The intestinal barrier plays a central role in maintaining mucosal homeostasis by regulating nutrient absorption while preventing the entry of antigens and microbes. In celiac disease (CD), impaired barrier function increases intestinal permeability, facilitating gliadin-induced immune activation and epithelial damage that results in crypt hyperplasia and villous atrophy.[1,2] To better understand the effects of gliadins on epithelial barrier function, investigate the role of increased permeability in CD pathogenesis and evaluate barrier-modulating compounds, microphysiological in vitro models of the intestinal barrier are required. Although organoids closely recapitulate the native intestinal epithelium, assessing barrier integrity in conventional organoid cultures remains challenging. This limitation can be addressed using organ-on-a-chip (OoC) platforms, which recreate key features of the intestinal microenvironments, including cellular organization and mechanical stimuli, such as fluid flow.
Here, we developed a membrane-based OoC platform for a patient-derived intestinal epithelial barrier model to study barrier integrity in CD. Computational fluid simulations were performed to select physiologically relevant flow conditions that promote differentiation and crypt-like tissue organization. The resulting shear-stress conditions are used to study the effect of mechanical stimulation on epithelial differentiation, barrier integrity and tissue remodelling processes associated with villous atrophy. The platform will then be employed to investigate gliadin-induced changes in barrier integrity by measuring the permeability of a fluorescent tracer using patient-derived intestinal cells from individuals with CD.
Overall, the developed OoC platform enables the investigation of the epithelial barrier integrity in CD, supporting mechanistic studies of gliadin-induced barrier dysfunction and the evaluation of barrier-modulating compounds.