TL1A-LTB axis induces perianal fistulising disease-associated changes in CD

Patients with Crohn’s disease (CD) and perianal fistulising complications had a higher expression of lymphotoxin beta (LTB) and TNF ligand 1A (TL1A) receptor. In vitro studies showed that TL1A induces expression of LTB, which induces a specific perianal signature in the fibroblasts, including an upregulation of TFPI2 and a downregulation of CTGF.

“Perianal fistulising disease is one of the complications of CD, which consists of the formation of new tracts connecting the anal canal or rectum to the perianal region,” explained Dr Victoria Gudino (Institut d’Investigacions Biomèdiques August Pi i Sunyer, Spain) [1,2]. The current study did not analyse the fistula directly but analysed the rectum of participants.

“We included 31 participants with CD, with or without perianal fistulising disease,” outlined Dr Gudino. The research team performed rectum biopsies and single-cell RNA sequencing (n=81,370 cells). The population included 14 participants without involvement of the rectum, of whom 7 had perianal fistulising disease. “In this way, we could study perianal fistulising disease-associated changes independent of inflammation,” clarified Dr Gudino.

Participants with perianal fistulising disease had a higher abundance of fibroblasts, with the highest number of differential gene expressions observed for the lamina propria S1 fibroblasts. “In vitro studies with intestinal fibroblasts showed that TGF-β downregulated the expression of genes that were upregulated in patients with perianal disease while inducing genes that were downregulated in that group, ruling out TGF-β as a driver of the perianal fistulising disease-associated fibroblasts.”

Subsequently, the study group discovered that lymphotoxin beta (LTB) was upregulated in intestinal CD4-positive T cells of participants with perianal fistulising disease. LTB interacts with its receptor LTBR, expressing in stromal, epithelial, and myeloid cells. “Participants with perianal disease had more of those interactions than participants without perianal disease, involving T cells as producers and fibroblasts as target cells,” mentioned Dr Gudino.

In vitro studies in primary fibroblasts showed that LTB upregulates TFPI2 while downregulating CTGF, reflecting the perianal fistulising disease-associated signature. Further analysis showed that TL1A was the most probable driver. “Although TL1A was not overexpressed in the epithelium of participants with perianal disease, its receptor DR3 was upregulated in the CD4-positive T cells of participants with perianal disease, suggesting that TL1A signalling could be more active in these participants.” This finding was confirmed in peripheral T cells that were stimulated with anti-CD3 and TL1A. Finally, the research team observed that while TNF can drive the perianal disease-associated signature in fibroblasts, it cannot induce LTB in T cells. “This indicates that TNF signalling and TL1A/LTB signalling are independent pathways in perianal fistulising disease,” Dr Gudino concluded.

1. Gudino V, et al. TL1A-activated T-cells as upstream regulators of perianal fistulising disease-associated changes in the rectum of Crohn’s disease patients. OP24, 20th Congress of ECCO, 19–22 February 2025, Berlin, Germany.
2. Rizzo G, et al. Cell Mol Gastroenterol Hepatol. 2023;15(3):741-764.

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Posted on 8 April 2025