Hes1通过调控小肠共生菌定植来调节REG3γ表达的机制和作用

Intestinal epithelial cells (IECs) are not only the first barrier surfaces that separate mammalian hosts from the external environmental microbes, but also are crucial cells that maintain intestinal immune homeostasis. Previous studies demonstrated that Hes1 plays a central function in these IEC fate decisions. However, the role of Hes1 in immune homeostasis regulation of IECs remains unclear. Our previous experiments showed that inducible Hes1-deficiency in adult mice would result in loss of specific commensal (Bacteroidetes) in small intestine, down-regulation of REG3γ, and promotion of susceptibility to intestinal pathogenic bacteria infection and the development of colitis. Based on our results, we will focus on three aspects including how IEC-intrinsic Hes1 regulates intestinal homeostasis, how Hes1 increases some antimicrobial signals or antimicrobial proteins to suppress commensal colonization, and which kind of Bacteroidetes is mainly responsible for induction of REG3γ. This project will elucidate how Hes1 controls commensal colonization of small intestine and regulates the expression of REG3γ, and how these outcomes influence the susceptibility to intestinal pathogenic bacteria infection and the development of colitis. Investigating this mechanism will provide important theoretical foundation for us to understand the pathogenesis of inflammatory bowel disease.

肠道上皮细胞不仅是肠道黏膜系统隔离外界微生物的第一道屏障，而且还是维持肠道免疫稳态的重要细胞。研究表明Hes1对于肠道上皮细胞分化发育起重要作用，但Hes1在肠道上皮细胞中的免疫稳态调节作用还不清楚。本课题前期结果显示，成年鼠Hes1诱导性缺失后小肠会出现特定共生菌（Bacteroidetes）大量丢失，并伴随着REG3γ表达下降，最终增强了肠道病菌易感性和结肠炎发展。在此基础上，本课题将利用肠道上皮细胞特异性敲除小鼠进一步鉴定：1）Hes1在肠道上皮细胞中的免疫稳态调节作用；2）Hes1可能通过上调抗菌信号或抗菌蛋白来调控共生菌定植的机制；3）哪种共生菌Bacteroidetes主要负责诱导REG3γ的表达。最终阐明Hes1调控小肠共生菌定植和REG3γ表达的机制，以及其对肠道病原菌易感性和结肠炎发展的调控作用，为炎症性肠病的致病机理提供重要理论依据。

肠道上皮细胞不仅是肠道黏膜系统隔离外界微生物的第一道屏障，而且还是维持肠道免疫稳态的重要细胞。研究表明Hes1对于肠道上皮细胞分化发育起重要作用，但Hes1在肠道上皮细胞中的免疫稳态调节作用还不清楚。本课题前期结果显示，成年鼠Hes1诱导性缺失后小肠会出现特定共生菌（Bacteroidetes）大量丢失，并伴随着REG3γ表达下降，最终增强了肠道病菌易感性和结肠炎发展。在此基础上，本课题利用肠道上皮细胞特异性敲除小鼠进一步鉴定：1）Hes1在肠道上皮细胞中的免疫稳态调节作用；2）Hes1可能通过上调抗菌信号或抗菌蛋白来调控共生菌定植的机制；3）哪种共生菌Bacteroidetes主要负责诱导REG3γ的表达。经过研究，我们发现肠道上皮细胞Hes1通过调节肠道黏膜的microhabitats来维持microbiota定植的机制，且Hes1通过抑制菌群紊乱来遏制结肠炎发展，为炎症性肠病的致病机理提供理论依据。