Patient-derived Colonoids From Disease-spared Tissue Retain Inflammatory Bowel Disease-specific Transcriptomic Signatures

Karakasheva, Tatiana A.; Zhou, Yusen; Xie, Hongbo; Soto, Gloria; Johnson, Timothy D.; Stoltz, Madison A.; Roach, David J.; Nema, Noor; Umeweni, Chizoba N.; Naughton, Kaitlyn E; Dolinsky, Lauren; Pippin, James A.; Wells, Andrew D.; Grant, Struan F.A.; Ghanem, Louis; Terry, Natalie A.; Muir, Amanda B.; Hamilton, Kathryn E.

doi:10.1016/j.gastha.2023.05.003

Cited by 3 publications

References 46 publications

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Type 1 diabetes human enteroid studies reveal major changes in the intestinal epithelial compartment

Bharadiya,

Rong,

Zhang

et al. 2024

Sci Rep

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Lack of understanding of the pathophysiology of gastrointestinal (GI) complications in type 1 diabetes (T1D), including altered intestinal transcriptomes and protein expression represents a major gap in the management of these patients. Human enteroids have emerged as a physiologically relevant model of the intestinal epithelium but establishing enteroids from individuals with long-standing T1D has proven difficult. We successfully established duodenal enteroids using endoscopic biopsies from pediatric T1D patients and compared them with aged-matched enteroids from healthy subjects (HS) using bulk RNA sequencing (RNA-seq), and functional analyses of ion transport processes. RNA-seq analysis showed significant differences in genes and pathways associated with cell differentiation and proliferation, cell fate commitment, and brush border membrane. Further validation of these results showed higher expression of enteroendocrine cells, and the proliferating cell marker Ki-67, significantly lower expression of NHE3, lower epithelial barrier integrity, and higher fluid secretion in response to cAMP and elevated calcium in T1D enteroids. Enteroids established from pediatric T1D duodenum identify characteristics of an abnormal intestinal epithelium and are distinct from HS. Our data supports the use of pediatric enteroids as an ex-vivo model to advance studies of GI complications and drug discovery in T1D patients.

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Type 1 diabetes human enteroid studies reveal major changes in the intestinal epithelial compartment

Bharadiya,

Rong,

Zhang

et al. 2024

Sci Rep

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3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

Trang,

Sharma,

Cook

et al. 2024

Preprint

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A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of genecis-regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by thesecis-regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by theFDFT1gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of genecis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.

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Intestinal microecology dysbiosis in inflammatory bowel disease: Pathogenesis and therapeutic strategies

Yin,

Feng,

Chen

et al. 2024

TIME

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<p>Inflammatory bowel disease (IBD) is an autoimmune disease characterized by non-infectious, chronic, and recurrent inflammation in the intestine, with unclear pathogenesis and increasing incidence. Currently, immunosuppressive drugs are commonly used in the clinical treatment of IBD to alleviate intestinal inflammation, but their effectiveness is not ideal. Therefore, it is crucial to investigate the pathogenesis of IBD and develop new therapeutic strategies. As a significant component of the intestinal barrier, the microbiota is closely related to metabolism, barrier protection, and immune regulation. With advances in research technology, the pivotal role of intestinal microecology dysbiosis in the progression of IBD has gained attention in recent years. Microbial therapies, including microecological modulators, fecal microbiota transplantation, and phage therapy have also become research hotspots in IBD treatment, showing promising applications. However, the complex relationship between intestinal microecology and IBD remains unclear, and clinical trials investigating microbial therapies face limitations. To inspire further research, this review thoroughly summarizes the physiological structure and function of intestinal microecology, as well as the characteristics and pathogenesis of microecology dysbiosis in IBD patients. We also analyze the research status of microbial therapies for IBD and the application of organoid models in preclinical studies.</p>

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Patient-derived Colonoids From Disease-spared Tissue Retain Inflammatory Bowel Disease-specific Transcriptomic Signatures

Cited by 3 publications

References 46 publications

Type 1 diabetes human enteroid studies reveal major changes in the intestinal epithelial compartment

Type 1 diabetes human enteroid studies reveal major changes in the intestinal epithelial compartment

3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

Intestinal microecology dysbiosis in inflammatory bowel disease: Pathogenesis and therapeutic strategies

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