Objective Mutations in presenilin genes are the major cause of Alzheimer’s disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis. Design Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis. Results Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation. Conclusion Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD. Data are available in a public, open access repository. Data are available on reasonable request. Transcriptomic data of the IBDome cohort will be made available to the scientific community on acceptance of the manuscript. Bulk RNA sequencing data of Psen1 and Psen2 deficient mice have been submitted to ArrayExpress. The publicly available datasets used in this study are published under the accession codes: E-MTAB-9850 and GSE6731.

中文翻译：

---

阿尔茨海默病相关的早老素是肠上皮细胞功能和肠道免疫稳态的关键

目的早老素基因突变是阿尔茨海默病的主要原因。然而，人们对它们在肠道中的表达和功能知之甚少。在这项研究中，我们将早老素 Psen1 和 Psen2 确定为维持肠道稳态的关键分子。设计 分析人类炎症性肠病 (IBD) 和对照样本的 Psen1 表达。新生成的肠上皮特异性 Psen1 缺陷型、Psen2 缺陷型和可诱导型 Psen1/Psen2 双缺陷型小鼠被用来剖析早老素在肠道稳态中的功能作用。结果 Psen1 表达在实验性肠道炎症和 IBD 患者中受到调节。诱导小鼠 Psen1 和 Psen2 缺失会导致小鼠体重快速减轻和肠道炎症自发发展。小鼠表现出上皮屏障破坏、细菌易位和营养吸收关键途径失调。消耗性疾病与肠道炎症和生态失调无关，因为微生物群的耗竭可以使 Psen 缺陷动物免于自发性结肠炎的发展，但不能使体重减轻。在分子水平上，缺乏 Psen 的肠上皮细胞表现出 Notch 信号传导受损和上皮分化失调。结论 总的来说，我们的研究提供了证据，表明 Psen1 和 Psen2 是肠道稳态的重要守护者，也是 IBD 屏障促进治疗策略的未来目标。数据可在公共、开放访问存储库中获取。可根据合理要求提供数据。 IBDome 队列的转录组数据将在稿件被接受后提供给科学界。 Psen1 和 Psen2 缺陷小鼠的批量 RNA 测序数据已提交至 ArrayExpress。本研究中使用的公开数据集以登录代码发布：E-MTAB-9850 和 GSE6731。