Effect of cisapride on intestinal bacterial and endotoxin translocation in cirrhosis

AIM: To investigate the effects of cisapride on intestinal bacterial overgrowth (IBO), bacterial and endotoxin translocation, intestinal transit and permeability in cirrhotic rats. METHODS: All animals were assessed with variables including bacterial and endotoxin translocation, intestinal bacterial overgrowth, intestinal transit and permeability. Bacterial translocation (BT) was assessed by bacterial culture of MLN, liver and spleen, IBO by a jejunal bacterial count of the specific organism, intestinal permeability by determination of the 24-hour urinary (99m)Tc-DTPA excretion and intestinal transit by measurement of the distribution of (51)Cr in the intestine. RESULTS: Bacterial translocation (BT) and IBO was found in 48 % and 80 % cirrhotic rats respectively and none in control rats. Urinary excretion of (99m)Tc-DTPA in cirrhotic rats with BT (22.2+/-7.8) was greater than these without BT (10.5+/-2.9). Intestinal transit (geometric center ratio) was significantly delayed in cirrhotic rats (0.31+/-0.06) and further more delayed in cirrhotic rats with BT (0.24+/-0.06) than these without BT (0.38+/-0.11). Cirrhotic rats with IBO had significantly higher rates of intestinal bacterial and endotoxin translocation, slower intestinal transit time and higher intestinal permeability than those without IBO. It was also found that BT was closely associated with IBO and the injury of intestinal barrier. Compared with the placebo group, cisapride-treated rats had lower rates of bacterial/endotoxin translocation and IBO, which was closely associated with increased intestinal transit and improved intestinal permeability by cisapride. CONCLUSION: These results indicate that endotoxin and bacterial translocation in cirrhotic rats may be attributed to IBO and increased intestinal permeability. Cisapride that accelerates intestinal transit and improve intestinal permeability might be helpful in preventing intestinal bacterial and endotoxin translocation.     

西沙比利对肝硬化大鼠小肠细菌及内毒素转位的影响

目的：研究西沙比利对肝硬化大鼠小肠细菌过度生长(IBO)，细菌及内毒素转位，小肠转运时间及小肠通透性的作用。方法：正常对照组大鼠25只，肝硬化对照组大鼠25只，肝硬化治疗组20只(用等渗盐水)，另20只肝硬化大鼠用西沙比利治疗，动物均测定各种参数如细菌和内毒素转位，小肠细菌过度生长，小肠转运时间及通透性。结果：48％肝硬化大鼠发生细菌转位，与无IBO肝硬化大鼠比较，IBO肝硬化大鼠的内毒素和细菌转位发生率高，肠转远时间延长，小肠通透性增高。BT的细菌与IBO主菌群一致。与对照组比较，西沙比利处理的肝硬化大鼠肠细菌和内毒素转位及IBO发生率降低，这与肠转运时间增快及通透性降低密切相关。结论：肝硬化大鼠内毒素和细菌转位可能是由于IBO和肠通透性增加的结果，而IBO的发生可能是由于肠转运时间延长所致。西沙比利可加速小肠转运时间，改善小肠通透性，这有助于防治小肠细菌和内毒素转位。     

Intestinal mucosal oxidative damage and bacterial translocation in cirrhotic rats

BACKGROUND: Bacterial translocation plays an important role in the pathogenesis of spontaneous bacterial peritonitis mainly due to intestinal bacterial overgrowth. Alterations in the functional integrity of the intestinal barrier caused by an increased production of free radical metabolites as a consequence of portal hypertension could also facilitate bacterial translocation in cirrhotic rats. OBJECTIVE: The aim of the study was to determine intestinal mucosal lipid peroxidation and neutrophil infiltration and their relationship with portal hypertension and bacterial translocation in cirrhotic rats. DESIGN: Eighteen male Sprague-Dawley rats with cirrhosis induced by carbon tetrachloride, administered by gavage, and eight control rats were included in the study. METHODS: Samples of jejunum, ileum and caecum were obtained by laparotomy for the determination of malondialdehyde and myeloperoxidase as indexes of lipid peroxidation and neutrophil infiltration, respectively. Samples of ascitic and pleural fluids, mesenteric lymph nodes and ileal stools were obtained for the culture of microoganisms. RESULTS: The concentration of malondialdehyde was significantly higher in ileal and caecal, but not in jejunal mucosa, in cirrhotic rats, mainly in those with ascites (P< 0.01), as compared to control rats (P< 0.01), and in cirrhotic rats with bacterial translocation compared to those without bacterial translocation (P< 0.01). No differences between groups were observed in the concentrations of myeloperoxidase in jejunum, ileum or caecum. A direct correlation between ileal malondialdehyde and portal pressure was observed (P< 0.01). CONCLUSIONS: Cirrhotic rats, particularly those with ascites and bacterial translocation, show increased malondialdehyde levels in ileal and caecal mucosa. These results suggest that mucosal oxidative damage in ileum and caecum could favour bacterial translocation in cirrhotic rats.     

Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites

Background/Aims: Translocation of indigenous bacterial from the gut lumen of cirrhotic animals to mesenteric lymph nodes appears to be an important step in the pathogenesis of spontaneous bacterial peritonitis. However, the sequence of events leading to translocation remains unclear. One of the most predictable risk factors for translocation is overgrowth of gut bacterial flora. The present study was designed to compare the intestinal aerobic bacterial flora of cecal stools at the time of sacrifice between cirrhotic and normal rats and to evaluate the role of intestinal aerobic bacterial overgrowth in bacterial translocation in cirrhotic rats.Methods: Thirty-five male Sprague-Dawley rats with carbon tetrachloride-induced cirrhosis and ascites and 10 normal rats were included in this study. Cirrhotic rats were sacrificed when ill and samples of ascitic fluid, mesenteric lymph nodes and cecal stool were taken for detecting quantitatively aerobic bacteria.Results: Total intestinal aerobic bacterial count in cecal stool at the time of sacrifice was significantly increased in cirrhotic rats with bacterial translocation with or without spontaneous bacterial peritonitis compared to cirrhotic rats without bacterial translocation (p<0.001 and p<0.001, respectively) and to normal rats (p<0.001 and p<0.001, respectively). Of the 42 species of bacteria translocating to the mesenteric lymph nodes, 41 (97.6%) were found in supranormal numbers in the stool at the time of sacrifice.Conclusions: Carbon tetrachloride-induced cirrhotic rats with bacterial translocation have increased total intestinal aerobic bacteria count, and intestinal bacterial overgrowth appears to play an important role in bacterial translocation in this experimental model of cirrhosis in rats.     

Role of intestinal bacterial overgrowth and intestinal motility in bacterial translocation in experimental cirrhosis.

BACKGROUND: Intestinal bacterial overgrowth (IBO) is related to small bowel motility and has been involved in the pathogenesis of bacterial translocation (BT) in experimental models, and both overgrowing gut flora and translocating bacteria to mesenteric lymph nodes are common features in cirrhosis. OBJECTIVES: The aims of this study were to analyze cecal aerobic bacteria and intestinal transit in cirrhotic rats, and their relationship with BT, evaluating the role of intestinal bacterial overgrowth and small bowel dismotility in the development of BT in experimental cirrhosis. MATERIAL AND METHODS: We included twenty-seven male Sprague-Dawley rats with carbon tetrachloride-induced cirrhosis without ascites and ten controls. Cultures of mesenteric lymph nodes (MLN), peripheral and portal blood, liver, spleen and cecal samples were carried out. Small intestinal transit was determined in ten cirrhotic rats and in ten control rats. RESULTS: The prevalence of bacterial translocation was 56%. Total cecal aerobic bacteria count was significantly higher in cirrhotic rats than in control rats (p < 0.001). Cirrhotic rats with translocated bacteria had higher total aerobic intestinal counts than culture-negative MLN bacteria (p < 0.05). The prevalence of total intestinal bacterial overgrowth in cirrhotic animals was 67%, and 0% in control animals (p < 0.001). According to BT, total IBO was more frequent in cirrhotic rats with BT versus those without BT (93 vs. 33%) (p < 0.001). Of the translocating bacteria, 95.6% were found to be overgrown in the cecum. The small-intestinal transit was slower in cirrhotic rats (60.5 +/- 12.7 cm vs. 81.2 +/- 5.7 cm) than in control animals (p < 0.001). CONCLUSIONS: These results suggest that the increase of intestinal aerobic bacteria in experimental cirrhosis is associated with translocation. In addition, IBO is frequent in cirrhotic rats, and is supposed to play an important role in the development of BT. Impaired motility of the small intestine is a common feature in cirrhosis and may be implicated in the pathogenesis of IBO.     

Oral bile acids reduce bacterial overgrowth,bacterial translocation,and endotoxemia in cirrhotic rats

Experiments were performed to test whether conjugated bile acid administration would decrease bacterial overgrowth, bacterial translocation, and endotoxemia in ascitic cirrhotic rats. Cholylsarcosine, a deconjugation-dehydroxylation resistant and cholylglycine, a deconjugation-dehydroxylation susceptible bile acid were used. Rats with CCl(4)-induced cirrhosis and ascites were fed cholylsarcosine, cholylglycine (both at 70 mg/kg/d), or placebo for 2 weeks. Healthy rats, as controls, were treated similarly. In cirrhotic rats receiving placebo, bile secretion from an acute biliary fistula was lower than in healthy rats (27.2 +/- 6.5 vs. 53.0 +/- 3.1 microL/kg/min; mean +/- SE, P<.05). The administration of conjugated bile acids to cirrhotic rats normalized bile secretion (cholylsarcosine, 51.8 +/- 6.29; cholylglycine, 52.72 +/- 8.9 microL/kg/min). Total ileal bacterial content was 6-fold higher in ascitic cirrhotic rats than in healthy rats. Conjugated bile acid administration reduced bacterial content to normal levels. Bacterial translocation was less in cirrhotic animals receiving conjugated bile acids (cholylsarcosine, 33%; cholylglycine, 26%) than in animals receiving placebo (66%). Endotoxemia was decreased in cirrhotic rats by conjugated bile acid feeding (cholylsarcosine, 0.098 +/- 0.002; cholylglycine 0.101 +/- 0.007 EU/mL) compared with placebo (0.282 +/- 0.124, P <.001). Survival was greater in animals receiving conjugated bile acids (cholylsarcosine, 10/15; cholylglycine, 11/15; placebo, 5/15). In conclusion, the administration of conjugated bile acids to ascitic cirrhotic rats increased bile acid secretion, eliminated intestinal bacterial overgrowth, decreased bacterial translocation, decreased endotoxemia, and increased survival. Oral conjugated bile acids may be useful in preventing bacterial translocation, endotoxemia, and spontaneous bacterial perotonitis in cirrhotic patients.     

Bacterial translocation in cirrhotic rats. Its role in the development of spontaneous bacterial peritonitis.

Bacterial translocation occurs in ascitic cirrhotic rats, but its association with ascites infection is unknown. The aim of this study was to assess the relation between bacterial translocation and ascites infection in cirrhotic rats. Male Sprague-Dawley rats were induced to cirrhosis with intragastric CCl4. Ascitic fluid, portal and peripheral blood, mesenteric lymph nodes, liver and spleen samples were cultured before death in those cirrhotic rats with less (group A) or more (group B) than 250 polymorphonuclear neutrophils/mm3 in ascitic fluid, as well as in healthy control rats. Histological examination of jejunum, ileum, and caecum was also performed. Bacterial translocation occurred in 45% of ascitic rats (without differences between groups A and B), but in 0% controls (p = 0.01). Bacterial translocation was associated with positive ascitic fluid culture in 60% of the cases. In all of them the same bacterial species was isolated in both mesenteric lymph node and ascitic fluid. Submucosal caecal oedema (100%), ileal lymphangiectasia (41%), and caecal inflammatory infiltrate (41%) occurred in ascitic rats, the last being associated with ascitic fluid positive culture (p = 0.04). These results suggests that bacterial translocation occurs frequently in ascitic cirrhotic rats, and may play a permissive, but not unique, part in a number of ascites infections. Whether histological changes seen in cirrhotic ascitic rats favour bacterial translocation remains to be elucidated.     

Failure of Lactobacillus spp. to prevent bacterial translocation in a rat model of experimental cirrhosis

BACKGROUND/AIMS: Prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients with norfloxacin is associated with emergence of quinolone-resistant Enterobacteriaceae. We investigated whether an alternative strategy with Lactobacillus prevents bacterial translocation and ascitic fluid infection in cirrhotic rats. METHODS: CCl(4)-induced cirrhotic rats with ascites (n=34) were allocated to treatment with oral Lactobacillus strain GG at 1-2 x 10(9) cfu/day for 8-10 days (group LGG) or milk (group MILK). In addition, 20 cirrhotic rats were given a single dose of 15 mg norfloxacin orally and then allocated to Lactobacillus (group NOR-LGG) or milk (group NOR-MILK). Ten healthy rats served as control. After sacrifice the cecal flora were analyzed and the prevalence of bacterial translocation and ascitic fluid infection assessed. RESULTS: Cecal colonization with Lactobacillus was achieved in 90% of treated rats. The prevalence of bacterial translocation to mesenteric lymph nodes was 10% in control rats and 93, 84, 70 and 100% in groups MILK, LGG, NOR-MILK and NOR-LGG, respectively (P>0.1 for comparison of treatment groups), the prevalence of ascitic fluid infection was 60, 32, 40 and 40% (P>0.1). Bacterial translocation of Lactobacillus was observed in 24% of rats treated. CONCLUSION: Lactobacilli fail to prevent bacterial translocation and ascitic fluid infection in experimental cirrhosis in spite of successful intestinal colonization.     

Effects of Octreotide on Intestinal Transit and Bacterial Translocation in Conscious Rats with Portal Hypertension and Liver Fibrosis

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 liver fibrosis secondary to dimethylnitrosamine (DMNA) administration. Twenty-nine conscious rats were randomly assigned to three groups (sham rats + placebo as controls, DMNA + placebo, DMNA + octreotide, 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 radioactivity 50%: controls: 5.3 ± 1.5, DMNA + placebo: 3.2 ± 1.2, DMNA + octreotide: 2.7 ± 1.9, P < 0.01). 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: 3.1 ± 3.6, DMNA + placebo: 12.3 ± 4.4, DMNA + octreotide: 10.6 ± 6.0, P < 0.001]. 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.     

Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis

Deranged intestinal motility, which occurs in cirrhosis, may facilitate the development of intestinal bacterial overgrowth (IBO), which can lead to bacterial translocation (BT). To assess the effect of cisapride on IBO and BT in cirrhosis, cirrhotic rats received cisapride or a placebo for 7 days, and measurements of jejunal bacterial content and BT studies were performed. In addition, jejunal fluid from 46 cirrhotic patients was obtained for quantitative bacterial culture. Those patients in whom gram-negative IBO was detected were randomized to receive or not to receive cisapride (20 mg twice per day) for 1 week. Cisapride significantly reduced IBO in cirrhotic rats. In addition, no BT was documented in treated animals, whereas it occurred in 40% in nontreated cirrhotic rats. Total IBO was documented in 23 of 46 cirrhotic patients, which was caused by gram-negative organisms in 10 cases. Orocecal transit time (OCT) significantly decreased after cisapride therapy, and was associated with the abolishment of bacterial overgrowth caused by gram-negative organisms in 4 out of 5 treated patients, whereas it persisted in nontreated cases. Cisapride administration to cirrhotic rats resulted in a reduction of the IBO, which is associated with a marked decrease in BT. On the other hand, cisapride facilitates the abolition of IBO caused by gram-negative organisms in cirrhotic patients.     

肝硬化患者腹水中细菌DNA与相关因素的关系

目的 探讨肝硬化患者腹水中细菌DNA与血浆内毒素、肠通透性、肠道菌群等因素的关系. 方法 选取失代偿期肝硬化伴腹水患者55例,于入院当日或次日抽取腹水行腹水中细菌DNA的提取及PCR扩增,同时行腹水常规、需氧菌及厌氧菌培养检查,于入院次日测定血浆内毒素、肠通透性并进行肠道菌群分析,同时测定血常规、肝肾功能、凝血功能等生物化学指标.30例健康成年人作为正常对照,行除腹水之外的上述检查. 结果 55例肝硬化患者腹水细菌培养均为阴性,其中19例(34.55%)患者腹水中检测到细菌DNA.与细菌DNA阴性组比较,细菌DNA阳性组患者的凝血酶原活动度明显降低(t=-3.184,P=0.002),而肝功能Child-Pugh评分(t=3.224,P=0.002)和腹水白细胞计数(t'=4.088,P=0.001)明显升高.与正常对照组比较,肝硬化患者血浆内毒素水平(t=13.705,P=0.000)、尿中乳果糖/甘露醇(L/M,t'=28.568,P=0.000)和肠道肠杆菌数量(t=2.912,P=0.005)明显升高,而肠道双歧杆菌数量明显减少(t=-3.669,P=0.000).与腹水中细菌DNA相关的指标为肠道肠杆菌数量(P=0.007)和凝血酶原活动度(P=0.011).结论 肝硬化患者发生腹水细菌移位的关键因素是肠腔细菌过度生长,并与肝病的严重程度相关.     

Alterations in intestinal motility and microflora in experimental acute pancreatitis

Summary Conclusion A delay in intestinal transit time appears as an early event in acute pancreatitis, preceding intestinal bacterial overgrowth and translocation. Background Septic complications, primarily caused by bacteria of enteric origin, are frequent in severe acute pancreatitis. Impairment in intestinal motility probably plays a pathophysiological role in the development of bacterial overgrowth and ensuing translocation. Methods In the present study, the influence of acute pancreatitis on intestinal motility was evaluated by measuring small intestinal transit time in the rat. Acute pancreatitis was induced by the retrograde intraductal infusion of 0.2 mL taurodeoxycholate. Intestinal transit time was studied by intraduodenal injection of Krebs’ phosphate-buffered solution labeled with Na₂ ⁵¹CrCO₄, and 1 h small intestinal transit was measured at 1, 3, 12, and 24 h, after induction of pancreatitis. Bacterial overgrowth was evaluated by measuringEscherichia coli counts in the colon and distal small intestine, and bacterial translocation to mesenteric lymph nodes, the liver, spleen, and pancreas was determined. Results A delayed small intestinal transit time was noted from 3 h on after induction of acute pancreatitis, with most of the radioactivity retained in the first two intestinal segments. Overgrowth ofE. coli was noted 12 h after induction of pancreatitis in both the colon and distal small intestine, and at the same time-point, a significant increase in the incidence of bacterial translocation to mesenteric lymph nodes was seen.     

Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis

OBJECTIVE: Animal studies show that small intestinal bacterial overgrowth and infusion of bacterial antigens into portal blood cause hepatic histological changes similar to those seen in primary sclerosing cholangitis in man. It has been suggested that aa similar mechanism involving bacterial overgrowth with increased small-bowel permeability may play a pathogenic role in patients with primary sclerosing cholangitis (13 M, 9 F, median age 37 years, range 21-74 years), 19 of whom (83%) had quiescent inflammatory bowel disease, were included in the study along with 18 healthy volunteers (9 F, ( M, median age 36 years, range 23-80 years). Small-bowel bacterial overgrowth was defined as the presence of colonic flora>10(5) colony-forming units (cfu)/ml from duodenal aspirations. Small-bowel intestinal permeability was assessed as the differential urinary excretion of lactulose/L-rhamnose. RESULTS: Bacterial overgrowth was evident in one patient with primary sclerosing cholangitis (4.5%) (Enterobacter) and in none of the controls. Intestinal permeability in patients with primary sclerosing cholangitis (0.034 (0.026-0.041) (median, interquartile range (IQR)) did not differ significantly from that of the controls (0.033 (0.025-0.041). CONCLUSIONS: Small intestinal bacterial overgrowth and increased intestinal permeability does not seem to play an important pathogenic role in patients with primary sclerosing cholangitis.     

Leaky Gut and Gut-Liver Axis in Liver Cirrhosis: Clinical Studies Update

Portal blood flows into the liver containing the gut microbiome and its products such as endotoxin and bacterial DNA. The cirrhotic liver acts and detoxifies as the initial site of microbial products. In so-called “leaky gut,” the increased intestinal permeability for bacteria and their products constitutes an important pathogenetic factor for major complications in patients with liver cirrhosis. Prolonged gastric and small intestinal transit may induce intestinal bacterial overgrowth, a condition in which colonic bacteria translocate into the small gut. Cirrhotic patients further show gut dysbiosis characterized by an overgrowth of potentially pathogenic bacteria and a decrease in autochthonous nonpathogenic bacteria. Pathological bacterial translocation (BT) is a contributing factor in the development of various severe complications. Bile acids (BAs) undergo extensive enterohepatic circulation and play important roles in the gut-liver axis. BT-induced inflammation prevents synthesis of BAs in the liver through inhibition of BA-synthesizing enzyme CYP7A1. A lower abundance of 7α-dehydroxylating gut bacteria leads to decreased conversion of primary to secondary BAs. Decreases in total and secondary BAs may play an important role in the gut dysbiosis characterized by a proinflammatory and toxic gut microbiome inducing BT and endotoxemia, as addressed in my previous reviews. Selective intestinal decontamination by the use of various antimicrobial drugs for management of complications has a long history. Lactobacillus GG decreasing endotoxemia is reported to improve the microbiome with beneficial changes in amino acid, vitamin and secondary BA metabolism. Current approaches for hepatic encephalopathy are the use of nonabsorbable antibiotics and disaccharides. Probiotics may become an additional therapeutic option for advanced liver cirrhosis. (Gut Liver 2021;15:-676)     

Why do bacteria reach ascitic fluid?

Spontaneous bacterial peritonitis (SBP) is the most common and serious infection that develops in cirrhotic patients. Translocation of bacteria from their intestinal origin, alterations in immune defence mechanisms and deficiencies in the ascitic fluid antimicrobial activity seem to represent the main steps in the pathogenesis of SBP in cirrhosis. Among the factors determining the development of bacterial translocation, intestinal bacterial overgrowth (mainly related to decreased intestinal motility) and changes in the intestinal barrier appear to play an outstanding role. In conclusion, greater understanding of the pathogenesis of SBP will allow better identification of patients at high risk of developing this complication and contribute to the search for new strategies for its prevention.     

Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling

BACKGROUND & AIMS: Arterial vasodilation plays a role in the pathogenesis of the complications of cirrhosis. This vasodilation is caused by the overproduction of arterial nitric oxide (NO). Bacterial translocation may be involved in NO synthase (NOS) up-regulation by activating both endothelial NOS (eNOS) and inducible NOS (iNOS). The prevention of intestinal gram-negative translocation by norfloxacin administration corrects systemic circulatory changes by decreasing NO production in cirrhosis. However, the signaling mechanisms for NO overproduction from bacterial translocation are unknown. In this study, we investigated the signal transduction pathway of bacterial translocation-induced aortic NOS up-regulation in cirrhotic rats. METHODS: Proinflammatory cytokine levels, Akt and NOS activities, eNOS phosphorylation, and NOS expressions were assessed in aorta from norfloxacin-treated and untreated cirrhotic rats. Norfloxacin was administered to reduce intestinal bacterial translocation. RESULTS: Aortic eNOS and iNOS protein expressions, Akt activity, and eNOS phosphorylation by Akt at serine 1177 were up-regulated in cirrhotic rats. Norfloxacin administration significantly decreased the incidence of gram-negative translocation and proinflammatory cytokine (tumor necrosis factor-alpha, interferon-gamma, and interleukin-6) levels; norfloxacin also decreased aortic Akt activity, eNOS phosphorylation, and NOS expressions and activities. The decrease in aortic Akt activity and NOS expressions also was obtained after colistin or anti-tumor necrosis factor-alpha antibody administration to cirrhotic rats. CONCLUSIONS: This study identifies a signaling pathway in which bacterial translocation induces aortic NOS up-regulation and thus NO overproduction in cirrhotic rats. These results strongly suggest that bacterial translocation and proinflammatory cytokines play a role in systemic NO overproduction in cirrhosis by the Akt pathway.     

Intestinal permeability in liver cirrhosis.

OBJECTIVE: To determine the changes in intestinal permeability in liver cirrhosis and to investigate whether intestinal permeability relates to the stage and aetiology of cirrhosis or existence of spontaneous bacterial peritonitis (SBP). DESIGN: A prospective study of intestinal permeability in patients with cirrhosis. SETTING: Gastroenterology and Nuclear Medicine Departments of Ege University Hospital. PARTICIPANTS: Intestinal permeability was assessed in 44 consecutive patients with cirrhosis and 10 healthy volunteers by measuring 24 h urine excretion of (99m)technetium diethyl triamine penta-acetic acid (99mTc DTPA). Cases with an associated disease, impaired renal function, continuing alcohol consumption and drug intake which is known to have an effect on intestinal permeability were excluded. MAIN OUTCOME MEASURES: Comparisons of 24 h urine excretion of 99mTc DTPA were made between the groups of cirrhotics and controls, different grades of cirrhosis (according to Child-Pugh criteria), alcoholic and non-alcoholic cirrhotics and cirrhotic patients with and without SBP. RESULTS: Patients with cirrhosis excreted 99mTc DTPA significantly more than controls (11.56 +/- 8.96% in cirrhotics and 4.30 +/- 1.49% in controls, P < 0.0001). There was no relationship of 24 h urine excretion of the tracer with the grade and aetiology of cirrhosis (12.20 +/- 9.47%, 11.41 +/- 9.84%, and 11.09 +/- 8.42%, in Child A, B, and C groups and 8.45 +/- 6.57% and 12.05 +/- 9.25% in alcoholic and non-alcoholic cirrhotics, respectively). No significant difference was found between cirrhotic patients with and without SBP in terms of excretion of the administered dose of 99mTc DTPA (9.98 +/- 9.47% and 12.20 +/- 8.82%, respectively). CONCLUSIONS: This study shows that intestinal permeability increased in cirrhotic patients regardless of the grade and aetiology of disease. The presence of SBP does not seem to be due to increased intestinal permeability.     

Pathological bacterial translocation in cirrhosis: pathophysiology,diagnosis and clinical implications

Bacterial translocation (BT) is defined by the passage of viable indigenous bacteria from the intestinal lumen to mesenteric lymph nodes (MLNs) and other territories, and its diagnostic criteria rely on the isolation of viable bacteria in MLNs. Small intestinal overgrowth, increased intestinal permeability and immunological alterations are the main factors involved in its pathogenesis. BT is obviously difficult to identify in patients with cirrhosis, and alternative methods have been proposed instead. Bacterial DNA detection and species identification in serum or ascitic fluid has been proposed as a reliable marker of BT. Bacterial products, such as endotoxin, or bacterial DNA can translocate to extra‐intestinal sites and promote an immunological response similar to that produced by viable bacteria. Therefore, pathological BT plays an important role in the pathogenesis of the complications of cirrhosis, not only in infections, but by exerting a profound inflammatory state and exacerbating the haemodynamic derangement. This may promote in turn the development of hepatorenal syndrome, hepatic encephalopathy and other portal hypertension‐related complications. Therapeutic approaches for the prevention of BT in experimental and human cirrhosis are summarized. Finally, new investigations are needed to better understand the pathogenesis and consequences of translocation by viable bacteria (able to grow in culture), or non‐viable BT (detection of bacterial fragments with negative culture) and open new therapeutic avenues in patients with cirrhosis.     

Bacterial translocation and its consequences in patients with cirrhosis

Bacterial translocation is the passage of viable bacteria from the intestinal lumen to mesenteric lymph nodes and other extraintestinal sites. Spontaneous bacterial peritonitis is the main clinical consequence of bacterial translocation in cirrhosis. Translocation of bacterial products of viable or non-viable bacteria, such as endotoxin and/or bacterial DNA, through the intestinal wall could stimulate the immune system and the hyperdynamic circulatory state in cirrhosis with clinical consequences that are under evaluation. Bacterial translocation is currently considered the passage of viable gut flora across the intestinal barrier to extraluminal sites. Aerobic Gram-negative bacilli are the most common translocating bacteria. Intestinal bacterial overgrowth, impairment in permeability of the intestinal mucosal barrier, and deficiencies in local host immune defences are the major mechanisms postulated to favour bacterial translocation in cirrhosis. Bacterial translocation is a key step in the pathogenesis of spontaneous bacteraemia and spontaneous bacterial peritonitis in cirrhosis. Translocation of intestinal bacterial products from viable or non-viable bacteria, such as endotoxin and bacterial DNA, has recently been associated with pathophysiological events, such as activation of the immune system and derangement of the hyperdynamic circulatory status in cirrhosis. Clinical consequences of these effects of bacterial products are presently under investigation.     

Intestinal dysfunction in liver cirrhosis: Its role in spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis is a common illness in patients with cirrhosis and ascites that occurs without any apparent focus of infection. Bacterial translocation plays an important role in spontaneous bacterial peritonitis and it is evident from a variety of studies that the gut is a major source of this bacteria. Gut motility alterations, along with bacterial overgrowth and changes in intestinal permeability, probably play a role in this bacterial translocation. The present review looks at the role of the intestine in spontaneous bacterial peritonitis induced by liver cirrhosis and the factors influencing bacterial translocation in this disease.