFA.



ARGININE

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

relaxation,



which regulates blood pressure. Nitric oxide also regulates cardiac contractility via nNOS and

acts as a neurotransmitter that facilitates numerous functions, including memory formation. In

addition, a nitric oxide – dependent mechanism is responsible for mediating neurogenic

vasodilatation and for regulating functions of the respiratory, genitourinary, and gastrointestinal

tracts. Platelet aggregation is also controlled by nitric oxide. The oxide also has cytotoxic

properties and is thought to mediate the cytotoxic effects of macrophages on microbes, parasites,

and tumors. (Zhou and Martindale, 2007)

Dietary supplementation with arginine enhances immunocompetence in adults in humans and in

animal models. Dietary L-arginine modulates the activities of immune cells in several ways. For

example, dietary arginine can increase the weight of the thymus in healthy animals, an effect that

is directly correlated with an increase in the number of thymic T lymphocytes. Intravenous

infusion of arginine is also associated with an increase in the release of T cells from the thymus.

Arginine also enhances phagocytosis by neutrophils and adhesion of polymorphonuclear cells;

activities that help produce nitric oxide for immunomodulation. (Zheng et.al, 2009)

Arginine in crically ill patients:

Arginine plasma levels rapidly decline in critical illness, trauma, and sepsis. This decrease in

plasma levels is thought to result from decreased intake, increased tissue uptake, and increased

metabolism, mainly from arginase and iNOS.

The numerous potential beneficial effects of arginine in the critically ill patient include: 1)

stimulation of immune function via its influence on lymphocyte, macrophage, and dendritic

cells; 2) improved wound healing; 3) increased net nitrogen balance; 4) increased blood flow to

key vascular beds; and 5) decreased clinical infections and length of hospital stay.

(Stechmiller and Childress, 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. Consequently, delivering supplemental

arginine as the substrate for upregulated iNOS will result in increased NO. This increased NO

could result in vasodilation and hypotension, leading to greater hemodynamic instability.

(Heyland et.al, 2001)



Surgery:

In early studies,immunonutrition with arginine led to improvements in cellular immunity in

patients with postoperative or posttraum-atic stress. 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. He reported that in 12 of the 13 studies, the

experimental groups had improved outcomes. Specifically, hospital and ICU lengths of stay,

number of days of mechanical ventilation required, and number of infections decreased after

immunonutrition with arginine. There is also decrease in rate of infectious complications.

Arginine by stimulating T-cell proliferation, IL-2 production, 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 post-

operative patients. (Zheng et.al, 2009)

Sepsis, SIRS and trauma:

In patients with severe SIRS and sepsis, administration of enteral formulas containing arginine

can cause transient hypotension, increases in cardiac index, and decreases in systemic and

pulmonary vascular resistance. Bower et al compared the effect of IMPACT, an

immunonutritional supplement with arginine, and Osmolite HN in 326 critically ill patients. The

results indicated that more deaths occurred in patients who received the arginine-supplemented

formula (15.7%) than in the control group (8.4%).

(Flaherty and Bouchier-Hayes, 1999)

Arginine in cancer: (controversial)

Both arginine and its product nitric oxide (NO) are important mediators in the defense against

tumor cells, because both influence T cell – mediated immunity, cytokine induction, and

macrophage-mediated tumor toxicity. In some animal tumor models, arginine augments both

specific and nonspecific antitumor mechanisms, retards tumor growth, and prolongs survival.

Arginine has been shown to potentiate IL-2 antitumour immunotherapy.

Arginine-derived NO is also implicated in carcinogenesis in several other organs. NO may

contribute to tumor progression from a colorectal adenoma to a colorectal carcinoma. NO

promotes several steps required for tumor angiogenesis including endothelial cell proliferation,

vascular permeability and stimulation of angiogenic growth factors.



Increased NOS activity is also associated with metaplastic changes in the breast and the

esophagus

NOS isoforms (iNOS, eNOS, nNOS) may be involved in tumor cell proliferation, survival,

migration, and invasiveness. 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. In

some animal tumor models, arginine augments both specific and nonspecific antitumor

mechanisms, retards tumor growth, and prolongs survival. (Lind, 2004)

Arginine is required for synthesis of polyamines, which are in turn regulators of cell growth, and

in some tumour types arginine is essential for cell growth. (Edwards et.al, 2005)

Dosage:

• Normal arginine intake is between 5 and 7 g/d and endogenous production of arginine is

estimated at 15 – 20 g.

• Orally delivered arginine supplementation up to 30 g/d is safe with few gastrointestinal

(GI) side effects. In normal healthy controls, 1-time doses >30 g usually result in mild

diarrhea indicating 30g/d as a safe level.



Disease condition I.v. dose Outcome

Surgical wound 28 g/d Decrease collagen

deposition

Preterm labor 30 g/30 min Decrease uterine

contraction

Cardiac 30 g/45 min Normalized vasomotor

tone in smokers

Pulmonary HTN 0.5 g/kg Decreased pulmonary HTN

Sepsis 1.2 mmol/kg/min for 72 h No adverse hemodynamics

Surgical ICU Total parenteral nutrition

enriched with arginine

(129.2 mmol/L vs. 86.1

mmol/L)

Increased nitrogen balance

Decreased protein

myofibriller catabolism

(Source : Zhou and Martindale, 2007)

Recommendations:

Sepsis

Patients with a mild sepsis (APACHE II<15) should receive immune modulating ENformula enriched with ω-3 fatty acids, arginine and nucleotides.

No benefit could be established in patients with severe sepsis, in whom an

immunemodulating formula may be harmful and is therefore not recommended.



Surgery

With special regard to patients with obvious severe nutritional risk, those undergoing

major cancer surgery of the neck (laryngectomy, pharyngectomy) and of the abdomen

(oesophagectomy, gastrectomy, and pancreatoduodenectomy) as well as after severe

trauma benefit from the use of immune modulating EN formulae (enriched with arginine,

omega-3 fatty acids and nucleotides).

Whenever possible administration of these supplemented formulae should be started

before surgery and continued postoperatively for 5 – 7 days after uncomplicated surgery.

Burns

No recommendation regarding supplementation with ω-3 fatty acids, arginine, glutamine

or nucleotides can be given for burned patients due to insufficient data.

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, nucleotides and ω-3 fatty acids.

(ESPEN Guidelines)

TAURINE

Taurine is one of the most abundant amino acids in many cell types, where its roles include

membrane stabilization, osmoregulation and Ca flux regulation. 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. Intestinal absorption

of taurine has been shown to be reduced under stressful conditions in vitro and depleted in

trauma and elective cholecystectomy patients.

Supplemental taurine given to stressed intestinal cells in vitro can maintain absorption rates ,

promote the enterocyte cell cycle and prevent stress-induced apoptosis or cell death, which

clearly indicates a gastrointestinal trophic effect. In a murine model of sepsis taurine

supplementation conferred immune benefits by down regulating TNF- release and upregulating

anti-bacterial capacity, as assessed by peritoneal macrophage superoxide generation.

The trial was conducted in seventeen elderly elective surgery patients. This trial was a

randomized placebo-controlled study, comparing a standard enteral feed with a taurine

supplemented feed (1 mg/ml) in the peri-operative period. Mortality rates, length of hospital stay



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

acid, and its uptake was proportional to its



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).



• Glutamine supplementation (0.57g/kg bdwt) in severly burned patient has an effect: on

gram – ve bacteria, as it enhance gut barrier function and prevent bacterial translocation

from the gut. Decreased overall inflammation,as decreases in serum concentrations of

soluble tumor necrosis factor receptors. These results suggest that glutamine decreases

the overall systemic inflammatory response. Improve measures of nutritional status→

+ve N balance, proinflammatory cytokines, protein synthesis, reduce catabolic state.

• 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.

• It has been estimated to have as much as 25g (o.35g/kg/day) to 30g (0.42g/kg/day) of

glutamine.

• Dietary sources of L-glutamine include beef, chicken, fish, eggs, milk, dairy products,

wheat, cabbage, beets, beans, spinach, and parsley. Small amounts of free L-glutamineare also found in vegetable juices and foods such as tofu.

Ornithine alpha-ketoglutarate (OKG):

• OKG is a salt formed from one molecule of alpha- ketoglutarate and two of ornithine.

• It is recognized as a nutritional modulator with anticatabolic activity, an

immunomodulator & promoter of wound healing.

• Its mode of action is not fully clear but the secreation of anabolic hormones (insulin &

GH) & synthesis of metabolites such as glutamine, arginine, polyamines and proline may

be involved.

• Supp of TPN with OKG → improve nitrogen balance and preserved intramuscular

glutamine as equally effective as glutamine.

• It is through enternal nutrition studies in septic, trauma and burns patients where 0KG has

shown clinical benefits.

• Burn patient were randomly assigned a single 10g bolus or a continous infusion in three

doses 10,20,30g/d → glutamine, arginine and proline were the main metabolites leading

greater production.

• Prior to tumor-bearing and surgically treated animals, diet containing 50g, 67g and 100g

OKG/kgbdwt during wk 1,2 & 3 wk of tumor growth, respectively.

• Compare with glycine, OKG had no effect on tumor growth in untreated tumor rats but

showed more +ve N balance, higher conc of glutamine and BCAA in muscle in

postoperated tumor rats.

http://en.wikipedia.org/wiki/Parsley






• 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

further input from prospective randomised trials.

http://www.evitamins.com/encyclopedia/assets/nutritional-supplement/amino-acids-overview/~default



http://www.evitamins.com/encyclopedia/assets/toc/meat-and-poultry/~default




http://www.evitamins.com/encyclopedia/assets/toc/fish/~default









ROLE OF IMMUNONUTRIENTS IN COPD

AND HYPERMETABOLIC CONDITION.

- BHAKTI MEHTA



KRUPA PAREKH

NUDRAT KHAN

SAFINA SHARIFF

(Sr. Msc CND)

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