Effects of Octreotide on Intestinal Transit and Bacterial Translocation

Effects of Octreotide on Intestinal Transit and Bacterial Translocation in Conscious Rats with Portal Hypertension andLiver FibrosisNARY VEAL,PhD,*HE´LE`NE AUDUBERTEAU,MD,*CAROLE LEMARIE,MD,†FRE´DE´RIC OBERTI,PhD,MD,*and PAUL CALE`S,MD*In cirrhosis,delayed intestinal transit may be responsible for increased endoluminal bacterial overgrowth and increased bacterial translocation.Octreotide has been reported to reduce intestinal transit.Therefore,we evaluated whether octreotide administration influences bacterial translocation in a model of liverfibrosis secondary to dimethylnitrosamine(DMNA) administration.Twenty-nine conscious rats were randomly assigned to three groups(sham ratsϩplacebo as controls,DMNAϩplacebo,DMNAϩoctreotide,1.5␮g/kg thrice daily subcutaneously),and including portal pressure,intestinal transit(radioactive method),and bacterial translocation were measured.Three of four variables measuring intestinal transit suggested a significant delay in intestinal transit in DMNA rats compared to controls(eg, cumulated radioactivity50%:controls:5.3Ϯ1.5,DMNAϩplacebo:3.2Ϯ1.2,DMNAϩoctreotide:2.7Ϯ1.9,PϽ0.01).This delay tended to be enhanced by octreotide but the effect was only significant with one of the intestinal transit variables.Bacterial translocation was significantly increased in DMNA rats compared to controls but octreotide did not increase translocation[eg,germ count(log)in lymph nodes:controls:3.1Ϯ3.6,DMNAϩplacebo:12.3Ϯ4.4,DMNAϩoctreotide:10.6Ϯ6.0,PϽ0.001].There was no significant correlation of portal pressure,intestinal transit,and bacterial translocation in this study.In conclusion,our results show that,although octreotide worsens delayed intestinal transit,it has no influence on the level of bacterial translocation.KEY WORDS:portal hypertension;rats;motility;small intestine;bacterial translocation;portal pressure.Patients with cirrhosis have an increased tendency to develop severe infections(1–3),mainly spontaneous bacterial peritonitis and septicemia,about75%of which are due to aerobic bacteria from the digestive tract.The main mechanism may be bacterial translo-cation,which is defined as the passage of bacteria through the epithelium of the intestinal mucosa to-wards mesenteric lymph nodes(4,5).Moreover,sev-eral studies have shown delayed intestinal transit in cirrhosis or portal hypertension(PHT)(6–10).This dysfunction in motility could be responsible for in-creased endoluminal bacterial overgrowth(11)and, consequently,bacterial translocation.However,the relationship between delayed transit and bacterial translocation has not been demonstrated.In addition, impaired motility of the small intestine,causing bac-terial overgrowth,might play a role in spontaneousManuscript received October10,2000;revised manuscript re-ceived February22,2001;accepted February28,2001.From the*Laboratoire HIFIH,UPRES EA2170,Universite´,and†Laboratoire de Bacte´riologie,CHU,Angers,France.Address for reprint requests:Dr.Paul Cale`s,Service d’He´pato-Gastroente´rologie,CHU,49033Angers Cedex01,France.Digestive Diseases and Sciences,Vol.46,No.11(November2001),pp.2367–2373(©2001)bacterial peritonitis in cirrhotic patients(12)or cir-rhotic rats(13).Octreotide is frequently used to treat ruptured esophageal varices.This drug may alter intestinal motor activity(14–17)and,thus,the level of bacterial translocation.Moreover,infection is an independent predictive factor of early rebleeding(18).Thus,oct-reotide administration may limit its own effects on bleeding in patients with cirrhosis.In addition,soma-tostatin analogs,especially a long-acting compound, could be used in the near future in the prevention of variceal rebleeding when administered over several months(19).Therefore,the hypothetical risk of an increase in bacterial translocation should be studied to evaluate this aspect of the safety profile of soma-tostatin analogs in the treatment of portal hyperten-sion.Thus,the main aim of this study was to assess whether octreotide worsened bacterial translocation in a model of cirrhosis from dimethylnitrosamine (DMNA)administration.MATERIAL AND METHODSStudy Design.Twenty-nine adult Sprague-Dawley rats were randomly assigned to three groups on day1:group A: sham operated rats as controls(Nϭ11),group B:rats with PHT(Nϭ9),group C:rats with PHT treated with octreotide(Nϭ9).PHT was induced by intraperitoneal injection of1%dimethylnitrosamine(DMNA)solution as follows:one daily injection of0.1ml/100g body weight was performed on three consecutive days a week for three weeks(20,21).A similar amount of isotonic saline was injected into group A with the same modalities.In group C, 1.5␮g/kg octreotide was subcutaneously administrered ev-ery8hr from day21to day24.Serum saline was injected in group A and B in the same manner.The dose of octreotide was chosen according to a previous study showing that a single dose of2␮g/kg octreotide administered subcutane-ously produced a significant decrease in portal pressure in the DMNA model(22).All rats had free access to food and water until14–16hr before the surgical procedures on day 21and measurements on day24.Body temperature was maintained at37°C with a homeothermic blanket system (Harvard Apparatus Ltd)for all measurements.Measure-ments were performed blind.Protocols performed in this laboratory were approved by the French Agriculture Office in conformity with European legislation for research involv-ing animals.Surgical Procedures and Hemodynamic Study.Catheters were inserted while rats were under ether anesthesia on day 21.The abdomen was opened and a polyethylene catheter (PE-10,0.28mm ID,0.61mm OD,Clay Adams)was inserted into a small ileal vein and gently advanced to the bifurcation of the superior mesenteric and splenic veins to measure portal vein pressure.Mean arterial pressure and heart rate were measured with a catheter(PE-10,0.28mm ID,0.61mm OD,Clay Adams)inserted in the left femoral artery.Pressures and heart rate were monitored using a multichannel recorder(Nihon Kohden,Tokyo,Japan).All catheters were passed through subcutaneous tunnels at the back of the neck.Surgical procedures were performed under aseptic conditions three days before hemodynamic measurements.All rats could more freely in cages and were fully conscious when measurements were performed.On day24,mean arterial pressure,heart rate,and portal pres-sure were measured in conscious rats.Intestinal Transit.On day21,during laparotomy,a cath-eter(PE-50,0.58mm ID,0.96mm OD,Clay Adams)was inserted1cm into the duodenum through a small longitu-dinal incision and attached to the duodenal wall.The distal portion of the catheter emerged from the abdominal wall and was passed through a subcutaneous tunnel at the back of the neck.Intestinal transit was measured by the radio-active method described by Miller et al(23).On day24,40 min before being killed,1␮Ci of sodium chromate (Na2CrO4)radiolabeled with51Cr(Cr51-S1M039-14,Cis Biointernational,Gyf/Yvette,France)diluted in0.2ml iso-tonic saline was injected into the distal tip of the duodenal catheter.The catheter was rinsed with0.2ml of isotonic saline.Forty minutes later,the animal was killed by cervical section.The small intestines and colon were dissected and ligated at each end.They were then divided into10equal segments(10cm long).Each segment was numbered and placed in a separate tube for counting with a gamma-counter(Minaxi g,Autogamma5000series,Packard). Intestinal transit was evaluated by three variables:(1) cumulated radioactivity(CR),defined as the sum of radio-activity in the intestinal segment studied and previous seg-ments,(2)CR50and CR80segments,defined by the number of thefirst segment when CR wasՆ50%and80%, respectively,of total radioactivity of the intestines,and(3) geometric center,defined by the following formula:͸iϭ1ll.Rlwhere lϭis the number of the segment and Rlϭis the radioactivity of segmentBacteriological Study.Mesenteric lymph nodes were dis-sected and taken up by transillumination.One milliliter of portal vein blood was also aspirated.All lymph nodes were weighed and then manually crushed under aseptic condi-tions.Each specimen was placed in a sterile tube containing sterile water.Six successive1:10dilutions were performed with each specimen(from10Ϫ1to10Ϫ6).Then,0.1ml of each of the diluted solutions was seeded onto two agars: Colombia agar(Oxoid Ltd.Basingtone,Hampshire,En-gland)with5%blood(defibrinated horse blood,Eurobio, Les Ulis,France)and CLED(cystine lactose electrolyte deficients)agar(SanofiPasteur,Paris,France).Agar plates were incubated at37°C for48hr and then bacterial colonies were counted.The identification of bacteria was performed after isolation and using commercial kits(API20E and API NE,Biome´rieux,Marcy l’Etoile,France).These bacterio-logical studies were performed by the same biologist under blind conditions.Bacterial translocation was defined by the presence of enteric bacteria(log germ countϾ5),regard-less of whatever the species.When several species wereVEAL ET ALisolated,only the most numerous enteric species was taken into account.Histological Analysis.After HES staining,liver sections in the three rat groups were used to determine the degree offibrosis as follows:0:nofibrosis,1:discrete centrolobular fibrosis,2:somefibrous septa,3:bridgingfibrosis,4:cirrho-sis.Statistics.Qualitative variables were compared using the ␹2test with Yates’correction or the Fisher test when necessary.Quantitative variables were expressed as meanϮSD.Multiple quantitative variables were compared using analysis of variance with post hoc comparisons or by the Kruskal-Wallis test when the variances were heteroge-neous.The differences between the control and octreotide groups are not shown since they are less relevant.Correla-tions were tested with Pearson’s coefficient.To test the influence of a possible confounding factor(eg,the influence of the rat group),the correlation was calculated after ad-justment for a qualitative variable using Pearson’s coeffi-cient with the Snedecor method,including an interaction test.A significant interaction indicates that the correlation is significantly different in relation to a confounding factor.The independence of multiple correlations was tested by the partial correlation analysis.An␣riskϽ5%for a two-sided test was considered statistically significant.No sample size was calculated because there was no previous study on the effect of octreotide on bacterial translocation.We de-cided that the expected number of available rats with com-plete data would be10in each group and no intermediate analysis was performed.RESULTS Hemodynamics and weights are presented in Table 1.As expected,portal pressure was significantly higher in DMNA rats.The three-day octreotide ad-ministration did not change portal pressure in these rats.Thefibrosis score was significantly higher in the DMNA groups than in the sham group(data not shown),but no cirrhosis and no ascites wereobservedFig1.Cumulated radioactivity as a function of intestinal segment.Analysis of variance:a,PϽ0.05;b,PϽ0.01(C vs B:PϽ0.05);c,PϽ0.05;d,PϽ0.01(A vs C:PϽ0.05).Group A:controls,B:DMNAϩplacebo,C:DMNAϩoctreotide.T ABLE1.H EMODYNAMICS AND W EIGHTControls(A)DMNAPlacebo(B)Octreotide(C)PANOVA A vs B B vs C Body weight(g)350Ϯ72296Ϯ60294Ϯ62NSSpleen weight(g)0.9Ϯ0.2 1.0Ϯ0.3 1.2Ϯ0.3Ͻ0.05*NS NSLymph node weight(g)0.22Ϯ0.090.29Ϯ0.060.22Ϯ0.06NSLiver weight(g)12.8Ϯ1.710.9Ϯ2.511.5Ϯ2.3NSPortal pressure(mm Hg)8.3Ϯ1.212.9Ϯ1.612.9Ϯ1.5Ͻ0.0001Ͻ0.0001NS*Due to the significant difference between A and C.OCTREOTIDE AND BACTERIAL TRANSLOCATIONin the DMNA groups.Extensivefibrosis in the cen-trolobular area was observed in several DMNA rats. Results of intestinal transit are presented in Figure 1and Table2.CR(Figure1),CR50,and CR80,but not the geometric center(Table2),were significantly decreased in DMNA rats compared to controls.CR 50,CR80,and the geometric center were decreased in DMNA rats treated with octreotide compared to untreated DMNA rats but the differences were not significant(Table2).However,Figure1shows that the curve of CR was significantly delayed in DMNA rats treated with octreotide compared to untreated DMNA rats.The level and frequency of bacterial translocation were significantly increased either in the lymph nodes or in the portal vein in DMNA rats compared to control rats(Table3).There was no significant dif-ference between untreated and octreotide-treated DMNA rats.There was no significant correlation between intes-tinal transit time,bacterial translocation,or portal pressure(Pearson’s coefficient in the three rat groups with adjustment for group according to the Snedecor method,interaction test:NS,details not shown).An example of the correlations is given in Figure2.On the other hand,as expected,parameters were well correlated within each technique—germ counts,(ex-pressed in log n)in the portal vein and in lymph nodes (rϭ0.84,PϽ0.0001;r adjustedϭ0.74,PϽ0.01) and CR80and geometric center(r adjustedϭ0.87, PϽ0.0001).DISCUSSIONStudy Protocol.Several models of portal hyperten-sion and cirrhosis have been used to study intestinal transit or bacterial translocation,especialy portal vein ligation.However,Garcia-Tsao et al have shown that bacterial translocation was only increased in thefirst days following portal vein ligation(24).This short duration makes a reliable study of intestinal motility after laparotomy impossible.Although other studies have been based on a model of cirrhosis induced by the intragastric administration of carbon tetrachlo-ride(CCl4),CCl4has not been clearly shown to be harmless to intestinal mucosa(25),thus raising doubts about its possible effects on intestinal motility. On the other hand,DMNA-induced cirrhosis is a quick and easy model that has not been used in intestinal transit or bacterial translocation studies. The radioactive method for measuring intestinal tran-sit is well established(6,23),and duodenal catheter-ization can be used to study intestinal transit alone without gastric motility.Indeed,as in models of portal hypertension(26,27),we have observed accelerated gastric emptying in cirrhosis(28).This,as well as the effect of octreotide on gastric motility(14),could interfere with the interpretation of intestinal transit measurements if intragastric administration was used. Intestinal Transit.As expected and as in other studies(6–10),intestinal transit measured by three variables(CR,CR50,and CR80),was significantly decreased in DMNA rats compared to controls.The fourth variable,the geometric center,reported by Miller et al(23)to be a sensitive and reliable method for quantifying intestinal transit,was not significantly decreased in DMNA rats.This discrepancy may indi-cate that cumulative radioactivity is more sensitive than the geometric center for measuring intestinal transit.None of the variables of intestinal transit time was correlated with the degree of portal pressure in our study.Several mechanisms have been suggested to explain alterations in intestinal motor activity in cirrhosis or portal hypertension:structural alterations of the intestinal mucosa or other layers(5),modifi-cations in the autonomic nervous system(29),and humoral abnormalities such as increased glucagon levels(30).However,Chesta et al did notfind any relationship between serum glucagon levels and in-testinal transit or the migrating motor complex dura-tion(31).The suggested role of nitric oxide(NO)on intestinal motility(32,33)is not known in cirrhosisT ABLE2.R ESULTS OF I NTESTINAL T RANSITControls (A)DMNAPlacebo(B)Octreotide(C)PANOVA A vs B B vs CGeometric center466Ϯ141386Ϯ122305Ϯ78Ͻ0.05*NS NSCR50† 5.3Ϯ1.5 3.2Ϯ1.2 2.7Ϯ1.9Ͻ0.01Ͻ0.01NSCR80 6.1Ϯ0.8 4.9Ϯ1.3 4.4Ϯ1.5Ͻ0.05Ͻ0.05NS*With a significant difference between groups A and C.†CR:cumulated radioactivity.VEAL ET ALbut bacterial translocation increases NO production in cirrhotic rats (34).Bacterial Translocation.As expected,in this study,bacterial translocation was signi ficantly increased in DMNA rats with portal hypertension compared to control rats.However,none of the variables of bac-terial translocation were correlated with the degree of portal pressure in our study.Chiva et al (35)also found no correlation between the severity of portal hypertension and bacterial translocation in the CCl 4-induced model of cirrhosis.Thus,the presence of,but not the degree of,portal hypertension seems to be related to bacterial translocation.Moreover,none of the variables of bacterial trans-location were correlated with those of intestinal tran-sit.This could suggest that delayed intestinal transit is not directly responsible for increased bacterial trans-location.On the other hand,a close relationship between transit alterations and the endoluminal bac-teriological system has been suggested by others.Thus,Scott and Cahall have shown that the injection of morphine or phenylephrine in normal rats induced myoelectric intestinal alterations with a signi ficant increase in transit time and jejunal bacterial count (36).The same alterations have been observed in a model of subtotal hepatectomy in rats (37).Wang et al have recently shown that prokinetic substances,such as cholecystokinine (38)or cisapride (39),de-creased intestinal transit time,bacterial overgrowth,and bacterial translocation in this same model in rats.The lack of in fluence of delayed intestinal transit on bacterial translocation observed in our study suggests that nonmotor factors,such as functional or morpho-logical intestinal modi fications,might explain the in-crease in bacterial translocation in cirrhosis.These factors may be pathological (40,41),hemodynamic (42),or immunological (43,44)modi fications.More-over,intestinal mucosal permeability has recently been reported to be increased in cirrhotic patients (45),and a defective mesenteric in flammatory re-sponse was observed in portal hypertensive rats (46).These alterations in mucosal barrier defenses might favor bacterial translocation.Finally,a loop could worsen these dysfunctions since:(1)endolumi-nal bacteria (47)or bacterial translocation (34)may increase NO synthase activity,and (2)overproduction of NO may contribute to intestinal barrier dysfunc-tion (48).Octreotide.In this study,octreotide signi ficantly delayed the CR curve (Figure 1)in DMNA rats compared to untreated DMNA rats,suggesting de-layed intestinal transit.However,octreotide did not signi ficantly decrease the three other variables mea-sures intestinal transit (ie.,CR 50,CR 80,and geo-metric center).Delayed intestinal transit with oct-reotide has been clearly demonstrated in healthy volunteers (14–17).We can not clearly explain the absence of a signi ficant effect of octreotide ontheseFig 2.Correlation between CR 80(motor index)and bacterial translocation.The term r was adjusted by rat group (there was no signi ficant correlation in any group).CR:cumulated radioactivity.T ABLE 3.B ACTERIAL C OUNTANDT RANSLOCATION F REQUENCY Controls (A)DMNAPlacebo (B)Octreotide (C)PANOVA A vs B B vs C Lymph nodeBacterial count (log) 3.1Ϯ3.612.3Ϯ4.410.6Ϯ6.0Ͻ0.001Ͻ0.001NS Translocation (%)05644*Ͻ0.01NS Portal veinBacterial count (log) 1.0Ϯ2.78.5Ϯ8.111.7Ϯ3.6Ͻ0.05Ͻ0.05NS Translocation (%)5667*Ͻ0.01NS*Calculation impossible due to small theoretical numbers.OCTREOTIDE AND BACTERIAL TRANSLOCATIONthree variables.The effect of octreotide on motility might depend on the dose used(49).Although oct-reotide prolongs transit time at moderate to high doses(17),we cannot exclude a significant effect at higher doses of octreotide,especially since the dose used in the present study was rather low compared to that used in other models of liverfibrosis(50).On the other hand,the power of the test was2%for the observed difference in bacterial translocation of lymph nodes.Whatever the precise nature of this effect,in this study octreotide did not increase bacte-rial translocation in DMNA rats.This result needs to be confirmed during gastrointestinal bleeding since it has been suggested that hemorrhagic shock increases bacterial translocation in portal hypertension(51). However,we did not observe an increase in infectious complications in cirrhotic patients with variceal bleeding treated with somatostatin analoges(52,53). Moreover,Khan et al found that octreotide does not increase the degree of hepatic encephalopathy in patients with liver diseases(54).Octreotide has several other effects on the splanch-nic territory—reduced gastrointestinal secretions and splanchnic bloodflows,and induction of phase III of the migrating motor complex(15).Moreover,Helton and Garcia have observed that octreotide decreased bacterial translocation in a model of trinitrobenzene-sulfonic acid-induced colitis in rats(55).These au-thors suggested that octreotide could act locally on intestinal mucosal defenses.In addition,octreotide might improve intestinal pathological alterations in cirrhotic rats(56).On the other hand,it has been shown that propranolol accelerates intestinal transit, decreasing the rates of bacterial translocation and overgrowth in cirrhotic rats(13).Taken together, these results suggest that the interrelationship be-tween motor activity,bacterial translocation,and oc-treotide may be more complex than a 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