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Glycyl-Glutamine-Enriched Long-Term Total Parenteral NutritionAttenuates Bacterial Translocation Following Small Bowel

Transplantation in the Pig

You-Sheng Li, M.D.,*,1 Jie-Shou Li, M.D.,* Jian-Wen Jiang, M.D.,* Fang-Nan Liu, M.D.,*Nin Li, M.D.,* Wei-Song Qin, M.D.,† and Hong Zhu, M.D.‡

*Department of Surgery, †Department of Microbiology, and ‡Department of Radioimmunology,

ournal of Surgical Research 82, 106–111 (1999)rticle ID jsre.1998.5525, available online at http://www.idealibrary.com on

Jinling Hospital, Nanjing University Medical School, Nanjing, 210002, China

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Background. Improvements in immunosuppression,perative procedure, and posttransplant managementave made clinical small bowel transplantation (SBT)

easible. Ischemia and reperfusion injury, total paren-eral nutrition (TPN), and devoidment of enteral feed-ng lead to graft atrophy, gut barrier dysfunction, andacterial translocation. Glutamine (Gln) is the princi-al fuel for the enterocyte. The influence of Glnipeptide-supplemented TPN, especially long-termPN, on intestinal graft permeability and bacterial

ranslocation is not clear following SBT in the largenimal model. Therefore, we studied the effect of glu-amine dipeptide, glycyl-glutamine (Gly-Gln), on bac-erial translocation following SBT in the pig, whichas a physiology similar to humans.Materials and methods. The outbred pigs underwent

egmental small bowel autotransplantation and wereivided into two groups. In the STPN group (n 5 5), thenimal received standard TPN devoid of Gly-Gln for 28ays. In the GTPN group (n 5 5), the animal received

sonitrogenous (0.3 g/kg.day) and isocaloric (33 kcal/g.day) TPN solution with 2% Gly-Gln for 28 days.Results. At the end of the experiment, Gly-Gln-

nriched TPN could maintain the plasma Gln level,raft mucosal Gln and protein concentrations, andkeletal muscle Gln and protein concentrations. Gly-ln-enriched TPN significantly decreased the bacte-

ial number of mesenteric lymph nodes in the livernd spleen and intestinal permeability to 99mTc-DTPA.here were no significant differences in body weightain.Conclusions. The Gly-Gln–enriched long-term TPN

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1 To whom correspondence should be addressed at Department ofurgery, Nanjing University, School of Medicine, 305 East Zhong-han Road, Nanjing 210002, China.

106022-4804/99 $30.00opyright © 1999 by Academic Pressll rights of reproduction in any form reserved.

tion July 16, 1998

ay maintain the plasma Gln level, mucosal and mus-le Gln, and protein concentrations and attenuate thentestinal permeability to 99mTc-DTPA and bacterialranslocation following small bowel transplantationn the pig. © 1999 Academic Press

Key Words: glutamine; glycyl-glutamine; small bowelransplantation; bacterial translocation; transplan-ation/immunology.

INTRODUCTION

Improvements in immunosuppression, operativerocedure, and posttransplant management haveade clinical small bowel transplantation (SBT) feasi-

le [1–3]. All patients receiving SBT requiring totalarenteral nutrition (TPN) are at increased risk fortrophy and hypofunction of the transplanted smallntestine; these risks may be further increased becausehe graft is commonly transplanted into a heterotopicocation (Thiry-Vella loop) out of intestinal continuitynd devoid of enteral feeding, which leads to grafttrophy, gut barrier dysfunction, and bacterial trans-ocation. Donors usually undergo hemodynamic unsta-le situations that affect the correct perfusion of thosergans to be transplanted. Local and systemic reperfu-ion phenomena occur after intensive resuscitationaneuvers. Inadequate nutrition and hypercatabolic

tates cause additional injury to the mucosa. Ischemiauring organ retrieval and preservation and posterioreperfusion after the graft was transplanted cause se-ere damage to the mucosa, and multiple factors alter

ut permeability and barrier function, favoring theassage of germs and toxin through the gut barrier [4].acterial translocation probably relates to septic epi-odes in SBT patients [2].

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Glutamine (Gln), a nonessential amino acid, is theost aboundant free amino acid in whole blood and in

he intracellular amino acid pool [5]. Gln is an impor-ant respiratory fuel and nucleotide precursor for theastrointestinal tract. In stressed states, e.g., traumand sepsis, the intestinal uptake of Gln from the bloods significantly increased [6–8]. Gln supplementationf either TPN or enterial diet prevents bacterial trans-ocation from the gut to the mesenteric lymph nodes [9,0] and Gln may be an important gut immune modu-ator [9]. Recently, Frankel and associates [11, 12] haveeported that Gln-enriched TPN significantly reduceducosal atrophy and improved glucose absorption ineterotopic and orthotopic transplanted small bowel

sografts in the rat. Schroeder et al. [13] have reportedhat Gln prevented mucosal injury after SBT. In theirtudy, rats received TPN with 2% Gln for only 10 days;he effect of Gln, especially Gln dipeptide, on bacterialranslocation was not investigated in these studies [11,2]. Lymph node regeneration needs 4 weeks or moreollowing SBT [14]; therefore, the patients receivingBT should be given parenteral nutrition for 4 weeksr more. As we know, there are species differences inPN-induced intestinal atrophy and increased muco-al permeability, both phenomena being much moreignificant in rats than in humans or other animals. Inumans, only prolonged starvation is associated witharked change in intestinal mucosa. The present

tudy examines the effect of long-term (28 days) glycyl-lutamine-enriched TPN on bacterial translocation ofutotransplanted small intestine in the pig, which issed as an animal model similar to humans whentudying problems dealing with the alimentary tract.

MATERIALS AND METHODS

Animals. Outbred white pigs of both sexes, weighing 18.5–27.0g, were used. Animals were housed in individual cages and pro-ided pig chow and water ad libitum for at least 5 days prior to thetudy. The cages were maintained in a light- and temperature-ontrolled environment. Operative techniques were performed fol-owing an overnight fast, and anesthesia was induced using ket-mine (20 mg/kg) and atropine (0.05 mg/kg) intramuscularly andas maintained using sodium pentobarbital (2%) intravenously.entral venous catheterization was performed on all animals by theercutaneous external jugular vein catheterization technique prioro small bowel transplantation.

Small bowel transplantation. Small bowel autotransplantationas performed with a technique modified from Kimura et al. [14, 15].600-cm jejunal segment was isolated on a vascular pedicel that

ncluded the jejunal artery and vein. After harvesting the segmentnd clamping the proximal vessels for reanastomosis, the remainingmall intestine continuity was restored by end-to-end anastomosis.he isolated jejunal graft was kept in a Ringer’s lactated bath andach vascular bed was perfused by gravity flow via the artery with00 ml Ringer’s lactated solution at 4°C until the venous effluent was

LI ET AL.: Gly-Gln-ENRICHED LON

leared. The graft lumen was perfused with 100 ml of cold (4°C) 5%etronidazole solution. Both ends to which perfusion had not been

deal were removed. A 450-cm jejunal graft (approximately 30% ofhe total small bowel) was placed heterotopically. Revascularizationas performed between the donor jejunal artery and vein and a

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ranch of the recipient superior mesenteric artery and vein. This wasccomplished in an end-to-end fashion with 6-O monofilament nylonuture. Both ends of the graft were brought out as stomas (Thiry–ella loop). Two groups of postoperative animals were placed in

ndividual cages and given TPN for 28 days.

TPN and experimental groups. Ten animals were randomized toeceive standard TPN devoid of Gly-Gln (STPN group, n 5 5) or 2%ly-Gln-enriched TPN (GTPN group, n 5 5).In the GTPN group, animals received isonitrogenous and isocaloric

PN solution with 2% Gly-Gln (GLAMIN Pharmacia Inc.). TPNrovided 0.3 g of nitrogen and 33 kcal of nonprotein calorie/kg bodyt per day. The composition of TPN solution is shown in Table 1.PN was delivered from the first day to the 28th day after operation.ody weight was measured daily. On postoperative day (POD) 29,PN infusion was stopped, and the animal was reanesthetized andelaparotomied. Blood was drawn from the superior vena cava into aeparinized syringe for measurement of Gln, and plasma Gln waseasured according to high-performance liquid chromatography

HPLC) as previously described [16]. Gln and protein concentrationsf graft and skeletal muscle were studied prior to transplantationnd on POD 28, a 1-cm length of intestine (1 cm from the proximatetoma) and a 1-g weight of muscle were taken from the right mus-ulus quadriceps femoris, and the mucosa was scraped. The mucosand muscle were homogenized and stored in liquid nitrogen. Gln ofucosa and muscle was measured using the HPLC method [16], and

rotein of mucosa and muscle was measured by the method of Lowry17].

Intestinal permeability. Intestinal permeability was estimatedsing the 99mTc-DTPA (diethylentriaminepentaacetic acid) method.ntestinal permeability to 99mTc-DTPA was measured on POD 1 andOD 28. One and one-half milliliters of water containing 1.5 mCi of

9mTc-DTPA was given by gavage through the proximal stoma. The

TABLE 1

Composition of TPN Solution

STPN GTPN

otal amino acid (g/liter) 17.3 17.3ly-Gln (g/liter)a — 3.90% intralipid (ml/liter)b 75 750% dextrose (ml/liter) 75 75aCl (mEq/liter) 100 100Cl (mEq/liter) 20 20PO4

2 (mEq/liter) 5 5aCl2 (mEq/liter) 1.1 1.1ddamel (ml/liter)b 2.5 2.5oluvit (ml/liter)c 5 5italipid (ml/liter)d 5 5alories (kcal/liter) 300 300

a Gly–Gln (Pharmacia Inc.), 20% Intralipid (Pharmacia Inc.).b In 10 ml: 5 mmol Ca21, 20 mmol Zn21, 50 mmol F2, 1.5 mmol Mg21,

0 mmol Mn21, 1 mmol I23, 50 mmol Fe31, and 5 mmol Cu21.c In 10 ml: 3.0 mg thiamin hydrochloride, 3.6 mg Na–riboflavin–

–phosphate, 40 mg nicotic acid amide, 4.0 mg pyridoxin hydrochlo-ide, 0.4 mg folic acid, 60 mg biotin, 100 mg Na-ascorbate, 15 mga-pantothenate, and 5.0 mg cyanocobalamine.

d In 10 ml: 330 IU vitamin A, 200 IU vitamin D2, 10 IU vitamin E,nd 150 mg vitamin K.

107TERM PARENTERAL NUTRITION

tomas were closed with Foley’s catheters for 24 h. Twenty-four-hourrine collections were obtained, and paired 1-ml urine samples werenalyzed with 100-ml samples of the administered 99mTc-DTPA solu-ion in a gamma counter (Beckman). The percentage uptake of thedministered dose was calculated as

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Bacterial translocation. Quantitative bacterial studies of tissueomogenates of the graft’s mesenteric lymph nodes (MLN) and theost’s liver and spleen were assessed on the operative day and onOD 28. The MLN, pieces of liver, and piece of spleen were sequen-ially harvested prior to transplantation on operative day and onOD 28 prior to taking a mucosa sample. The samples were weighed

ndividually and thoroughly homogenized and then plated on bloodgar following incubation for 48 h at 37°C. The number of viableolonies on each plate was counted. Bacteria were identified usingtandard microbiological procedures. The number of aerobiocally andacultative anaerobes was shown as log10Cfu (colony forming units)/gissue wt.

Statistical analysis. Data are expressed as means 6 SD. Dataere analyzed by analysis of variance. Differences with a P value

ess than 0.05 were considered to be statistically significant.

RESULTS

Body weight. Body weight values lossed in the pigseceiving Gly-Gln–enriched TPN or Gly-Gln-depletedPN were 7.7 and 5.9%, respectively (Fig. 1).Plasma Gln level. A significant increase in plasmaln level was detected in the GTPN group on POD 28

ompared with the STPN group (P , 0.05). Plasma Glnevel was significantly different between POD 0 andOD 28 in the GTPN group (Fig. 2).Mucosal Gln and protein concentrations. Mucosalln concentration significantly decreased in the STPN

TAB

Mucosal Gln and Pr

Gln (mmol/g wet wt)

POD 0 POD 28

STPN 1.17 6 0.20 0.40 6 0.18*,1

FIG. 1. Changes of body weight in two groups: STPN group (solidine, F) and GTPN group (broken line, Œ). All values expressed as

eans 6 SD. At the end of study, body weight loss was 5.9% (GTPNroup) and 7.7% (GTPN group), respectively.

08 JOURNAL OF SURGICAL RESEA

GTPN 1.03 6 0.22 1.14 6 0.20*

Note. Wet wt, wet weight* P , 0.05 relative to POD 0.1 P , 0.05 relative to STPN group.

roup on POD 28 compared with POD 0. In the GTPNroup, mucosal Gln concentration was maintained (Ta-le 2). Mucosal protein concentration significantly de-reased on POD 28 compared with POD 0 in the STPNroup and in the GTPN group.Skeletal muscle Gln and protein concentrations.uscle Gln concentration was significantly higher (P ,

.05) in the GTPN group compared with the STPNroup on POD 28. Muscle protein was lost in bothroups on POD 28 compared with POD 0. However, itas significantly higher (P , 0.05) in the GTPN group

ompared with the STPN group (Table 3).Intestinal permeability. The graft of pig receivingly-Gln–enriched TPN or Gly-Gln-depleted TPN had

ignificantly increased (P , 0.01) intestinal permeabil-ty to 99mTc-DTPA on POD 1 compared with the normalntestinal loop (2.74 6 1.20%, data not shown). OnOD 28, intestinal permeability significantly de-reased (P , 0.01); however, it was significantly higherP , 0.05) in the STPN group compared with the GTPNroup (Table 4).Bacterial translocation. The number of bacteria in

he tissue homogenates of MLN and host liver andpleen is shown in Table 5. Bacterial number wasinimally elevated (P , 0.05) in the MLN, liver, and

pleen on POD 28 compared with POD 0. On POD 28,

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Protein (mg/g wet wt)

POD 0 POD 28

127.84 6 27.14 72.40 6 48.41*,1

FIG. 2. Plasma Gln level on POD 0 and POD 28. All valuesxpressed as means 6 SD. P , 0.05 considered significant, avs PODnd bvs STPN group. On POD 28 plasma Gln concentration in theTPN group was significantly increased and was significantly highompared with the STPN group.

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DISCUSSION

In the present study, we compared the effects ofly-Gln–enriched TPN with Gly-Gln-depleted TPN onacterial translocation in a small bowel autotransplan-ation model in the pig receiving long-term TPN sup-ort. Gly-Gln-supplemented TPN maintained plasmaln level, increased mucosal Gln and protein concen-

rations and skeletal muscle Gln and protein concen-rations, and ameliorated intestinal permeability andacterial translocation.Ischemia/reperfusion injury is an immediate event

ollowing cold preservation and transplantation ofmall intestinal grafts. Ischemia/reperfusion injuryauses damage to the mucosa and alters gut perme-bility, favoring the passage of germs and toxinhrough the gut barrier. SBT necessitates extrinsicenervation, disruption of intrinsic (enteric) neuralontinuity, and lymphatic drainage, which impact en-eric function. Sarr et al. [18] have reported that netbsorption of the graft was decreased within 2 weeksnd returned to normal by 8 weeks. Therefore, in pa-ients receiving long-term TPN, which causes graftucosal atrophy and hypofunction, especially witheterotopic small bowel graft, the graft lacks not onlynteral nutrients but also biliary and pancreatic secre-ion, which are enterotrophic in the small intestine.

TABLE 4

Percentage of Urinary Excretion of 99mTc-DTPA

POD 1 POD 28

STPN 42.58 6 8.23 24.01 6 7.44*GTPN 38.84 6 6.74 7.77 6 3.04**,1

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TAB

Skeletal Muscle Gln and

Gln (mmol/g wet wt)

POD 0 POD 28

STPN 0.52 6 0.23 0.20 6 0.11*GTPN 0.52 6 0.19 1.17 6 0.38*,1

Note: Wet wt, wet weight.* P , 0.05 relative to POD 0.1 P , 0.05 relative to STPN group.

LI ET AL.: Gly-Gln-ENRICHED LON

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Note. Percentage of urinary excretion of Tc-DTPA in the normalntestinal Thiry–Vella loop (n 5 4) is 2.74 6 1.20%.

* P , 0.05 relative to POD 1.** P , 0.01 relative to POD 1.1 P , 0.05 relative to the STPN group.

inally, immunologic reaction specific and nonspecificlso alters gut permeability and causes bacterial trans-ocation [19]. Bacterial translocation was one of themportant reasons which caused infection in the SBTatient. Sepsis caused the failure of SBT [20].Intestinal permeability can be assessed by a variety

f techniques, and it was evaluated herein by measur-ng intestinal permeability to 99mTc-DTPA. This is aonvenient, sensitive, and simple method [19]. Ourtudy demonstrated that breakdown of the gut barriers associated with ischemia/reperfusion injury. OnOD 1, intestinal permeability to 99mTc-DTPA was in-reased 15-fold. Ischemia/reperfusion injury was short-ived with architectured changes being repaired rap-dly. At the end of the experiment, intestinalermeability of the graft was still significantly highompared with that of normal intestinal permeability.PN devoid of luminal substances induced mucosaltrophy and increased intestinal permeability to 99mTc-TPA.Gln is the principle fuel of enterocytes. It provides

recursor nitrogen for the synthesis of purines andyrimidines, which are essential to cell mitosis. Glnonsumption by the intestine is significantly increasedn various stress situations, such as prolonged fasting,rauma, and sepsis stress. The demand for Gln wasarkedly enhanced when the intestinal mucosa was

ctively regenerating 3 days after transplantation [8].uring the postoperative period the small intestinextracts large amounts (20 to 30%) of Gln, far in excessf other amino acids [7]. Supplementation of TPN withln diminished gut atrophy and hepatic steatosis [9,1], stimulated small bowel disaccharidase activity22], enhanced immune function [1, 9], and preventedschemia/reperfusion injury of the small intestinalraft [13]. Recent reports [11, 12] demonstrated thatln supplementation with TPN enhanced the mucosal

tructures and graft absorption to glucose after intes-inal transplantation in a rat model. The correlation

3

rotein Concentrations

Protein (mg/g wet wt)

POD 0 POD 28

79.62 6 21.94 93.39 6 21.93*170.24 6 24.34 132.45 6 15.14*,1

109TERM PARENTERAL NUTRITION

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ble amino acid solutions because of sterilization, anduring storage Gln is unstable in solution and tends toorm a cyclic compound (pyroglutamic acid) or breaknto glutamate and ammonia. The pharmacologic effectf stable dipeptides provides a sufficient source of Glnn TPN solution because they remain stable after heatterilization. Our results demonstrated that Gly-Glnas rapidly hydrolyzed and provided a sufficient

ource of Gln. Mucosa Gln concentration was high inhe GTPN group compared with the STPN group. As aesult, the graft mucosa concentrations of Gln androtein were high and intestinal permeability to 99mTc-TPA decreased. In the present study, the number ofacteria in graft MLN and host liver and spleen wasignificantly increased; although the pigs receivedong-term Gly-Gln-enriched TPN, the number of bac-eria in the MLN, liver, and spleen was still high com-ared with that prior to transplantation. Our resultsndicate that Gly-Gln-enriched TPN ameriorated thentestinal permeability to 99mTc-DTPA and bacterialranslocation and could not prevent bacterial translo-ation completely.

The mechanisms by which Gly-Gln (or Gm) reducesacterial translocation following SBT are not entirelylear, but there are several possible explanations.irst, Gln has a direct trophic effect on intestinal mu-osa [11]. Second, Gln increases the level of secretoryIgA, which subsequently decreases adherence of lu-en bacteria to the mucosa and enhances gut-

ssociated lymphoid tissue and systemic immune func-ion [23]. Third, Gln may influence the composition ofhe intestinal flora, favoring bacterial species that lackhe characteristics necessary for translocation [24].ourth, as precursor for the synthesis of purine andyrimidines, Gln prevents hepatic glutathione and in-estinal mucosal glutathione store depletion; it haseen assumed that Gln could contribute to replenish-ent of the depleted glutathione store during stress

nd thereby counteract free-radical-induced cellularnjury [25]. Finally, the uptake of Gln into muscle andiver cells would be expected to increase cellular hydra-

TAB

The Number of Bacteria in ML

MLN

POD 0 POD 28 POD 0

TPN 1.43 6 1.12 5.52 6 1.04* 1.05 6 1TPN 1.34 6 1.04 3.01 6 1.281 1.42 6 1

* P , 0.05 relative to POD 0.1 P , 0.05 relative to STPN.

10 JOURNAL OF SURGICAL RESEA

ion, thereby triggering a protein anabolic signal [26].In summary, in the swine small bowel autotrans-

lantation model, Gly-Gln-enriched long-term TPNignificantly reduced intestinal permeability and bac- 1

erial translocation and increased plasma Gln levelnd intestinal and skeletal muscle Gln and proteinoncentrations when compared with TPN-depletedly-Gln. It is proposed that Gly-Gln-enriched long-

erm TPN could assist in maintaining the integrity ofhe intestinal barrier to the luminal bacteria and re-ucing the infection complications following smallowel transplantation.

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111TERM PARENTERAL NUTRITION

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