肠黏膜屏障功能异常与炎症性肠病

正常肠黏膜屏障由机械屏障、化学屏障、免疫屏障、生物屏障构成,能有效阻止肠道内细菌和内毒素易位。检测肠黏膜通透性可反映肠黏膜屏障功能。肠黏膜屏障受营养、感染、损伤等多种因素影响。研究表明肠黏膜屏障功能损伤与炎症性肠病（IBD）密切相关,然而其为IBD的病因还是继发性改变目前仍存在争议。保护和恢复肠黏膜屏障功能对IBD的治疗具有重要意义。     

炎症性肠病肠黏膜屏障功能障碍研究及治疗进展

近年来对肠道功能的认识已经从最初的营养物质的消化吸收发展到对屏障功能的关注。肠黏膜屏障在防御外来抗原物质对机体的侵袭,保持机体内环境相对稳定,维持机体的正常生命活动等方面有重要的作用。炎症性肠病（IBD）的发病机制尚未完全明确,主要与遗传、环境、自身免疫、感染等有关。研究表明,IBD患者都存在不同程度的肠黏膜屏障功能障碍。本文就此作一综述。     

肠黏膜屏障与炎症性肠病

炎症性肠病（Innammatory bowel disease，IBD）是一组病因不明的慢性肠道炎症性疾病，主要包含两个独立的疾病，溃疡性结肠炎（Ulcerative colitis，UC）和克罗恩病（Crohn’s disease，CD）。近年研究发现，肠黏膜屏障功能异常在IBD发病机制中发挥重要作用。更好地了解正常及疾病状态下肠黏膜屏障的结构和功能可以为IBD的治疗提供新的思路。     

肠黏膜屏障及其在炎症性肠病中的作用

炎症性肠病(IBD)是一种以慢性炎性反应和胃肠道上皮损伤为特征的自身免疫性肠道疾病,其与肠黏膜屏障有密切的关系,具体发病机制尚不明确。肠黏膜屏障是肠道能够防止肠内的微生物及其相关产物穿过肠黏膜进入人体内的结构和功能的总和,分为机械屏障、化学屏障、生物屏障以及免疫屏障。肠黏膜屏障功能的完整性能防止微生物引发的过度免疫反应,后者被认为是IBD的主要发病机制。该文就肠黏膜屏障及其在IBD中的作用作一综述。     

紧密连接蛋白与炎症性肠病

紧密连接是构成肠道黏膜机械屏障上皮细胞的重要结构,可防止肠道有害物质侵入肠黏膜组织,维持肠上皮的通透性和细胞的极性。在炎症性肠病(IBD)发病过程中,炎性细胞因子影响紧密连接蛋白的表达,使连接复合物遭到破坏,引起肠上皮通透性增加。目前在IBD的发病机制中侧重于肠上皮细胞和细胞间紧密连接结构和功能的改变,维持和修复肠上皮屏障可望成为治疗IBD的新策略。     

炎症性肠病肠黏膜屏障损伤机制

肠黏膜屏障是指将肠腔内细菌、抗原等物质与肠黏膜固有层免疫细胞隔离开,避免固有层免疫细胞激活的肠黏膜结构,要由肠黏膜基底膜、上皮细胞层及其表面的黏液层所构成.炎症性肠病(innammatory bowel diseasc,IBD)肠黏膜屏障损伤的机制为:IBD发病时,肠黏膜所产生的大量炎症细胞因子、炎症介质等损伤肠上皮细胞,诱导上皮细胞凋亡;影响上皮细胞紧密连接蛋白的表达及分布,破坏上皮细胞间紧密连接;抑制黏蛋白的产生,破坏上皮细胞表面的黏液层,造成肠黏膜屏障障碍.     

肠碱性磷酸酶在肠黏膜屏障中的作用

肠碱性磷酸酶(intestinal alkaline phosphatase, IAP)是一种碱性磷酸酶,在维持肠黏膜屏障的稳定和肠道功能具有重要作用,其中包括调节十二指肠pH、反映肠道的发育情况及小肠上皮细胞的吸收能力,降低肠道脂多糖毒力、预防和减少肠道炎症、调节肠道菌群分布、抑制细菌位移、改善肠道钙吸收等功能.本文对近年来IAP在肠黏膜屏障中的作用研究进展做一综述.     

肠黏膜免疫与炎症性肠病

炎症性肠病(IBD)包括溃疡性结肠炎(UC)和克罗恩病(CD),是除恶性肿瘤外最严重的肠道疾病之一,其病因和发病机制目前仍不清楚,难以用单一原因解释.多认为是易感性宿主对细菌的异常免疫反应引起.IBD的标志是肠道炎症,被破坏的肠道保护屏障、腔内细菌与黏膜免疫系统三者相互作用产生炎症.本研究从肠黏膜屏障的破坏、各种免疫细胞参与及机体发生的免疫反应3方面阐述肠黏膜免疫与IBD的关系.     

黏液屏障在炎症性肠病中的研究进展

炎症性肠病(IBD)是一种慢性非特异性肠道炎症性疾病,主要包括溃疡性结肠炎(UC)和克罗恩病(CD)。IBD的发病原因尚未完全阐明,主要与基因、环境、免疫功能紊乱以及肠道黏膜屏障功能失调有关。黏液屏障作为肠道黏膜屏障的第一道防线,在IBD发生、发展中发挥重要作用。本文就黏液屏障在IBD中的研究进展作一综述。     

肠内营养与肠黏膜屏障的保护

肠黏膜屏障主要由机械屏障、生物屏障、化学屏障和免疫屏障肠黏膜屏障组成.根据肠屏障的结构、受损原因及病理生理过程的变化,可将肠屏障功能保护措施分为针对维持肠道微生态平衡及针对保护肠上皮细胞功能两大类.     

炎症性肠病发病机制新进展

炎症性肠病（IBD）的病因和发病机制至今仍未完全明确。近年研究认为其发病与免疫、遗传、环境、微生物等因素均有着密切的联系。本文对近年IBD发病机制研究的新进展，包括IBD的易感基因、环境因素对IBD的影响、宿主防御反应与肠道菌群的相互作用以及IBD的肠黏膜屏障和内环境、先天性免疫和获得性免疫情况作一综述。     

Adherent-invasive Escherichia coli target the epithelial barrier

Involvement of intestinal microbes in the pathogenesis of chronic inflammatory bowel diseases (IBD, including Crohn disease and ulcerative colitis) is well established. However, the mechanisms by which bacteria lead to intestinal injury in IBD remain unclear and are the focus of current research. Using adherent-invasive Escherichia coli (AIEC) strain LF82, which is linked to Crohn disease, we recently demonstrated the ability of these intestinal microbes to disrupt the integrity of epithelial cells in an in vitro cell model. This disruption provides the bacteria a capacity to penetrate into and beyond the epithelial monolayer, replicate in cells, disseminate within the host, and induce a chronic immune response. These findings provide a link between microbes related to IBD, disruption of the intestinal epithelial cell barrier, and disease pathogenesis.In this addendum, we provide a synopsis on current data concerning the role of AIEC in the pathogenesis of intestinal inflammation, summarise our recent findings, and highlight the central role of the epithelium in mucosal defence. We also discuss, in more detail, the potential implications of our findings and present ideas for future studies and targets for intervention.     

Adherent-invasive Escherichia coli target the epithelial barrier

Involvement of intestinal microbes in the pathogenesis of chronic inflammatory bowel diseases (IBD, including Crohn disease and ulcerative colitis) is well established. However, the mechanisms by which bacteria lead to intestinal injury in IBD remain unclear and are the focus of current research. Using adherent-invasive Escherichia coli (AIEC) strain LF82, which is linked to Crohn disease, we recently demonstrated the ability of these intestinal microbes to disrupt the integrity of epithelial cells in an in vitro cell model. This disruption provides the bacteria a capacity to penetrate into and beyond the epithelial monolayer, replicate in cells, disseminate within the host, and induce a chronic immune response. These findings provide a link between microbes related to IBD, disruption of the intestinal epithelial cell barrier, and disease pathogenesis.

In this addendum, we provide a synopsis on current data concerning the role of AIEC in the pathogenesis of intestinal inflammation, summarise our recent findings, and highlight the central role of the epithelium in mucosal defence. We also discuss, in more detail, the potential implications of our findings and present ideas for future studies and targets for intervention.     

Potential roles of neutrophils in regulating intestinal mucosal inflammation of inflammatory bowel disease

Inflammatory bowel diseases (IBD), comprising of ulcerative colitis and Crohn's disease, are inflammatory disorders of the gastrointestinal tract characterized by chronically relapsing mucosal inflammation. Neutrophils, as the effector cells of acute inflammation, have long been reported to play a role in the maintenance of intestinal homeostasis and pathogenesis of IBD. At the early stage of mucosal inflammation in patients with IBD, neutrophils flood into intestinal mucosa, phagocytose pathogenic microbes, and promote mucosal healing and resolution of inflammation. However, large numbers of neutrophils infiltrating in the inflamed mucosa and accumulating in the epithelia cause damage of mucosal architecture, compromised epithelial barrier and production of inflammatory mediators. In this review we discuss the critical roles of neutrophils in modulating innate and adaptive immune responses in intestinal mucosa, and, importantly, clarify the potential roles of neutrophils related to their production of inflammatory mediators, transenthothelial and transepithelial migration into intestinal mucosa, and the underlying mechanisms in regulating mucosal inflammation of IBD. Moreover, we also describe a new subset of neutrophils (i.e., CD177⁺ neutrophils) and illustrate its protective role in modulating intestinal mucosal immune responses in IBD.     

Recent advances in basic and clinical aspects of inflammatory bowel disease： Which steps in the mucosal inflammation should we block for the treatment of inflammatory bowel disease？

There are four steps in the interaction between intestinal microbes and mucosal inflammation in genetically predisposed individuals from the viewpoints of basic and clinical aspects of inflammatory bowel disease （IBD）. The first step is an interaction between intestinal microbes or their components and intestinal epithelial cells via receptors, the second step an interaction between macrophages and dendritic cells and mucosal lymphocytes, the third step an interaction between lymphocytes and vascular endothelial cells, and the fourth step an interaction between lymphocytes and granulocytes producing proinflammatory cytokines or free radicals and mucosal damage and repair. Recent therapeutic approaches for IBD aim to block these four steps in the intestinal inflammation of patients with IBD.     

TGF-β in inflammatory bowel disease: a key regulator of immune cells,epithelium, and the intestinal microbiota

Inflammatory bowel disease (IBD) is defined as chronic intestinal inflammation, and includes ulcerative colitis and Crohn’s disease. Multiple factors are involved in the pathogenesis of IBD, and the condition is characterized by aberrant mucosal immune reactions to intestinal microbes in genetically susceptible hosts. Transforming growth factor-β (TGF-β) is an immune-suppressive cytokine produced by many cell types and activated by integrins. Active TGF-β binds to its receptor and regulates mucosal immune reactions through the TGF-β signaling pathway. Dysregulated TGF-β signaling is observed in the intestines of IBD patients. TGF-β signal impairment in specific cell types, such as T-cells and dendritic cells, results in spontaneous colitis in mouse models. In addition, specific intestinal microbes contribute to immune homeostasis by modulating TGF-β production. In this review, we describe the role of TGF-β in intestinal immunity, focusing on immune cells, epithelium, and intestinal microbes. In addition, we present potential therapeutic strategies for IBD that target TGF-β.

     

Mucosal healing and inflammatory bowel disease: Therapeutic implications and new targets

Mucosal healing (MH) is vital in maintaining homeostasis within the gut and protecting against injury and infections. Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair. However, when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results, particularly inflammatory bowel disease (IBD). Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions, with the mechanisms of regulation just beginning to be understood. Consequently, there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes, so tissue damage in the gastrointestinal tract of patients, even those in clinical remission, persists. With increased understanding of the molecular mechanisms of IBD and MH, tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response. In this review, we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.     

Mucins in inflammatory bowel diseases and colorectal cancer

The gastrointestinal tract is protected by a mucus barrier with both secreted and cell-surface mucins contributing to the exclusion of luminal microbes and toxins. Alterations in the structure and/or quantity of mucins alter the barrier function of mucus and could play roles in initiating and maintaining mucosal inflammation in inflammatory bowel diseases (IBD), and in driving cancer development in the intestine. The aim of this review is to focus on the roles of the mucins in IBD. The polymorphisms of mucin genes that have been associated with susceptibility to IBD, and alterations in mucin expression as well as factors that regulate production of the mucins in IBD, are summarized. Data from animal models of intestinal inflammation, which support the importance of mucins in IBD and cancer development, are also discussed.     

炎症性肠病基础研究进展——与临床的联系

炎症性肠病（IBD）包括溃疡性结肠炎（UC）和克罗恩病（CD）,是一组反复发作的非特异性慢性肠道炎症性疾病,其病因尚未完全阐明。近年来随着基因组学、免疫遗传学、分子生物学等的发展以及DNA重组动物模型技术的日趋成熟,IBD病因学和发病机制的研究进展迅猛．取得了巨大的成绩。IBD易感基因的发现,驱动了肠道共生菌与肠上皮屏障相互作用致肠黏膜免疫失衡以及天然性免疫与适应性免疫的相互作用等多方面的进展,对IBD发病机制和疾病本质的揭示起到了重要作用。