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

原发性硬化性胆管炎(PSC)与炎症性肠病(IBD)密切相关。然而，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，Foxp3+Treg的关键基因IL2RA基因的多态性与PSC和IBD都有关。此外，粪便微生物区系已知会影响Foxp3+Treg，并在PSC和IBD患者中发生改变，这表明肠道微生物区系有进一步的作用。我们假设PSC和IBD的联系是由于Treg功能受损所致，Treg功能受损引发了恶性循环，然后推动了这两种疾病。事实上，我们的初步发现表明，在不同的小鼠模型中，IBD对PSC具有保护作用，反之亦然。这种保护依赖于Foxp3+Treg。然而，到目前为止，我们使用的是Foxp3+Treg完全耗尽或缺失的小鼠模型。因此，目前还不清楚这些数据是否能解释在人类身上看到的联系。为了克服这一警告，我们将分析人类样本，并使用概括IL2RA基因突变的小鼠模型。最后，我们将使用患者特定的灵知生物群小鼠来评估肠道微生物区系的作用。因此，本研究将阐明Foxp3+Treg功能受损和微生物区系改变对PSC与IBD相关性的影响。因此，如果这项研究成功，可以为未来旨在恢复或促进PSC和IBD的Foxp3+Treg功能的治疗奠定基础。

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.