IRE1beta links the gut microbiota and epithelial differentiation to protect against colitis

IRE1beta 将肠道微生物群和上皮分化联系起来以预防结肠炎

• 批准号: 10906588
• 负责人: Michael J Grey
• 金额: $ 9.72万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-11 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10906588
• 关键词: IRE1beta; links; gut; microbiota; epithelial

Project Summary Ulcerative colitis (UC) is a common, chronic form of inflammatory bowel disease characterized by superficial inflammation and damage to the epithelium of the colon and rectum. While causes of UC are unknown, genetic studies point to inappropriate immune signaling, mishandling of the gut microbiota, and altered epithelial repair mechanisms as contributing factors. A common feature of UC is an altered mucus layer in the colon epithelium, which may be due to changes in mucin biosynthesis as well as to defects in differentiation of goblet cells. As the mucus layer normally serves as a protective innate immune barrier, separating microbes from the epithelial surface, defects in mucus assembly allow gut bacteria to interface with the colonic epithelium more closely. This has been implicated in triggering immune responses or increasing susceptibility to infections that contribute to UC pathophysiology. ER stress and the unfolded protein response is intimately linked to secretory cell function and inflammation in the intestinal epithelium. The intestinal epithelium and other mucosal epithelia are unique in that they express an additional ER stress sensor called IRE1β. IRE1β appears to protect against colonic injury and inflammation by unknown mechanisms. We recently found that IRE1β functions in the unfolded protein response in intestinal epithelial cells, and discovered that the colon of IRE1β-/- mice closely resembles human UC. IRE1β-/- mice have fewer mature goblet cells in the colon compared to IRE1β+/+ littermates. This is associated with a nearly abolished inner mucus layer that places the gut microbiota immediately adjacent to the colonic epithelium. Under steady state conditions IRE1β-/- colonic crypts do not express elevated markers of a UPR, suggesting that unresolved ER stress cannot explain this phenotype. Instead, it appears that IRE1β is required for expression of transcription factors that specify goblet cell development. Notably, we find IRE1β expression and assembly of the colon mucus layer are stimulated by the gut microbiota. These data place IRE1β's function at the interface of the microbiota and the epithelium, regulating the innate barrier that protects the host from inflammatory signals and infection. The purpose of this grant is to understand how IRE1β protects against colitis, where our central hypothesis is IRE1β protects against colitis by controlling microbiota-induced goblet cell differentiation and assembly of the colon mucus layer. We will use in vitro and in vivo models to understand how the microbiota regulates IRE1β function (Aim 1), define how IRE1β regulates goblet cell differentiation (Aim 2), and establish the relevance of IRE1β function in protecting against colitis in experimental models and human UC (Aim 3).

项目概要 溃疡性结肠炎 (UC) 是一种常见的慢性炎症性肠病，其特征为浅表性炎症 结肠和直肠上皮的炎症和损伤。虽然 UC 的病因尚不清楚，但遗传性 研究指出免疫信号传导不当、肠道微生物群处理不当以及上皮修复改变 机制作为影响因素。 UC 的一个共同特征是结肠粘液层的改变 上皮细胞，这可能是由于粘蛋白生物合成的变化以及杯状细胞分化的缺陷所致 细胞。由于粘液层通常充当保护性先天免疫屏障，将微生物与 上皮表面，粘液组装缺陷使肠道细菌能够更多地与结肠上皮接触 密切。这与触发免疫反应或增加对感染的易感性有关 对 UC 病理生理学做出贡献。内质网应激和未折叠蛋白反应与分泌密切相关 肠上皮细胞功能和炎症。肠上皮和其他粘膜上皮 其独特之处在于它们表达了一种额外的内质网应激传感器，称为 IRE1β。 IRE1β 似乎可以防止 未知机制引起的结肠损伤和炎症。我们最近发现 IRE1β 在 展开肠上皮细胞中的蛋白质反应，并发现 IRE1β-/- 小鼠的结肠密切相关 类似于人类UC。与 IRE1β+/+ 相比，IRE1β-/- 小鼠结肠中成熟杯状细胞较少 同窝的。这与几乎被废除的内部粘液层有关，该层将肠道微生物群置于 紧邻结肠上皮。在稳态条件下，IRE1β-/-结肠隐窝不 表达升高的 UPR 标记，表明未解决的 ER 应激不能解释这种表型。 相反，IRE1β 似乎是特定杯状细胞的转录因子表达所必需的 发展。值得注意的是，我们发现 IRE1β 的表达和结肠粘液层的组装受到 肠道微生物群。这些数据将 IRE1β 的功能置于微生物群和上皮细胞的界面上， 调节保护宿主免受炎症信号和感染的先天屏障。这样做的目的 赠款旨在了解 IRE1β 如何预防结肠炎，我们的中心假设是 IRE1β 可以预防结肠炎 通过控制微生物诱导的杯状细胞分化和结肠粘液组装来对抗结肠炎 层。我们将使用体外和体内模型来了解微生物群如何调节 IRE1β 功能（目标 1)、定义IRE1β如何调节杯状细胞分化（目标2），并建立IRE1β功能的相关性 在实验模型和人类 UC 中预防结肠炎（目标 3）。