Goblet cells mechanically breach the epithelial barrier in gut homeostasis

Abstract

Abstract The intestinal epithelium forms a tight barrier against the harsh luminal environment. Absorptive enterocytes have a polygonal, columnar morphology, while mucus-producing goblet cells exhibit a rounded apical shape and a voluminous cell body, raising the question of how epithelial integrity is preserved in tissues with such morphological heterogeneity. Here, we show that, under homeostatic conditions in vivo, goblet cells mechanically induce tight-junction fractures between neighboring enterocytes. This effect is exacerbated by goblet cell hypertrophy and is associated with increased gut permeability. Using in vivo and organoid models, combined with pharmacological, genetic and mechanical perturbations and theoretical modeling, we demonstrate that these fractures arise from a force imbalance at cell interfaces: goblet cells exert pressure on adjacent enterocytes, whose junctional rupture depends on tissue rheology controlled by myosin II. Our findings uncover a mechanical role for goblet cells in epithelial cohesion and barrier regulation, revealing how cellular heterogeneity shapes tissue integrity.