肠道上皮Hes1介导抗菌信号调节拟杆菌定植在炎症性肠病中的作用机制

In the recent years, there has been a significant increase in the incidence of inflammatory bowel disease (IBD) in our country while its underlying pathogenic mechanisms remain elusive. A recent study from our laboratory demonstrated that transcription repressor Hes1 plays a key role in fine-tuning macrophage-mediated inflammatory responses (Nature Immunology 2016). To further explore the function of Hes1 in the immune system, we examined expression of Hes1 in various immune organs and tissues and found that Hes1 is highly expressed in intestinal epithelial cells (IECs), yet knowledge regarding Hes1 in gut mucosal immunity is scarce. We set to employ rigorous genetic approaches using inducible as well as tissue-specific conditional knockout mice to characterize the function of Hes1 in gut mucosal immunity under homeostatic and inflammatory conditions. Interestingly, we found that Hes1 deficiency in IECs resulted in drastic loss of specific commensal bacteria belonging to the Bacteroidetes phylum in small intestine. Hes1 deficiency-induced dysbiosis led to diminished expression of commensal-dependent anti-microbial peptides (AMPs), increased susceptibility to intestinal pathogenic bacteria infection, and exacerbated enteritis, all of which were indicative of severe disruption of gut homeostasis. Based on these findings, we propose to systematically investigate the mechanisms by which Hes1 contributes to the maintenance of a balanced gut microbiota and thus of mucosal homeostasis as well as physio-pathological significance of Hes1-mediated regulation in the context of IBD pathogenesis. We will focus our investigative efforts on three fruitful areas: (1) mechanisms by which Hes1 inhibits detrimental AMP activities to sustain Bacteroidetes colonization; (2) how Bacteroidetes colonization regulates IEC function to maintain gut homeostasis; (3) the potential involvement of Bacteroidetes in IBD pathogenesis. If successfully implemented, this project will establish Hes1 as a host derived factor that critically controls Bacteroidetes colonization and elucidate novel molecular mechanisms of epithelium-commensal interaction that contributes to maintenance of a balanced microbiota. Moreover, our work will also provide important insights into mechanisms underlying IBD-associated dysbiosis and help develop new therapeutic strategies targeting IBD.

近年来我国炎症性肠病发病率显著增加，但致病机理尚不明了。本课题组最新研究显示转录抑制子Hes1在调节巨噬细胞炎症反应中起到关键作用。为了进一步研究Hes1的免疫调节作用，我们筛查多种免疫组织，发现Hes1在肠道上皮细胞中高表达，但是Hes1在肠道黏膜免疫中的作用尚不清楚。本课题建立了诱导性和组织特异性Hes1缺失小鼠，发现肠道上皮细胞Hes1缺失后小肠共生菌，特别是拟杆菌门大量丢失、细菌依赖性抗菌肽表达下降，以及肠道病菌感染和肠炎加重，提示了肠道稳态被破坏。基于此，本课题将系统地研究Hes1调节肠道菌群稳态和炎症性肠病发展的机制，具体方向为：1）Hes1通过抑制抗菌信号来维持拟杆菌定植；2）拟杆菌调节肠道上皮细胞来维持肠道稳态；3）拟杆菌调节炎症性肠病的发展。如果进展顺利，我们将揭示一种肠道上皮细胞与共生菌相互作用调节肠道稳态的新机制，为人们深入理解炎症性肠病中菌群紊乱的机理提供有力依据。

近年来我国炎症性肠病发病率显著增加，但致病机理尚不明了。本课题组的研究显示转录抑制子Hes1在调节巨噬细胞免疫反应中起到关键作用。为了进一步研究Hes1的免疫调节作用，我们筛查多种免疫组织，发现Hes1在肠道上皮细胞中高表达，但是Hes1在肠道黏膜免疫中的作用尚不清楚。本项目主要研究了肠道上皮细胞Hes1调控共生菌定植的作用机制及其在特定生理状态下上皮细胞Hes1调节肠道黏膜抗菌防御的分子机制。本研究发现，肠道上皮细胞Hes1通过调节肠道黏液微环境来维持共生菌定植的机制，并且Hes1缺失小鼠来源的共生菌会加重结肠炎的发展。另外，本研究还发现哺乳动物通过营养感知信号mTOR途径控制肠道上皮细胞Hes1的翻译，进而调节α-防御素的成熟以抵抗肠道病原菌感染的分子机制。该研究首次将哺乳动物肠道上皮细胞的营养感知系统与宿主防御功能联系起来，将代谢免疫研究拓展到了肠道上皮抗菌防御领域，暗示了这种营养感知信号调控抗菌防御的作用机制在哺乳动物进化过程中的生物学意义，为人们更好地理解宿主与微生物协同进化提供了重要线索。