肠黏膜屏障与肠道菌群的相互关系

摘要：人类肠道中微生物群与肠道环境相互作用以维持机体健康。肠黏膜屏障主要由黏液层、肠道菌群、肠道免疫系统和肠上皮细胞本身的完整性等构成。肠道作为直接与大量菌群接触的器官,其屏障功能在肠道健康中的作用尤为显著。肠道菌群与肠道屏障相互作用,保持肠道菌群与肠道屏障相对稳定,肠道菌群参与肠道免疫反应的建立,共同建立机体天然防御系统,在保持肠道免疫的动态平衡中具有重要作用。当两者之间的平衡被打破时,可诱发功能性胃肠病（如肠易激综合征）及免疫相关性疾病（如炎症性肠病）。本文主要阐述肠黏膜屏障与肠道菌群之间的相互关系以及与肠道屏障功能障碍相关的肠道疾病。     

肠道微生物与肠上皮细胞互作的免疫调节机制

人体肠道中寄居着数量众多、种类繁异的微生物,其在机体营养吸收、物质代谢以及免疫调节等方面发挥着积极作用,但肠道微生物(gut microbiota)群落结构失调或组织易位则与多种疾病的发生发展密切相关。肠上皮细胞(intestinal epithelial cells)作为机体直接接触众多肠道微生物的第一道屏障,在响应肠道微生物定植、调节肠道微生物群落结构以及维持肠黏膜屏障功能等方面发挥着至关重要的作用。本文将主要从肠黏膜免疫调控的角度,介绍肠道微生物与肠上皮细胞互作分子机制的最新研究进展。     

后生元(postbiotics):调节肝硬化患者肠道菌群及疾病进程的新策略

肝硬化是慢性肝炎发展的终末阶段,患者出现有不同程度的肠道菌群失调,并伴有肠道屏障功能的缺失和菌群移位,是引发肝硬化并发症的重要原因。尽管益生菌能在多个层面保护肠道屏障功能,但其在肝硬化肠道菌群紊乱中的疗效并不明确。现在的研究发现一些益生菌的组分或代谢产物有着与益生活菌类似的益生功效,包括稳定肠道菌群、加强肠上皮屏障功能和调节肠黏膜免疫反应等,其重要的优点是具有明确的分子结构和显著的生物活性,可能是未来调节肝硬化肠道菌群及疾病进程的新方向。本文主要总结了肝硬化肠道菌群失调对于肝硬化并发症及疾病进程的影响,探讨了益生菌的作用及局限性,并重点讨论后生元在调控肝硬化肠道菌群及疾病进程中的应用前景。     

活血化瘀法对肠道菌群结构及 肠屏障功能影响的研究

随着人们对于肠道菌群种类以及作用认识的逐渐深入,我们发现作为人体庞大而又复杂的微生态系统,肠道菌群的结构及和菌群分布有紧密联系的肠屏障功能的改变与人体的健康息息相关。中药作为传统医学的一种治疗方法,其对人体的治疗作用是十分显著的,而活血化瘀法是使用具有消散作用及攻逐体内淤血作用的药物来治疗人类各种疾病的一种方法,这种方法对于肠道菌群以及肠屏障功能也产生了深远的影响。本文围绕肠道菌群结构改变及肠黏膜屏障功能的变化,对近十年关于肠道菌群与活血化瘀方药的相关文献进行综述,探究活血化瘀法(中药及中药复方)对于肠道菌群的影响,为临床治疗提供新思路。     

短链脂肪酸对肠黏膜屏障的影响

肠黏膜屏障具有将致病性抗原等肠内物质与内环境隔离的功能,以维持内环境的相对稳定和机体的正常生命活动。其功能的维持依赖于人肠黏膜上皮细胞、肠道内正常菌群、肠道内分泌物和肠相关免疫细胞之间的功能协调,而其功能的发挥又受体内许多信号分子的影响。短链脂肪酸（short-chain fatty acids,SCFAs）就是其中一种重要的信号分子。SCFAs是肠道菌群的主要代谢产物之一,是肠道菌群与宿主代谢相互作用的媒介。宿主体内的SCFAs主要来自肠道菌群对膳食纤维的酵解,越来越多的研究证实,SCFAs不仅可以被肠道菌群利用,还可调节肠黏膜屏障及多种组织器官的代谢。本文主要就SCFAs对肠黏膜屏障的影响进行综述。     

白细胞介素-10在维持肠道稳态中的作用研究进展

肠道稳态是宿主肠道黏膜和免疫屏障、肠道环境、营养物质和代谢产物等相互作用而形成的动态平衡状态。白细胞介素-10(interleukin-10, IL-10)是IL-10细胞因子家族的成员之一,是免疫反应中重要的抗炎细胞因子,在维持肠道稳态中发挥重要作用。该文从IL-10在维持肠上皮细胞稳态、肠屏障完整性、肠道菌群平衡以及在肠道中的抗炎作用四个方面对IL-10在维持肠道稳态中作用的研究进展作一综述,并对IL-10在肠道疾病中的治疗前景进行展望。     

抗生素所致腹泻大鼠肠屏障功能损伤及乳酸杆菌保护机制的研究

目的探讨抗生素对所致腹泻大鼠肠道屏障功能、肠道菌群结构和肠道细菌移位的影响及乳酸杆菌制剂的保护机制。方法采用细菌培养法动态测定抗生素所致腹泻大鼠肠道菌群变化及肠系膜淋巴结、肝脏、脾脏和结肠组织的移位细菌量;应用光镜和电子显微镜观察肠黏膜组织超微结构变化。结果应用抗生素可致大鼠腹泻,肠道菌群失调,肠黏膜组织受损,发生肠道细菌移位。大肠埃希菌攻击可加重肠道菌群失调和肠黏膜损伤程度,促发细菌移位发生。乳酸杆菌可扶正肠菌群结构,修复损伤的肠黏膜,抑制肠细菌移位发生。结论阐明了抗生素、肠黏膜屏障功能、肠道菌群结构和肠道细菌移位间的互为因果,相互影响的关系。微生态制剂在维持机体微生态平衡、修复肠黏膜方面具有保护作用。     

肠道菌群在非甾体类抗炎药肠病中的作用及机制

非甾体类抗炎药(NSAIDs)是全球范围内广泛使用的解热镇痛抗炎药,但存在明显的胃肠道不良反应,可导致胃肠道溃疡、出血和穿孔等。目前,NSAIDs引起的肠病的发病率较高,且作用机制尚不明确。其中,肠黏膜屏障损伤在NSAIDs肠病发病机制中起着主要作用。近期研究表明肠道菌群与NSAIDs在机体内相互影响,且肠道微生物对肠黏膜屏障功能的维持有重要作用。肠道菌群失衡逐渐成为NSAIDs肠病的病理生理机制之一。本文综述了肠道菌群与NSAIDs药物作用的密切关系,并从肠黏膜屏障损伤和修复的角度阐述肠道菌群在NSAIDs肠病发生发展中的作用及机制,为以肠道菌群为靶标治疗NSAIDs肠病提供理论基础。     

加味四君子汤改善小鼠肠黏膜屏障作用的研究

目的 观察加味四君子汤和思密达改善小鼠肠黏膜屏障的作用.方法 盐酸林可霉素灌胃建立小鼠肠黏膜破损及肠道菌群失调模型.昆明种鼠随机分5组,进行肠道菌群检测、细菌易位分析及通透性(血浆二胺氧化酶)的检测.结果 盐酸林可霉素灌服小鼠3 d,肠道菌群失调、细菌平均易位率从正常对照组的12.5%增加到59%,血浆二胺氧化酶从正常对照组的2.08 mg/ml增加到7.18 mg/ml,肠黏膜屏障功能受损.分组分别给加味四君子汤、思密达后,肠道菌群得以调整,细菌平均易位率降低到9.35%以下,血浆二胺氧化酶减低到3.88 mg/ml以下.结论 加味四君子汤和思密达均能调整失调的菌群、降低肠道通透性和细菌易位率,改善小鼠肠黏膜屏障功能.     

肠上皮与肠道微生物相互作用研究进展

肠道不仅是消化和吸收的主要场所,也是机体重要的免疫器官。人类肠道中存在着超过百万亿的微生物,其在漫长的自然选择及共同进化中与宿主形成了紧密的共生关系。肠上皮是先天免疫的一个组成部分,通过各种黏膜保护屏障将肠腔内容物与机体内环境分隔开。各种肠上皮细胞相互协调维持肠道内稳态,并与肠道微生物、肠黏膜免疫系统共同形成抵御肠腔内有害抗原的第一道防线。肠上皮作为肠道微生物和肠黏膜免疫系统相互作用的枢纽,在黏膜免疫防御体系中具有重要作用,本文就肠上皮与肠道微生物之间的相互作用进行综述,旨在深入理解肠上皮,为探索肠道相关疾病的治疗提供新思路。     

Modulation of stem cell fate in intestinal homeostasis,injury and repair

The mammalian intestinal epithelium constitutes the largest barrier against the external environment and makes flexible responses to various types of stimuli. Epithelial cells are fast-renewed to counteract constant damage and disrupted barrier function to maintain their integrity. The homeostatic repair and regeneration of the intestinal epithelium are governed by the Lgr5⁺ intestinal stem cells (ISCs) located at the base of crypts, which fuel rapid renewal and give rise to the different epithelial cell types. Protracted biological and physicochemical stress may challenge epithelial integrity and the function of ISCs. The field of ISCs is thus of interest for complete mucosal healing, given its relevance to diseases of intestinal injury and inflammation such as inflammatory bowel diseases. Here, we review the current understanding of the signals and mechanisms that control homeostasis and regeneration of the intestinal epithelium. We focus on recent insights into the intrinsic and extrinsic elements involved in the process of intestinal homeostasis, injury, and repair, which fine-tune the balance between self-renewal and cell fate specification in ISCs. Deciphering the regulatory machinery that modulates stem cell fate would aid in the development of novel therapeutics that facilitate mucosal healing and restore epithelial barrier function.     

肠道微生物对肠道屏障功能完整性的维护机制研究概况

肠道微生物群是一个稳定且复杂的生态系统,可以通过形成菌膜屏障或促进肠道上皮细胞增殖分化等方式形成保护屏障,并在肠道病原菌感染和威胁期间维持和促进免疫稳态中起积极作用。本文重点叙述宿主-肠道微生物相互作用过程中抗病原菌感染的方式,以及肠道微生物参与合成抗菌化合物抵御肠道病原菌入侵和威胁的机制,为调控肠道微生物解决临床胃肠道疾病及其相关症状提供理论参考依据。     

益生菌与肠黏膜互作的分子机制研究进展

益生菌是一类定植于动物肠道,可辅助动物消化功能,维护肠道菌群平衡并可影响肠道免疫系统,有益于动物健康的重要调节性菌群。该类菌群与动物肠上皮细胞间互作的分子机制包括菌体表面分子如磷脂壁酸（phosphatidicacid,LTA）、表面层蛋白（Slayerprotein）等与宿主的粘附相关蛋白分子结合,通过占位效应抑制有害菌群在肠道内的定植;益生菌还可刺激肠道细胞分泌B防御素2、细菌素和有机酸等可抑制甚至杀灭有害菌群;在益生菌作用下,肠道上皮细胞可增强粘液糖蛋白、紧密连接蛋白occludin和ZO-1等分子的表达,加厚并加固肠道黏膜屏障;益生菌相关抗原可通过与抗原递呈细胞表面模式识别受体（TLRs等）分子结合,激活递呈细胞,启动各免疫细胞的交互作用,调节肠道免疫状态。     

Control of cell adhesion and compartmentalization in the intestinal epithelium

Continuous cell renewal in the intestinal mucosa occurs without disrupting the integrity of the epithelial layer. Despite the restrictions imposed by strong cell-to-cell adhesions, epithelial intestinal cells migrate constantly between tissue compartments. Alterations in cell adhesion and compartmentalization play key roles in diseases of the intestine. In particular, decreased E-cadherin-mediated adhesion during inflammatory bowel disease and loss of EphB/ephrin-B-mediated compartmentalization in colorectal cancer have recently emerged as key players of these prevalent pathologies. Here we will review our current knowledge on how cell-to-cell adhesion, migration and cell positioning are coordinated in the intestinal epithelium. We will highlight what the in vivo genetic analysis of intestinal epithelium has taught us about the complex regulation of cell adhesion and migration in homeostasis and disease.     

Disturbance of intraepithelial lymphocytes in a murine model of acute intestinal ischemia/reperfusion

Strategically located at the epithelial basolateral surface, intraepithelial lymphocytes (IELs) are intimately associated with epithelial cells and maintain the epithelial barrier integrity. Intestinal ischemia–reperfusion (I/R)-induced acute injury not only damages the epithelium but also affects the mucosal barrier function. Therefore, we hypothesized that I/R-induced mucosal damage would affect IEL phenotype and function. Adult C57BL/6J mice were treated with intestinal I/R or sham. Mice were euthanized at 6 h after I/R, and the small bowel was harvested for histological examination and to calculate the transmembrane resistance. Occludin expression and IEL location were detected through immunohistochemistry. The IEL phenotype, activation, and apoptosis were examined using flow cytometry. Cytokine and anti-apoptosis-associated gene expressions were measured through RT-PCR. Intestinal I/R induced the destruction of epithelial cells and intercellular molecules (occludin), resulting in IEL detachment from the epithelium. I/R also significantly increased the CD8αβ, CD4, and TCRαβ IEL subpopulations and significantly changed IEL-derived cytokine expression. Furthermore, I/R enhanced activation and promoted apoptosis in IELs. I/R-induced acute intestinal mucosal damage significantly affected IEL phenotype and function. These findings provide profound insight into potential IEL-mediated epithelial barrier dysfunction after intestinal I/R.     

A role for IL-22 in the relationship between intestinal helminths,gut microbiota and mucosal immunity

The intestinal tract is home to nematodes as well as commensal bacteria (microbiota), which have coevolved with the mammalian host. The mucosal immune system must balance between an appropriate response to dangerous pathogens and an inappropriate response to commensal microbiota that may breach the epithelial barrier, in order to maintain intestinal homeostasis. IL-22 has been shown to play a critical role in maintaining barrier homeostasis against intestinal pathogens and commensal bacteria. Here we review the advances in our understanding of the role of IL-22 in helminth infections, as well as in response to commensal and pathogenic bacteria of the intestinal tract. We then consider the relationship between intestinal helminths and gut microbiota and hypothesize that this relationship may explain how helminths may improve symptoms of inflammatory bowel diseases. We propose that by inducing an immune response that includes IL-22, intestinal helminths may enhance the mucosal barrier function of the intestinal epithelium. This may restore the mucosal microbiota populations from dysbiosis associated with colitis and improve intestinal homeostasis.     

TKT maintains intestinal ATP production and inhibits apoptosis-induced colitis

Inflammatory bowel disease (IBD) has a close association with transketolase (TKT) that links glycolysis and the pentose phosphate pathway (PPP). However, how TKT functions in the intestinal epithelium remains to be elucidated. To address this question, we specifically delete TKT in intestinal epithelial cells (IECs). IEC TKT-deficient mice are growth retarded and suffer from spontaneous colitis. TKT ablation brings about striking alterations of the intestine, including extensive mucosal erosion, aberrant tight junctions, impaired barrier function, and increased inflammatory cell infiltration. Mechanistically, TKT deficiency significantly accumulates PPP metabolites and decreases glycolytic metabolites, thereby reducing ATP production, which results in excessive apoptosis and defective intestinal barrier. Therefore, our data demonstrate that TKT serves as an essential guardian of intestinal integrity and barrier function as well as a potential therapeutic target for intestinal disorders.Subject terms: Apoptosis, Mechanisms of disease, Inflammatory bowel disease     

The gut as a lymphoepithelial organ: The role of intestinal epithelial cells in mucosal immunity

Mucosal surfaces covered by a layer of epithelial cells represent the largest and most critical interface between the organism and its environment. The barrier function of mucosal surfaces is performed by the epithelial layer and immune cells present in the mucosal compartment. As recently found, epithelial cells, apart from their participation in absorptive, digestive and secretory processes perform more than a passive barrier function and are directly involved in immune processes. Besides the well known role of epithelial cells in the transfer of polymeric immunoglobulins produced by lamina propria B lymphocytes to the luminal content of mucosals (secretory Igs), these cells were found to perform various other immunological functions, to interact with other cells of the immune system and to induce an efficient inflammatory response to microbial invasion: enzymic processing of dietary antigens, expression of class I and II MHC antigens, presentation of antigens to lymphocytes, expression of adhesive molecules mediating interaction with intraepithelial lymphocytes and components of extracellular matrix, production of cytokines and probable participation in extrathymic T cell development of intraepithelial lymphocytes. All these functions were suggested to influence substantially the mucosal immune system and its response. Under immunopathological conditions,e.g. during infections and inflammatory bowel and celiac diseases, both epithelial cells and intraepithelial lymphocytes participate substantially in inflammatory reactions. Moreover, enterocytes could become a target of mucosal immune factors. Mucosal immunosurveillance function is of crucial importance in various pathological conditions but especially in the case of the most frequent malignity occurring in the intestinal compartment,i.e. colorectal carcinoma. Proper understanding of the differentiation processes and functions of epithelial cells in interaction with other components of the mucosal immune system is therefore highly desirable. Dedicated to Professor J. Šterzl on the occasion of his 70th birthday