Interaction between Batf3 dependent dendritic cells and the microbiota during experimental colitis

实验性结肠炎期间 Batf3 依赖性树突状细胞与微生物群之间的相互作用

• 批准号: 280526818
• 负责人: Professor Dr. Kai Hildner
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280526818?language=en
• 关键词: Interaction; between; Batf3; dependent; dendritic

The entity of intestinal microbes, also called microbiota, exerts critical functions, e.g. digestive properties and maintenance of barrier integrity in favor of the host. In order to control the close interaction between commensal flora and host cells a sophisticated immunological network has developed at mucosal surfaces to prevent on the one hand uncontrolled dissemination of microbiota beyond the intestine and on the other hand overshooting immune responses against apathogenic commensals. Mucosal dendritic cells (DCs) crucially contribute to the generation of an antimicrobial immune response and the maintenance of gut homeostasis. Previously, own work identified the transcription factor Batf3 as a central regulator of lymphoid resident CD8alphapos. and mucosal CD103pos.CD11bneg.DC development. Batf3 deficient mice therefore represent an excellent in vivo mouse model system allowing the analysis of the role of Batf3 dependent DCs during intestinal inflammation and infections. Interestingly, Batf3 deficient mice are relatively resistant to intestinal infection with Citrobacter rodentium, a rodent pathogen mirroring human pathogenic E. coli (e.g. EHEC) mediated colitis. Results from flora depletion studies via long term antibiotic treatment imply that the infection resistance is predominately mediated by the preexisting microbial colonization in the absence of Batf3. Interestingly cohousing and stool transplantation respectively are able to transfer relative protection against Citrobacter rodentium infection from Batf3 deficient to wildtype mice. Data derived from the noninfectious experimental transfer colitis model also demonstrate that colitis susceptibility is communicable via transfer of the intestinal flora. Preliminary analyses of the stool by next generation sequencing show that Batf3 deficiency is associated with significant alterations of intestinal microbiota composition compared to controls. Together these results show that Batf3 dependent DCs critically influence the composition or function of the gut microbiota and that the modulation seems to account for both the decreased infectious and increased immune-mediated colitis susceptibility in the absence of Batf3.So far studies addressing the consequences of selective DC deficiencies on the composition and function of the intestinal microbiota are limited. Therefore analyses addressing the contribution of Batf3 dependent DCs to the composition of gut microbiota on the one hand and the nature of the microbiota-dependent immunological effector mechanisms underlying the infection resistance against Citrobacter rodentium in Batf3 deficient mice on the other hand are in the center of the proposed research project. Results from these studies will provide the basis to develop targeted strategies to intentionally modulate the composition or function of the microbiota and of the immune system respectively as treatment options of infectious and inflammatory disease states of the gut.

肠道微生物的实体，也被称为微生物群，发挥关键的功能，如消化特性和维持屏障的完整性，有利于宿主。为了控制共生菌群和宿主细胞之间的密切相互作用，在粘膜表面形成了一个复杂的免疫网络，一方面防止微生物群在肠道外的不受控制的传播，另一方面防止对致病性共生菌的过度免疫反应。粘膜树突状细胞（DCs）对产生抗微生物免疫反应和维持肠道稳态至关重要。在此之前，我们自己的研究发现转录因子Batf3是淋巴细胞驻留cd8 α pos的中枢调节因子。粘膜cd103pos， cd11bneg。直流发展。因此，Batf3缺陷小鼠代表了一种优秀的体内小鼠模型系统，可以分析Batf3依赖性dc在肠道炎症和感染中的作用。有趣的是，Batf3缺陷小鼠对啮齿柠檬酸杆菌（一种啮齿类病原体，与人类致病性大肠杆菌（如肠出血性大肠杆菌）介导的结肠炎相似）的肠道感染具有相对抗性。通过长期抗生素治疗的菌群消耗研究结果表明，感染耐药性主要是由在缺乏Batf3的情况下预先存在的微生物定植介导的。有趣的是，共居和粪便移植分别能够将蝙蝠3缺陷小鼠对啮齿柠檬酸杆菌感染的相对保护转移到野生型小鼠。来自非传染性实验性转移性结肠炎模型的数据也表明，结肠炎的易感性是通过肠道菌群的转移而传染的。通过下一代测序对粪便进行的初步分析表明，与对照组相比，Batf3缺乏与肠道微生物群组成的显著改变有关。总之，这些结果表明，依赖Batf3的dc严重影响肠道微生物群的组成或功能，并且在缺乏Batf3的情况下，这种调节似乎可以解释感染性结肠炎的降低和免疫介导的结肠炎易感性的增加。到目前为止，研究选择性DC缺乏对肠道微生物群组成和功能的影响是有限的。因此，研究Batf3依赖性dc对肠道菌群组成的贡献，以及Batf3缺陷小鼠对啮齿柠檬酸杆菌（Citrobacter rodentium）感染抗性的微生物依赖免疫效应机制的性质，是本研究项目的核心。这些研究的结果将为制定有针对性的策略提供基础，以有意地调节微生物群和免疫系统的组成或功能，分别作为肠道感染性和炎症性疾病状态的治疗选择。