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Intestinal Villus-on-Chip with Dynamic Magnetic Actuation for Identifying EGR1 as IBD Therapeutic Target

ABSTRACT: The pathogenesis of inflammatory bowel disease (IBD) is closely related to the mechanical microenvironment of the intestine, but existing in vitro models lack the key physiological feature of dynamic intestinal villus oscillation. Here, a magnetic intestinal villus chip (IVC) was constructed using a dual-channel microfluidic structure and embedded with biomimetic intestinal villi (BioVilli) membranes. The magnetically driven BioVilli replicated physiological villus oscillation (8 - 10°, 0.15 Hz), while controllable fluid perfusion applied physiological fluid shear stress at the intestinal vascular interface. This platform uniquely integrated structural fidelity, rhythmic mechanical actuation, and multicellular interactions into a single system. We found that through the IVC system, mechanical signals mediated by FOXO1 could enhance barrier integrity, absorption function, and epithelial cell proliferation. Under inflammatory stimulation, by replicating pathological villus oscillation (>12°, 0.15 Hz), the IVC system realistically reproduced the characteristics of IBD, revealing that the imbalance of EGR1 caused by inflammatory stress is a key factor in the pathogenesis of IBD. Spatial transcriptomic analysis of clinical IBD tissues confirmed that the downregulation of EGR1 expression is associated with metabolic dysregulation and barrier dysfunction, and pharmacological inhibition of EGR1 can alleviate inflammation and promote barrier repair, thereby establishing it as a promising therapeutic target. This work sets a new benchmark for intestinal chip technology and opens up new avenues for mechanism-based drug discovery for IBD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329353 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function, enhanced inflammation, and increased cancer risk, with symptoms sometimes being exacerbated in women during pregnancy. To investigate the IBD phenotype and disease progression in human intestine, we leveraged organ-on-a-chip (Organ Chip) technology to engineer human Colon Chips lined by homotypic or heterotypic recombinants of intestinal epithelium interfaced with stromal fibroblasts isolated from Healthy or IBD patient-derived colon resections. Chips created with both epithelial and stromal cells from the same ulcerative colitis or Crohn's disease patient showed increased IBD-associated gene pathway activation, elevated pro-inflammatory cytokines, reduced mucus layer thickness, increased intestinal barrier permeability, compared to homotypic Healthy Colon Chips. When heterotypic tissue recombinants were created, the IBD stromal fibroblasts induced the IBD phenotype in healthy epithelium, and healthy colonic fibroblasts partially reduced inflammation in the IBD epithelium. Using this system, we discovered that peristalsis-like mechanical deformations directly impact colon tissue physiology by increasing mucin gene expression, mucus thickness, and barrier permeability in both Healthy and IBD Chips, and that they only stimulate a fibrotic response in IBD Chips. We also found that both inflammation and fibrosis were accentuated in IBD Chips created with cells from a female patient that were exposed to pregnancy-associated hormones. Interestingly, exposure to a carcinogen (N-ethyl-N-nitrosourea) for 3 weeks in vitro induced histological changes and gene duplication in the IBD Chips, but not in the Healthy Chips. These data suggest that the stroma plays a key role in driving inflammation and disease progression in IBD patients and that human Organ Chip technology may represent a new preclinical tool to gain insight into these mechanisms as well as to identify novel diagnostic biomarkers and therapeutics.

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Intestinal Villus-on-Chip with Dynamic Magnetic Actuation for Identifying EGR1 as IBD Therapeutic Target

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