Impact of microbiota on the intestinal macrophage compartment

炎症性肠病(IBD)的发病机制尚不完全清楚。值得注意的是，全基因组关联研究只解释了大约四分之一的疾病病例。与此同时，自第二次世界大战以来，IBD的发病率一直在稳步上升，这表明环境因素和随后肠道微生物区系的变化有助于这种发展。由此可以得出结论，肠道微生物区系在肠粘膜的动态平衡中起着至关重要的作用。巨噬细胞亚群强烈地决定着粘膜免疫系统的平衡。虽然在健康调节中M2亚型占主导地位，但炎症性M1亚型主要存在于肠道炎症中，如炎症性肠病。在本项目中，我们的目标是确定微生物区系在肠腔内巨噬细胞亚型发育中的作用。这种影响是否仅限于新生阶段，或者也可能发生在成年阶段，将通过比较出生后直接或五周大的小鼠保持无菌或与微生物群相关的小鼠来阐明。为了能够确定微生物区系介导的肠道巨噬细胞间隔变化与IBD的功能相关性，将纳入各种慢性肠道炎症模型。最终，单个细菌或细菌化合物将被识别出来，它们有可能将巨噬细胞隔间调节到调节亚型，从而维持体内平衡。同时，一个由患者和对照组的体外极化巨噬细胞或肠道巨噬细胞组成的人体体外系统将被用于将研究结果从小鼠系统转移到人类情况。这一翻译系统还将使评估疾病相关突变对巨噬细胞亚型上微生物区系依赖效应的功能影响成为可能。这些研究将表征定义的微生物区系在肠粘膜巨噬细胞发育中的作用。所获得的结果有望帮助开发未来治疗IBD的治疗策略。

The pathogenesis of inflammatory bowel diseases (IBD) is incompletely understood. Remarkably the genome wide association studies explain only about one fourth of the disease cases. In parallel the incidence IBD has been increasing steadily since the Second World War, suggesting that environmental factors and ensuing changes in the intestinal microbiota contribute to this development. It may be concluded that intestinal microbiota play a crucial role in the homeostasis of the intestinal mucosa. Macrophage subpopulations strongly determine the balance of the mucosal immune system. While in health regulatory M2 subtypes are predominant, the inflammatory M1 subtype has primarily been found in intestinal inflammation such as inflammatory bowel diseases. With the present project we aim to define the role of microbiota in the development of macrophage subtypes in the intestinal compartment. Whether such effects are restricted to the neonatal phase or can also occur in the adult phase will be elucidated by comparing mice that stay germfree or are associated with microbiota directly after birth or at five weeks of age. To be able to define the functional relevance of microbiota-mediated changes in the intestinal macrophage compartment for IBD, various models of chronic intestinal inflammation will be included. Ultimately, single bacteria or bacterial compounds will be identified that have the potential to modulate the macrophage compartment to the regulatory subtype and thus maintain homeostasis. In parallel, a human in-vitro system with in vitro-polarized macrophages or intestinal macrophages from patients and controls will be used to transfer the findings from the mouse system to the human situation. This translational system will in addition make it possible to assess the functional impact of disease-associated mutations on the microbiota-dependent effects on macrophage subtypes.These studies will characterize the role of defined microbiota in the development of the macrophage development in the intestinal mucosa. The obtained results are expected to help in the development of future therapeutic strategies for the treatment of IBD.