Fig. 4 |. Core mechanisms of intestinal fibrogenesis.

Mesenchymal cells in intestinal fibrosis are highly heterogeneous and are exposed to direct contact with intestinal immune and non-immune cells, their soluble mediators, and microbial components and metabolites. A ‘leaky’ epithelial barrier owing to cellular injury permits contact of mesenchymal cells with the microbiota and their products. Those factors can directly or indirectly activate mesenchymal cells through, for example, Toll-like receptors (TLRs) or inflammasome signalling. Activated epithelial cells and immune cells are able to produce profibrotic mediators, such as IL-11, IL-33, IL-34, IL-36 and tumour necrosis factor superfamily protein TNF-like 1A (TL1A). Fibroblasts can signal in a homotypic fashion through cadherin 11, IL-11 or TL1A. The cellular environment provides biochemical and mechanical cues to mesenchymal cells independently of intestinal inflammation. This complex environment gives rise to heterogeneous fibroblast populations linked to fibrostenosis, such as IL-33–lysyl oxidase–tumour necrosis factor superfamily member 14-positive (IL33⁺LOX⁺TNFSF14⁺), Wingless related integration site–matrix metalloproteinase–CXCL14-positive (WNT5A⁺MMP⁺CXCL14⁺) or CD90–podoplanin–chitinase triple helix repeat-containing 1–chitinase 3-like 1-positive (CD90⁺PDPN⁺CTHRC1⁺CH13L1⁺) cells. Creeping fat can release pro-inflammatory mediators and free fatty acids that act on intestinal muscularis propria smooth muscle cells and fibroblasts, leading to thickening of the muscularis propria. ECM, extracellular matrix.