The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro¹, but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging². Here we generate a functional small intestinalized colon (SIC) by replacing the native colonic epithelium with ileum-derived organoids. We first find that xenotransplanted human ileum organoids maintain their regional identity and form nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer further reveals an essential role for luminal mechanistic flow in the formation of villi. We then develop a rat SIC model by repositioning the SIC at the ileocaecal junction, where the epithelium is exposed to a constant luminal stream of intestinal juice. This anatomical relocation provides the SIC with organ structures of the small intestine, including intact vasculature and innervation, villous structures, and the lacteal (a fat-absorbing lymphatic structure specific to the small intestine). The SIC has absorptive functions and markedly ameliorates intestinal failure in a rat model of SBS, whereas transplantation of colon organoids instead of ileum organoids invariably leads to mortality. These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment.

小肠是吸收营养的主要器官，其广泛切除会导致吸收不良和消瘦，称为短肠综合征 (SBS)。类器官技术能够在体外有效扩张肠上皮组织¹，但重建整个小肠，包括复杂的淋巴血管系统，仍然具有挑战性². 在这里，我们通过用回肠衍生的类器官替换天然结肠上皮细胞来生成功能性小肠化结肠 (SIC)。我们首先发现异种移植的人类回肠类器官保持其区域特性并在小鼠结肠中形成新生绒毛结构。类器官单层的体外培养进一步揭示了管腔机械流动在绒毛形成中的重要作用。然后，我们通过在回盲部连接处重新定位 SIC 来开发大鼠 SIC 模型，其中上皮细胞暴露于恒定的肠液腔流。这种解剖学重新定位为 SIC 提供了小肠的器官结构，包括完整的脉管系统和神经支配、绒毛结构和乳突（小肠特有的吸收脂肪的淋巴结构）。在 SBS 大鼠模型中，SIC 具有吸收功能并显着改善肠衰竭，而移植结肠类器官而不是回肠类器官总是会导致死亡。这些数据为将肠道类器官用于再生目的提供了原理证明，并为 SBS 治疗提供了可行的策略。