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

炎症性肠病(IBD)是迄今无法治愈的疾病，其特点是反复发作和严重的肠道炎症。尽管关于基本的和一般的疾病机制仍存在争议，但肠道屏障处不平衡的微生物-上皮相互作用的主要作用在临床医生和研究人员中是普遍接受的。在这一点上，我们的小组专注于潜在的上皮分化障碍。在我们的研究方法中，我们和其他人连续发现了IBD的一个亚型--小肠克罗恩病(CD)患者中一个重要的Wnt途径转录因子(TCF7L2，也称为TCF4)的紊乱。随后的研究也在类似的背景下发现了Wnt辅助受体(LRP6)。Wnt途径在维持细胞增殖和再生方面起着重要作用，同时也指导着胃肠道上皮细胞的分化。特别是，潘氏细胞的成熟和功能是由β-连环蛋白依赖的途径分支控制的。潘氏细胞通常专门位于隐窝的底部，紧挨着小肠中的干细胞。它们是抗菌肽的专业生产者，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途径的转录控制，并显示出回肠CD的主要减少。HD5和HD6以及其他潘氏细胞AMP在抵御致病威胁方面至关重要，但在控制肠道共生关系方面也是至关重要的。它们在患者体内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涉及的网络，进一步的研究是必不可少的。因此，我们计划在WNT控制的抗微生物防御的背景下分析微生物区系的作用，并确定可能导致患者上皮屏障宿主-微生物区系不平衡相互作用的潜在额外因素。

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.