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Perianal fistulising disease (PFD) remains one of the most disabling complications of Crohn’s disease (CD), affecting roughly one-fifth of patients and often proving refractory to current biological treatments and surgical approaches.1 Understanding why only a subset of individuals develops fistulas and why these lesions persist despite apparently quiescent luminal disease is an important unmet need. Gudiño et al address this gap by interrogating the rectal mucosa of patients with CD with and without PFD using single-cell RNA sequencing and complementary functional assays. Their work identifies a cell-specific transcriptional signature associated with fistula formation, involving lymphocyte activation by tumour necrosis factor-like ligand 1A(TL1A) independently of tumour necrosis factor (TNF) signalling, nominating TL1A as a tractable upstream player in fistula pathogenesis.2 This work has potentially broad implications for PFD, a field in which both mechanistic understanding and therapeutic progress have been slow.