New Insights Into the Stromal‐Immune Crosstalk During IBD: GLIS3 as a Potential Marker for the Inflammation‐To‐Fibrosis Transition

Plain Language Summary Many patients affected by Inflammatory Bowel Disease (IBD) do not respond well to treatment and for this reason can develop severe complications, such as intestinal scarring (fibrosis), resulting in the narrowing of the intestinal lumen. In this study, the authors found that interaction between immune cells (macrophages) and structural cells (fibroblasts) plays a key role in worsening disease. In particular, a specific group of fibroblasts that produce a molecule called Interleukin (IL)‐11 rises and expands in inflamed and scarred intestinal tissue and helps drive fibrosis by producing proteins that build up scar tissue. Researchers found that macrophages release signals (notably IL‐1β and Transforming Growth Factor (TGF‐β)) that push fibroblasts to produce IL‐11 and promote scarring. A gene called GLIS3 was identified as a central switch controlling this process. When GLIS3 is active, fibroblasts become pathologic and promote inflammation and fibrosis. Importantly, higher GLIS3 activity was found in patients with more severe disease. Experiments performed in mice showed that removing GLIS3 reduce inflammation and fibrosis, making GLIS3 a promising marker of disease severity and a potential target for future treatments.