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A "living biobank" of Crohn's Disease

ABSTRACT: Patient-derived organoids (PDOs) from the colons of patients with Crohn's Disease (or healthy controls) were subjected to in-depth genotype, transcriptome and phenotype assessment. These studies revealed that CD may be classified broadly into two molecular subtypes, each with its unique profile of dysregulated celluar processes. We further show that these phenotypes can be rectified with matched therapeutics, hence making such intervention personalized. Findings show that CD-PDOs could serve as pre-clinical platforms for drug discovery and personalized medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192819 | GEO | 2024/03/31

REPOSITORIES: GEO

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Project description:Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with E. coli were shown to release attenuated levels of TNF and IFNM-NM-3 with normal secretion of IL8, IL10 and IL6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with siRNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD. Total RNA obtained from monocyte derived macrophages from Crohn's disease patients (n=58) or healthy volenteers (n=42) were cultured for six days before being stimulated with heat killed E. coli for four hours or left unstimulated.

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A "living biobank" of Crohn's Disease

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