Gut 1994; supplement 1: S23-S27

Bacterial translocation: the influence of dietaryvariables

E A Deitch

AbstractTransmucosal passage of bacteria incritically ill patients may lead to asignificant incidence of systemic sepsis.This has attracted much clinical interest,as it has been shown that malnutrition initself, impairs various aspects of barrierfunction. Bacterial translocation is in-creased in animal models where nutrientsare given by the parenteral route, whileenteral feeding reverses this. Trans-location is also considerably increased inresponse to a non-lethal endotoxinchallenge, if there is pre-existing proteinenergy malnutrition. Similar results havebeen obtained where the insult is causedby the inflammatory agent, zymosan.Dietary fibre reduces the deleteriouseffects of either agent on translocation,although the type of fibre is important.Bulk forming but non-fermentable fibresare more effective than easily fermentabletypes (for example, pectin). Glutaminewas not effective in preventing elementaldiet induced bacterial translocation.Thus, although fermentable fibre andglutamine have positive effects onmucosal mass, they do not affect trans-location. Enteral nutrition thus seems tobe superior to parenteral nutrition inmaintaining the functional barrier of thegut. A clearer understanding of thephysiology of these effects may lead to useofspecifically modified enteral diets in thecritically ill patient.(Gut 1994; supplement 1: S23-S27)

LSU Medical Center,Shreveport, LA, USAE A Deitch

Correspondence to:Professor E A Deitch,Department of Surgery, POBox 33932, LSU MedicalCenter, Shreveport, LA71130, USA.

One of the key functions of the intestine is toprevent luminal bacteria and endotoxins fromreaching systemic organs and tissues. Failureof intestinal barrier function resulting in thesystemic spread of bacteria from the gut tosystemic organs has been termed bacterialtranslocation. The phenomenon of bacterialtranslocation has assumed increasing clinicalimportance, as loss of intestinal barrierfunction and the subsequent translocation ofbacteria or endotoxin, or both have beenimplicated in the development of systemicinfection or multiple organ failure in selectedpatients.1 2 Our initial interest in investigatingthe role of intestinal barrier failure as a cause ofsystemic infection was based on the findingthat life threatening infections with gutassociated bacteria in which no infectiousfocus could be found commonly occurred intrauma victims, burn and intensive care unitpatients, and patients developing multipleorgan failure. Therefore, the goals of our

experimental studies have been theinvestigation of the basic mechanisms by whichbacteria contained within the gastrointestinaltract can translocate to cause systemicinfections.Our earlier studies show that although

bacterial translocation can be induced in avariety of animal models, one or more of threebasic pathophysiological conditions are neces-sary for bacterial translocation to occur.1 2These are: (1) disruption of the ecologicalbalance of the normal indigenous microflora,resulting in bacterial overgrowth with Grampositive enteric bacilli; (2) impaired hostimmune defences; and (3) physical loss of themucosal barrier. These same conditions arecommonly seen in the critically ill or injuredpatient at risk of developing entericbacteraemia or multiple organ failure. Forexample, these patients have often experiencedconsiderable blood loss or a hypotensiveepisode leading to mucosal injury; they areusually immunocompromised and the drug,treatment, or dietary regimens they receivemay disrupt the normal ecology of the gutflora, resulting in subsequent overgrowthby certain members of the indigenousmicroflora or colonisation with exogenouspathogens.As starvation and protein malnutrition have

been reported to impair host immune andantibacterial defences,3 disrupt the normalecology of the gut microflora4 and lead tomucosal atrophy,5 there are many reasons tobelieve that nutritional variables are importantmodulators of gut barrier function andbacterial translocation. For example, Lowry6showed that human volunteers given a totalparenteral nutrition diet have a greatersplanchnic and systemic cytokine and meta-bolic response to parenteral endotoxin thanenterally fed volunteers. This study and theresults of other human and animal studies7-11show that the route by which patients arefed may influence the immunoinflammatoryand metabolic response to injury,6-8 affectthe incidence of infectious complications,9 andmodulate clinical outcome.1012 One hypo-thesis to explain the finding that enteral feed-ing seems clinically superior to parenteralfeeding is that parenteral feeding predisposesto an exaggerated cytokine response as a resultof the loss of intestinal barrier function.6 13 14As will be discussed, the composition of thediet as well as the route by which it is givenhave profound effects on intestinal morphol-ogy and function as well as on the incidenceand susceptibility to systemic infection and thedevelopment of hypermetabolism.1-2 Thus,because nutritional deficiencies are common in

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Figure 1: (A) Distal ileum from control mouse and (B) mice maintained on a proteindeficient dietfor seven days, (C) 14 days, or (D) 21 days. Progressive atrophy of villousheight and crypt depth is seen although no gaps in the epithelium are seen (originalmagnification X 190).

severely traumatised or critically ill surgicalpatients, nutritionally induced changes inintestinal barrier function seem to be of clinicalimportance.

Experimental resultsMost of our work investigating potentialrelations between nutrition and bacterialtranslocation has focused on whether thecomposition or route of administration ofspecific diets promotes bacterial translocationand, if so, if diet induced bacterial trans-location is associated with changes in hostimmune defences, intestinal morphology, ordisruption of the normal intestinal micro-ecology, or all three.

Effect ofprotein malnutrition onbacterial translocation, intestinalmorphology, and host immune defencesBecause nutritional deficiencies are com-paratively common in patients in hospital andmay impair anti-bacterial host defences anddisrupt the normal ecological balance of theintestinal microflora, experiments wereperformed to determine the influence ofprolonged protein malnutrition in promotingbacterial translocation.'5 In this study, micereceived either normal chow or a solid,specially formulated protein deficient diet fromTeklad Laboratories (Madison, Wisconsin).The two diets had an equal energy value with

the Teklad diet containing 20% fat, 67%carbohydrate, and 0-03% protein by weight.They also contained fibre, trace elements,minerals, and vitamins. The animals werekilled and their organs cultured fortranslocated bacteria after 7, 14, or 21 days.Animals fed the Teklad diet for 21 days hadlost about 30% of their original body weight.Although the Teklad fed mice had lost weight,had their intestinal mucosal height reduced bygreater than 75%, and had the normal ecologyof their gut microflora mildly disrupted,bacterial translocation did not occur (Fig 1).

In the second half of the study, mice werechallenged with a non-lethal dose of endotoxin(intraperitoneal) after receiving 0, 7, 14, or 21days of the Teklad diet to discover if endotoxinwould act synergistically with protein mal-nutrition to promote bacterial translocation.The combination of protein malnutrition plusendotoxaemia was associated with a higherincidence of bacterial translocation to thesystemic organs than was seen in the normallynourished mice (p>0-01). Additionally, themice fed the Teklad diet were more susceptibleto the lethal effects of endotoxin. Theendotoxin induced death rates were directlyrelated to the length of time the mice were fedthe Teklad diet and ranged from 7% on day 0to 66% on day 21 of the Teklad diet (r2=0-89;p<0 05).

In a subsequent study,'6 we sought todiscover if there was a correlation between theextent of histological damage and the magni-tude of bacterial translocation in Teklad dietfed mice challenged with endotoxin inducedmucosal injury. We compared the resultsof normally nourished mice with those ofmice fed the Teklad diet for 14 or 21 days.There was no correlation between the grossappearance of the epithelial mucosal barrierand the extent of endotoxin induced bacterialtranslocation. This finding suggests that thesynergistic effects of endotoxin with proteinmalnutrition on bacterial translocation do notcorrelate with the histological appearance ofthe gut mucosal barrier.To see if our findings were unique to

endotoxin, we repeated the series of experi-ments described above with the inflammatoryagent, zymosan. 17 Zymosan was chosen forstudy because it induces a systemic inflam-matory state, which had been implicated inthe pathogenesis of adult respiratory distresssyndrome and multiple organ failure. Theresults of this study, in so far as bacterialtranslocation and death were concerned, werealmost identical to that found after endotoxinchallenge. That is, the protein malnourishedmice were more susceptible to zymosaninduced bacterial translocation than thenormally nourished mice, and the extent ofbacterial translocation and death correlatedwith the length of time the mice were fed theTeklad diet (Table I). One importantdifference between the response of the proteinmalnourished mice to zymosan in contrast withendotoxin was that the intestinal mucosa didnot become 'resistant' to zymosan inducedmucosal injury after 14 or 21 days ofthe Taklad

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Bacterial translocation

TABLE I P-rotein malnutriticzymosan

Group

Normally nourishedPM (7 days)PM (14 days)PM (21 days)

PM=protein malnourished.

TABLE II Oral and intrave,is reversed with dietary fibre

IIb'0?Group

ChowIV-TPNIV-TPN+fibreOral TPNOral TPN+fibre

*p<O Ol v all other groups anatotal parental nutrition.

00-

c

C.

0

Ca)

C

0

a)

c

C.,

.

C

C.)

~0

C

100-

80-

60-

40-

20-

on tncreases susceptibility to lethal effects of endotoxin or the enteral or parenteral administration of a

total parenteral nutrition solution (28%Death (%) % Weight loss (mean) glucose, 4-25% amino acids, and 0°/O fat) to rats

- . was associated with bacterial translocation.Endotoxin Zymosan Endotoxin Zymosan The results of this study were somewhat7 0 0 0 surprising as our previous work had shown that

34 20 23 24 protein malnutrition did not induce bacterial66 80 31 36 translocation despite weight loss.'5 Yet, in the

Alverdy study, bacterial translocation occurredeven though the diet contained adequateamounts of protein and the animals gained

zous total parenteral nutrition induced bacterial translocation weight. One important difference between(cellulose) these two studies was that in our previous

Incidence of Ileal Caecal log10 work on protein malnutrition, the micewacterial mucosal protein Gram negative received a pelleted diet containing fibre. Inranslocation (%) mg/cm (x 10)2 enterics (CFU/g) the Alverdy study, however, the rats were

0 88 (18)* 6-3 (0-4)* fed exclusively through the intravenous route0 43 (71) 741 (10) or received a fully absorbable liquid diet.0* 50 (16) 7-7 (0-6) Because dietary fibre is important in main-8 47 (6) 8 1 (0 5) taining the normal ecological balance of the gut

alysis of variance. Data are mean (SEM). IV-TPN= intravenous microflora'8 and because the bacterial fermen-tation end products of fibre are trophic forintestinal epithelial cells,'9 the presence or

diet, as was seen after endotoxin challenge. In absence of dietary fibre may have been anfact, the extent of mucosal injury became important variable in determining the presenceslightly greater the longer the mice were protein or absence of bacterial translocation. There-malnourished before zymosan challenge. The fore, we tested the hypothesis that elementalreason for this differential effect of endotoxin v intravenous total parenteral nutrition or oralzymosan on the intestinal mucosa is unknown. total parenteral nutrition diet induced bacterialThe two important conclusions of these translocation could be reduced by dietary

studies were that Teklad diet induced protein fibre. 14malnutrition did not promote bacterial trans- The results of our study, based on Alverdy'slocation (though it led to profound mucosal model verified that both an intravenous and anatrophy), but that protein malnourished orally given total parenteral nutrition solutionanimals had a higher incidence of systemic will induce bacterial translocation in rats andspread of translocating bacteria and were more that both intravenous and oral total parenteralsusceptible to the lethal effects of endotoxin or nutrition induced bacterial translocationzymosan. can be prevented by the oral ingestion of a

dietary fibre (cellulose) (Table II). Interest-ingly, although dietary fibre prevented

Effect of intravenous or oral total bacterial translocation, it did not reverse theparenteral nutrition on bacterial total parenteral nutrition induced decreasetranslocation (p<0-01 v chow fed controls) in jejunal or ilealThe initial study evaluating the route of mucosal protein content (Table II).nutrient administration on bacterial trans- Our next study was carried out to answerlocation was by Alverdy et al,'3 who found that two questions20: whether oral total parenteral

nutrition solution (28% glucose, 4-25% aminoacids, 0% fat) will cause bacterial translocationin mice as well as rats, and, if so, whichproperties (fermentability, bulk, or both) ofdietary fibre are important in preventing oraltotal parenteral nutrition induced bacterialtranslocation. The results of this studyreported that oral total parenteral nutrition willinduce bacterial translocation in rats and thatthe bulk forming properties of dietary fibre aremore important than fermentability inpreventing bacterial translocation. This secondconclusion is based on the fact that cellulose orkaolin (bulk forming agents) but not citruspectin (a fully fermentable, non-residue fibre)reduced the incidence of bacterial trans-location (Fig 2). Similar results have sub-

'I 'l l __sequently been seen in rats, where theincidence of oral total parenteral nutrition

_____________________ _ ___________________________ induced bacterial translocation was reduced inmental ED+ ED+ ED+ ED+ the kaolin fed but not in the citrus pectin feddiet cellulose kaolin pectin glutamine animals (unpublished data).)) induced bacterial translocation is reversed by cellulose and Because none of the diets containedpectin or glutamine. glutamine and because glutamine is one of the

Chow Eler

Figure 2: Elemental diet (ELkaolin (p. 0 05) but not citru.

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Deitch

important fuels of enterocytes,21 the lack ofdietary glutamine may have contributed toimpaired intestinal barrier function. Thispossibility is strengthened by experimentalstudies showing that glutamine protects theintestinal mucosa from a variety of injuriousagents.8 The argument is also strengthened bya recent study showing that total parenteralnutrition induced bacterial translocation canbe prevented by supplementing the totalparenteral nutrition solution with glutamine.22Thus, we tested whether glutamine (as 30%of amino acids) would prevent oral totalparenteral nutrition induced bacterial trans-location.23 As the incidence of bacterialtranslocation was not different between theglutamine supplemented (88%) and non-supplemented (75%) oral total parenteralnutrition diets, it seems that glutamine doesnot prevent elemental diet induced bacterialtranslocation (Fig 2).The mechanism by which dietary fibre

protects against total parenteral nutritioninduced bacterial translocation could not bedetermined from the results of our studies,although the intestinal mucosa of the fibrefed animals looked more normal.14 Fibreexerts a trophic effect, however, on theintestinal mucosaI9 24 and is necessary for themaintenance of normal mucosal turnover andintestinal cytokinetics.25 The fact that dietslacking fibre may lead to loss of functionalintegrity of the epithelium is not completelysurprising because the addition of dietary fibreto a low residue oral diet exerts a favourableeffect on the preservation of intestinal structureand function.26 Whether fibre exerts thisprotective effect by directly stimulating theintestinal mucosa or by inducing the release oftrophic gut hormones or other factors is notclear. If fibre protected against parenteral ororal elemental diet induced bacterial trans-location by stimulating trophic hormones, thaninhibition of hormone secretion should negateits protective effects. Conversely, stimulationof the appropriate intestinal hormones, inthe absence of fibre, should protect againstdiet induced bacterial translocation. Wetested this hypothesis using sandostatin toinhibit and bombesin to stimulate intestinalhormone secretion.27 28 The results of thisstudy reported that bombesin reduced dietinduced bacterial translocation from 75 to20% (p<0 05), while sandostatin abrogatedthe protective effects of fibre in oral totalparenteral nutrition fed rats (unpublisheddata).The results of these studies can be

summarised as follows: (1) dietary fibre butnot glutamine protects against total parenteralnutrition induced mucosal changes andbacterial translocation; (2) cellulose is effectivein preventing intravenous or oral totalparenteral nutrition induced bacterial trans-location, even though it does not prevent totalparenteral nutrition induced loss of mucosalmass; (3) the bulk forming properties of fibreare more important than fermentability inpreventing bacterial translocation; (4) theprotective effects of cellulose fibre seem to be

related to its ability to stimulate trophic guthormones.

DiscussionOne important problem with many of thepublished studies examining the intestinalmucosal arm of the relation betweennutritional modulation and intestinal barrierfunction is that these studies have notmeasured barrier function in itself.8 22 29-31Instead, they have measured nutritionallyinduced changes in selected morphological orbiochemical parameters (such as intestinalprotein content, villus height or intestinalweight), assuming that a decrease in one ormore of these parameters of mucosal atrophywould correlate with impaired intestinal barrierfunction. This assumption equating mucosalatrophy with impaired barrier function is toosimplistic, because our studies clearly showthat there is no direct correlation between thedevelopment of intestinal atrophy and bacterialtranslocation. 15-17 Furthermore, although fibrereversed total parenteral nutrition inducedbacterial translocation, fibre given orally wasnot associated with the reversal of total paren-teral nutrition induced changes in intestinalmorphology, weight, or protein content. 14Thus, the presence of mucosal atrophy doesnot mean that intestinal permeability tobacteria or endotoxin, or both will be increasedand, conversely, the prevention of mucosalatrophy is not synonymous with the preventionof bacterial translocation.As presented in the results section, we have

reported that bacterial translocation occurs inrats or mice fed a total parenteral nutritionsolution containing 4.5% amino acids, 28%glucose, electrolytes, and trace elements (300kcal/kg/day) intravenously or enterally and thatbulk forming fibres but not glutamine preventthis diet induced loss of intestinal barrierfailure.'4 20 Although there seems to be littledoubt that glutamine promotes small intestinalgrowth and limits intestinal atrophy,glutamine's ability to prevent diet inducedbacterial translocation is less clear. WhileBurke, in Alverdy's laboratory, reported thatintravenous total parenteral nutrition inducedbacterial translocation can be prevented bysupplementing the total parenteral nutritionsolution with glutamine (2% wt/vol),22 Barberet al could not reverse bacterial translocationpromoted by an oral defined diet (CriticareHN) merely by glutamine supplementation(2% wt/vol). The glutamine supplemented dietgiven by Barber et al largely prevented loss ofintestinal mass32 but did not preventtranslocation. The ability of glutamine supple-mentation to prevent translocation in othermodels is also variable. Souba et al reportedthat oral glutamine (3% wt/vol) preventedradiation induced bacterial translocation,33while Wells et al found that glutaminesupplementation (40/o wt/vol) of an oral dietdid not prevent endotoxin induced orantibiotic induced bacterial translocation.34Thus, although glutamine supports mucosalgrowth, there is disagreement on whether

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Bacterial translocation S27

glutamine will bolster intestinal barrierfunction.

In summary, enteral nutrition seems to besuperior to parenteral nutrition. This con-clusion is based on clinical studies showing thathigh protein enteral diets improve systemicimmunity, reduce the incidence of importantinfections, and improve survival.9 10 12 Further,enteral nutrition bolsters anti-bacterial hostdefences," blunts the hypermetabolic responseto injury,7 maintains mucosal mass andintestinal barrier function, and limits or pre-vents disruption of the normal gut microflora.2 814As more information on the physiology of theintestinal barrier is generated, it is probable thatour therapeutic regimens will include the use ofspecific agents to maintain or bolster intestinalmucosal structure and function. Undoubtedlythis therapeutic regimen will include immediateenteral feeding,35 specific nutrients, andmucosal trophic factors, such as fibres, trophicgut hormones,36 and growth factors.37

1 Deitch EA. Does the gut protect or injure patients in theICU. Prospectives in critical care. St Louis, Mo: QualityMedical Publishing, 1988; 1: 15-32.

2 Deitch EA. Gut failure: its role in the multiple organ failuresyndrome. In: Deitch EA, ed. Multiple organ failure. NewYork, NY: Thieme, 1990: 40-59.

3 Chandra RK. Nutrition infection and immunity: presentknowledge and future directions. Lancet 1983; i: 688-91.

4 Tannock GW, Savage DC. Influences of dietary andenvironmental stress on microbiological populations inthe murine gastrointestinal tract. Infect Immun 1974; 9:591-8.

5 Johnson LR, Copeland EM, Dudrick SJ, et al. Structuraland hormonal alterations in the gastrointestinal tract ofparenterally fed rats. Gastroenterology 1975; 68: 1177-83.

6 Fong Y, Marano MA, Moldawer LL, et al. The acutesplanchnic and peripheral tissue metabolic response toendotoxin in man. Jf Clin Invest 1990; 85: 1896-904.

7 Mochiuzuki H, Trocki 0, Dominioni L, et al. Mechanismsof prevention of postburn hypermetabolism andcatabolism by early enteral feeding. Ann Surg 1984; 200:297-310.

8 Wilmore DW, Smith RJ, O'Dwyer ST, et al. The gut: acentral organ after surgical stress. Surgery 1988; 104:917-24.

9 Moore FA, Moore EE, Jones TN, McCroskey BL, PetersonVM. TEN versus TPN following major torso trauma:reduced septic morbidity. Jf Trauma 1989; 29: 916-23.

10 Alexander JW, MacMillan JC, Stinnet JD, et al. Beneficialeffects of aggressive protein feeding in severely burnedchildren. Ann Surg 1980; 192: 505-17.

11 Kudsk KA, Stone JM, Carpenter G, Sheldon GF. Enteraland parenteral feeding influences mortality afterhemoglobin E coli peritonitis in normal rats. J7 Traumna1983; 23: 605-9.

12 Border JR, Hasset JM, LaDuca J, et al. Gut origin septicstates in blunt multiple trauma (ISS=40) in the ICU. AnnSurg 1987; 206: 427-48.

13 Alverdy JC, Aoys E, Moss GS. Total parenteral nutritionalsupport promotes bacterial translocation from the gut.Surgery 1990; 108: 240-7.

14 Spaeth G, Berg RD, Specian RD, Deitch EA. Food withoutfiber promotes bacterial translocation from the gut.Surgery 1988; 104: 185-90.

15 Deitch EA, Winterton J, Ma L, Berg RD. Gut as a portal ofentry for bacteremia; role of protein malnutrition. AnnSurg 1987; 205: 681-92.

16 Ma L, Specian RD, Betg RD, Deitch EA. Effects of proteinmalnutrition and endotoxin on the intestinal mucosalbarrier to the translocation of indigenous flora in mice.JPEN 1989; 13: 572-8.

17 Deitch EA, Ma WJ, Ma L, Berg RD, Specian RD. Proteinmalnutrition predisposes to inflammatory-induced gut-origin septic states. Ann Surg 1990; 211: 560-8.

18 Savage DC. Factors involved in colonizion of the gutepithelial surface. AmJClin Nutr 1978; 31: S131-5.

19 Topping DL, Illman RJ. Bacterial fermentation in thehuman large bowel. Time to change from the roughagemodel of dietary fibre? Med JAust 1986; 144: 307-9.

20 Spaeth G, Specian RD, Berg RD, Deitch EA. Bulk preventsbacterial translocation induced by the oral administrationof total parenteral nutrition solution. JPEN 1990; 14:442-7.

21 Souba WW, Smith RJ, Wilmore DW. Glutaminemetabolism by the intestinal tract. JPEN 1985; 9: 608-17.

22 Burke D, Alverdy JC, Aoys E, Moss GS. Glutamine-supplemented total parenteral nutrition improves gutimmune function. Arch Surg 1989; 124: 1300-96.

23 Xu D, Lu Q, Thirstrup C, Berg R, Deitch EA. Elementaldiet-induced bacterial translocation and immunosuppres-sion is not reversed by glutamine. Jf Trauma (in press).

24 Goodlad RA, Wright NA. Effects of addition of kaolin orcellulose to an elemental diet on intestinal cell prolifera-tion in the mouse. Br7Nutr 1983; 50: 91-8.

25 Vohouny GV, Le T, Ifrim I, et al. Stimulation of intestinalcytokinetics and mucin turnover in rats fed wheat bran orcellulose. AmJf Clin Nutr 1985; 41: 895-900.

26 Hosoda N, Nishi M, Nakagawa M, et al. Structural andfunctional alterations in the gut of parenterally or enterallyfed rats. _JSurg Res 1989; 47: 129-33.

27 Thompson JC. Humoral control of gut function. Am J Surg1991; 161: 6-18.

28 Debas HT, Mulvihill SJ. Neuroendocrine design of the gut.AmJSurg 1991; 161: 243-9.

29 Jones WG, Minei JP, Barber AE, et al. Bacterial trans-location and intestinal atrophy following thermal injuryand burn wound sepsis. Ann Surg 1990; 211: 399-405.

30 Barber AE, Jones WG, Minei JP, et al. Bacterial overgrowthand intestinal atrophy in the etiology of gut barrier failurein the rat.Am7Surg 1991; 161: 300-4.

31 Saito HS, Trocki 0, Alexander JW, et al. The effect of routeof nutrient administration on the nutritional state,catabolic hormone secretion and gut mucosal integrityafter burn injury. JPEN 1987; 11: 1-7.

32 Barber AE, Jones WG, Minei JP, et al. Glutamine or fibresupplementation of a defined formula diet: impact onbacterial translocation, tissue composition, and responseto endotoxin.J7PEN 1990; 14: 335-43.

33 Souba WW, Klimberg VS, Hautamaki RD, et al. Oralglutamine reduces bacterial translocation followingabdominal radiation. J7 Surg Res 1990; 48: 1-5.

34 Wells CL, Jechorek RP, Erlandsen SL, et al. The effect ofdietary glutamine and dietary RNA on ileal flora, ilealhistology, and bacterial translocation in mice. Nutrition1990; 6: 70-5.

35 McDonald WS, Sharp CV, Deitch EA. Immediate enteralfeeding in burn patients is safe and effective. Ann Surg1991; 213: 177-83.

36 Jacobs DO, Evans DA, Mealy K, et al. Combined effects ofglutamine and epidermal growth factor on the ratintestine. Surgery 1988; 104: 358-64.

37 Evers BM, Townsend CM, et al. Differential effects of guthormones on pancreatic and intestinal growth duringadministration of an elemental diet. Ann Surg 1990; 211:630-8.

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