Fig. 1: Schematic of the intestinal wall architecture under physiological conditions (not to scale).

A The epithelial barrier represents the first line of mechanical separation between the lumen and the intestinal mucosa. A polarised layer of epithelial cells lies on the complex mix of molecules of the ECM, which gives biophysical support and contributes to molecular signalling. The epithelial and ECM compartments maintain a fine balance by interacting with the mesenchyme, which contributes to tissue remodelling and repair, and adaptation to bacterial stimuli. B The interplay between intestinal stem cells (ISCs) and the mesenchymal compartment defines the environment of the crypt niche. Paneth cells and mesenchymal cells (MCs) maintain a fine balance between promoting Wnt/β-catenin and inhibiting BMP pathways, allowing constant epithelial renewal. Once ISCs differentiate into transit-amplifying (TA) cells, asymmetric activation of the Notch signalling pathways is required for cell differentiation into absorptive or secretory lineages. When newly differentiated cells are generated, Hedgehog signalling is activated, promoting BMP pathways, thus stopping further differentiation of epithelial cells [36]. C The ECM is a scaffolding structure of the intestinal wall characterised by a pericellular matrix (PM) and an interstitial matrix (IM). PM is composed of fibrous proteins linked by crosslinking enzymes, such as lysyl oxidases (LOX), whose role is to surround and support cells. A type of pericellular matrix specific to epithelial and endothelial cells is the basement membrane, mainly characterised by laminins, collagen IV, perlecan and nidogen. IM is made of fibrous proteins rich in glycosaminoglycan elements and non-fibrous proteins, whose distribution within cells allows them to crosstalk and interact [21]. Created with BioRender.com.