Analysis of the connection between inflammatory bowel disease and primary sclerosing cholangitis (PSC)

炎症性肠病与原发性硬化性胆管炎（PSC）的关系分析

• 批准号: 290523000
• 负责人: Professor Dr. Samuel Huber
• 金额: --
• 依托单位: I. Medizinische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290523000?language=en
• 关键词: Analysis; connection; between; inflammatory; bowel

Primary sclerosing cholangitis (PSC) is highly associated with inflammatory bowel disease (IBD). However, it is unclear, whether PSC favors the development of IBD or vice versa. This knowledge is critical in order to understand PSC and to develop novel treatments. Interestingly, polymorphisms in the IL2RA gene, a key gene for Foxp3+ Treg, are associated with both PSC and IBD. Also, the fecal microbiota is known to impact Foxp3+ Treg and is altered in patients with PSC and IBD, suggesting a further role of the intestinal microbiota. We hypothesize that the connection of PSC and IBD is due to impaired Treg function, which initiates a vicious circulus, which then drives both diseases. Indeed, our preliminary findings show that IBD protects from PSC and vice versa in different mouse models. This protection was dependent on Foxp3+ Treg. However, so far we have used mouse models in which Foxp3+ Treg were completely depleted or absent. Therefore, it is unclear, if these data could explain the association seen in humans. To overcome this caveat, we will analyze human samples and use mouse models which recapitulate IL2RA gene mutations. Finally, we will use patient-specific gnotobiotic mice to assess the role of the intestinal microbiota. Therefore, this study will clarify the influence of an impaired Foxp3+ Treg function and an altered microbiota on the association of PSC with IBD. Thus, if successful this study could build the basis for future therapies aiming at restoring or promoting Foxp3+ Treg function in PSC and IBD.

原发性硬化性胆管炎（PSC）与炎性肠病（IBD）高度相关。然而，目前尚不清楚PSC是否有利于IBD的发展，反之亦然。这些知识对于理解PSC和开发新的治疗方法至关重要。有趣的是，IL2RA基因（Foxp3+ Treg的关键基因）的多态性与PSC和IBD都有关。此外，已知粪便微生物群会影响Foxp3+ Treg，并在PSC和IBD患者中发生改变，这表明肠道微生物群的进一步作用。我们假设PSC和IBD的联系是由于Treg功能受损，这引发了一个恶性循环，然后驱动这两种疾病。事实上，我们的初步研究结果表明，在不同的小鼠模型中，IBD可以保护PSC，反之亦然。这种保护作用依赖于Foxp3+ Treg。然而，到目前为止，我们使用的小鼠模型中Foxp3+ Treg完全耗尽或缺失。因此，目前尚不清楚这些数据是否可以解释在人类中看到的关联。为了克服这一警告，我们将分析人类样本并使用重现IL2RA基因突变的小鼠模型。最后，我们将使用患者特异性的益生小鼠来评估肠道微生物群的作用。因此，本研究将阐明Foxp3+ Treg功能受损和微生物群改变对PSC与IBD关联的影响。因此，如果这项研究成功，将为未来旨在恢复或促进PSC和IBD中Foxp3+ Treg功能的治疗奠定基础。