role of glutamine in health and disease

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Vol. 22, No. 12 December 2000

Refereed Peer Review

FOCAL POINT

KEY FACTS

#Glutamine, a conditionally

essential amino acid, can become

depleted during critical illness,

thereby precipitating metabolic

and organ dysfunction.

Role of Glutamine inHealth and DiseaseColorado State University

Elisa Mazzaferro, DVM, MSTimothy Hackett, DVM, MS Wayne Wingfield, DVM, MSGreg Ogilvie, DVMMartin Fettman, DVM, PhD

ABSTRACT: Glutamine maintains tissue function. Intestinal mucosal integrity, immune cell ac-

tivation, renal buffering mechanisms, DNA and protein synthesis, and generation of metabolic

fuels are dependent on body glutamine stores. During states of illness (e.g., sepsis, trauma,

neoplasia), glutamine use can exceed the body’s synthetic capacity, thereby causing its deple-

tion. Glutamine depletion can have negative consequences, including protein catabolism, de-

pressed immune function, intestinal mucosal atrophy, and metabolic acidosis. Dysfunction of

the intestinal tract and immune system can lead to bacteremia, sepsis, and multiorgan failure.

Glutamine supplementation during critical illness may be associated with improved clinical

outcome.

Glutamine, the most abundant amino acid in plasma and the extracellularfluid compartment,1 constitutes the largest labile source of nitrogen inthe body.2 Traditionally classified as a nonessential amino acid, glutamine

serves a variety of functions in healthy individuals, including transporting nitro-gen and carbon between tissue2–4; regulating protein synthesis5,6; generating sub-strates for renal ammoniagenesis7; synthesizing nucleic acid; and providing fuelfor gastrointestinal (GI),8 renal tubular,9 immune,10 and vascular endothelialcells11 (Figure 1). Glutamine also plays a central role in carbohydrate metabolismas a gluconeogenetic precursor.5 Because of its involvement in various metabolicevents, glutamine is essential for optimal cell growth and function.

The classification of glutamine as a nonessential amino acid is misleading be-

cause numerous studies have demonstrated that it is indispensable during criticalillness. In disease states, glutamine becomes a conditionally essential aminoacid.12 In human medicine, there is an intense interest in glutamine metabolism.This paper describes glutamine synthesis and degradation, glutamine flux be-tween tissue, consequences of glutamine depletion during critical illness, and po-tential benefits of glutamine therapy in critically ill animals.

GLUTAMINE SYNTHESIS AND DEGRADATIONIn animals, glutamine is readily synthesized from glutamic acid and ammonia

CE

V

I In disease states, when glutamine

requirements often exceed

synthesis, glutamine becomes a

conditionally essential amino acid

that must be supplemented.

I Glutamine depletion occurs early

during critical illness.

I Glutamine depletion may

contribute to sepsis, multiorgan

failure, and even death in

critically ill humans.

I Feeding glutamine-enriched diets

to human cancer patients and

some animal models has been

shown to have significant positive

effects.



in an ATP-dependent reaction catalyzed by glutaminesynthetase, an enzyme found in most tissue (e.g., mus-cle, liver, lung, brain, adipocytes, lymphocytes, heart,small intestine).13 In humans, skeletal muscle is themain site of glutamine synthesis and storage in thepostabsorptive state.2 Under normal conditions, intra-muscular glutamine synthesis and proteolysis balancethe release of glutamine into the circulation, where it istransported for use by other tissue.13

Glutamine is degraded by the enzyme glutaminase.Most organs have glutamine synthetase and glutami-nase activity and are, therefore, capable of synthesis anddegradation.2 In most cases, the activity of one of theenzymes predominates, thus making the organ a netproducer or net consumer of glutamine. In healthy hu-mans, intracellular glutamine synthesis exceeds glu-tamine use during states of health, resulting in a netproduction of glutamine.13 Organs that consume glu-tamine include the GI tract, pancreas, kidney, and im-mune cells.2 Depending on metabolic conditions, theliver can be a net producer or net consumer of glu-tamine. Under normal physiologic conditions duringstates of health, the balance of glutamine synthesis andbreakdown by the liver is almost equal.7

GLUTAMINE FLUXCirculating glutamine concentration is dependent onrelative rates of glutamine uptake, synthesis, and re-lease.3 During states of health, the plasma glutaminepool is maintained at a fairly constant level. In mam-mals, the plasma glutamine concentration normally ranges from 0.6 to 0.9 mmol/L.1 Intracellular glu-tamine concentration in humans (i.e., 20 mmol/L) isapproximately 30 times its serum concentration.14 Cat-

abolic states (e.g., metabolic acidosis, sepsis, starvation)elicit significant changes in interorgan glutamine flowand can cause the redistribution of glutamine betweentissue.15

NORMAL GLUTAMINE FUNCTIONSNitrogen Transport

Glutamine contains two amine groups that allow thetransportation of carbon and nitrogen through thebody. Glutamine reactions serve to scavenge and trans-port ammonia in a nontoxic form from peripheral tis-sue to the liver and kidneys, where gluconeogenesis andureagenesis occur, respectively.2,3,16,17 Glutamine alsoplays a role in renal acid–base balance by transportingnitrogen and acting as a buffer, thereby facilitating ex-cretion of acid equivalents (e.g., ammonium) in theurine.17

Gastrointestinal FunctionThe importance of glutamine as a competence factor

for enterocytes is unequivocal.18 Glutamine is the mainmetabolic substrate that exerts trophic effects on entero-

cytes, thereby supporting their normal function (Figure2). Enterocytes can extract as much as 25% of glu-tamine from circulation or obtain it via luminal absorp-tion.19 A small amount of glutamine synthesis can alsooccur within enterocytes. The overall synthetic capaci-ty, however, is small and often inadequate to meet themetabolic needs of enterocytes, particularly duringstates of illness or stress. The maintenance of intestinalmucosal integrity, therefore, is dependent primarily on

Compendium December 2000 Small Animal/Exotics

C A T A B O L I C S T A T E I G L U C O N E O G E N E S I S I U R E A G E N E S I S

Figure 1—Functions of glutamine during states of health.

Glutamine

Fuel forendothelial cells

Protein andnucleic acidsynthesis

Cell growthand division

Nitrogentransport

Renal and hepaticgluconeogenesis

Renalammoniagenesis

and buffering

Fuel for renaltubular cells

Fuel forenterocytes

Fuel forimmune cells

Figure 2—Glutamine, which is required for normal entero-cyte health and function, is used as a primary fuel for entero-cyte and immune cells and plays a role in glutathione and

mucin production.

Glutamine

Mucinproduction

Dilation ofsubmucosal

arteries

Enterocytesubstrate

Fuel forimmune cells

Mucus defenseagainstbacterial

translocation

Enhancedgastrointes-tinal blood

flow

Glutathionesynthesis

Free radicalscavenging

Upregulationof cytotoxic

T cells;enhanced

natural killercell activity;

inflammatorycytokine

production



an adequate supply of glutamine fromother sources.20 Glutamine nitrogen isused for hexosamine synthesis, whichserves as a precursor for carbohydratemolecules used to form intracellulartight junctions needed for mucosal

barrier function.21

GI glutamine is alsoused for synthesis of a protective mu-cus gel, which provides the first line of defense against luminal pathogens.22

Immune FunctionGlutamine is an essential nutrient

for proper function of immune cellssuch as macrophages, lymphocytes,and neutrophils.23 It provides precur-sors for purine and pyrimidine synthe-sis during phagocytic cell activation,antigen-presenting cell stimulation and

differentiation, lymphocyte blastogene-sis, expression of cell-surface markers,and antibody production.23 Glutaminealso upregulates activation of cytotoxicT cells, which play a central role in de-fense against bacterial infection.24,25

Furthermore, glutamine is required forsynthesis of the inflammatory cy-tokines interleukin-1β, interleukin-2,interleukin-6, interferon-γ , and tumornecrosis factor-α (TNF-α).14,26

ALTERATIONS IN GLUTAMINEMETABOLISMCritical Illness

In critical illness, glutamine metabolism is altered intissue. Profound changes in amino acid distribution oc-cur as plasma and intracellular glutamine concentra-tions fall.2 The release of glucocorticoids and inflamma-tory cytokines (e.g., interleukin-1β, TNF-α) results in aunidirectional flux of glutamine from muscle and lungin excess of glutamine production.27,28 The release of glucocounterregulatory hormones (e.g., epinephrine,glucagon) during stress and disease stimulates glu-tamine uptake and use by the GI mucosa.29 The accel-

erated export of glutamine in excess of its synthesis de-pletes muscle glutamine concentrations by 30% ormore, causing protein catabolism and muscle wasting.Ultimately, body glutamine stores can become deplet-ed.14,30 This occurrence has been documented in hu-mans with trauma, sepsis, and necrotizing pancreati-tis.31 When glutamine synthesis does not meet diseaserequirements, it becomes a conditionally essential aminoacid that must be supplemented14 (Figure 3).

SepsisGut-specific nutrients (e.g., glutamine) are important

for normal GI homeostasis and immune function. 32

Glutamine depletion, therefore, can lead to dysfunc-tion. Healthy dogs given parenteral glutaminase to de-plete circulating glutamine developed emesis, diarrhea,intestinal villous atrophy, mucosal ulceration, andnecrosis.33 In vitro, glutamine-starved intestinal cellsupregulate protein synthesis, inducing apoptosis or pro-grammed cell death.34

Deterioration of the gut mucosal barrier and in-creased intestinal permeability have been reported in

various critically ill humans with endotoxemia, multi-ple trauma, and major burns.31 In states of health, theintestinal epithelium normally restricts the passage of bacteria and toxic macromolecules.35 Glutamine deple-tion can result in increased intestinal mucosal perme-ability, allowing migration of intestinal bacteria into thebloodstream. The circulating bacteria can then stimu-late mesenteric mononuclear cell activation. Known asthe second hit theory, this event may play a role in the

Small Animal/Exotics Compendium December 2000

C E L L - S U R F A C E M A R K E R S I G L U T A M I N E D E P L E T I O N I S E C O N D H I T T H E O R Y

Figure 3—In states of critical illness and neoplasia, glutamine requirements often ex-ceed synthesis; therefore, glutamine becomes a conditionally essential amino acid.Circulating glutamine pools must be maintained to support normal intestinal andimmune function, renal ammoniagenesis and buffer mechanisms, and whole-body protein synthesis. (Modified from Souba WW: Glutamine: Physiology, Biochemistry and Nutrition in Critical Illness . Georgetown, TX, RG Landes, 1992, p 84; withpermission.)

Sepsis,trauma

Inflammation

Endotoxemia

KidneysCombat acidosisby excretion of

ammonium

LiverGluconeogenesis,

ureagenesis

GutSupports energy

requirements,promotes

mucosal repair

FibroblastsSubstrate for energy

metabolismMononuclear cellsSubstrate for cell

proliferation

Endothelial cells,macrophages,lymphocytes

Tumor necrosis factor, interleukin-1, interleukin-6

Pituitary/adrenalaxis

Cortisol

Skeletalmuscle

Circulatingglutamine pool

Lungs



development of multiorgan dysfunction syndrome(MODS) and systemic inflammatory response syn-drome (SIRS) in response to sepsis24,36 (Figure 4).

CancerIn cases of neoplasia, the cause of glutamine deple-

tion is multifactorial (e.g., increased utilization of glu-tamine, abnormal glutamine metabolism).1 Althoughhost glutamine depletion is normally a characteristic of advanced malignancy, depletion often occurs early inthe disease while the patient still appears healthy andhas a good appetite.1 Fibrosarcoma, mammary carcino-ma, and other tumors can consume glutamine as theirprincipal amino acid source, thus acting as glutaminetraps. Changes in interorgan glutamine metabolism oc-cur because malignant cells import glutamine faster

than do nonmalignant cells.3

In an adaptive response toincreased glutamine uptake and degradation by neo-plastic cells, muscle glutamine synthetase activity in-creases to maintain adequate circulating stores. Early inneoplasia, TNF-α stimulates enhanced glutamine re-lease from hepatocytes, causing the liver to switch froman organ of net glutamine extraction to one of net syn-thesis and release.

Over time, tumors become the primary tissue for glu-

tamine uptake, extracting as much as 50% of glutaminefrom the circulating pool.1 Tumor growth is positively correlated with increased glutaminase activity.37–40 Withprogressive tumor growth and advanced malignancy,muscle glutamine synthetic capacity and hepatic glu-tamine stores become exhausted.1,41 In human cancer

patients, glutamine transport activity into the tumor ismaintained even at the expense of the host when ca-chexia is present. Tumor glutaminase activity increaseseven when intestinal glutamine extraction decreases, de-pleting the supply of glutamine needed for normal entero-cyte function.42,43 The resulting defective GI mucosal in-tegrity can lead to increased bacterial translocation.

POTENTIAL BENEFITS OF GLUTAMINESUPPLEMENTATIONCancer

Feeding glutamine-enriched diets to human cancerpatients and some animal models has been shown to

have some significant positive effects, including replet-ing host glutamine stores, increasing glutamine syn-thetase activity, normalizing host catabolic changes, andimproving clinical outcome.43,44

Glutamine is required for the synthesis of glu-tathione, which in turn is needed for interleukin-2 acti-vation of cytotoxic T cells and natural killer cell activi-ty.25 Oral glutamine supplementation during exposureto radiation or chemotherapy increases glutathione lev-els in the gut, liver, heart, kidney, and muscle.45 In ratfibrosarcoma cells, glutamine supplementation is asso-ciated with increased tumor cell glutathione levels, re-sulting in increased susceptibility to chemotherapy anddecreased tumor expansion.46 Oral glutamine supple-mentation administered to tumor-bearing rats47 upreg-ulated host glutathione synthesis and natural killer cellactivity in a dose-dependent manner. This activity may improve host defense against blood-borne metastasis25

and decrease tumor growth.47

Glutamine supplementation in cancer patients may enhance tumoricidal effectiveness of antitumor drugsand improve patients’ tolerance to the toxic effects of chemotherapy and radiation therapy.48 Numerous studiesin humans undergoing chemotherapy have demonstrat-ed a significantly decreased incidence of mucositis and

stomatitis with glutamine supplementation.44,49

Otherstudies have failed to produce similar results.50–52 Supple-mental glutamine increases tumor glutamine concentra-tions and appears to decrease the efflux of methotrexatefrom tumor cells.43 These supplements, therefore, may help prevent the development of drug resistance. Clinicalstudies53,54 investigating supplemental glutamine in ani-mals with cancer are few in number and have demon-strated equivocal results. Marks and colleagues53 found


M U L T I O R G A N D Y S F U N C T I O N S Y N D R O M E I G L U T A T H I O N E I M E T H O T R E X A T E

Figure 4—Glutamine plays a critical role in various metabolicpathways throughout the body. Glutamine depletion canlead to many negative consequences, including multiorgandysfunction.

Glutamine depletion

Protein catabolism Decreasedgastrointestinalbarrier function

Immune systemdysfunction

Negative nitrogenbalance, proteolysis,

muscle wasting,cachexia

Increased bacterialtranslocation

Hypermetabolism, pyrexia,altered glucose kinetics,

impaired urinary acidexcretion, impaired

nitrogenous waste metabolism

Multiorgan dysfunctionsyndrome

Stimulation ofinflammatory

cytokines



that glutamine supplementation provided no benefit incats with methotrexate-induced enterocolitis. Otherstudies54 have demonstrated that glutamine supplementsgiven to dogs undergoing radiation therapy showed posi-tive effects in reducing mucositis.

Critical IllnessIn critically ill humans and animals, decreased foodintake is deleterious to proper GI function and integri-ty. A growing trend has developed in human medicinetoward the use of supplemental nutrients that can be-come selectively depleted during catabolic states.55

These supplements can improve clinical outcome incritical illness. The dose of supplemental glutaminevaries widely. In human enteral and parenteral formu-las, glutamine supplementation (0.285 to 0.36 g/kg/day) has been shown to increase peripheral leukocytenumbers, increase fractional protein synthesis by theliver, restore muscle glutamine levels, and improve over-

all nitrogen balance.56–58 These supplements have alsobeen shown to reduce the incidence of infection, im-prove recovery from illness, decrease the length of hos-pital stay, and increase 6-month survival rates in criti-cally ill humans after MODS (see Potential Benefits of Glutamine Supplementation).58

In experimental models associated with bacterialtranslocation and sepsis, glutamine supplementationimproved intestinal barrier function by decreasing in-testinal villous atrophy and increasing intestinal IgA levels.12,45,48 Although numerous experimental modelshave demonstrated that glutamine supplementationmay be beneficial, other studies have found little bene-fit.59 Beneficial results have also been demonstrated

when glutamine has been added to total parenteral nu-trition (TPN) formulations for humans with multipletrauma, surgical trauma, neoplasia, and inflammatory bowel disease. The use of TPN in patients with nor-mally functioning GI tracts is controversial becauseTPN may not provide enough trophic stimuli to pre-vent enterocyte atrophy, even with glutamine supple-mentation.60 In patients with normally functioning GItracts, enteral nutrition is preferred.

Oral glutamine exerts trophic effects on the GI tractby increasing DNA content and mucosal protein syn-

thesis, both of which may serve to improve growth andrepair of small bowels and reduce the incidence of bac-terial translocation.43,45,61 The incidence of bacterialpneumonia, bacteremia, and sepsis are subsequently de-creased.62 Oral glutamine supplementation in humancolorectal surgery patients has been shown to preventmononuclear cell activation, which contributes to ex-cessive production of inflammatory cytokines and sub-sequent SIRS.63

RECOMMENDATIONS FORGLUTAMINE THERAPY

Previously, glutamine was not routinely included inmost parenteral and enteral formulations because of itsinstability during storage.20 However, the advent of

heat-stable glutamine dipeptides (e.g., L-alanine-L-glu-tamine, glycyl-L-glutamine), which are stable in solu-tion and readily hydrolyzed following infusion, hasmade it possible for glutamine to be added to humanenteral formulas and veterinary preparations. Gluta-mine powder is available in crystalline form and can beadded to enteral or parenteral formulas, provided thatsterile technique is used during preparation of TPN so-lution.64 Furthermore, recent evidence has demonstrat-


O R A L G L U T A M I N E I T O T A L P A R E N T E R A L N U T R I T I O N I C R Y S T A L L I N E F O R M

Immune system

I Stimulates macrophage and lymphocyte function

I Improves natural killer cell activity

Nitrogen balance

I Increases muscle and liver protein synthesis

Gastrointestinal tract

I Improves intestinal barrier function

I Increases mucosal IgA levels

I Increases mucosal DNA synthesis

I Promotes mucin production

I Decreases bacterial translocation

I

Decreases incidence of bacteremia/sepsis

Cancer in humans

I Increases host glutathione production

I Enhances free radical scavenging

I Decreases chemotherapy-induced cardiotoxicity

I Decreases stomatitis and mucositis

I Enhances tumoricidal effects of chemotherapeutic

agents

Critical illness in humans

IDecreases infections and multiorgan dysfunctionsyndrome

I Decreases morbidity and mortality

I Decreases length of hospital stay

I Improves 6-month survival

Potential Benefits ofGlutamine Supplementation



ed that L-glutamine is stable in TPN solution for atleast 22 days at room temperature.65

Glutamine is an essential nutrient during stress andcritical illness. Studies have validated its use as a nu-traceutical in human critical care and cancer patients as

well as in animal models of critical illness (e.g., sepsis).

Thus the concept that glutamine may be beneficial inanimals is not without reason. Its use in veterinary med-icine has not yet been emphasized.

Recommendations for glutamine therapy in veteri-nary medicine are speculative because only a limitednumber of studies have investigated the use of glu-tamine supplementation in animals with equivocal re-sults.53,54 Dosages of glutamine used in animals havelargely been extrapolated from those recommended inhumans. Cats may require larger doses of glutamine ormay be resistant to the potential benefits of its supple-mentation at a dose of 1.08 g/kg/day. One study 54

showed that L-glutamine (4 g/m2/day) in suspension

was beneficial to dogs undergoing radiation therapy,suggesting that L-glutamine is adequately absorbed inthe GI tract. Further, glutamine infusion in anes-thetized dogs failed to produce any detrimental effects,particularly to the liver or kidneys,66 indicating its safe-ty as a nutraceutical in dogs.

Additional clinical research must be conducted tovalidate the use of glutamine supplements in critically ill animals. Potential benefits are promising and meritfurther investigation. The doses we have used havebeen extrapolated from those recommended for hu-mans; therefore, further study is needed to determineefficacy in small animals. The addition of glutamine toenteral or parenteral formulations at a dose of 0.24 to0.32 g/kg/day may potentially have a positive effect by improving nitrogen balance and immune function, anddecreasing morbidity and mortality in critically ill ani-mals. Its use, therefore, may be beneficial in a variety of illnesses, including acquired or surgical trauma, inflam-matory conditions (e.g., sepsis, pancreatitis, SIRS), dis-ease states that promote ileus and subsequent bacterialtranslocation, and conditions associated with negativenitrogen balance (e.g., cancer).

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mula diet: Impact on bacterial translocation, tissue composi-tion, and response to endotoxin. J Parenter Enteral Nutri 14(4):335–343, 1990.

60. Shou J, Lieberman MD, Hofmann K, et al: Dietary manipu-lation of methotrexate-induced enterocolitis. J Parenter En- teral Nutr 15(3):307–312, 1991.

61. Jacobs DO, Evans A, Mealy K, et al: Combined effects of glutamine and epidermal growth factors (EGF) on the ratintestine. Surgery 104:358–364, 1988.

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About the AuthorDrs. Mazzaferro, Hackett, and Wingfield are affiliated with

the Critical Care Unit, Dr. Ogilvie with Oncology, and Dr.

Fettman with Clinical Pathology/Nutrition, Veterinary

Teaching Hospital, College of Veterinary Medicine, Col-

orado State University, Fort Collins. Drs. Hackett and

Wingfield are Diplomates of the American College of Vet-

erinary Emergency and Critical Care. Dr. Wingfield is also

a Diplomate of the American College of Veterinary Sur-geons. Dr. Ogilvie is a Diplomate of the American College

of Veterinary Internal Medicine (Oncology).


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59. Barber AE, Jones 2d WG, Minei JP, et al: Harry M Vars Award: Glutamine or fiber supplementation of a defined for-

role of glutamine in health and disease

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