Crohn's病（CD）是一种复杂的、临床上异质的、多因素起源的疾病；目前没有完美的临床前模型，对于这种异质性的基础还知之甚少，也还没有根治方法。为了解决这些亟需的问题，我们尝试探索成体干细胞源性器官的转化潜力，这些器官不仅保留其组织认同，而且还保留了其基因和表观遗传性疾病驱动特征。我们预期地创建了来自所有临床亚型（蒙特利尔分类B1-B3和会阴部疾病）的34个连续受试者结肠组织中的CD患者衍生的器官样本库（PDO）以及健康受试者的PDO。通过比较基因表达分析，确定了PDO作为活动性疾病的结肠上皮建模工具的基准线，并揭示了尽管有临床上的异质性，但有两个重要的分子亚型：免疫缺陷感染性CD [IDICD]和压力和衰老诱导的纤维化硬化综合征CD [S2FCD]。转录组、基因组和表型显示了在每个分子亚型中具有惊人的内部一致性。在“存活生物库”的形态学、表型和功能变化范围中，显示了不同分子亚型之间明显的差异。这些观察结果使得我们可以进行药物筛选，翻转亚型特异性表型，例如，在IDICD中受损的微生物清除使用核受体激动剂被逆转，而在S2FCD中的衰老则被使用抗衰老药物纠正，但反之不然。定量表型和基因型的CD-PDO 可以通过进行前临床0期人体试验，弥补基础生物学和患者试验之间的差距，实现个性化治疗。该研究提供了有前途的细菌培养物库及有表型-基因型的 Crohn疾病患者衍生的器官（CD-PDO）作为疾病分子亚型的平台，并列举了这些器官的优势，以及他们在未来如何用来实现个性化治疗的方法。前瞻性的定量表型和基因型的CD-器官样品在患者中重现了疾病的表皮。CD-器官样品的表象-转录组-基因组聚合成两种分子亚型。一种亚型表现为微生物清除减退，另一种表现为细胞衰老增加。将表型-基因型的PDO用于整合和个性化治疗。

Crohn's disease (CD) is a complex, clinically heterogeneous disease of multifactorial origin; there is no perfect pre-clinical model, little insight into the basis for such heterogeneity, and still no cure. To address these unmet needs, we sought to explore the translational potential of adult stem cell-derived organoids that not only retain their tissue identity, but also their genetic and epigenetic disease-driving traits. We prospectively created a biobank of CD patient-derived organoid cultures (PDOs) using biopsied tissues from colons of 34 consecutive subjects representing all clinical subtypes (Montreal Classification B1-B3 and perianal disease). PDOs were generated also from healthy subjects. Comparative gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and revealed that despite the clinical heterogeneity there are two major molecular subtypes: immune-deficient infectious-CD [IDICD] and stress and senescence-induced fibrostenotic-CD [S2FCD]. The transcriptome, genome and phenome show a surprising degree of internal consistency within each molecular subtype. The spectrum of morphometric, phenotypic, and functional changes within the "living biobank" reveals distinct differences between the molecular subtypes. These insights enabled drug screens that reversed subtype-specific phenotypes, e.g., impaired microbial clearance in IDICD was reversed using agonists for nuclear receptors, and senescence in S2FCD was rectified using senotherapeutics, but not vice versa . Phenotyped-genotyped CD-PDOs may fill the gap between basic biology and patient trials by enabling pre-clinical Phase '0' human trials for personalized therapeutics.This work creates a prospectively biobanked phenotyped-genotyped Crohn's disease patient-derived organoids (CD-PDOs) as platforms for molecular subtyping of disease and for ushering personalized therapeutics.Prospectively biobanked CD-organoids recapitulate the disease epithelium in patientsThe phenome-transcriptome-genome of CD-organoids converge on two molecular subtypesOne subtype shows impaired microbial clearance, another increased cellular senescencePhenotyped-genotyped PDOs are then used for integrative and personalized therapeutics.