Satb2 deletion in colon approach to treat short bowel syndrome

Loss of the transcription factor Satb2 converts mouse colonic epithelium into an ileal type. Here, we report that Satb2 gene deletion alleviates SBS by replacing diminished absorptive function and by inducing lymphovascular channels in the proximal colon. Enhanced nutrient absorption following Satb2 loss increased body weight and survival of mice with SBS. Deletion of SATB2 by adeno-associated viral delivery of CRISPR Split Cas9 to human colon organoids, followed by xenotransplantation into mice, resulted in ileal morphology and expression of ileal marker genes. This approach offers a feasible strategy for future treatment of SBS. Overall design: Here we deleted Satb2 to remodel the colon into nutrient-absorbing ileum-like tissue in a mouse model of SBS. The resulting ileum-like colon developed lacteal vessels, subepithelial lymphatic channels normally restricted to the small intestine and responsible for fat absorption, indicating that Satb2 deletion directs formation of small intestinal structures in the colon.

转录因子Satb2的缺失可将小鼠结肠上皮转化为回肠表型。本研究发现，Satb2基因缺失可通过代偿受损的吸收功能，并在近端结肠诱导淋巴管通道，从而缓解短肠综合征（Short Bowel Syndrome, SBS）。Satb2缺失后增强的营养吸收能力，可提升短肠综合征模型小鼠的体重与存活率。利用腺相关病毒（adeno-associated virus, AAV）递送分裂型Cas9 CRISPR系统敲除人类结肠类器官中的SATB2，随后将其异种移植至小鼠体内，可使其呈现回肠形态并表达回肠标记基因。该策略为未来短肠综合征的治疗提供了可行方案。

实验整体设计：本研究在短肠综合征小鼠模型中敲除Satb2，将结肠重塑为具备营养吸收功能的回肠样组织。所获得的回肠样结肠可生成乳糜管与上皮下淋巴管通道——这类结构通常仅见于小肠，负责脂肪吸收——这表明Satb2缺失可诱导结肠内形成小肠特异性结构。