Notch信号通路在肠黏膜屏障中的研究进展

Notch信号通路是一种介导细胞与细胞之间信号级联反应的高度保守的通路。其对于多种细胞的分化、增值和凋亡具有调节作用。该信号通路的激活或失活在肠黏膜屏障中发挥着非常重要的作用。对指导各种疾病中所引起的肠黏膜屏障损伤的治疗提供新的视野和思路。     

肠黏膜屏障在1型糖尿病中的作用研究进展北大核心CSCD

1型糖尿病(T1DM)是儿童和青少年常见的以胰岛β细胞破坏和胰岛素缺乏为特征的自身免疫性疾病。近期研究表明,肠道菌群失衡和肠黏膜屏障变化与T1DM发生发展相关,但具体机制尚不清楚。本文就近年肠道菌群、肠黏膜屏障在T1DM中的作用研究进行综述,并探讨孕期治疗、粪菌移植、益生菌、短链脂肪酸治疗维持健康肠黏膜屏障改善T1DM的研究进展,为T1DM防治提供新方法。     

肠道微生态与肠道疾病

人类肠道微生态是一个包含大量肠道微生物的复杂生态系统,近年来研究发现肠道细菌过度繁殖可导致胃肠道动力失调及内脏神经敏感性改变,最终导致肠易激综合征的发生,而肠道菌群引起的肠粘膜异常免疫应答损伤被认为是炎症性肠病发病机制的关键所在,另外,肠道微生态还可过参与炎症性肠病的病理生理过程或直接代谢产生致癌物质影响肠道肿瘤的发生发展。由此我们发现,肠道微生态不仅参与了消化吸收、物质代谢等胃肠道基本生理过程,还直接关系到肠道疾病的发生。本文将就目前肠道微生态与肠道疾病的研究进展进行简单综述。     

肠道微生态与风湿免疫病关系的研究进展

肠道菌群紊乱在风湿免疫病的发病中起着关键性作用,失衡的肠道细菌可通过直接迁移至肠外组织、产生小分子进入血液循环、作用于肠道Toll样受体(TLR)信号传导通路等机制引起风湿免疫病。国内外最新研究发现,类风湿关节炎、系统性红斑狼疮、强直性脊柱炎、痛风、银屑病、白塞综合征、系统性硬化等多种风湿免疫病的发病均与肠道菌群失调密切相关。因此,本文对肠道菌群与风湿免疫病的关系进行综述,将为风湿免疫病的诊治提供新的思路。     

肠黏膜屏障功能检测的研究现状

肠黏膜屏障是指肠道能防止肠腔内有害物质如毒素或细菌穿过肠黏膜进入体内其他组织器官和血液循环的结构和功能总和。近年来随着基础医学研究的深入，人们逐渐认识到肠黏膜不仅仅有消化和吸收功能，而且具有重要的防御性屏障功能，发现肠道屏障功能障碍、肠内细菌及内毒素移位是导致SIRS、MODS，甚至MSOF的一个重要因素。肠道屏障功能已成为判断危重病人预后的一个重要指标，[第一段]     

黏蛋白-2与肠黏膜屏障损伤的研究进展

黏蛋白-2(MUC2)是肠黏液层主要成分,覆盖于肠上皮细胞顶端,主要由杯状细胞分泌,在润滑肠道、为肠内抗菌蛋白及共生菌群提供黏附位点、抵御肠内致病菌及有害物质入侵等方面发挥着重要功能.近年来MUC2在肠道黏膜屏障损伤中的作用研究日趋受到学者重视,这也可能是肠黏膜屏障损伤的一个重要治疗突破口.     

自噬在肠黏膜屏障功能作用机制的研究进展

自噬是细胞通过膜囊泡结构降解胞质内大分子物质和受损细胞器维持机体稳态的生物学过程。在肠黏膜屏障功能发生障碍过程中,自噬对于维持肠上皮细胞的存活起关键性作用。负调控自噬可导致肠道炎性反应和肿瘤的发生。     

内质网应激在危重病肠黏膜屏障损伤中的作用

肠屏障是机体防御系统的重要组成部分.肠屏障损伤,尤其是肠黏膜屏障损伤,成为全身炎症反应失控和多器官衰竭的主要机制之一.过度的内质网应激(ERS)参与了肠黏膜上皮细胞损伤过程,成为肠黏膜屏障损伤的重要因素之一.本文综述了ERS参与失血性休克、严重烧伤、重症急性胰腺炎、脓毒症等危重病引起肠黏膜屏障损伤的研究进展,希望以ER...     

肠道菌群在高原低氧肠道损伤中的作用研究

目的　探讨肠道菌群在高原低氧环境中参与肠道损伤的作用机制。 方法　将20只C57 BL/6小鼠按1：1比例随机分为对照组和暴露组,建立6000 m高原低氧模型,造模成功后收集两组小鼠粪便、血液和近端结肠组织。采用16S rDNA测定粪便中肠道菌群结构;检测小鼠血液生化指标;HE和PAS染色观察结肠肠道黏膜结构的改变;RT-qPCR测定结肠组织ZO-1、Occludin、IL-6和TNFα的mRNA表达水平。 结果　与对照组相比,暴露组小鼠血细胞、血红蛋白和红细胞压积值显著升高,高原低氧模型建模成功;16 SrDNA结果显示肠道菌群紊乱、多样性下降,黏蛋白降解菌艾克曼菌,普雷沃氏菌、梭状芽胞杆菌XVIII等致病菌含量上升,短链脂肪酸产生菌罗斯氏菌、Odoribacter菌、Lachnospiracea菌、Butyricicoccus菌和欧氏菌等益生菌含量下降;HE和PAS染色结果显示结肠组织上皮连续性中断、腺体萎缩、隐窝变短、杯状细胞数量减少,提示肠道结构损伤且黏膜屏障破坏;结肠组织紧密连接蛋白Occludin和 ZO-1 mRNA表达水平下降,进一步暴露组小鼠肠道黏膜受损,炎症因子IL-6和TNFα 的mRNA表达量上升,可能与肠道炎症反应有关。 结论　高原低氧环境导致的肠道损伤可能与肠道菌群改变有关。肠道菌群紊乱、多样性下降,致病菌相对丰度上升,益生菌相对丰度下降,菌群的这些改变造成肠道黏膜损伤,引起肠道炎症,进而出现肠道损伤,最终导致高原肠道相关疾病。     

Research progress on the relationship between intestinal microecology and intestinal bowel disease

Intestinal microecology is the main component of human microecology. Intestinal microecology consists of intestinal microbiota, intestinal epithelial cells, and intestinal mucosal immune system. These components are interdependent and establish a complex interaction network that restricts each other. According to the impact on the human body, there are three categories of symbiotic bacteria, opportunistic pathogens, and pathogenic bacteria. The intestinal microecology participates in digestion and absorption, and material metabolism, and inhibits the growth of pathogenic microorganisms. It also acts as the body''s natural immune barrier, regulates the innate immunity of the intestine, controls the mucosal barrier function, and also participates in the intestinal epithelial cells'' physiological activities such as hyperplasia or apoptosis. When the steady‐state balance of the intestinal microecology is disturbed, the existing core intestinal microbiota network changes and leads to obesity, diabetes, and many other diseases, especially irritable bowel syndrome, inflammatory bowel disease (IBD), and colorectal malignancy. Intestinal diseases, including tumors, are particularly closely related to intestinal microecology. This article systematically discusses the research progress on the relationship between IBD and intestinal microecology from the pathogenesis, treatment methods of IBD, and the changes in intestinal microbiota.     

SIRT在肠屏障中作用的研究进展

沉默信息调节子(SIRT)是一组保守的NAD+依赖的蛋白去乙酰化酶,参与调控细胞的基因稳定、代谢、衰老和凋亡等过程。研究表明,SIRT对肠屏障具有保护作用,其通过参与调节炎性因子的释放、肠上皮细胞间紧密连接蛋白的表达、改变肠道潘氏细胞和杯状细胞的数量等影响肠屏障的结构与功能。     

黄芩苷调控自噬保护肠黏膜屏障干预肠道急性移植物抗宿主病

文题释义：移植物抗宿主病：是由于移植后异体供者移植物中的T淋巴细胞,经受者发动的一系列“细胞因子风暴”刺激,显著增强了其对受者抗原的免疫反应,以受者靶细胞为目标发动细胞毒攻击,其中皮肤、肝及肠道是主要的靶目标。根据移植物抗宿主病在移植后发生的时间,如在100 d内发生者称为急性移植物抗宿主病,在100 d后发生者称为慢性移植物抗宿主病。黄芩苷：黄芩汤的君药黄芩,《神农本草经》谓可治“肠辟泄利”,性苦寒,可清肺胃胆及大肠经之湿热,黄芩苷是黄芩中提取的一种黄酮类化合物,具有抑菌、清除氧自由基等作用,减轻蛋白酶与炎性因子对组织的损害。 摘要背景：急性移植物抗宿主病是造血干细胞移植后早期最容易致死的并发症之一,如何干预急性移植物抗宿主病病程是个热点问题。目的：探讨黄芩苷调控自噬干预肠道急性移植物抗宿主病的机制。方法：⁶⁰Co照射CB6F1小鼠4 h,立即尾静脉输注Balb/c小鼠单个核细胞悬液(骨髓+脾),建立单倍体造血干细胞移植模型。造模后当天开始模型组灌胃生理盐水,治疗组灌胃黄芩苷,剂量为30 mg/(kg·d),共14 d。治疗后进行小鼠急性移植物抗宿主病临床评分、小肠黏膜急性移植物抗宿主病病理评级,透射电镜观察小肠黏膜自噬泡结构,流式细胞仪检测小肠黏膜上皮细胞活性氧水平,Western blot检测自噬相关蛋白LC3Ⅱ、LC3-Ⅰ、Beclin1的表达。结果与结论：①治疗组临床急性移植物抗宿主病评分、小肠黏膜病理评级明显优于模型组;②透射电镜下模型组存在自噬泡但线粒体结构毁坏严重,治疗组自噬泡增多且线粒体结构相对完整;③治疗组小鼠小肠黏膜上皮细胞活性氧水平低于模型组(P < 0.01),治疗组LC3Ⅱ/Ⅰ、Beclin1的表达水平明显高于模型组(P < 0.01);④结果表明,黄芩苷可以通过降低活性氧的产生,提高小肠黏膜细胞的自噬水平,保护肠黏膜屏障,进而降低移植后肠道急性移植物抗宿主病的发病率。ORCID: 0000-0002-8771-5898(崔兴) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Protective effect of salvianolic acid B on NASH rat liver through restoring intestinal mucosal barrier function

Aim: To investigate the effect of Salvianolic acid B (Sal B) on the disease progress of NASH and change of intestinal barrier function. Methods: Sixty Sprague-Dawley (SD) rats were randomly divided into control group, model group and treated group, with the former given normal diet and the latter 2 groups rats fed high-fat diet. In treated group, rats were infused through the stomach with 1 mg/ml Sal B every day at a dose of 20 mL/kg body weight. All animals were killed at the 24th week and plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), endotoxin (ET) and diamine oxdase (DAO) were analyzed using the blood samples. The histopathology of liver was observed by H&E staining. The expression changes of tight junction protein occludin and ZO-1 were analyzed by immunocytochemistry. Ultrastructural morphology of small intestinal tissues was investigated by transmission electron microscopy. Results: Plasma levels of ALT, AST, TG, TC, ET and DAO were significantly higher in model group than those in both control group and group treated with Sal B. In model group, vacuolated swelling of the cytoplasm with aggregates of chronic inflammatory cells was observed in the liver tissue but not in Sal B-treated group. NAFLD Activity Score in the treated group was significantly lower than that in model group. Immunohistochemical staining showed that Sal B administration recovered the expression of occludin and ZO-1, which was downregulated in the model group. Transmission electron microscopy analysis demonstrated that cell surface microvilli and major intercellular junctional complex including tight junction, gap junction and adherens junction were restored in Sal B-treated group. Conclusion: Sal B exerted protective function against high-fat diet-induced liver damage by restoring healthy barrier function of intestine in NASH rat model.     

Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease

Intestinal mucosal barrier dysfunction is closely related to liver diseases, which implies impaired gut-liver axis may play a role in the pathogenesis of NAFLD. In our study, rats were divided into three groups: normal chow diet (NCD) group, high-fat diet (HFD) group and TNBS-induced colitis with high-fat diet (C-HFD) group. Liver tissues were obtained for histological observation and TNF-α, IL-6 mRNA determination and blood samples were collected for liver enzymes and LPS analysis. Ultrastructural changes of jejuna epithelium, SIBO and amounts of CD103⁺MHCII⁺DCs and CD4⁺CD25⁺FoxP3⁺T-regs in terms of percentage in mesenteric lymph nodes (MLN) were observed by electron microscope, bacterial cultivation and flow cytometry, respectively. The results demonstrated the pathological characteristics accorded with nonalcoholic simple fatty liver (NAFL) and NASH in HFD group by week 8 and 12, respectively. Besides, the degree of hepatic steatosis and steatohepatitis was more severe in C-HFD group compared with HFD-group at the same time point. NAFLD activity score (NAS), liver enzymes, concentration of LPS and mRNA expressions of TNF-α, IL-6 were higher significantly in C-HFD group compared with HFD and NCD group at week 4, 8 and 12, respectively. In HFD group, epithelium microvilli atrophy, disruptive tight junctions and SIBO were present, and these changes were more severe in NASH compared with NAFL. The percentage of CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs decreased significantly in NAFL and NASH compared with NCD group. Our conclusion was that gut-liver axis was impaired in NAFLD, which played crucial role in the pathogenesis of NAFLD.     

布拉氏酵母菌对DSS诱导的实验性结肠炎小鼠肠黏膜的屏障作用

目的观察布拉氏酵母菌对葡聚糖硫酸钠(dextran sulfacte sodium,DSS)诱导的实验性结肠炎小鼠肠黏膜屏障的影响。方法将50只BALB/c小鼠随机分成5组,分别为:正常对照组(A)、模型组(B)、美沙拉嗪组(C)、布拉氏酵母菌组(D)、联合治疗组(E)。采用2.5%DSS溶液诱导小鼠实验性结肠炎动物模型,将C、D、E组小鼠分别给予美沙拉嗪、布拉氏酵母菌、美沙拉嗪加布拉氏酵母菌联合灌胃治疗,计算小鼠疾病活动指数(disease activity index,DAI)评分,评估结肠黏膜组织损伤程度,并用Western blot法检测结肠黏膜紧密连接蛋白ZO-1、Occludin表达水平。结果模型组小鼠的DAI评分及结肠黏膜组织损伤程度明显高于正常组(p0.05),ZO-1及Ocluddin表达水平明显低于正常组(p0.05)。与模型组相比,美沙拉嗪组、布拉氏酵母菌组、联合治疗组的DAI评分及结肠黏膜组织损伤程度均明显减低(p0.05),ZO-1及Ocluddin表达水平明显增多(p0.05),联合治疗组效果更好。结论布拉氏酵母菌可对DSS诱导的结肠炎肠黏膜屏障功能起到保护作用,与美沙拉嗪联合应用效果更佳。     

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

The intestinal epithelium forms a barrier between the microbiota and the rest of the body. In addition, beyond acting as a physical barrier, the function of intestinal epithelial cells (IECs) in sensing and responding to microbial signals is increasingly appreciated and likely has numerous implications for the vast network of immune cells within and below the intestinal epithelium. IECs also respond to factors produced by immune cells, and these can regulate IEC barrier function, proliferation and differentiation, as well as influence the composition of the microbiota. The mechanisms involved in IEC–microbe–immune interactions, however, are not fully characterized. In this review, we explore the ability of IECs to direct intestinal homeostasis by orchestrating communication between intestinal microbes and mucosal innate and adaptive immune cells during physiological and inflammatory conditions. We focus primarily on the most recent findings and call attention to the numerous remaining unknowns regarding the complex crosstalk between IECs, the microbiota and intestinal immune cells.     

Expression of TLR2 and TLR5 in distal ileum of mice with obstructive jaundice and their role in intestinal mucosal injury

IntroductionThe aim was to investigate the expression of TLR2 and TLR5 in the distal ileum of mice with obstructive jaundice (OJ) and their role in intestinal mucosal injury.Material and methodsA total of 100 male C57BL/6J mice were randomly assigned to two groups: (I) sham operation (SH); (II) bile duct ligation (BDL). The mice were respectively sacrificed before operation and on the 1^st, 3^rd, 5^th and 7^th days after operation to collect specimens. Various indicators were detected by PCR, immunohistochemistry and other methods.ResultsTLR2 was increased gradually with the extension of OJ time in the BDL group (p < 0.05). However, the changes in the expression of TLR5 were not obvious at different time points. The amount of Bifidobacteria and Lactobacillus showed downward trends in intestinal tract of the BDL group. Furthermore, the amount of Escherichia coli was increased in intestinal tract of the BDL group. The pathological score of intestinal mucosa and the expression of NF-κB increased gradually in the BDL group with the extension of OJ time. There were positive correlations between the pathological score of intestinal mucosa and expressions of TLR2(r = 0.767, p < 0.05) and NF-κB (r = 0.817, p < 0.05) in BDL group. NF-κB expression was positively correlated with TLR2 expression(r = 0.706, p < 0.05).ConclusionsDisturbance of intestinal flora caused by OJ could increase the expression of NF-κB via up-regulating the expression of TLR2 to activate the downstream signaling pathway, thus aggravated the injury of intestinal mucosa.