肝硬化与肠源性内毒素血症关系的研究进展

<正>肝硬化是一种或多种原因引起的,以肝组织弥漫性纤维化、假小叶和再生结节为组织学特征的进行性慢性肝病,是我国常见疾病和主要死亡病因之一。引起肝硬化的病因很多,我国以病毒性肝炎所致的肝硬化为主,而国外以酒精性肝硬化多见。当机体发生肝硬化时,由于肠道细菌过度生长、肠道黏膜通透性增高、内毒素灭活功能减退等原因导致肠道的细菌及其相关产物(如内毒素)突破肠道屏障,从肠道转移到肠系膜淋巴结及其他肠外器官,从而     

谷氨酰胺对创伤后肠粘膜通透性的影响

在创伤的情况下,肠道通透性将发生改变,继而引起细菌移位和内毒素血症。谷氨酰胺可以通过降低肠粘膜通透性来减少细菌移位、减轻内毒素血症。     

肝硬化病人能喝酸奶吗？

Q肝硬化病人经常吃酸奶好不好？ A肝硬化病人，特别是发展到晚期时，肠道的有益细菌减少，致病菌增加，导致肠道菌群失调，如细菌移位到小肠上段，过度繁殖后会产生大量有毒代谢产物，如内毒素等，人体吸收后会刺激脾脏肿大，引起微循环障碍，加重肝坏死。酸奶含有活的乳酸菌，     

不同营养干预对肠道缺血再灌注大鼠肠屏障和系统炎症影响

目的探讨不同营养干预对大鼠肠道缺血再灌注损伤时肠道通透性、细菌内毒素移位和系统炎症反应的影响。方法40只SD大鼠胃造瘘后随机分为普通饮食组（OF）、普通肠内营养组（EN）、谷氨酰胺肠内营养组（Gin）、免疫增强型肠内营养组（IEEN）和假手术组（Sham）。7天营养干预后用动脉夹夹闭肠系膜上动脉60分钟，继续原营养3天后分别测定肠道通透性、肠黏膜形态、细菌培养和循环细胞因子。结果OF组、EN组和Sham组肠道缺血再灌注可引起体重下降和肠道通透性增加（P〈0．05），Gln组的内毒素水平明显低于OF组（P〈0．05），IEEN组的肿瘤坏死因子α（TNF—α）、白细胞介素6（IL-6）和白细胞介素1β（IL-1β）水平显著低于EN组（P〈0．05），Gin组和IEEN组的肠黏膜厚度和绒毛高度明显高于OF组和EN组（P〈0．05）。结论大鼠肠道缺血再灌注损伤时可引起肠道通透性增加、细菌内毒素移位和系统炎症反应。谷氨酰胺和免疫增强型肠内营养可明显弱化肠道损伤，减少细菌内毒素移位，减轻系统炎症反应。     

肝脏疾病与肠黏膜屏障

肝脏疾病可以引起肠黏膜屏障受损，进而肠道内细菌发生移位，导致菌血症和内毒素血症，并进一步加重肝损伤。     

艾司洛尔对脓毒症大鼠肠黏膜屏障的影响

目的:探讨艾司洛尔对脓毒症大鼠肠黏膜屏障的保护作用. 方法:建立脓毒症大鼠模型,将大鼠随机分为对照组(脓毒症组)和艾司洛尔组(脓毒症模型+艾司洛尔组),每组8只.观察大鼠的基本生命体征、体外肠道的通透性和血清内毒素变化.同时,通过肝、脾和肠系膜淋巴结细菌培养观察细菌易位情况.最后,根据H-E染色结果评估大鼠肠道损伤. 结果:艾司洛尔组大鼠心率明显低于基础值(P＜0.05).与对照组比,艾司洛尔组大鼠细菌易位减少,体外肠道通透性降低.两组大鼠血清内毒素水平无显著性差异.艾司洛尔组大鼠肠道病理评分明显低于对照组. 结论:艾司洛尔能保护脓毒症大鼠肠黏膜屏障,减轻肠损伤.     

早期肠道营养对严重烧伤病人早期肠道的保护作用

为探讨早期肠道营养能否防治严重烧伤后早期肠源性感染，检测了２２例严重烧伤病人血浆内毒素、血清肿瘤坏死因子（ＴＮＦ）、尿乳果糖和甘露醇。结果显示，早期肠道营养组尿乳果糖与甘露醇比值显著低于延迟喂养组，提示肠粘膜通透性有所改善；血浆内毒素和血清ＴＮＦ水平...     

重症急性胰腺炎时细胞因子与肠源性细菌和内毒素移位的实验研究

目的 探讨重症急性胰腺炎(SAP)时血浆细胞因子与肠道屏障损害后肠源性细笛和内毒素移位的关系。方法 将SD大鼠(清洁级)72只随机分为假手术组(n=36)和SAP组(n=36)。采用胰管内逆行注射4％牛磺胆酸钠溶液的方法制作SAP模型。观察胰腺和回肠的病理改变，动态测定血浆TNF-a、IL-6、IL-10和DAO活性、LPS水平以及腹腔脏器细菌移位率。结果 制模后血浆TNF-a、IL-6水平明显升高，48h达到高峰，IL-106h后才明显升高；血浆DAO活性早期升高，24h后明显降低；LPS水平早期即有明显升高，48h达到高峰；SAP24h脏器细笛移位率明显升高，72h达到58．3％。结论 SAP早期即有细胞因子水平的升高和肠道屏障的损害，细胞因子通过损害肠遗屏障，引起肠源性细菌和内毒素移位；同时，肠源性细菌和内毒素移位又促进细胞因子的大量释放。加重肠黏膜屏障本身的损害，遣成恶性循环，引起SIPS和MODS的发生，两者关系密切。     

腹腔感染病人肠黏膜通透性的变化

目的:观察腹腔感染病人肠黏膜通透性的变化,了解腹腔感染对肠黏膜屏障功能的影响. 方法:将20例病人在确诊腹腔感染24 h内测定肠道乳果糖与甘露醇吸收比值(L/M)、血清内毒素和肿瘤坏死因子α(TNF-α)水平,并同期采集病情严重度(APACHEⅡ评分和SOFA评分)、ICU滞留时间、住院时间和病情转归等. 结果:腹腔感染组LMR水平较正常组明显升高(P<0.01);血清内毒素和TNF-α水平与LMR间呈显著正相关(P<0.01,P<0.05);肠黏膜通透性与病人病情严重程度有显著相关性(P<0.01);腹腔感染病人肠黏膜通透性变化程度与病死率也有明显相关性(P<0.05). 结论:腹腔感染病人的肠黏膜通透性显著增加,腹腔感染可导致肠黏膜屏障功能损害.     

早期肠道喂养在降低烧伤后肠黏膜通透性中的作用

目的　研究早期肠道喂养在保护烧伤患者肠黏膜屏障中的作用。方法　 2 2例严重烧伤患者随机分为早期肠道喂养组 (EF)和延迟肠道喂养组 (DF)。动态检测了两组患者伤后血浆TNF -α和内毒素水平 ;同时采用两种非代谢糖类 (乳果糖和甘露醇 ) ,在伤后 1、3、5d给予口服 ,观察尿中的浓度及两者比值 ,以后者表示肠黏膜通透性。结果　烧伤后血浆内毒素和TNF -α水平均明显高于正常 (P <0 0 1) ;两组中TNF -α与内毒素水平呈显著正相关 (rEF=0 93 ,P <0 0 1;rDF=0 80 ,P <0 0 5 ) ;两组患者尿乳果糖含量明显高于正常 (P <0 0 1) ,尿甘露醇含量无明显改变 ;尿乳果糖 /甘露醇比值均明显高于正常 (P <0 0 1) ,尿乳果糖 /甘露醇比值与血浆内毒素水平呈显著正相关 (r =0 95 ,P <0 0 1) ;EF组尿乳果糖含量和尿乳果糖 /甘露醇比值均明显低于DF组 ( P <0 0 1) ,血浆TNF -α和内毒素水平也明显低于DF组。结论　严重烧伤后肠黏膜通透性明显升高 ,且与严重烧伤后肠源性内毒素血症相关。早期肠道喂养可降低肠黏膜通透性 ,保护肠黏膜屏障     

Potential mechanisms for the emerging link between obesity and increased intestinal permeability

Recently, increased attention has been paid to the link between gut microbial composition and obesity. Gut microbiota is a source of endotoxins whose increase in plasma is related to obesity and insulin resistance through increased intestinal permeability in animal models; however, this relationship still needs to be confirmed in humans. That intestinal permeability is subject to change and that it might be the interface between gut microbiota and endotoxins in the core of metabolic dysfunctions reinforce the need to understand the mechanisms involved in these aspects to direct more efficient therapeutic approaches. Therefore, in this review, we focus on the emerging link between obesity and increased intestinal permeability, including the possible factors that contribute to increased intestinal permeability in obese subjects. We address the concept of intestinal permeability, how it is measured, and the intestinal segments that may be affected. We then describe 3 factors that may have an influence on intestinal permeability in obesity: microbial dysbiosis, dietary pattern (high-fructose and high-fat diet), and nutritional deficiencies. Gaps in the current knowledge of the role of Toll-like receptors ligands to induce insulin resistance, the routes for lipopolysaccharide circulation, and the impact of altered intestinal microbiota in obesity, as well as the limitations of current permeability tests and other potential useful markers, are discussed. More studies are needed to reveal how changes occur in the microbiota. The factors such as changes in the dietary pattern and the improvement of nutritional deficiencies appear to influence intestinal permeability, and impact metabolism must be examined. Also, additional studies are necessary to better understand how probiotic supplements, prebiotics, and micronutrients can improve stress-induced gastrointestinal barrier dysfunction and the influence these factors have on host defense. Hence, the topics presented in this review may be beneficial in directing future studies that assess gut barrier function in obesity.     

Effect of Colonic Bacterial Metabolites on Caco-2 Cell Paracellular Permeability In Vitro

One common effect of tumor promoters is increased tight junction (TJ) permeability. TJs are responsible for paracellular permeability and integrity of the barrier function. Occludin is one of the main proteins responsible for TJ structure. This study tested the effects of physiological levels of phenol, ammonia, primary bile acids (cholic acid, CA, and chenodeoxycholic acid, CDCA), and secondary bile acids (lithocholic acid, LCA, and deoxycholic acid, DCA) on paracellular permeability using a Caco-2 cell model. Paracellular permeability of Caco-2 monolayers was assessed by transepithelial electrical resistance (TER) and the apical to basolateral flux of [ ¹⁴ C]-mannitol. Secondary, but not primary, bile acids increased permeability as reflected by significantly decreased TER and increased mannitol flux. Both phenol and ammonia also increased permeability. The primary bile acid CA significantly increased occludin expression (P < 0.05), whereas CDCA had no significant effect on occludin expression as compared to the negative control. The secondary bile acids DCA and LCA significantly increased occludin expression (P < 0.05), whereas phenol had no significant effect on the protein expression as compared to the negative control. This suggests that the increased permeability observed with LCA, DCA, phenol, and ammonia was not related to an effect on occludin expression. In conclusion, phenol, ammonia, and secondary bile acids were shown to increase paracellular permeability and reduce epithelial barrier function at doses typical of levels found in fecal samples. The results contribute to the evidence these gut microflora-generated products have tumor-promoting activity.     

Effect of colonic bacterial metabolites on Caco-2 cell paracellular permeability in vitro

One common effect of tumor promoters is increased tight junction (TJ) permeability. TJs are responsible for paracellular permeability and integrity of the barrier function. Occludin is one of the main proteins responsible for TJ structure. This study tested the effects of physiological levels of phenol, ammonia, primary bile acids (cholic acid, CA, and chenodeoxycholic acid, CDCA), and secondary bile acids (lithocholic acid, LCA, and deoxycholic acid, DCA) on paracellular permeability using a Caco-2 cell model. Paracellular permeability of Caco-2 monolayers was assessed by transepithelial electrical resistance (TER) and the apical to basolateral flux of [14C]-mannitol. Secondary, but not primary, bile acids increased permeability as reflected by significantly decreased TER and increased mannitol flux. Both phenol and ammonia also increased permeability. The primary bile acid CA significantly increased occludin expression (P < 0.05), whereas CDCA had no significant effect on occludin expression as compared to the negative control. The secondary bile acids DCA and LCA significantly increased occludin expression (P < 0.05), whereas phenol had no significant effect on the protein expression as compared to the negative control. This suggests that the increased permeability observed with LCA, DCA, phenol, and ammonia was not related to an effect on occludin expression. In conclusion, phenol, ammonia, and secondary bile acids were shown to increase paracellular permeability and reduce epithelial barrier function at doses typical of levels found in fecal samples. The results contribute to the evidence these gut microflora-generated products have tumor-promoting activity.     

二氧化硫对大鼠肺细胞膜通透性的损伤效应

目的 探讨二氧化硫(SO2)吸入对大鼠肺组织及肺细胞通透性的影响。方法 用生理盐水灌洗大鼠支气管肺泡，收集肺泡灌洗液(BALF)和肺泡巨噬细胞(AM)，从整体、细胞和亚细胞水平研究SO2对肺组织和细胞的通透性的影响。结果 SO2吸入后，大鼠体重增加减慢，肺组织湿重增大，干重减小；肺泡BALF中蛋白质含量和肺通透指数增加；肺血管通透性增大；BALF中乳酸脱氢酶(LDH)和酸性磷酸酶(ACPase)活力升高，而AM LDH和ACPase活力降低。结论 SO2导致大鼠肺组织损伤，肺血管通透性增加，AM膜通透性增加，细胞器(如溶酶体)结构和功能发生改变。     

Effect of lactobacilli on paracellular permeability in the gut

Paracellular permeability is determined by the complex structures of junctions that are located between the epithelial cells. Already in 1996, it was shown that the human probiotic strain Lactobacillus plantarum 299v and the rat-originating strain Lactobacillus reuteri R2LC could reduce this permeability in a methotrexate-induced colitis model in the rat. Subsequently, many animal models and cell culture systems have shown indications that lactobacilli are able to counteract increased paracellular permeability evoked by cytokines, chemicals, infections, or stress. There have been few human studies focusing on the effect of lactobacilli on intestinal paracellular permeability but recently it has been shown that they could influence the tight junctions. More precisely, short-term administration of L. plantarum WCSF1 to healthy volunteers increased the relocation of occludin and ZO-1 into the tight junction area between duodenal epithelial cells.     

The significance of bowel permeability

PURPOSE OF REVIEW: In clinical research, increased permeability has been scrutinized as a potential indicator of the severity of gastrointestinal disease and as a potential cause of the perpetuation of severe inflammatory activity in infectious states. This review discusses old and recent epidemiological and clinical evidence to establish whether increased permeability in sepsis is a sequel or a cause of multiple organ failure. In addition, old and new evidence linking inflammation and permeability in abnormal gastrointestinal anatomy and function to liver abnormalities in susceptible patients will be reviewed. RECENT FINDINGS: Intestinal permeability has been found to be increased in several gastrointestinal diseases but not to be a very good marker of the severity of disease. Evidence is put forward supporting the claim that increased intestinal permeability is part of generalized leakiness of tight junctions in multiple organ failure and to play a less strong role as a primary event in its pathogenesis. Endemic malnutrition has been shown to be caused by interplay between malnutrition and intestinal inflammation. Recently experimental evidence has been put forward suggesting that enteral fat has anti-inflammatory effects on the intestine via the autonomic nervous system. Old clinical and new epidemiological evidence links intestinal inflammation, disruption of the enterohepatic cycle of bile acids, and liver disease. SUMMARY: The implications of the described findings are that inflammatory activity, locally induced by abnormal intestinal anatomy and disruption of the bile acid pool, or systemically by severe and uncontrolled inflammation/infection, should be the focus of treatment or research. In addition, the connection between intestinal inflammation and liver disease should be investigated.     

Health implications of fructose consumption: A review of recent data

Background

An increase in the intestinal permeability is considered to be associated with the inflammatory tone and development in the obesity and diabetes, however, the pathogenesis of the increase in the intestinal permeability is poorly understood. The present study was performed to determine the influence of obesity itself as well as dietary fat on the increase in intestinal permeability.

Methods

An obese rat strain, Otsuka Long Evans Tokushima Fatty (OLETF), and the lean counter strain, Long Evans Tokushima Otsuka (LETO), were fed standard or high fat diets for 16 weeks. Glucose tolerance, intestinal permeability, intestinal tight junction (TJ) proteins expression, plasma bile acids concentration were evaluated. In addition, the effects of rat bile juice and dietary fat, possible mediators of the increase in the intestinal permeability in the obesity, on TJ permeability were explored in human intestinal Caco-2 cells.

Results

The OLETF rats showed higher glucose intolerance than did the LETO rats, which became more marked with the prolonged feeding of the high fat diet. Intestinal permeability in the OLETF rats evaluated by the urinary excretion of intestinal permeability markers (Cr-EDTA and phenolsulfonphthalein) was comparable to that in the LETO rats. Feeding the high fat diet increased intestinal permeability in both the OLETF and LETO rats, and the increases correlated with decreases in TJ proteins (claudin-1, claudin-3, occludin and junctional adhesion molecule-1) expression in the small, but not in the large intestine (cecum or colon). The plasma bile acids concentration was higher in rats fed the high fat diet. Exposure to bile juice and the fat emulsion increased TJ permeability with concomitant reductions in TJ protein expression (claudin-1, claudin-3, and junctional adhesion molecule-1) in the Caco-2 cell monolayers.

Conclusion

Excessive dietary fat and/or increased levels of luminal bile juice, but not genetic obesity, are responsible for the increase in small intestinal permeability resulting from the suppression of TJ protein expression.     

Dietary fructooligosaccharides increase intestinal permeability in rats

We showed previously that fructooligosaccharides (FOS) decrease the resistance to salmonella infection in rats. However, the mechanism responsible for this effect is unclear. Therefore, we examined whether dietary FOS affects intestinal permeability before and after infection with Salmonella enterica serovar Enteritidis. Male Wistar rats were fed restricted quantities of a purified diet that mimicked the composition of a Western human diet. The diet was supplemented with 60 g/kg cellulose (control) or 60 g/kg FOS and with 4 mmol/kg of the intestinal permeability marker chromium EDTA (CrEDTA) (n = 8 or 10). After an adaptation period of 2 wk, rats were orally infected with 10(8) colony-forming units (cfu) of S. enteritidis. Mucin concentrations in intestinal contents and mucosa were measured fluorimetrically, as markers of mucosal irritation. Intestinal permeability was determined by measuring urinary CrEDTA excretion. Translocation of salmonella was quantified by analysis of urinary nitric oxide metabolites with time. Before infection, FOS increased mucosal lactobacilli and enterobacteria in cecum and colon, but not in the ileum. However, FOS increased cytotoxicity of fecal water and intestinal permeability. Moreover, FOS increased fecal mucin excretion and mucin concentrations in cecal and colonic contents, and in cecal mucosa before infection. After infection, mucin excretion and intestinal permeability in the FOS groups increased even further in contrast to the control group. In addition, FOS increased translocation of salmonella to extraintestinal sites. Thus, FOS impairs the intestinal barrier in rats, as indicated by higher intestinal permeability. Whether these results can be extrapolated to humans requires further investigation.     

The Effects of Paraquat and Superoxide Dismutase on Pulmonary Vascular Permeability and Edema in Mice

Intraperitoneal administration of 50 mg/kg paraquat dichloride to mice significantly increased pulmonary vascular permeability at 24 and 48 hr, as measured by ¹²⁵I-albumin content of alveolar lavage. Lung edema, measured by lung weight as percent body weight, was significantly increased 48 hr after paraquat treatment. Intravenous administration of four doses of superoxidase dismutase at 12-hr intervals (i.e., one before and three after paraquat treatment) failed to inhibit paraquat-induced increased pulmonary vascular permeability and pulmonary edema. Superoxide dismutase treatment also failed to reduce mortality and had no significant effect on the death time course in animals challenged with paraquat. The results of this study suggest that acute toxic effects of paraquat, such as increased pulmonary vascular permeability and pulmonary edema, may not be mediated through the generation of superoxide anion.