A Prospectively Created Living Organoid Biobank of Crohn’s Disease Patients Enables Integrative Therapeutics

Abstract

Adult stem cells from various organs can be propagated as epithelial organoids that not only retain their tissue identity, but also their genetic and epigenetic disease-driving traits. We report the establishment of Crohn’s Disease (CD) patient-derived organoid cultures (PDOs) using biopsied tissues from colons of 50 consecutive subjects representing all clinical subtypes (Montreal Classification B1–B3 and perianal disease). Organoids were also generated from healthy subjects. The spectrum of phenotypic and genotypic changes within the “living biobank” agrees well with many observations reported in CD tissues. Gene expression analyses show that despite the heterogeneity of clinical subtypes, there are two major molecular subtypes, each with unique phenotypic features: immune-deficient infectious-CD [IDICD] and senescence-induced fibrostenotic-CD [SIFCD]. CD-PDOs are amenable to high-throughput drug screens allowing for the detection of phenotype reversal. As examples, defective barrier integrity in B1-PDOs was restored with pre-/pro-biotics, impaired microbial clearance in IDICD was reversed using agonists for nuclear receptors, and SIFCD was rectified using senolytics and - morphics. Phenotyped-genotyped CD-PDOs may fill the gap between basic biology and patient trials by enabling pre-clinical Phase ‘0’ human trials for personalized and integrative therapeutics.