Multiple organ dysfunction syndrome is a dominant cause of mortality in the intensive care unit. Experimentally, a condition similar to the multiple organ dysfunction syndrome can be induced by the intraperitoneal injection of sterile zymosan. In the present study we investigate potential alterations in multiple organ functions, endothelial permeability, and antiproteinases after intraperitoneal injection of zymosan at various doses. Zymosan-induced generalized inflammation lead to endothelial barrier injury in multiple organs/tissues, a decrease in systemic arterial pressure, impaired organ function and gut defence function, and consumption of protease inhibitors, particularly the consumption of alpha2 antiplasmin. Endothelial barrier injury appears to present a dose- and organ-dependent pattern in multiple organs/tissues, and the increase in endothelial barrier permeability occurred prior to organ dysfunction. Zymosan induced the development of multiple organ dysfunction syndrome, probably initiating multiple protease-antiprotease systems, particularly the fibrinolytic system, leading to endothelial barrier injury, tissue edema, parenchymal cell damage, and eventual organ dysfunction, potentially augmented by a secondary bacterial infection.

BACKGROUND:Platelet-activating factor (PAF) may play a pivotal role in the pathogenesis of intestinal ischemic injury.METHODS:The potential role of PAF in intestinal ischemia and reperfusion (I/R) and the development of gut endothelial and epithelial barrier dysfunction and distant organ injury were investigated by pretreatment with a PAF antagonist, lexipafant. Bidirectional permeability of the intestinal barrier, enteric bacterial translocation, protease-antiprotease balance and mucosal histology, and also changes in pulmonary and liver endothelial barrier permeability were measured following intestinal ischemia for 40 min with 6 h of reperfusion in rats.RESULTS:Intestinal mucosal endothelial and epithelial permeabilities significantly increased in animals with I/R. Lexipafant prevented the increase in albumin leakage from blood to the mucosal interstitium and the intestinal lumen during reperfusion, and the mucosal albumin leakage from the gut lumen to blood during I/R. Bacterial translocation was frequently noted in animals with I/R, while only a few positive cultures were obtained in animals with I/R administered lexipafant. Less leakage of fluorescein isothiocyanate dextran 70,000 into the interstitial space and gut lumen in I/R animals with lexipafant pretreatment was found under fluorescein microscopy. Lexipafant also partly prevented C1 inhibitor, prekallikrein, and factor X consumption in I/R animals and partly prevented changes in pulmonary and liver albumin leakage.CONCLUSIONS:PAF seems to play an important role in I/R-associated intestinal dysfunction and the development of distant organ dysfunction, probably by triggering endothelial and epithelial barrier dysfunction. Furthermore, PAF seems to be partly involved in activation of the protease-antiprotease system. The use of PAF antagonists may provide a mode of treatment against I/R-associated organ dysfunction.

Platelet-activating factor (PAF) may play a critical and primary role in the pathogenesis of acute pancreatitis and pancreatitis-associated distant organ injury. The present study evaluated the effect of a PAF antagonist, lexipafant (an (S)-4-methyl-2 (methyl-imidazo {4,5-c} pyridin-l-ylmethyl)-benzenesulphonyl]-amino} pentanoic acid ethyl ester, BB-882; British Biotech Ltd.), on the potential prevention of gut barrier dysfunction, by measuring gut origin sepsis, bidirectional permeability of the intestinal barrier, and pancreatic capillary endothelial barrier integrity, in acute pancreatitis induced by intraductal infusion of 5% sodium taurodeoxycholate. Pancreatic endothelial permeability significantly increased in animals with acute pancreatitis, whereas pretreatment with lexipafant had a preventive effect (p <0.05 vs. pancreatitis with saline). Similarly, alterations noted in hematocrit and plasma levels of lipase and calcium were counteracted by the PAF antagonist. It also prevented the increase in albumin leakage from blood to the mucosal interstitium and from blood to the intestinal lumen in acute pancreatitis. Albumin passage from the gut lumen to blood in animals with pancreatitis pretreated with saline increased from 3 h and on, and lexipafant prevented alterations in mucosal epithelial permeability. Bacterial translocation was commonly seen in pancreatitis, whereas only a few positive cultures were observed in pancreatitis animals given lexipafant. Microthrombosis in intestinal villi seemed less frequent after lexipafant pretreatment. We conclude that (a) PAF may play a role in the pathogenesis of pancreatitis-associated intestional dysfunction, (b) PAF may be involved in the development of distant organ dysfunction by triggering endothelial barrier dysfunction, and (c) PAF antagonists may provide potential agents for preventing pancreatitis-associated gut barrier dysfunction.

The aim of this study was to assess the effect of intravenous dextran on bacterial translocation and intestinal vascular endothelial and epithelial barrier function after experimental partial hepatectomy. We determined systemic arterial pressure, enteric bacterial growth (proximal and distal small intestine and colon) and bacterial translocation (BT) to mesenteric lymph nodes (MLN), liver, lungs, spleen, kidneys and blood, as well as intestinal vascular endothelial and epithelial barrier permeability, after sham operation or partial hepatectomy (50% and 90%) with preoperative intravenous administration of saline, albumin or dextran 70. Subtotal hepatectomy induced a significant decrease in arterial pressure and an increase in the number of Escherichia coli in the distal small intestine. BT was not observed in sham-operated animals or in rats with 50% hepatectomy administered dextran. The number of positive cultures of enteric bacteria was significantly increased after hepatectomy, whereas dextran treatment decreased the number of animals with BT. Increased permeability of the intestinal vascular endothelial and epithelial barriers was noted in hepatectomized animals, while dextran prevented hepatectomy-induced vascular endothelial barrier injury. Enteric bacterial translocation occurred following partial hepatectomy in the rat, associated with bacterial overgrowth in the distal small intestine. Intravenous administration of dextran 70 prevented bacterial overgrowth and translocation, at least in part, by maintaining gut vascular endothelial barrier integrity

(1997). The Significance and Potential Molecular Mechanisms of Gastrointestinal Barrier Homeostasis. Scandinavian Journal of Gastroenterology: Vol. 32, No. 11, pp. 1073-1082.

Enteric bacterial overgrowth resulting from compromised gastrointestinal motility has been suggested to be important for the development of enteric bacterial translocation. In the present study, the effect of cisapride, a 5-hydroxytryptamine-4-receptor agonist and stimulant of intestinal motility, was evaluated concerning intestinal motility, as measured by intestinal transit time, enteric bacterial overgrowth, and bacterial translocation from the gut in rats with acute liver failure induced by 90% hepatectomy. The results demonstrated that (1) the incidence of bacterial translocation to the systemic and portal circulation as well as to the liver, spleen, kidneys, and lungs was nil, and 17-33% to MLN in hepatectomized animals treated with cisapride, i.e. significantly lower than in hepatectomized rats administered saline; (2) overgrowth of E. coli in the intestine was noted in hepatectomized animals given saline, but not following cisapride treatment; (3) cisapride improved the otherwise delayed intestinal transit time following hepatectomy as shown by an increase in the leading edge of isotopic propulsion and the linear slope of the cumulative percent of radioactivity through each intestinal segment. Thus, we conclude that intravenous administration of cisapride prevents enteric bacterial overgrowth and bacterial translocation by improving intestinal motility in rats with acute liver failure induced by subtotal hepatectomy.

Enteric bacterial translocation into extraintestinal sites has been proposed as a potential route for bacterial infection in acute liver failure. Bacterial overgrowth in the intestine plays an important role in the etiology of bacterial translocation from the gut. The aim of the present study was to evaluate the influence of exogenous cholecystokinin (CCK) on intestinal transit time, enteric bacterial overgrowth and translocation in experimental acute liver failure induced by 90% hepatectomy. A delayed intestinal transit time was noted in animals subjected by subtotal hepatectomy after 1 h, followed by enteric bacterial overgrowth and translocation into the systemic circulation, mesenteric lymph nodes, and systemic organs at 2 and 4 h. Intravenous infusion of CCK stimulated intestinal transit time in animals with sham operation and subtotal hepatectomy, though a restoration to sham levels could not be obtained in the later. Moreover, enteric bacterial overgrowth and translocation were prevented in hepatectomized animals. The present data imply that impaired intestinal motility, followed by enteric bacterial overgrowth and translocation in experimental acute liver failure, could be prevented by CCK infusion.

Bacterial infections constitute a major cause of morbidity and mortality after major liver resection and mechanisms of this type of complication have been poorly understood. The present study evaluated the translocation of enteric bacteria to mesenteric lymph nodes, viscera, and the systemic circulation and gut capillary permeability of a fine ultrastructural tracer in rats subjected to sham hepatectomy or 70% hepatectomy. Furthermore, the preventive effects of water-soluble ethylhydroxyethyl cellulose (EHEC) were studied. Cultures of all samples from rats subjected to sham hepatectomy or 70% hepatectomy with preoperative intravenous administration of EHEC were bacteriologically negative. The incidence of bacterial translocation from the gut to the systemic circulation and mesenteric lymph nodes was 30 and 80%, respectively (P < 0.01), and to the liver and kidneys 50 and 40%, respectively (P < 0.05), 12 hr after 70% hepatectomy. Intestinal capillary permeability and endothelial cell membrane permeability increased with the development of bacterial translocation. Translocating bacteria appeared within the cytoplasm of capillary endothelial cells. EHEC restored the changes in gut capillary permeability induced by major liver resection. These results indicate that gut capillary permeability may play an important role in maintaining the integrity of the gut barrier function and that increased permeability may be associated with the development of gut barrier failure.

BACKGROUND:Previous experimental studies showed that a disturbed ecology of the enteric bacterial population might contribute to the occurrence of bacterial translocation from the gut in acute liver failure (ALF). METHODS:In the present study the effects of oral administration of exogenous Lactobacillus reuteri R2LC and oat fiber on bacterial overgrowth and translocation and on enterocyte protein contents were investigated in rats with ALF induced by subtotal liver resection. The oatmeal soup base was anaerobically inoculated with L. reuteri R2LC and fermented for 15 h. The animals were then fed with fermented or unfermented oatmeal or saline daily for 6 days before the experimental procedure. RESULTS:The incidence of bacterial translocation to the systemic circulation was nil and 17% in rats subjected to sham operation with saline or 90% hepatectomy with fermented oatmeal, respectively, and 80-90% and 34-50% in rats subjected to hepatectomy with saline or unfermented oatmeal. One rat treated with fermented oatmeal had positive bacterial growth in mesenteric lymph nodes (MLN), which was significantly lower than in hepatectomized rats with saline or unfermented oatmeal (80-100% and 50-67%). No significant differences was demonstrable between hepatectomized animals with oral administration of fermented or unfermented oatmeal as compared with sham-operated rats. The number of anaerobic bacteria, Gram-negative anaerobes, and Lactobacillus decreased significantly, and the number of Escherichia coli increased in the distal small intestine and colon in hepatectomized animals with saline or unfermented oatmeal, as compared with animals subjected to sham operation or hepatectomy with fermented oatmeal. CONCLUSIONS:The occurrence of bacterial translocation from the gut in 90% hepatectomy-induced ALF could be prevented by fermented oatmeal, which implies possibilities for biologically balancing the enteric bacterial ecology.

Bacterial infection and bacteremia are common complications in patients with acute liver failure. Bacterial translocation from the gut has been suggested to be a major cause of bacterial infections in experimental acute liver failure. In the present study, a water-soluble ethylhydroxyethyl cellulose (EHEC) was administered orally 1 and 24 hours prior to 90% hepatectomy in the rat in order to prevent bacterial translocation in experimental acute liver failure induced by subtotal liver resection in the rat. Ninety percent hepatectomy alone resulted in 80 to 100% translocation to mesenteric lymph nodes or blood 2 and 4 hours after operation. There was no translocation in rats undergoing sham operation or 90% hepatectomy with EHEC administration prior to operation (p < .01). Bacterial overgrowth, increased bacterial adherence onto the intestinal surface, and diminished intestinal and mucosal mass were also observed in animals with subtotal liver resection, but not in those administered EHEC. A delayed 2-hour intestinal transit time occurred in both groups receiving subtotal liver resection, with or without oral EHEC. EHEC inhibited bacterial growth and DNA synthesis and altered bacterial surface properties after 1-hour incubation with bacteria in vitro, an interaction that was not further influenced by time. These results imply that EHEC may alter enterobacterial capacities of metabolism, proliferation, and invasion by effects on the bacterial surface. Furthermore, EHEC seems to possess a trophic action on the intestine, though without enhancing the intestinal motility.

Abstract. Biomaterials in the peritoneal cavity disrupt the physiology of the host and may cause bacterial translocation. The current study was performed to determine whether biomaterials exacerbate intraabdominal infections. Adult male rats were divided into four groups: group 1, celiotomy + intraperitoneal (i.p.) saline; group 2, celiotomy + i.p. Escherichia coli (3 times 108 cfu); group 3, i.p. rubber + i.p. saline; and group 4, i.p. rubber + i.p. E. coli(3 times 108 cfu). Twelve h after the challenge, enteric bacterial translocation, bacterial population levels in the cecum and serum levels of IL‐6 and TNF were measured. Bacterial translocation to mesenteric lymph nodes and the liver was observed in animals from groups 2 and 3, but significantly increased in group 4 with a concomitant elevation of serum levels of TNF and IL‐6, as compared with group 1. Histological examination revealed a more pronounced inflammatory reaction in the peritoneum and distal ileum in group 4 than in groups 2 and 3. These results suggest that the presence of rubbers in the peritoneal cavity aggravates intraabdominal sepsis.

Objective: To test the hypothesis that intestinal motility is delayed after hepatectomy, which alters the ecology of the enteric microflora and contributes to the development of bacterial translocation from the gut.Design: Open experimental study.Setting: University department of surgery.Material: Adult male Sprague-Dawley rats (n = 6 in each group at each time point).Interventions: Sham operation, 90% hepatectomy, and portal venous obstruction.Main outcome measures: Intestinal morphology, immunocytochemistry of the enteric nervous system, enteric bacterial growth in the small intestine and colon, and intestinal transit time.Results: Intestinal transit was already delayed one hour after 90% hepatectomy, and histopathological alterations and overgrowth by Escherichia Coli had developed after two hours. There were significant differences in intestinal transit time between sham operated rats and those subjected to portal venous obstruction on the one hand, and those that underwent 90% hepatectomy on the other. There was no difference in intestinal transit time between rats with portal venous obstruction and the sham operated animals.Conclusion: Delayed intestinal transit after 90% hepatectomy may contribute to enteric bacterial overgrowth and thereby contribute to the development of bacterial translocation from the gut.

BACKGROUND:Bacterial translocation from the gut to extraintestinal sites has been demonstrated as a mechanism explaining bacterial infectious complications after various insults.METHODS:To explore the potential therapeutic value of water-soluble ethylhydroxyethyl cellulose (EHEC). Its effects on macrophage phagocytic capacity, bacterial adherence on the intestinal surface, and bacterial growth were evaluated both in vivo and in vitro.RESULTS:Preoperative administration of EHEC reduced the incidence of bacterial translocation from the gut to mesenteric lymph nodes and blood and prevented overgrowth by enteric bacteria after 70% or 90% hepatectomy. Uptake of macrophages harvested from blood decreased after intravenous administration of EHEC. EHEC diminished the otherwise increased bacterial adherence on the intestinal surface induced by major liver resection. EHEC in bacterial cultures for over 1 h was capable of inhibiting bacterial growth and delaying bacterial DNA synthesis in vitro.CONCLUSIONS:The present study indicates that EHEC could be a potential agent for the prevention of gut-origin sepsis.

The process and route of bacterial translocation from the gut after major liver resection remain unclear. In the present study enteric bacterial translocation, enterocyte ultrastructure in the ileum and colon, the process and route of bacterial invasion and the permeability of the cell membrane system and blood-tissue barrier were evaluated in rats receiving sham operation, and 70 or 90 per cent hepatectomy. The incidence of bacterial translocation to mesenteric lymph nodes was 80-100 per cent in rats 6 h after 70 per cent and 2-4 h after 90 per cent hepatectomy, and 80-100 per cent to the systemic circulation 2-4 h after 90 per cent hepatectomy but only 20 per cent to the portal vein. An increase in bacterial adherence to the intestinal surface, damage to the permeability of the cell membrane system and blood-tissue barrier, and pathological alterations in the ileum and colon developed, correlating with the extent of Liver removed and the time that had passed after hepatectomy. Most translocating bacteria appeared in morphologically intact enterocytes with increased membrane permeability, in antigen-presenting cells and in submucosal lymphatics, but some bacteria were also seen within damaged enterocytes 4 h after 90 per cent hepatectomy. These results indicate that altered permeability of the cell membrane system may be one of the earliest characteristics of challenged enterocytes, and that enteric bacteria translocate through both morphologically normal and abnormal enterocytes. Translocation occurred mainly into the lymphatics, bacteria either being 'carried' by antigen-presenting cells or entering by active invasion.

*Departments of Surgery and Clinical Microbiology, Lund University Hospital, S-221 85 Lund, Sweden.

Septic complications and renal insufficiency following biliary tract surgery are frequently seen in patients with obstructive jaundice. The precise mechanisms for understanding the susceptibility of the jaundiced patients to sepsis are, however, not clear. The present study aimed at investigating the influence of biliary obstruction on the reticuloendothelial function and bacterial translocation at various time intervals in the rat. Reticuloendothelial system (RES) function, as evaluated by measuring blood clearance of intravenously injected 125I-labeled Escherichia coli, and bacterial translocation were studied 3 days and 1, 2, and 3 weeks following either sham operation or common bile duct ligation (CBDL) and transection in the rat. RES function was significantly impaired and renal uptake of radiolabeled E. coli was significantly higher in jaundiced animals from Day 3 and on after CBDL (P < 0.01) concomitant with elevation of plasma levels of bilirubin and liver enzymes (P < 0.001) compared with their corresponding controls. The incidence of bacterial translocation 3 days and 1 and 2 weeks after biliary obstruction significantly increased (P < 0.05). We conclude that RES phagocytic function is impaired and the incidence of bacterial translocation is increased in jaundiced rats. These findings might contribute to explain the high susceptibility of postoperative septic complications and renal dysfunction in patients with obstructive jaundice.

Background: Bacterial infections and bacteremia in acute liver failure may at least partly be attributed to translocation of enteric bacteria. Attempts to prevent or treat such infections by the use of antibiotics may instead result in overgrowth of surviving microbes. Methods: In the present study, normal saline (1.5 ml/100 g body weight), phosphatidylcholine (1.5 ml/100 g body weight), and phosphatidylinositol (1.5 ml/100 g body weight) were orally administered by means of a gastric tube both 12, h and 30 min before operation. Effects of enteric administration of phospholipids on the prevention of enteric bacterial translocation, intestinal and mucosal mass, and enterocyte protein contents in acute liver failure induced by subtotal liver resection in the rat were evaluated. Results: The incidence of bacterial translocation increased significantly 2 and 4h after 90% hepatectomy as compared with sham-operated animals. Enteric administration of phospholipids, however, significantly reduced the incidence of bacterial translocation after 90% hepatectomy. Phospholipid treatment prevented the postoperative decrease in intestinal mucosal mass and enterocyte protein content. Conclusions: Enteral administration of phospholipids thus seems to protect against translocation of enteric bacteria and prevent against a decrease in intestinal mucosal mass and enterocyte protein content after subtotal hepatectomy in the rat.

Patients with obstructive jaundice are prone to septic complications after biliary tract operations. Restoring bile flow to the intestine may help to decrease the complication rate. The present study is aimed at evaluating the effect of biliary decompression on bacterial translocation in jaundiced rats. Sixty-six male Sprague-Dawley rats were randomly allocated to six groups subjected to common bile duct ligation (CBDL) and transection (groups 2-6) or sham operation (group 1). In groups 1 and 2 the incidence of enteric bacterial translocation was determined 2 weeks after sham operation or CBDL. In groups 3-6, biliary decompression was achieved by performing a choledochoduodenostomy after 2 weeks of biliary decompression. Bacterial translocation was then studied 1, 2, 3 and 5 weeks following biliary decompression. The rate of bacterial translocation to mesenteric lymph nodes in obstructive jaundice was significantly higher as compared with controls and decreased with time to nil three weeks following biliary decompression. The incidence of bacterial translocation was closely correlated (r = 0.844; p = 0.034) with serum alkaline phosphatase activity and seemed to fit with the morphological changes noted in the small intestine. The decrease in bacterial translocation, however, lags behind the recovery of liver function as measured by routine liver function tests and antipyrine clearance. Obstructive jaundice thus promotes bacterial translocation in the rat. Biliary decompression gradually decreases the rate of bacterial translocation.