肠神经胶质细胞与体外循环致肠损伤相关性的研究进展

近年来,体外循环术后所引起的肠道功能改变及反映肠损伤的相关炎性介质变化越来越受到人们的关注。当肠屏障发生损害时,将会导致肠道内细菌移位、大量毒素及炎性因子释放,产生系统性炎症反应,进而引起脑、肺、肝、肾等多脏器功能衰竭。肠神经胶质细胞(EGCs)作为肠神经系统的重要组成部分,具有保护肠屏障功能及调节肠神经系统活动的作用。基础研究已证实,肠神经胶质细胞可作为肠屏障功能保护的相应靶点,通过激活EGCs的α7n Ach R来减轻肠屏障损伤所致的炎性反应。本文通过对近年体外循环所致肠屏障功能损伤机制和肠神经胶质细胞特点及其相关性的研究进展作一综述,从而为临床寻求防治肠损伤措施提供理论依据。     

M细胞在肠黏膜免疫中作用的研究进展

M细胞是肠道一种免疫细胞,同时,也是一种特殊的抗原运转细胞。M细胞具有特殊的形态结构特点,与肠黏膜免疫功能密切相关。目前认为,位于肠淋巴滤泡上皮中特化的M细胞是大多数黏膜病原体侵入机体的靶细胞,它能特异性的结合肠道大分子物质及微生物,并将其摄取、转运至位于其下的APC进行识别、处理,并激活T、B淋巴细胞,继而激发肠道黏膜免疫应答作用。本研究就目前国内外学者所做M细胞在肠黏膜免疫中作用的研究进展做一综述。     

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。     

防御素在肠黏膜屏障功能中的作用

肠黏膜不仅有消化和吸收功能,而且还具有重要的防御性屏障功能,它可以使机体的内环境保持相对稳定以维持机体的正常生命活动。当肠黏膜屏障受到损伤时,肠道中的微生物和毒素会突破肠黏膜屏障,进入门静脉和淋巴系统从而引起细菌移位,甚至发展为全身性的炎症反应综合征（systemic inflammatory response syndrome,SIRS）以及多器官功能衰竭综合征（multiple organs defic iency syndrome,MODS）。     

肠黏膜通透性的评估方法

肠黏膜屏障(intestinal mucosal barrier, IMB)包括机械屏障、化学屏障、生物屏障和免疫屏障,在维持肠上皮的完整性,防御细菌、内毒素及抗原的入侵等方面发挥着重要作用。IMB受损表现为肠黏膜通透性(intestinal mucosal permeability,IMP)增加以及跨膜电阻(transmembrane resistance, TR)降低,与消化、泌尿、循环、神经、代谢等机体多系统功能紊乱密切相关。利用短路电流(short circuit current, SCC)记录系统或跨上皮细胞电阻仪(transepithelial electrical resistance meter)检测肠黏膜或肠上皮电阻,以及生化检测外源性糖分子探针(口服)或特定内源性蛋白分子跨肠黏膜或肠上皮通透量,是评价肠黏膜或肠上皮通透性的常用方法。本文简介IMB的组成及其功能,重点讨论IMP的评估方法。     

小胶质细胞极化与抑郁症关系的研究进展

小胶质细胞控制着中枢神经系统主要的免疫功能,在各种精神疾病中发挥重要作用. 某些信号通路的激活引发的神经炎症与抑郁症的发生有着密切的关系. 小胶质细胞是神经炎症的主要介导者,不同的刺激促进小胶质细胞极化,不同极化类型的小胶质细胞能分泌多种炎性细胞因子,在神经炎症调节中具有重要的作用. 临床研究和体内外实验研究表明,抑郁症与小胶质细胞极化介导的神经炎症有关. 小胶质细胞极化参与抑郁症发生发展的可能机制包括NF-κB信号通路激活、呼吸爆发、补体受体3信号通路、NLRP3炎症激活、cannibalism受体1、Notch-1信号通路和过氧化物酶体增殖物激活受体γ的激活. 本文就小胶质细胞极化与抑郁关系的研究进展作一综述.     

基于脑-肠轴理论探讨针灸治疗认知障碍的机制

认知障碍是一种主要影响认知能力（包括学习、记忆、感知和问题解决等）的心理健康障碍。认知障碍常见于阿尔茨海默病、血管性痴呆、轻度认知障碍等患者。与药物治疗相比，针灸治疗具有低成本、可耐受性和安全等特点，已成为改善认知功能的潜在工具。许多研究表明，在认知障碍的患者中，针灸治疗具有明显改善认知功能的作用。但针灸改善认知功能的机制仍不清楚。基于中医从肠治脑的理论基础以及目前实验研究，脑-肠轴与针灸改善大脑认知功能关系密切。对于针灸改善认知的脑-肠轴机制的理解能促进肠道微生物微观机制研究，但肠道微生物存在个体差异、动态变化、种类繁多等特征，以肠道稳态为调控目标的新针灸方案有待研究完善与规范。本文综述了针灸干预脑-肠轴治疗认知障碍，针灸通过维持肠道生态平衡、保持肠道菌群多样性、调整有益菌群丰度、调节代谢、促进生成脑源性神经营养因子（BDNF）、抑制小胶质细胞激活、降低神经炎症反应、减少Aβ蛋白沉积等机制，实现对认知障碍的治疗。     

中国对虾中肠的超微结构与细胞化学研究

(1)在透射电镜下观察中国对虾 (PenaeuschinensisOsbeck)中肠肠壁的超微结构。结果显示 :中国对虾中肠肠壁由内向外依次为上皮细胞层、结缔组织层、肌层和结缔组织层四层结构。中肠上皮有明、暗两种细胞 ,以暗细胞占多数 ,两种上皮细胞都具有从肠腔吸收营养物质和向结缔组织中转运营养物质的功能。 (2 )运用酶细胞化学技术 ,显示中肠组织细胞中的酸性磷酸酶 (ACP)和酚氧化酶 (PO)活性 ,电镜观察显示 :ACP阳性反应出现在明细胞顶部的圆形小泡和明、暗两种细胞的溶酶体中 ,暗细胞顶部聚集着大量ACP阴性反应的酶原颗粒 ,酶原颗粒主要由暗细胞合成并分泌。PO颗粒出现在患病虾肠壁结缔组织内解体的颗粒细胞上和游离于结缔组织中。结缔组织除具有维持上皮细胞的形态、贮存营养物质的功能 ,还在对虾免疫反应中发挥作用     

缺氧环境下自噬对肠黏膜屏障的影响

肠黏膜屏障是机体屏障系统的重要组成部分,可有效阻止肠道寄生菌及其毒素向肠腔外组织移位,防止机体受内源性微生物及其毒素的侵害.自噬在各种生命活动中发挥着重要作用.在缺血缺氧等应激状态下,自噬对细胞存活、清除细胞内衰老细胞器等起重要作用.缺氧可诱导自噬.多数情况下自噬被认为是细胞的一种保护作用,然而在某些条件下细胞过度自噬也能导致细胞凋亡.肠黏膜屏障损伤的研究是目前医学研究领域的一个重要课题,本文就自噬在缺氧环境下对肠黏膜屏障的影响做一综述.     

肠内营养支持治疗对炎症性肠病患者肠黏膜屏障功能及炎症反应的影响

目的探讨早期肠内营养(EN)支持治疗对炎症性肠病(IBD)患者肠黏膜屏障功能及炎症反应的影响。方法将80例IBD患者按营养支持治疗途径分为EN组(48例)和肠外营养(PN)组(32例),在常规治疗的基础上分别给予早期EN、PN支持治疗。比较治疗前后2组患者营养学相关指标[白蛋白(ALB)、前白蛋白(PA)、转铁蛋白(TF)]、肠黏膜屏障功能指标(内毒素、D-乳酸)及炎症相关指标[C-反应蛋白(CRP)、降钙素原(PCT)、粪便钙卫蛋白(FCP)]水平。结果治疗前,2组患者各观察指标水平差异无统计学意义(P0.05);治疗后,与治疗前相比,2组患者血清ALB、PA及TF水平均显著升高(P0.05),血清内毒素、D-乳酸、CRP、PCT及FCP水平均显著降低(P0.05);与PN组患者治疗后相比,EN组治疗后血清PA水平显著升高(P0.05),血清内毒素、D-乳酸、CRP、PCT及FCP水平均显著降低(P0.05)。治疗后2组患者的血清ALB及TF水平之间差异无统计学意义(P0.05)。结论在常规治疗的基础上,早期EN支持治疗对IBD患者肠黏膜屏障功能的改善及炎症缓解作用优于PN支持治疗。     

哺乳动物肠上皮屏障中非编码RNAs的调控作用

哺乳动物肠上皮是一种拥有快速自我更新能力的组织,在维持机体免疫稳态与肠道应激后的损伤修复中发挥重要作用。源于隐窝底部的多能肠干细胞不断进行增殖、迁移与分化,并沿隐窝 绒毛轴向上移动,从而维持肠上皮完整性。该过程受严格而复杂的基因调控网络参与。越来越多的数据表明,肠上皮完整性受到广泛的非编码RNA的调控,主要包括肠黏膜再生、保护与上皮屏障功能等方面。本文重点讨论了两类非编码RNA(包括microRNAs和lncRNAs)转录后调控肠上皮屏障功能的研究进展。其中,miR-503、miR-146和lnc-uc.173、lnc-SPRY4-IT1、lnc-plncRNA1、lnc-Gata6等,能够促进肠黏膜的更新,增强上皮屏障功能;相反,miR-222、miR-29b、miR-195和lnc-H19与lnc-BC012900等,抑制肠上皮再生并破坏肠上皮屏障功能。miRNAs、mRNAs与lncRNAs间构成复杂的分子网络,共同调控肠上皮稳态。深入研究与肠上皮相关的miRNAs和IncRNAs分子及其作用机制,探寻引起肠黏膜炎症的关键分子靶标,为肠道炎症临床诊治提供新方向与新方法。     

哺乳动物肠上皮屏障中非编码RNAs的调控作用

哺乳动物肠上皮是一种拥有快速自我更新能力的组织,在维持机体免疫稳态与肠道应激后的损伤修复中发挥重要作用。源于隐窝底部的多能肠干细胞不断进行增殖、迁移与分化,并沿隐窝 绒毛轴向上移动,从而维持肠上皮完整性。该过程受严格而复杂的基因调控网络参与。越来越多的数据表明,肠上皮完整性受到广泛的非编码RNA的调控,主要包括肠黏膜再生、保护与上皮屏障功能等方面。本文重点讨论了两类非编码RNA(包括microRNAs和lncRNAs)转录后调控肠上皮屏障功能的研究进展。其中,miR-503、miR-146和lnc-uc.173、lnc-SPRY4-IT1、lnc-plncRNA1、lnc-Gata6等,能够促进肠黏膜的更新,增强上皮屏障功能;相反,miR-222、miR-29b、miR-195和lnc-H19与lnc-BC012900等,抑制肠上皮再生并破坏肠上皮屏障功能。miRNAs、mRNAs与lncRNAs间构成复杂的分子网络,共同调控肠上皮稳态。深入研究与肠上皮相关的miRNAs和IncRNAs分子及其作用机制,探寻引起肠黏膜炎症的关键分子靶标,为肠道炎症临床诊治提供新方向与新方法。     

Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF

Wound healing of the gastrointestinal mucosa is essential for the maintenance of gut homeostasis and integrity. Enteric glial cells play a major role in regulating intestinal barrier function, but their role in mucosal barrier repair remains unknown. The impact of conditional ablation of enteric glia on dextran sodium sulfate (DSS)-induced mucosal damage and on healing of diclofenac-induced mucosal ulcerations was evaluated in vivo in GFAP-HSVtk transgenic mice. A mechanically induced model of intestinal wound healing was developed to study glial-induced epithelial restitution. Glial-epithelial signaling mechanisms were analyzed by using pharmacological inhibitors, neutralizing antibodies, and genetically engineered intestinal epithelial cells. Enteric glial cells were shown to be abundant in the gut mucosa, where they associate closely with intestinal epithelial cells as a distinct cell population from myofibroblasts. Conditional ablation of enteric glia worsened mucosal damage after DSS treatment and significantly delayed mucosal wound healing following diclofenac-induced small intestinal enteropathy in transgenic mice. Enteric glial cells enhanced epithelial restitution and cell spreading in vitro. These enhanced repair processes were reproduced by use of glial-conditioned media, and soluble proEGF was identified as a secreted glial mediator leading to consecutive activation of epidermal growth factor receptor and focal adhesion kinase signaling pathways in intestinal epithelial cells. Our study shows that enteric glia represent a functionally important cellular component of the intestinal epithelial barrier microenvironment and that the disruption of this cellular network attenuates the mucosal healing process.     

Innate immune signalling at the intestinal epithelium in homeostasis and disease

The intestinal epithelium-which constitutes the interface between the enteric microbiota and host tissues-actively contributes to the maintenance of mucosal homeostasis and defends against pathogenic microbes. The recognition of conserved microbial products by cytosolic or transmembrane pattern recognition receptors in epithelial cells initiates signal transduction and influences effector cell function. However, the signalling pathways, effector molecules and regulatory mechanisms involved are not yet fully understood, and the functional outcome is poorly defined. This review analyses the complex and dynamic role of intestinal epithelial innate immune recognition and signalling, on the basis of results in intestinal epithelial cell-specific transgene or gene-deficient animals. This approach identifies specific epithelial cell functions within the diverse cellular composition of the mucosal tissue, in the presence of the complex and dynamic gut microbiota. These insights have thus provided a more comprehensive understanding of the role of the intestinal epithelium in innate immunity during homeostasis and disease.     

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro‐inflammatory cytokines such as IL‐1β and IL‐18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial‐intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.     

肠道上皮与肠道微生物相互作用的研究现状

肠道上皮是肠上皮细胞及其分泌物有机构成的黏膜界面。随着技术的进步和对肠道菌群作用的逐渐重视,研究者对肠道上皮与肠道微生物相互作用的认识也不断深入。研究表明,肠道上皮调节并维持肠道微生物的定殖与分布,肠道微生物也影响肠道上皮的多种屏障功能,二者通过一系列细胞分子机制紧密联系,共同维持肠道稳态。此外,其过程中产生的宿主-肠道菌群共代谢物被发现可以反映宿主的生理病理状态,作为指标被应用于临床疾病诊断、治疗效果评估和预后推测。本文基于近年的研究,综述了肠道上皮与肠道微生物的相互作用及其细胞分子机制,为进一步研究和临床应用总结了理论基础,并探讨了未来可能的研究方向。     

Survivin is a guardian of the intestinal stem cell niche and its expression is regulated by TGF-β

As an inhibitor of apoptosis (IAP) family member, Survivin is known for its role during regulation of apoptosis. More recently its function as a cell cycle regulator has become evident. Survivin was shown to play a pivotal role during embryonic development and is highly expressed in regenerative tissue as well as in many cancer types. We examined the function of Survivin during mouse intestinal organogenesis and in gut pathophysiology. We found high expression of Survivin in experimentally induced colon cancer in mice but also in colon tumors of humans. Moreover, Survivin was regulated by TGF-β and was found to be highly expressed during mucosal healing following intestinal inflammation. We identified that expression of Survivin is essential early on in life, as specific deletion of Survivin in Villin expressing cells led to embryonic death around day 12 post coitum. Together with our recent study on the role of Survivin in the gut of adult mice our data demonstrate that Survivin is an essential guardian of embryonic gut development and adult gut homeostasis protecting the epithelium from cell death promoting the proliferation of intestinal stem and progenitor cells.     

The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response

IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells.IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an ‘immunological niche’, in which immune response, inflammation and local homeostasis are modulated.Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases.     

No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation

Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.     

The unfolded protein response and its role in intestinal homeostasis and inflammation

The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from the stress caused by misfolded or unfolded proteins [1, 2]. As such, ER stress is an ongoing challenge for all cells given the central biologic importance of secretion as part of normal physiologic functions. This is especially the case for cells that are highly dependent upon secretory function as part of their major duties. Within mucosal tissues, the intestinal epithelium is especially dependent upon an intact UPR for its normal activities [3]. This review will discuss the UPR and the special role that it provides in the functioning of the intestinal epithelium and, when dysfunctional, its implications for understanding mucosal homeostasis and intestinal inflammation, as occurs in inflammatory bowel disease (IBD).