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

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.