Defining the mucosal ecosystem: epithelial–mesenchymal interdependence in gastrointestinal health and disease

The crypt–villus architecture of the intestinal mucosa is underpinned by dynamic interactions between distinct populations of epithelial, stromal and immune cells. Although the epithelial compartment has attracted substantial attention, there is a growing appreciation for the critical role of mesenchymal cells in shaping epithelial stem cell function and dictating lineage specification. In this Review, we outline how the epithelial and mesenchymal compartments of the developing gut evolve in a mutually dependent manner to establish dynamic reciprocal signalling gradients that maintain adult tissue homeostasis. We discuss how perturbations to this delicate ecosystem result in rapid adaptive cellular responses that act to restore tissue function. Furthermore, we explore how the intricate nature of cell fate interdependence also renders the mucosa susceptible to pathological disruption. Drawing on the latest studies, we highlight the crosstalk networks between the epithelial and stromal compartments that underlie these processes and consider how these insights are informing future research directions and therapeutic strategies. In doing so, we advocate for a shift away from the conventional epithelial-centric paradigm toward a more integrated framework that considers the full spectrum of intercellular interactions maintaining intestinal tissue integrity and shaping disease progression.