Interaction between microbiota, antimicrobial defense and differentiation factors in Inflammatory Bowel Disease

炎症性肠病中微生物群、抗菌防御和分化因子之间的相互作用

• 批准号: 237716477
• 负责人: Professor Dr. Jan Wehkamp
• 金额: --
• 依托单位: Abteilung für Gastroenterologie, Hepatologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237716477?language=en
• 关键词: Interaction; between; microbiota; antimicrobial; defense

Inflammatory bowel diseases (IBD) are to date incurable and characterized be recurring and severe inflammations of the intestinal tract. Even though there is an ongoing dispute about basic and general disease mechanisms, a major role of an imbalanced microbial-epithelial interaction at the intestinal barrier is commonly accepted among clinicians and researchers. In this regard, our group focusses on a potentially disturbed epithelial differentiation. In our research approaches we and consecutively also others have found disturbances in an important Wnt pathway transcription factors (TCF7L2 also known as TCF4) in patients with small intestinal Crohn’s Disease (CD), a subgroup of IBD. Following studies also pinpointed a Wnt coreceptor (LRP6) in a similar context. The Wnt pathway is of major importance in maintaining proliferation, regeneration and paradoxically also directed differentiation of epithelia in the gastrointestinal tract. In particular, Paneth cell maturation and function is controlled by the β-catenin dependent branch of the pathway. Paneth cells are normally specifically found on the bottom of crypts right next to the stem cells in the small intestine. They are specialized producers of antimicrobial peptides which they store in granules and release upon stimulation of pattern recognition receptors. Their most abundant products, HD5 and HD6, are transcriptionally controlled by the Wnt pathway and exhibit a primary decrease in ileal CD. HD5 and HD6 as well as other Paneth cell AMPs are crucial in fending off pathogenic threats but also in controlling the relationship towards intestinal commensals. Their reduced expression in patients represents an interesting possibility for the development of targeted therapy approaches, but further studies are indispensable to gain a better understanding of the complicated system and the involved networks. We therefore plan to analyze the role of microbiota in the context of Wnt controlled antimicrobial defense, as well as to identify potential additional factors which might underlie the imbalanced host-microbiota interactions at the epithelial barrier in patients.

炎症性肠病（IBD）是迄今为止无法治愈的，其特征是肠道反复出现严重炎症。尽管关于基本和一般疾病机制仍存在争议，但临床医生和研究人员普遍接受肠道屏障中微生物-上皮相互作用不平衡的主要作用。在这方面，我们的研究小组专注于潜在的受干扰的上皮分化。在我们的研究方法中，我们和连续的其他人在小肠克罗恩病（IBD的一个亚组）患者中发现了一个重要的Wnt通路转录因子（TCF7L2也称为TCF4）的紊乱。随后的研究也在类似的情况下确定了Wnt辅助受体（LRP6）。Wnt通路在维持胃肠道上皮细胞的增殖、再生和诱导分化方面具有重要意义。特别是，Paneth细胞的成熟和功能是由该途径的β-catenin依赖分支控制的。Paneth细胞通常特异地位于小肠中紧邻干细胞的隐窝底部。它们是抗菌肽的专门生产者，它们储存在颗粒中，并在模式识别受体的刺激下释放。它们最丰富的产物HD5和HD6受Wnt通路的转录控制，并表现出回肠CD的主要减少。HD5和HD6以及其他Paneth细胞amp在抵御致病性威胁方面至关重要，但在控制肠道共生关系方面也至关重要。它们在患者中的表达减少为靶向治疗方法的发展提供了一个有趣的可能性，但为了更好地了解复杂的系统和相关的网络，进一步的研究是必不可少的。因此，我们计划分析微生物群在Wnt控制的抗菌防御中的作用，并确定可能导致患者上皮屏障中宿主-微生物群相互作用不平衡的潜在其他因素。