克朗基特-加拿大综合症 (CCS) 是一种罕见的非遗传性息肉病综合症，每百万人中就有一人受到影响。尽管 CCS 病例已有 50 多年的历史，但由于该病罕见且缺乏模型系统，CCS 的发病机制和最佳治疗方法仍然未知。为了更好地了解 CCS 的病因，我们利用从 2 名患者身上分离的肠道干细胞生成了人类肠道类器官 (HIO)。我们发现 CCS HIO 具有高度增殖性，并且产生血清素（也称为 5-羟色胺或 5HT）的肠内分泌细胞数量增加。这些特征也在患者组织活检中得到证实。重组5HT增加了非CCS供体HIO的增殖，而抑制CCS HIO中5HT的产生导致增殖减少，这表明局部上皮5HT的产生与上皮干细胞增殖的控制之间存在联系。这种联系在肠内分泌细胞数量增加的基因工程 HIO 中得到了证实。这项工作提供了一种解释 CCS 发病机制的新机制，并说明了 HIO 培养物对了解疾病病因和识别新疗法的重要贡献。我们的工作展示了使用类器官进行个性化医疗的原理，并揭示了肠道激素如何在肠上皮增殖中发挥作用。

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.