胃肠道依赖于粘膜的生成、成熟和传递来保护免受病原体的侵害，并润滑上皮内膜。尽管对调控粘膜生成和运动的分子和细胞机制的理解正在增加，但对贡献于粘膜调控的上游上皮信号仍不清楚。本文报道了由上皮产生的炎症细胞因子肿瘤坏死因子（TNF）通过调控细胞分化和囊性纤维囊膜导电调节因子（CFTR）活性，对粘膜稳态的贡献。我们使用遗传学小鼠模型和进行抗-TNF治疗的炎症性肠病（IBD）患者的非炎症样本来评估TNF体内干扰的效果。我们发现抑制上皮TNF促进分泌前体细胞向黏液产生的顶泡细胞分化。此外，肠道器官样体中的TNF处理和CFTR抑制表明，TNF通过CFTR促进离子转运和腔内流动。缺乏TNF导致肠道传输时间变慢，我们认为这是由于粘液积聚增加和腔内流体泵送减少所致。这些发现指出成年肠道中存在TNF-CFTR信号轴，并将上皮来源的TNF识别为粘膜稳态的上游调控因子。

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and non-inflamed samples from Inflammatory Bowel Disease (IBD) patients undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF-CFTR signaling axis in the adult intestine and identify epithelial-derived TNF as an upstream regulator of mucin homeostasis.