TL1A-activated Tcells as upstream regulators of perianal fistulizing disease-associated changes in the rectum of Crohn's Disease patients.

Summary

Perianal fistulizing disease (PFD) is a complication that affects about 20% of Crohn’s disease (CD) patients and whose etiology remains unknown. To identify predisposing events driving fistula formation, we investigated cell-specific alterations in the rectal mucosa of CD patients with PFD. Rectal biopsies from CD patients with or without PFD (CD+PFD and CD, respectively; n=31) were subjected to single-cell RNA sequencing. Functional analyses were conducted using peripheral CD3+ T cells, intestinal tissue explants, primary fibroblasts and 2D-epithelial monolayer cell cultures. The rectal mucosa of CD+PFD patients is imprinted with cellular and transcriptomic alterations specific to PFD and independent of luminal inflammation, potentially driven by TL1A activation in CD4+ T cells. We identified lymphotoxin beta (LTB or its functional heterotrimer LTα1β2) as a novel mediator downstream of TL1A that, along with IL-22, induces a PFD-associated signature in rectal fibroblast and epithelial cells, respectively. This signature includes an increased abundance of fibroblasts, an induction of matrix-degrading enzymes and transcriptomic rewiring of the lamina propria S1 fibroblasts, as well as an anti-bacterial and immune responses in epithelial cells. Notably, the induction of LTα1β2 and IL-22 occurs independently of TNF signaling, revealing a new TL1A-LTα1β2/IL-22 axis that remains active under anti-TNF therapy. Our findings revealed unique cellular alterations in the rectum of CD patients with PFD, highlighting the previously unrecognized involvement of TL1A in mediating this signature and supporting the need for exploring the role of TL1A inhibition as a therapeutic approach for PFD.

Details

Organism

Homo sapiens

Samples

8 samples

Publication Date

Jan 20, 2026

Platform

13667

Entry Type

GSE

Identifier