During reproduction, multiple species such as insects and all mammals undergo extensive physiological and morphological adaptions to ensure health and survival of the mother and optimal development of the offspring. Here we report that the intestinal epithelium undergoes expansion during pregnancy and lactation in mammals. This enlargement of the intestinal surface area results in a novel geometry of expanded villi. Receptor activator of nuclear factor-κΒ (RANK, encoded by TNFRSF11A) and its ligand RANKL were identified as a molecular pathway involved in this villous expansion of the small intestine in vivo in mice and in intestinal mouse and human organoids. Mechanistically, RANK–RANKL protects gut epithelial cells from cell death and controls the intestinal stem cell niche through BMP receptor signalling, resulting in the elongation of villi and a prominent increase in the intestinal surface. As a transgenerational consequence, babies born to female mice that lack Rank in the intestinal epithelium show reduced weight and develop glucose intolerance after metabolic stress. Whereas gut epithelial remodelling in pregnancy/lactation is reversible, constitutive expression of an active form of RANK is sufficient to drive intestinal expansion followed by loss of villi and stem cells, and prevents the formation of Apc^min-driven small intestinal stem cell tumours. These data identify RANK–RANKL as a pathway that drives intestinal epithelial expansion in pregnancy/lactation, one of the most elusive and fundamental tissue remodelling events in mammalian life history and evolution.

在繁殖过程中，昆虫和所有哺乳动物等多个物种都会经历广泛的生理和形态适应，以确保母亲的健康和生存以及后代的最佳发育。在这里，我们报道了哺乳动物的肠上皮在怀孕和哺乳期间经历扩张。肠道表面积的这种扩大导致了一种新的绒毛扩大几何形状。核因子-κΒ 受体激活剂 （RANK，由 TNFRSF11A 编码） 及其配体 RANKL 被确定为参与小鼠、肠道小鼠和人类器官体内小肠绒毛扩张的分子途径。从机制上讲，RANK-RANKL 保护肠道上皮细胞免受细胞死亡，并通过 BMP 受体信号传导控制肠道干细胞生态位，导致绒毛伸长和肠表面显着增加。作为跨代结果，肠上皮中缺乏 Rank 的雌性小鼠所生的婴儿在代谢应激后体重减轻并出现葡萄糖耐受不良。虽然妊娠/哺乳期的肠道上皮重塑是可逆的，但活性形式的 RANK 的组成型表达足以驱动肠道扩张，然后是绒毛和干细胞的损失，并防止 Apc^min 驱动的小肠干细胞肿瘤的形成。这些数据将 RANK-RANKL 确定为在怀孕/哺乳期驱动肠上皮扩张的途径，这是哺乳动物生活史和进化中最难以捉摸和最基本的组织重塑事件之一。