Intestinal exocrine secretory lineages, including goblet cells and Paneth cells, provide vital innate host defense to pathogens. However, how these cells are specified and maintained to ensure intestinal barrier function remains poorly defined. Here we show that endoplasmic reticulum membrane protein complex subunit 3 (Emc3) is essential for differentiation and function of exocrine secretory lineages. Deletion of Emc3 in intestinal epithelium decreases mucus production by goblet cells and Paneth cell population, along with gut microbial dysbiosis, which result in spontaneous inflammation and increased susceptibility to DSS-induced colitis. Moreover, Emc3 deletion impairs stem cell niche function of Paneth cells, thus resulting in intestinal organoid culture failure. Mechanistically, Emc3 deficiency leads to increased endoplasmic reticulum (ER) stress. Mitigating ER stress with tauroursodeoxycholate acid alleviates secretory dysfunction and restores organoid formation. Our study identifies a dominant role of Emc3 in maintaining intestinal mucosal homeostasis.

肠外分泌谱系，包括杯状细胞和潘氏细胞，为病原体提供重要的先天宿主防御。然而，如何指定和维护这些细胞以确保肠道屏障功能的定义仍然不明确。在这里，我们表明内质网膜蛋白复合物亚基 3 (Emc3) 对于外分泌谱系的分化和功能至关重要。肠上皮细胞中 Emc3 的缺失会减少杯状细胞和潘氏细胞群的粘液产生，以及肠道微生物失调，从而导致自发性炎症和对 DSS 诱导的结肠炎的易感性增加。此外，Emc3缺失会损害Paneth细胞的干细胞生态位功能，从而导致肠道类器官培养失败。从机械上讲，Emc3 缺乏会导致内质网 (ER) 应激增加。用牛磺熊去氧胆酸减轻内质网应激可减轻分泌功能障碍并恢复类器官形成。我们的研究确定了 Emc3 在维持肠粘膜稳态中的主导作用。