What happens in the rectal mucosa before — and potentially as part of — perianal fistulising Crohn’s disease? Gudiño et al. present “TL1A-activated T cells remodel the rectal mucosa in patients with Crohn’s disease with perianal fistulising disease” via bit.ly/3V1eEMH Using single-cell RNA sequencing of rectal biopsies from patients with Crohn’s disease with and without perianal fistulising disease, together with functional studies in T cells, tissue explants, fibroblasts and epithelial cultures, this study identifies a distinct molecular signature associated with fistulising disease. The rectal mucosa of patients with perianal fistulising disease showed cellular and transcriptional alterations that were independent of luminal inflammation. The researchers implicate TL1A activation in CD4+ T cells and identify lymphotoxin β and IL-22 as downstream mediators affecting fibroblast and epithelial compartments. Importantly, the TL1A–LTα1β2/IL-22 pathway operates independently of TNF signalling, suggesting that these molecular changes may persist even in the context of anti-TNF therapy. The findings provide new insight into the mechanisms that may predispose to perianal fistulising disease and support further investigation of TL1A-directed approaches in this challenging complication of Crohn’s disease. #CrohnsDisease #PerianalDisease #TL1A